KR101301533B1 - Novel pyrimidine derivatives for inhibiting cancer cell growth - Google Patents

Abstract

The present invention relates to a novel pyrimidine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient. The novel pyrimidine derivative of the present invention relates to cancer cells caused by overexpression of epidermal growth factor receptor and Can effectively inhibit the growth of resistant cancer cells.

Description

Novel pyrimidine derivative having cancer cell growth inhibitory effect {NOVEL PYRIMIDINE DERIVATIVES FOR INHIBITING CANCER CELL GROWTH}

The present invention relates to a novel pyrimidine derivative having a cancer cell growth inhibitory effect or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient.

Within the cell there are numerous signaling systems, each of which is organically linked to each other and regulates the proliferation, growth, and death of cells through the formation of complex mechanisms (William G. Kaelin Jr, Nature Reviews Cancer 5 , 689, 2005). Thus, if the intracellular regulatory function is lost due to genetic or environmental influences, abnormal signal transduction may be amplified or eliminated, leading to diseases such as tumors (Douglas Hanahan and Robert A. Weinberg, Cell 100 , 57, 2000).

Protein tyrosine kinase plays an important role in this intracellular signal transduction (Irena Melnikova and James Golden, Nature Reviews Drug Discovery 3 , 993, 2004), and it is reported that abnormal expression or mutation is frequent in cancer cells. . Protein tyrosine kinases are a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine located on protein substrates, whereby several growth factor receptor proteins perform intracellular signal transduction. Interactions between growth factors and these receptors are essential for the normal regulation of cell growth, but tumor cells or ultimately cancers are caused when the receptors are unable to regulate signals due to mutation or overexpression of the receptors.

Various growth factors and their receptors have been studied in relation to their role as protein tyrosine kinase, and among these, studies on epidermal growth factor (EGF) and its receptor (EGFR) tyrosine kinase are actively underway (Nancy). E. Hynes and Heidi A. Lane, Nature Reviews Cancer 5 , 341, 2005). EGFR tyrosine kinase is a protein consisting of a receptor moiety and a tyrosine kinase moiety, which translocates signals outside the cell into the cell by placing them through the cell membrane. The EGFR tyrosine kinase family is classified into four subtypes of EGFR (Erb-B1), Erb-B2, Erb-B3, and Erb-B4, depending on their structural properties, all of which are heterozygous with homodimers or other members of the family. As dimers, signal transduction complexes can be formed.

The first drug developed as an EGFR tyrosine kinase inhibitor as a small molecule is Gefitinib, a reversible inhibitor that selectively inhibits EGFR (Erb-B1) in the EGFR subtype. Erlotinib is a drug having such characteristics, and the EGFR-targeted therapeutic agent provides non-small cell lung cancer (NSCLC) as a main indication for providing a therapeutic convenience to a patient.

Recently, resistance expression in epidermal growth factor receptor target therapy has been reported to decrease the response rate of the drug. Already, it has been reported that about 50% of patients receiving approved gefitinib or erlotinib for non-small cell lung cancer are resistant to the drug by causing a second mutation, the EGFR T790M mutation (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, studies have shown that the approach of irreversible inhibitors to target epidermal growth factor receptors as low molecular weight substances is very advantageous in achieving excellent efficacy and overcoming resistance to existing EGFR inhibitors such as gefitinib or erlotinib. (Danan Li et al., Cancer Cell 12 , 81, 2007; and Anja Michalczyk et al., Bioorganic & Medicinal Chemistry 16 , 3482, 2008). Already with this approach BIBW-2992 (CH Mom et al., British Journal of Cancer 98 , 80, 2007), HKI-272 (Sridhar K. Rabindran, et al., Cancer Research ) according to formulas A, B and C 64 , 3958, 2004), AV-412 (Tsuyoshi Suzuki et al., Cancer Sci . 98 (12), 1977, 2007) is under development at the clinical stage. A representative structural feature of these drugs is that acrylamide functional groups are directly substituted at the 6 position of quinazoline or cyanoquinoline, as shown in formulas (A), (B) and (C) below. Drugs of this class are known to irreversibly block the autophosphorylation of EGFR by forming covalent bonds with cysteine 773 (Cys773) located in the ATP domain of EGFR (David W. Fry et al., Proc. Natl. Acad. Sci. USA 95 , 12022, 1998), show excellent performance compared to reversible inhibitors in in vitro activity and in vivo animal models of various carcinomas (Jeff B. Smaill et. al., J. Med. Chem. 42, 1803, 1999):

(A)

[Formula B]

≪ RTI ID = 0.0 &

To date, the results of clinical trials on non-small cell lung cancer of irreversible inhibitors have improved the drug response rate compared to the existing reversible inhibitors, but the therapeutic effect is still weak for resistant to cancer patients. Therefore, there is an urgent need for the development of new drugs that are more effective against resistant cancer and reduce side effects than existing irreversible inhibitors.

Accordingly, it is an object of the present invention to provide novel compounds that selectively and effectively inhibit cancer cell growth and resistance to drugs caused by epidermal growth factor receptors and mutations thereof, while having fewer side effects.

In addition, another object of the present invention to provide a pharmaceutical composition for inhibiting cancer cell growth containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides a novel pyrimidine compound.

In order to achieve the above another object, the present invention provides a pharmaceutical composition for inhibiting cancer cell growth containing the compound as an active ingredient.

The novel pyrimidine derivatives according to the present invention are directed against drugs caused by cancer cell growth and epidermal growth factor receptor tyrosine kinase mutations induced by overexpression of epidermal growth factor receptor (EGFR). Resistance can be selectively and effectively suppressed.

The present invention provides pyrimidine derivatives of the general formula (1) or pharmaceutically acceptable salts thereof:

Where

또는

이고, 이때 X₁은 N, CH 또는 CH₂이고, X₂는 N 또는 CH이고; X is

or

Wherein X ₁ is N, CH or CH ₂ , and X ₂ is N or CH;

Y is H, NH ₂ or N ( _C═O ) C _1-6 alkyl;

Z is C _1-6 alkyl substituted with aryl, heterocycle, or aryl having 1 to 5 substituents A;

n _a and n _b are each independently an integer from 0 to 6, where n _a and n _b are both 0, -X-CH ₂ -NH-R, and when n _a is 0, -X-CH _2- (CH ₂ ) n _b -NH-R, and when n _b is 0, -X-CH ₂ -N (CH ₂ ) n _a ) -R;

--- represents a bond that may exist when n _a and n _b are nonzero integers;

또는

이고; 이때, R_{1 ,} R₂ 및 R₃은 서로 독립적으로 수소 또는 치환기 B로 치환된 C_{1 - 3}알킬이고; R₄는 하이드록시 또는 C_{1 - 6}알콕시이고; n_c는 1 내지 6의 정수이고;R is

or

ego; At this time, R _{1 ,} R ₂ And R ₃ is independently a C ₁ is substituted by hydrogen or the substituent B each other _- and _3-alkyl; R ₄ is hydroxy or C _{1 - 6} alkoxy; n _c is an integer from 1 to 6;

The substituent A is hydrogen, halogen, C _1-6 alkyl, substituted aryl C _1-6 alkyl, aryl or heterocycle-substituted C _1-6 alkyloxy, aryloxy, heterocyclic oxy, or heterocyclyl Im O;

The substituent B is hydroxy, S- C _1-6 alkylsulfonyl, heterocycle, amino, or C _1-6 dialkyl, C- C _1-6 alkylcarbonyl or S- C _1-6 alkylsulfonyl Substituted amino;

The aryl is a C _5-12 monocyclic or bicyclic aromatic compound;

The heterocycle is a C _5-12 monocyclic or bicyclic aromatic or nonaromatic compound comprising 1 to 4 members selected from the group consisting of N, O, S, SO and SO ₂ ;

The aryl and heterocycle are unsubstituted; Or halogen, hydroxy, amino, nitro, cyano, C _1-6 alkyl, trihalogenoC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _{1 -} has a substituent selected from the group consisting of _{die-6 alkylamino-6} monoalkylamino and C _1.

Hereinafter, the present invention will be described in detail.

In the pyrimidine derivative of Formula 1 according to the present invention, Preferably,

또는

이고;X is

or

ego;

Y is H, NH ₂ or N (C═O) CH ₃ ;

Z is halogen, C _1-6 alkyl, fluorobenzyloxy, pyridinylmethoxy, phenoxy, chlorophenoxy, dichlorophenoxy, fluorophenoxy, pyridinyloxy, methylpyridinyloxy, methylimidazole cycle Phenyl having 1 to 3 substituents selected from the group consisting of methyl, pyrazolyloxy and 1-methyl-3-trifluoromethyl pyrazolyloxy; Phenyl C _1-6 alkyl; Or fluorobenzylindazole;

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

또는

이고; 이때, R_{1 ,} R₂ 및 R₃은 서로 독립적으로 수소, 다이메틸아미노메틸, 다이에틸아미노메틸, 하이드록시메틸, 모폴리노메틸, 피롤리딘-1-일메틸, 4-메틸피페라진-1-일메틸, 메틸설포닐메틸, 아미노메틸, 아세트아미도메틸 또는 메틸설폰아미도메틸로 이루어진 군으로부터 선택될 수 있으며; R₄는 하이드록시 또는 메톡시이고; n_c는 1 내지 3의 정수이다. R is

or

ego; At this time, R _{1 ,} R ₂ And R ₃ is independently of each other hydrogen, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, morpholinomethyl, pyrrolidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, methylsulfonyl May be selected from the group consisting of methyl, aminomethyl, acetamidomethyl or methylsulfonamidomethyl; R ₄ is hydroxy or methoxy; n _c is an integer of 1 to 3;

More preferred pyrimidine derivatives of the general formula (1) include Z in 3-chloro-4-fluorophenyl, 3,4-dichloro-2-fluorophenyl, 4-bromo-3-chloro- 2-fluorophenyl, 4-fluoro-3-methylphenyl, (R) -1-phenylethyl, 3-chloro-4- (3-fluorobenzyloxy) phenyl, 3-chloro-4- (pyridine-2 -Ylmethoxy) phenyl, 2-fluoro-4- (pyridin-2-ylmethoxy) phenyl, 3-fluoro-4- (pyridin-2-ylmethoxy) phenyl, 1- (3-fluorobenzyl)- 1 H -5-indazole, 3-chloro-4-phenoxyphenyl, 3-chloro-4- (2,3-dichlorophenoxy) phenyl, 3-chloro-4- (2,4-dichlorophene Oxy) phenyl, 3-chloro-4- (2,5-dichlorophenoxy) phenyl, 3-chloro-4- (2-fluorophenoxy) phenyl, 3-chloro-4- (3-fluorophene Oxy) 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) phenyl, 3- Ro-4- (6-methylpyridin-3-yloxy) phenyl, 3-chloro-4- (1-methyl -1 H - one thio-imidazol-2-yl) phenyl, 3-chloro-4- (1 -Methyl-1 H -pyrazol-5-yloxy) phenyl, or 3-chloro-4- (1-methyl-3- (trifluoromethyl) -1 H -pyrazol-5-yloxy) phenyl Things.

As used herein, the term "halogen" means fluorine, chlorine, bromine or iodine, unless stated otherwise.

As used herein, the term 'alkyl' refers to a saturated monovalent hydrocarbon compound having straight, cyclic or branched moieties unless stated otherwise.

Specific examples of the more preferable compound among the above compounds are as follows:

1) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

2) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) -4,5-dihydrooxazole- 4-yl) methyl) acrylamide;

3) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 2-((dimethylamino) methyl) acrylamide;

4) (E) -N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl ) Methyl) -4- (dimethylamino) but-2-enamide;

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

6) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 3-hydroxypropaneamide;

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

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

9) N -((2- (4-amino-6- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

10) N -((2- (4-amino-6- (3-chloro-4- (2,3-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;

11) N -((2- (4-amino-6- (3-chloro-4- (2,4-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;

12) N -((2- (4-amino-6- (3-chloro-4- (2,5-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;

13) N -((2- (4-amino-6- (3-chloro-4-phenoxyphenylamino) 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-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

16) N -((2- (4-amino-6- (3-chloro-4- (3-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

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

18) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

19) N -((2- (4-amino-6- (3-chloro-4- (pyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;

20) N -((2- (4-amino-6- (3-chloro-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-hydroxypropaneamide;

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

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

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-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazole- 4-yl) methyl) -4- (dimethylamino) but-2-enamide;

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

27) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-imidazol-2-ylthio) phenylamino) pyrimidin-5-yl) oxazole -4-yl) methyl) acrylamide;

28) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-pyrazol-5-yloxy) phenylamino) pyrimidin-5-yl) oxazole- 4-yl) methyl) acrylamide;

29) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino) pyri) Midin-5-yl) oxazol-4-yl) methyl) acrylamide;

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

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

32) N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;

33) N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-((dimethyl Amino) 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-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;

36) N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-(( Dimethylamino) methyl) acrylamide;

37) N -((2- (4-acetamido-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino ) Pyrimidin-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 ) Acrylamide;

39) (E) -N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 4- (dimethylamino) but-2-enamide;

40) N -((2- (4- (3,4-dichloro-2-fluorophenylamino) pyrimidin-5-yl) oxazol-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-chloro-4-fluorophenylamino) pyridin-5-yl) oxazol-4-yl) methyl) -2-((dimethylamino) methyl) acrylic Amides;

43) (E) -N -((2- (4- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- (dimethylamino ) But-2-enamide;

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

45) N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;

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

47) 1- (2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) pyrrolidine- 1-yl) prop-2-en-1-one;

48) 1- (3- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperidine- 1-yl) prop-2-en-1-one;

49) 1- (4- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperidine- 1-yl) prop-2-en-1-one;

50) N -((5- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylic Amides;

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

52) (R) -N -((5- (4- (1-phenylethylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;

53) (E) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino) but-2-enamide;

54) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (Dimethylamino) methyl) acrylamide;

55) (E) -N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino) but-2-enamide;

56) (Z) - N- ( (5- (4- (3- chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazole-3-yl) methyl) - 4-hydroxybut-2-enamide;

57) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (Diethylamino) methyl) acrylamide;

58) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) methyl) -2- (pi Rollidin-1-ylmethyl) acrylamide;

59) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Morpholinomethyl) acrylamide;

60) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (4-methylpiperazin-1-yl) methyl) acrylamide;

61) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Hydroxymethyl) acrylamide;

62) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Methylsulfonylmethyl) acrylamide;

63) 2- (aminomethyl) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl ) Methyl) acrylamide;

64) 2- (acetamidomethyl) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazole-3 -Yl) methyl) acrylamide;

65) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Methylsulfonamidomethyl) acrylamide;

66) N- (3- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) phenyl) acrylamide; And

67) N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -N -methyl Acrylamide.

Among the compounds of the formula (1) according to the present invention, the compound of the formula (1a) may be prepared, for example, according to the method shown in Scheme 1 or the following Scheme 2.

[Reaction Scheme 1]

Where

R and Z are as defined above.

As shown in Scheme 1, the compound of formula 11 is mixed with 1-2 equivalents of sulfuryl chloride in an organic solvent such as carbon tetrachloride in the presence of a catalytic amount of 2,2'-azobis (2-methylpropionitrile) After stirring at reflux at 80 ° C. to obtain a compound of Formula 10 that is an acid chloride of the compound of Formula 11, D in an organic solvent such as tetrahydrofuran or dichloromethane in the presence of an organic base such as N, N -diisopropylethylamine. The compound of formula 9 may be obtained by condensation reaction with , L -serine methyl ester hydrochloride at 0 ° C to room temperature.

Thereafter, the compound of Formula 9 was injected into ammonia gas at 60 ° C. in an organic solvent such as toluene or a mixed solvent of toluene and ethanol to obtain a compound of Formula 8 substituted with amine, and then tetrahydrofuran or dichloromethane P -toluenesulfonic acid, methyl N- (triethylammoniumsulfonyl) carbamate or (diethylamino) sulfurtrifluoro in an organic solvent at a temperature of -78 ° C to reflux, for example 70 ° C. The compound of formula (7) can be obtained by cyclization reaction under the conditions using a ride (DAST).

Subsequently, Z is introduced by substituting Z-NH _{2 in an} organic solvent such as 2-propanol or acetonitrile (compound of Chemical Formula 6), and then, in the organic solvent such as dichloromethane. The compound of formula 5 may be obtained by reacting, 8-diazabicyclo [5.4.0] undec-7-ene and bromotrichloromethane under -40 ° C to room temperature.

Thereafter, the compound of Formula 5 was obtained in a organic solvent such as dichloromethane using a reducing agent such as lithium aluminum hydride (for example, 1.0 M lithium aluminum hydride ether) at 0 ° C. to room temperature. By reacting this with sodium azide and triphenylphosphine in a mixture of N, N -dimethylformamide and carbon tetrachloride, a compound of formula 3 having azide introduced therein may be obtained.

Triphenylphosphine and distilled water are added to the compound prepared above in an organic solvent such as tetrahydrofuran, and the compound of Chemical Formula 2 reduced with amine can be obtained by heating at 60 ° C to 70 ° C. The compound of formula 2 thus obtained is condensed with R-Cl in the presence of an inorganic base such as sodium hydrogen carbonate or an organic base such as pyridine or triethylamine in a mixed solvent of water and an organic solvent such as tetrahydrofuran and methylene chloride; Or 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (EDC) or 2- ( 1H -7-azabenzotriazol-1-yl) -1,1,3,3-tetra The compound of formula 1a of the present invention can be obtained by condensation with R-OH in a solvent such as tetrahydrofuran or methylene chloride using a binder such as methyl europium hexafluorophosphate methanealuminum (HATU).

In addition, the compound of Formula 1b in the compound of Formula 1 according to the present invention may be prepared according to the method shown in Scheme 2 below.

[Reaction Scheme 2]

Where

R, Z, n _a And n _b is as defined above

Prt represents a protecting group of an amine.

As in Scheme 2, the compound of formula 20 is reacted with iodine or N -iodosuccinimide under basic conditions such as aqueous sodium hydroxide solution or acid conditions such as acetic acid to obtain an iodopyrimidinone compound of formula 19 Thereafter, the compound of formula 18 may be obtained by reacting with an inorganic acid such as phosphorus oxychloride under reflux conditions.

The compound prepared above is substituted with Z-NH _{2 in an} organic solvent such as 2-propanol or acetonitrile to prepare a compound of formula 17 having Z introduced therein. This was followed by palladium such as dichlorobis (triphenylphosphine) palladium (II) in catalytic amounts under an organic base such as triethylamine under an acetylene compound protected with trimethylsilane (TMS) and an organic solvent such as tetrahydrofuran. The compound of Formula 16 can be obtained by performing Sonogashira reaction using a catalyst and copper iodide (I).

An acetylene compound of Formula 15 may be obtained using tetrabutylammonium fluoride from the compound of Formula 16 prepared above. Subsequently, 1,3- and a mixture of the oxime compound of Formula 21 and N -chlorosuccinimide prepared from aldehyde in an organic solvent such as tetrahydrofuran in the presence of an organic base such as triethylamine By the dipole cyclization addition reaction, an isoxazole compound of the formula (14) can be obtained. This may be reacted under acidic conditions such as hydrazine hydrate or trifluoroacetic acid to obtain a compound of formula 13 through deprotection of an amine protected with phthalimide or tert -butyloxycarbonyl (Boc).

The compound of formula 13 thus obtained is condensed with R-Cl in the presence of an inorganic base such as sodium hydrogen carbonate or an organic base such as pyridine or triethylamine in a mixed solvent of water and an organic solvent such as tetrahydrofuran and methylene chloride; Or 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (EDC) or 2- ( 1H -7-azabenzotriazol-1-yl) -1,1,3,3-tetra Compounds of formula 1b of the present invention can be prepared by condensation with R-OH in an organic solvent such as tetrahydrofuran or methylene chloride using a binder such as methyl europium hexafluorophosphate methanealuminum (HATU).

The compound of formula 1 according to the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, with preferred salts being 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, And salts derived from salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like.

The compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention selectively and effectively inhibits the growth of cancer cells caused by epidermal growth factor receptor (EGFR) or variants thereof, and is administered in combination with other anticancer agents. Can enhance the therapeutic effect.

The present invention also provides a pharmaceutical composition for inhibiting cancer cell growth, comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical compositions of the invention include cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, anti-metabolic agents, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, biological response modifiers, anti-hormonal agents, and anti- It may further comprise an anticancer agent used in the treatment of cancer or other diseases, selected from the group consisting of androgens.

The dosage of the active ingredient, such as a compound of the present invention or a pharmaceutically acceptable salt thereof, depends on the subject being treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. As an active ingredient, the compound of formula 1 may be used in mammals including humans in an amount of 0.01 to 200 mg / kg body weight, preferably 30 to 100 mg / kg body weight once or twice a day or on / The off schedule may be administered by oral or parenteral routes. In some cases, lower dosage values than the above-mentioned ranges may be more suitable, higher dosages may be used without causing harmful side effects, and higher dosages may be several smaller dosages throughout the day. To be distributed.

The pharmaceutical compositions of the present invention may be formulated according to conventional methods and may be administered in various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions or parenteral administration such as intramuscular, intravenous or subcutaneous administration. It may be prepared in the form.

When the pharmaceutical composition of the present invention is prepared in oral dosage form, examples of the carrier used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate and stearic acid, magnesium stearate, calcium stearate , Gelatin, talc, surfactants, suspending agents, emulsifiers, diluents and the like. When the pharmaceutical composition of the present invention is prepared in the form of an injection, the carrier may be water, saline, aqueous glucose solution, pseudo-aqueous solution, alcohol, glycol, ether (e.g. polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride , Surfactants, suspending agents, emulsifiers and the like.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1: N Preparation of-((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

Step 1) Preparation of 4,6-dichloropyrimidine-5-carbonyl chloride

10 g of 4,6-dichloropyrimidine-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 at 80 캜. It was stirred at reflux for 1.5 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered under reduced pressure, and the filtrate was distilled under reduced pressure, and the solid obtained was dried under reduced pressure to give 11.4 g (yield: 95%) of the title compound.

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

Step 2) Preparation of methyl 2- (4,6-dichloropyrimidine-5-carboxamido) -3-hydroxypropanoate

8.6 g of the compound prepared in step 1) and 12.6 g of D, L -serine methyl ester were dissolved in 100 ml of tetrahydrofuran, and 14.2 ml of N, N -diisopropylethylamine was slowly added dropwise at 0 ° C. The temperature was raised to room temperature and stirred for 30 minutes. When the reaction was completed, the reaction mixture was added to water and extracted with chloroform. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: dichloromethane: methanol = 30: 30: 1) to obtain 10.2 g (yield: 85%) of the title compound.

¹ H-NMR (300 MHz, 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 , 3 H), 3.67 ( m , 1 H).

Step 3) Preparation of Methyl 2- (4-amino-6-chloropyrimidine-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 and stirred at 60 ° C. for 2 hours. Ammonia gas was further bubbled until the reaction was completed, followed by further reaction at the same temperature for 1 hour. When the reaction was completed, distillation under reduced pressure and the resulting solid was dried under reduced pressure to give 6.54 g of the title compound.

¹ H-NMR (300 MHz, 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-dihydrooxazole-4-carboxylate

5.0 g of the compound obtained in step 3) was dissolved in 50 ml of dichloromethane, and 2.65 ml of (diethylamino) sulfurtrifluoride was slowly added dropwise at -78 deg. The temperature was slowly raised to 0 ° C. and stirred for 2.5 hours. Upon completion of the reaction, the mixture was basified with saturated aqueous sodium bicarbonate solution (pH 8) and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was crystallized in a mixed solvent of ethyl acetate and diethyl ether (3: 1), filtered under reduced pressure, and dried under reduced pressure to obtain 2.38 g (yield: 51%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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) Methyl 2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) -4,5-dihydrooxazole-4- Preparation of Carboxylate

1.5 g of the compound obtained in step 4) and 1.37 g of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine prepared according to the method disclosed in WO 2008150118 are dissolved in 25 ml of t -butanol. To this was added dropwise 0.73 ml of a 1,4-dioxane solution of 4N hydrochloric acid. The temperature was raised to 70 ° C. and stirred for 1.5 hours, after which the reaction was distilled under reduced pressure. The solvent was removed and 25 ml of 2-propanol was added and stirred at 0 ° C. for 2 hours. The resulting solid was washed with 2-propanol and filtered under reduced pressure, and the obtained solid was dried under reduced pressure to give 2.10 g (yield: 79%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 11.24 ( s , 1H), 8.63 ( d , 1H), 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-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazole-4-carboxylate

After dissolving 2.0 g of the compound obtained in step 5) in 40 ml of dichloromethane, 1.9 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene was added at -40 ° C, and bromotrichloromethane. 1.3 ml was slowly added dropwise for 20 minutes. The temperature was raised to room temperature and stirred for 2 hours. Upon completion of the reaction, the solvent was distilled off under reduced pressure to remove the solvent and crystallized in ethyl acetate. The resulting solid was washed with ethyl acetate and filtered under reduced pressure, and the obtained solid was dried under reduced pressure to yield 0.4 g (yield: 20%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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-ylmethoxy) 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 aluminum hydride ether solution was added dropwise. After stirring for 1 hour at the same temperature, when the reaction is completed, an aqueous solution of Russell salt (Rochelle salt, potassium sodium tartrate, NaKC ₄ H ₄ O ₆ ) is added, the mixture is stirred for 1 hour, and a mixed solvent of chloroform and 2-propanol (3: 1) Extracted twice. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: dichloromethane: methanol = 10: 10: 1) to obtain 0.27 g (yield: 82%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.70 ( s , 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) (5- (4- (aminomethyl) oxazol-2-yl)- N ⁴ Preparation of-(3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrimidine-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, 50 mg of sodium azide and 400 mg of triphenylphosphine were added thereto, and the temperature was raised to 90 ° C. for 30 minutes. Stirred. After distillation under reduced pressure to remove carbon tetrachloride, water was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was dried under reduced pressure, dissolved in 10 ml of tetrahydrofuran, 437 mg of triphenylphosphine and 0.1 ml of distilled water were added thereto, and the mixture was stirred at 60 ° C for 2 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 1: 1) to obtain 50 mg (yield: 19%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.71 ( s , 1H), 8.58 ( d , 1H), 8.19 ( s , 1H), 7.72 ( m , 2H), 7.64 ( d , 2H), 7.41 ( m , 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) N Preparation of-((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 µl of acryloyl chloride was added thereto, followed by stirring at the same temperature for 10 minutes. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added and extracted twice with chloroform. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 20 mg (yield: 39%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 478.2 [M + H] ⁺ .

Example 2: N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) -4,5-dihydrooxazol-4-yl Preparation of Methyl) acrylamide

5 mg of the title compound was obtained in the same manner as in Example 1, except that the compound obtained in Step 5) of Example 1 was not subjected to Step 6), but subjected to the reaction of Step 7). 10%).

¹ H-NMR (300 MHz, CDCl 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 , 1H), 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: N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2- ( Preparation of (dimethylamino) methyl) acrylamide

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 containing tetrahydrofuran solution was added. The mixture was heated to 70 ° C. and stirred for 1 hour, after which the reaction was distilled under reduced pressure. Acetone was added to the concentrated liquid residue to crystallize, followed by filtration under reduced pressure to obtain 0.4 g (yield: 32%) of the title compound as white crystals.

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

MS (ESI ⁺ ): m / z = 130.0 [M + H] ⁺ .

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

Dissolving the compound 4 ㎎ prepared in Step 1) in dichloromethane ㎖ 2 and N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride 7 ㎎ and N - hydroxy-benzotriazol-1 ㎎ And 12 µl of N, N -diisopropylethylamine were added and stirred at room temperature for 5 minutes. Subsequently, 10 mg of the compound obtained in step 8) of Example 1 was added thereto, followed by stirring at room temperature for 2 hours. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 6 mg (yield: 47%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 535.4 [M + H] ⁺ .

Example 4: (E) - N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- ( Preparation of Dimethylamino) but-2-enamide

Step 1) ( E Preparation of) -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 2.0 M dimethylamine containing tetrahydrofuran solution was added at 0 ° C. After stirring for 1 hour at room temperature, the mixture was filtered under reduced pressure and distilled under reduced pressure. The concentrated residue was dissolved in 30 ml of 2-propanol solution, which was then acidified (pH 2) with 10% hydrochloric acid 2-propanol solution at 0 ° C. and the resulting solid was filtered under reduced pressure. The obtained solid was washed with 2-propanol and dried under reduced pressure to give 2.8 g (yield 33%) of the title compound.

¹ H-NMR (300 MHz, 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) ( E Preparation of 4--4- (dimethylamino) but-2-enoic acid

1 g of the compound prepared in step 1) was dissolved in 6.6 ml of methanol, 2.2 ml of 40% aqueous sodium hydroxide solution was added thereto, and the temperature was raised to 45 ° C. and stirred for 30 minutes. And it was acidified (pH 2) with 10% hydrochloric acid 2-propanol solution at 0 ℃ and filtered under reduced pressure. The filtrate was distilled under reduced pressure, and the concentrated residue was dissolved in 3 ml of 2-propanol solution. The temperature was raised to 35 ° C and stirred for 10 minutes. Then, 3 ml of acetone was added and stirred at 40 ° C. for 30 minutes, followed by stirring at room temperature for 12 hours. The resulting solid was washed with a mixed solvent of 2-propanol and acetone (1: 2) and filtered under reduced pressure, and the obtained solid was dried under reduced pressure to obtain 500 mg (yield: 54%) of the title compound.

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

Step 3) (E) - N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- ( Preparation of Dimethylamino) but-2-enamide

The same process as in Example 3 was conducted except that 2.3 mg of the compound obtained in Step 2) was used instead of 2-((dimethylamino) methyl) acrylic acid in Step 2). 2 mg (yield 31%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl 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 ( m , 1H), 6.98 ( d , 1H), 6.88 ( m , 1H), 6.26 ( m , 1H), 6.04 ( d , 1H), 5.29 ( s , 2H), 4.53 ( d , 2H ), 3.21 ( s , 2H), 2.34 ( s , 6H);

MS (ESI ⁺ ): m / z = 535.3 [M + H] ⁺ .

Example 5: N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-hydro Roxia Cetamide

5 mg of glycolic acid and 27 mg of 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl euronium hexafluorophosphate methaneaminium at room temperature It was dissolved in 1.0 ml of methane and stirred for 10 minutes. 30 mg of the compound obtained in step 8) of Example 1 and 42 μl of N, N -diisopropylethylamine were added thereto, and the resultant was stirred at the same temperature for 2 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure and extracted twice with a mixed solvent of chloroform and 2-propanol (3: 1). The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: methanol = 5: 1) to give 2 mg (yield: 5.9%) of the title compound.

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

Example 6: N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-hydro Roxypropaneamide

7 μl of 3-hydroxy propionic acid and 27 mg of 2- ( 1H- 7-azabenzotriazol-1-yl) -1, 1, 3, 3-tetramethyl uronium hexafluorophosphate methaneaminium at room temperature Was dissolved in 1.0 ml of dichloromethane and stirred for 10 minutes. 30 mg of the compound obtained in step 8) of Example 1 and 42 μl of N, N -diisopropylethylamine were added thereto, and the resultant was stirred at the same temperature for 2 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure and extracted twice with a mixed solvent of chloroform and 2-propanol (3: 1). The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: methanol = 5: 1) to obtain 2 mg (yield: 5.7%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( s , 2H), 4.46 ( s , 2H), 3.49 ( t , 2H), 2.53 ( t , 2H).

Example 7: N Of ((2- (4-amino-6- (2-fluoro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Produce

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 and stirred at 80 ° C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water was added to the reaction mixture, followed by extraction with chloroform. The separated organic layer was washed twice with water, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The obtained residue was dried under reduced pressure to give 3 g (yield: 95%) of the title compound.

¹ H-NMR (300 MHz, 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 dissolved in 10 ml of 50% ethanol aqueous solution, 0.4 ml of 35% hydrochloric acid aqueous solution was added, and the reaction temperature was raised to 110 ° C. To this was added 3 g of the compound prepared in step 1) and refluxed at 110 ° C. for 2 hours. After the reaction was completed, the mixture was filtered under reduced pressure with a celite pad and the filtrate was distilled under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, distilled under reduced pressure, and dried under reduced pressure to obtain 2.2 g (yield: 73%) of the title compound.

¹ H-NMR (300 MHz, 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 ( m , 1H), 5.05 ( m , 1H), 4.65 ( s , 2H).

Step 3) N Of ((2- (4-amino-6- (2-fluoro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Produce

In the same manner as in Example 1, except that 595 mg of the compound obtained in Step 2) was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in Step 5), the title compound 30 was carried out. Mg (final step yield: 76%) was obtained.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 462.2 [M + H] ⁺ .

Example 8: N -((2- (4-amino-6- (3-fluoro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide of Produce

In the same manner as in Example 7, except that 2 g of 2-fluoro-4-nitrophenol was used instead of 3-fluoro-4-nitrophenol in Step 1), 40 mg of the title compound (final) Step yield: 51%).

¹ H-NMR (300 MHz, CDCl 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 ( t , 1H), 6.36 ( m , 1H), 6.14 ( m , 1H), 6.00 ( m , 1H), 5.71 ( m , 1H), 5.27 ( s , 2H ), 4.54 ( m , 2 H);

MS (ESI ⁺ ): m / z = 462.2 [M + H] ⁺ .

Example 9: N Preparation of-((2- (4-amino-6- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

3-chloro-4- (3-fluoro-benzyloxy) prepared according to the method described in WO 2008150118 instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in step 5). Except for using phenylamine, the same process as in Example 1 was carried out to obtain 9 mg (final step yield: 47%) of the title compound.

¹ H-NMR (300 MHz, 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: N -((2- (4-amino-6- (3-chloro-4- (2,3-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Manufacture

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

2.6 g of potassium hydrogen carbonate 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 for 1.5 hours at 100 ° C. Stirred. After the reaction was completed, the reaction mixture was cooled to room temperature, and water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed twice with water, dried over anhydrous magnesium sulfate, filtered under reduced pressure and distilled under reduced pressure.

Then, 4.83 g of iron was dissolved in 70 ml of 50% ethanol aqueous solution, 2.0 ml of 35% hydrochloric acid aqueous solution was added, and the reaction temperature was raised to 110 ° C. The obtained residue was added and refluxed at 110 ° C for 3 hours. After the reaction was completed, the mixture was filtered under reduced pressure with a celite pad and the filtrate was distilled under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted twice with a mixed solvent of chloroform and 2-propanol (3: 1). The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, distilled under reduced pressure, and dried under reduced pressure to obtain 4.32 g (yield: 86%) of the title compound.

¹ H-NMR (300MHz, CDCl 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) N -((2- (4-amino-6- (3-chloro-4- (2,3-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Manufacture

The same process as in Example 1 was carried out except that the compound prepared in Step 1) was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in Example 5). 11 mg (final step yield: 39%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.20 ( s , 1H), 7.94 to 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: N -((2- (4-amino-6- (3-chloro-4- (2,4-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Manufacture

Except for using 2,4-dichlorophenol instead of 2,3-dichlorophenol in step 1), the same process as in Example 10 was carried out to obtain 14 mg (final step yield: 41%) of the title compound. .

¹ H-NMR (300MHz, CDCl ₃ + 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 , 1 H), 4.58˜4.56 ( m , 2H);

MS (ESI ⁺ ): m / z = 531.3 [M + H] ⁺ .

Example 12: N -((2- (4-amino-6- (3-chloro-4- (2,5-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Manufacture

Except for using 2,5-dichlorophenol instead of 2,3-dichlorophenol in step 1), the same process as in Example 10 was carried out to obtain 14 mg (final step yield: 40%) of the title compound. .

¹ H-NMR (300 MHz, CDCl ₃ + 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: N Preparation of-((2- (4-amino-6- (3-chloro-4-phenoxyphenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

Except for using phenol instead of 2,3-dichlorophenol in step 1), the same process as in Example 10 was carried out to obtain 29 mg (final step yield: 67%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.86 ( bs , 1H), 8.25 ( s , 1H), 7.92 to 7.91 ( d , 1H), 7.74 ( s , 1H), 7.55 to 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 (ESI ⁺ ): m / z = 463.3 [M + H] ⁺ .

Example 14: (E) - N -((2- (4-amino-6- (3-chloro-4-phenoxyphenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- (dimethylamino) but- Preparation of 2-enamide

Except for using 3-chloro-4-phenoxybenzeneamine in place of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine, the same process as in Example 4 was carried out to obtain 17 mg of the title compound (final). Step yield: 43%).

¹ H-NMR (300MHz, CDCl ₃ ) δ 8.23 ( s , 1H), 7.91`7.90 ( m , 1H), 7.72 ( s , 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 ⁺ ): m / z = 520.2 [M + H] ⁺ .

Example 15: N Preparation of-((2- (4-amino-6- (3-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

In the same manner as in Example 10, except that 2-fluorophenol was used instead of 2,3-dichlorophenol in Step 1), 7 mg (final step yield: 21%) of the title compound was obtained.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) 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 ( d , 2H).

Example 16: N Preparation of-((2- (4-amino-6- (3-chloro-4- (3-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

Except for using 3-fluorophenol instead of 2,3-dichlorophenol in step 1), the same process as in Example 10 was carried out to obtain 14 mg (final step yield: 38%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.24 ( s , 1H), 7.95 to 7.94 ( m , 1H), 7.72 ( s , 1H), 7.59 to 7.56 ( m , 1H), 7.25 to 7.24 ( m , 1H ), 7.09-7.06 ( m , 1H), 6.77-6.71 ( 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 (ESI ⁺ ): m / z = 481.3 [M + H] ⁺ .

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

21 mg (final step yield: 44%) of the title compound were obtained in the same manner as in Example 10, except that 4-fluorophenol was used instead of 2,3-dichlorophenol in Step 1).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.24 ( s , 1H), 7.90 to 7.89 ( m , 1), 7.73 ( s , 1H), 7.51 to 7.50 ( m , 1H), 7.02 to 6.63 ( m , 5H ), 6.40-6.34 ( m , 1H), 6.19-6.10 ( m , 1H), 5.74-5.70 ( m , 1H);

MS (ESI ⁺ ): m / z = 481.2 [M + H] ⁺ .

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

In the same manner as in Example 10, except that 2-hydroxy pyridine was used instead of 2,3-dichlorophenol in Step 1), 7 mg (final step yield: 30%) of the title compound was obtained.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 10.93 ( s , 1H), 8.20 ( s , 1H), 7.90 ( s , 1H), 7.73-7.71 ( m , 2H), 7.54 ( dd , 1H ), 7.18 ( d , 2H), 7.01-6.96 ( m , 2H), 6.37 ( d , 1H), 6.18 ( t , 1H), 5.68 ( d , 1H), 4.53 ( d , 2H).

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

Except for using 3-hydroxy pyridine instead of 2,3-dichlorophenol in step 1), the same process as in Example 10 was carried out to obtain 20 mg of the title compound (final step yield: 44%).

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

MS (ESI ⁺ ): m / z = 464.3 [M + H] ⁺ .

Example 20: N -((2- (4-amino-6- (3-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-hydro Preparation of Roxyacetamide

The same process as in Example 5 was conducted except that 3-chloro-4- (2-fluorophenoxy) benzeneamine was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine. 12 mg (final step yield: 20%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.18 ( s , 1H), 7.89 to 7.88 ( m , 1H), 7.70 ( m , 1H), 7.52 to 7.48 ( m , 1H), 7.11 to 6.61 ( m , 4H ), 4.54-4.52 ( d , 2H), 3.78 ( s , 2H);

MS (ESI ⁺ ): m / z = 485.3 [M + H] ⁺ .

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

The same process as in Example 6 was conducted except that 3-chloro-4- (2-fluorophenoxy) benzeneamine was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine. 15 mg (final step yield: 25%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.21 ( s , 1H), 7.89-7.88 ( m , 1H), 7.70 ( s , 1H), 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 ( t , 2H ).

Example 22: N -((2- (4-amino-6- (3-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -3-me Preparation of Toxypropaneamide

Except for using 3-methoxypropanoic acid instead of glycolic acid, the same process as in Example 20 was carried out to obtain 11 mg of the title compound (final step yield: 30%).

¹ H-NMR (300MHz, CDCl 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 ), 6.96-6.63 ( 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 (ESI ⁺ ): m / z = 513.4 [M + H] ⁺ .

Example 23: N -((2- (4-amino-6- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Preparation of Amide

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

6-methyl-pyridin-3-ol and 1-fluoro-2-methyl-4-nitrobenzene in place of 2,3-dichlorophenol and 3-chloro-4-fluoronitrobenzene in step 1) Except that, the same process as in Step 1) of Example 10 was carried out to obtain 10.6 g (final step yield: 81%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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) N -((2- (4-amino-6- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Preparation of Amide

The procedure above, except that 3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamine is used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in step 5). The same process as in Example 1 was carried out to obtain 34 mg of the title compound (final step yield: 76%).

¹ H-NMR (300 MHz, CDCl 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 , 1H), 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: N -((2- (4-amino-6- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- Preparation of 2-((dimethylamino) methyl) acrylamide

Same as Example 3, except that 3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamine is used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine The process was carried out to give 35 mg (final step yield: 55%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.77 (bs , 1H), 8.27 to 8.26 ( d , 1H), 8.23 ( s , 1H), 7.68 ( s , 1H), 7.54 to 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 (ESI ⁺ ): m / z = 515.0 [M + H] ⁺ .

Example 25: ( E ) - N -((2- (4-amino-6- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- Preparation of 4- (dimethylamino) but-2-enamide

Same as Example 4, except that 3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamine is used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine The process was carried out to give 20 mg (39% final yield) of the title compound.

¹ H-NMR (300MHz, CDCl ₃ ) δ 10.48 (bs , 1H), 8.25 ( m , 1H), 8.20 ( s , 1H), 7.70 ( s , 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 ( m , 2H ), 2.51 ( s , 3H), 2.25 ( s , 3H), 2.22 ( s , 6H);

MS (ESI ⁺ ): m / z = 515.6 [M + H] ⁺ .

Example 26: N -((2- (4-amino-6- (3-chloro-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Preparation of Amide

In the same manner as in Example 10, except that 5-hydroxy-2-methylpyridine was used instead of 2,3-dichlorophenol in Step 1), 1 mg of the title compound was obtained (final step yield: 2%). Got.

¹ H-NMR (300 MHz, CDCl 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: N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-imidazol-2-ylthio) phenylamino) pyrimidin-5-yl) oxazole-4- (1) Preparation of methyl) acrylamide

29 mg of the title compound (final step yield: 63) was carried out in the same manner as in Example 10, except that 2-mercapto-1-methylimidazole was used instead of 2,3-dichlorophenol in Step 1). %) Was obtained.

¹ H-NMR (300 MHz, 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 ( t , 1H), 4.48 ( s , 2H), 3.71 ( s , 3H);

MS (ESI ⁺ ): m / z = 483.2 [M + H] ⁺ .

Example 28: N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-pyrazol-5-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl Preparation of Methyl) acrylamide

In the same manner as in Example 10, except that 2-methyl-2H-pyrazol-3-ol was used instead of 2,3-dichlorophenol in Step 1), the title compound was 68 mg (final step yield). : 31%).

¹ H-NMR (300MHz, CDCl ₃ + CD ₃ OD) 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 , 1 H), 4.55-4.53 ( d , 2H), 3.80 ( s , 3H);

MS (ESI ⁺ ): m / z = 467.2 [M + H] ⁺ .

Example 29: N -((2- (4-amino-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino) pyrimidine-5 Preparation of -yl) oxazol-4-yl) methyl) acrylamide

The same procedure as in Example 10 was carried out except that 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole was used instead of 2,3-dichlorophenol in step 1). 25 mg (final step yield: 67%) were obtained.

¹ H-NMR (300 MHz, 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 ( m , 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 (ESI ⁺ ): m / z = 535.3 [M + H] ⁺ .

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

The same process as in Example 1 was performed except that 3,4-dichloro-2-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in step 5). 26 mg (final step yield: 45%) of the title compound were obtained.

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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 (ESI ⁺ ): m / z = 423.2 [M + H] ⁺ .

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

In the same manner as in Example 1, except that 4-fluoro-3-methylaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in Step 5), the title compound 30 Mg (final step yield: 20%) was obtained.

¹ H-NMR (300 MHz, CDCl 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: N Preparation of-((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

In the same manner as in Example 1, except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in Step 5), the title compound 19 was used. Mg (final step yield: 16%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.07 ( s , 1H), 7.75 ( dd , 1H), 7.69 ( s , 1H), 7.42-7.37 ( m , 1H), 7.06 ( t , 1H ), 6.28 ( d , 1 H), 6.20 ( d , 1 H), 5.63 ( d , 1 H), 4.42 ( s , 2H);

MS (ESI ⁺ ): m / z = 389.2 [M + H] ⁺ .

Example 33: N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-((dimethylamino) methyl Production of Acrylamide

43 mg (final step) of the title compound was carried out in the same manner as in Example 3, except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine. Yield: 32%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.90 ( bs , 1H), 9.65 ( bs , 1H), 8.14 ( s , 1H), 7.79-7.77 ( m , 1H), 7.60 ( s , 1H), 7.46- 7.42 ( m , 1 H), 7.08 ( t , 1 H), 6.21 ( s , 1 H), 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: (E) - N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4-((dimethylamino) but Preparation of 2-enamide

Except for using 3-chloro-4-fluoroaniline instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine, the same procedure as in Example 4 was carried out to give 63 mg of the title compound (final step) Yield: 47%).

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 8.75 ( s , 1H), 8.11 ( s , 1H), 8.03 ( m , 1H), 7.04 ( s , 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 ⁺ ): m / z = 446.3 [M + H] ⁺ .

Example 35: N Preparation of-((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

Step 1) Preparation of ethyl 4-hydroxy-pyrimidine-5-carboxylate

16 mL of 2-ethoxymethylene-malonic acid diethyl ester and 6.6 g of formamidine hydrochloride were added thereto, and the mixture was stirred under reflux at 160 ° C. for 20 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, distilled under reduced pressure, and the resulting solid was washed with acetone and filtered under reduced pressure. The obtained solid was dried under reduced pressure to obtain 7.7 g (yield: 56%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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-pyrimidine-5-carboxylate

2 g of the compound obtained in step 1) was dissolved in 3.5 ml of phosphorus oxychloride, and 18 ml of thionyl chloride and 50 µl of dimethylformamide were added, and the mixture was stirred under reflux at 120 ° C. for 5 hours. When the reaction was completed, distillation under reduced pressure was carried out, and 50 ml of toluene was added to the obtained residue, followed by distillation under reduced pressure twice, followed by drying under reduced pressure to obtain 2.1 g (yield: 95%) of the title compound.

¹ H-NMR (300 MHz, 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) -pyrimidine-5-carboxylate

2.1 g of the compound obtained in step 2) and 2.64 g of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine were dissolved in 20 ml of 2-propanol and stirred under reflux for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and then distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: dichloromethane: methanol = 7: 7: 1) to obtain 2.0 g of the title compound.

¹ H-NMR (300 MHz, CDCl 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) 4- [3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -pyrimidine-5-carboxylic acid

2.0 g of the compound obtained in step 3) was dissolved in 15 ml of ethanol, and 13 ml of 2N aqueous sodium hydroxide solution was added thereto, and the mixture was stirred under reflux at 80 ° C for 2 hours. When the reaction was completed, the mixture was distilled under reduced pressure, and 3N hydrochloric acid aqueous solution was slowly added dropwise to the obtained residue at 0 ° C, followed by acidification (pH 2-3). The obtained solid was filtered under reduced pressure and dried under reduced pressure to obtain 1.8 g (yield: 97%) of the title compound.

¹ H-NMR (300 MHz, 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 ( d , 1H), 7.46-7.43 ( m , 2H), 7.21 ( d , 1H), 5.29 ( s , 2H).

Step 5) of methyl 2-((4- (3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino) -pyrimidine-5-carbonyl) -amino) -3-hydroxypropanoate Produce

It was dissolved in 10 ㎖ dimethyl formamide, N, N - - Compound 1.9 g and 1-ethyl-3-kaboyi hydrochloride 1.53 g (3- dimethylaminopropyl) obtained in the step 4), N, N dia 2.8 ml of isopropylethylamine and 5 mg of N -hydroxybenzotriazole were added and stirred at room temperature. After 5 minutes, 828 mg of D, L -serine methyl ester was added, followed by stirring at room temperature for 4 hours. After the reaction was completed, water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: methanol = 15: 1) to obtain 1.2 g (yield: 49%) of the title compound.

¹ H-NMR (300 MHz, CD ₃ OD) δ 8.72 ( s , 1H), 8.60 ( s , 1H), 8.51 (s, 1H), 7.81 ( d , 2H), 7.67 ( d , 1H), 7.39 ( d , 1H), 7.30-7.28 ( m , 1H), 6.98 ( d , 1H), 5.22 ( s , 2H), 4.75-4.74 ( m , 1H), 4.05 ( d , 1H), 3.93 ( d , 1H), 3.79 ( s , 3 H).

Step 6) Methyl 2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino-pyrimidin-5-yl) -4,5-dihydro-oxazole-4-carboxylate Manufacture

Using the 1.3 g of the compound obtained in step 5), the residue obtained by the same process as in step 4) of Example 1 was separated by column chromatography (dichloromethane: methanol = 20: 1) to give 1.1 g of the titled compound. (Yield 89%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.91 ( s , 1H), 8.79 ( s , 1H), 8.72 ( s , 1H), 8.58 ( s , 1H), 7.83 ( s, 1H), 7.74-7.72 ( t , 1H), 7.65 ( d , 1H), 7.47 ( dd , 1H), 7.26-7.23 ( m , 1H), 6.98 ( d , 1H), 5.28 ( s , 2H), 5.03-4.99 ( m , 1H) , 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) -oxazole-4-carboxylate

Using the compound obtained in step 6), 1.1 g, the residue obtained by the same process as in step 6) was separated by column chromatography (dichloromethane: methanol = 20: 1) to give the title compound (709 mg). (Yield 65%) was obtained.

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

Step 8) Preparation of (2- (4- (3-Chloro-4- (pyridin-2-ylmethoxy) -phenylamino) -pyrimidin-5-yl) -oxazol-4-yl) -methanol

The residue obtained by the same process as in step 7) of Example 1 using 100 mg of the compound obtained in step 7) was isolated by column chromatography (dichloromethane: methanol = 20: 1) to obtain 40 mg of the title compound. (Yield 43%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD) δ 10.76 ( s , 1H), 8.94 ( s , 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) (5- (4-Aminomethyl-oxazol-2-yl) -pyrimidin-4-yl)-(3-chloro-4- (pyridin-2-ylmethoxy) -phenyl) -amine

The residue obtained by the same process as in step 8) of Example 1 using 20 mg of the compound obtained in step 8) was separated by column chromatography (dichloromethane: methanol = 5: 1) to obtain 16 mg of the title compound. (Yield 80%) was obtained.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 409.2 [M + H] ⁺ .

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

The residue obtained by the same process as in step 9) of Example 1 using 15 mg of the compound obtained in step 9) was separated by column chromatography (dichloromethane: methanol = 20: 1) to obtain 1.8 mg of the title compound. (Yield 10%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 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 (ESI ⁺ ): m / z = 463.3 [M + H] ⁺ .

Example 36: N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-((dimethylamino Preparation of Methyl) acrylamide

Example 3 dissolved in step 1) of the compound 2.5 ㎎ in dichloromethane ㎖ 1 and N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride 4.6 ㎎, N --hydroxybenzotriazole 0.6 mg of azole and 8 µl of N , N -diisopropylethylamine were added and stirred at room temperature for 5 minutes. Next, 6.5 mg of the compound obtained in Step 9) of Example 35 was added thereto, and the resultant was stirred at room temperature for 3 hours. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 3 mg (yield: 38%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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: N -((2- (4-acetamido-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino) pyrimidine Preparation of -5-yl) oxazol-4-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. When the reaction was completed, the residue was distilled under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 30: 1) to obtain 17 mg (yield: 69%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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: N -((2- (4-acetamido-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide Manufacture

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. When the reaction was completed, the residue was distilled under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 20: 1) to obtain 3 mg (yield: 29%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( m , 1H), 5.71 ( m , 1H), 5.29 ( s , 2H ), 4.95 ( s , 1 H), 4.55 ( d , 1 H), 2.55 ( s , 3 H).

Example 39: (E) - N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- (dimethylamino) Preparation of but-2-enamide

Example 4 dissolved in 2 steps) of the compound 3.9 ㎎ in dichloromethane ㎖ 1 and N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride 5.6 ㎎, N --hydroxybenzotriazole 0.8 mg of azole and 10 [mu] l of N , N -diisopropylethylamine were added and stirred for 5 minutes at room temperature. Subsequently, 8 mg of the compound obtained in Step 9) of Example 35 was added thereto, followed by stirring at room temperature for 3 hours. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 8: 1) to obtain 2 mg (yield: 19%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.55 ( s , 1H), 8.95 ( s , 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 ( s , 2H ), 4.54 ( d , 2H), 3.11 ( d , 2H), 2.19 ( s , 6H).

Example 40: N Preparation of-((2- (4- (3,4-dichloro-2-fluorofluoroamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

The same procedure as in Example 35 was carried out except that 3,4-dichloro-2-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) -phenylamine to give the title compound 4 Mg (final step yield: 18%) was obtained.

¹ H-NMR (300 MHz, CDCl 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: N Preparation of-((2- (4- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide

The same process as in Example 35 was carried out except that 3-chloro-4-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine to give 3 mg of the title compound (final step) Yield: 7%).

¹ H-NMR (300 MHz, CDCl 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 ( m , 1H), 5.74 ( d , 1H), 4.57 ( d , 2H );

MS (ESI ⁺ ): m / z = 374.2 [M + H] ⁺ .

Example 42: N Preparation of-((2- (4- (3-chloro-4-fluorophenylamino) pyridin-5-yl) oxazol-4-yl) methyl) -2-((dimethylamino) methyl) acrylamide

Except for using 3-chloro-4-fluoroaniline instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine, the same process as in Example 36 was carried out to obtain 10 mg of the title compound (final step) Yield: 49%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.87 ( s , 1H), 9.70 ( s , 1H), 8.99 ( s , 1H), 8.77 ( s , 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: (E) - N -((2- (4- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- (dimethylamino) but-2-enamide Manufacture

Except for using 3-chloro-4-fluoroaniline instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine, the same procedure as in Example 39 was carried out to obtain 12 mg of the title compound (final step) Yield: 44%).

¹ H-NMR (300 MHz, CDCl 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 ( d , 2H), 2.31 ( s , 6H );

MS (ESI ⁺ ): m / z = 431.2 [M + H] ⁺ .

Example 44: N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

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

10 g of 4 (3H) -pyrimidone was dissolved in 156 ml of acetic acid, 25.8 g of N -iodosuccinimide was added at 70 ° C, and the temperature was raised to 100 ° C and stirred for 30 minutes. Upon completion of the reaction, the mixture was cooled to room temperature and crystallized by adding ice, which was filtered under reduced pressure. The obtained solid was washed with water and dried under reduced pressure to obtain 16 g (yield 67%) of the title compound.

¹ H-NMR (300 MHz, 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) was added to 60 ml of phosphorus oxychloride, followed by stirring at 110 ° C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and distilled under reduced pressure to remove the solvent. Subsequently, toluene was added thereto, followed by distillation under reduced pressure to remove the solvent three times. The obtained solid was dried under reduced pressure to give 13 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 13.27 ( bs , 1H), 9.18 ( s , 1H), 8.98 ( s , 1H).

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

7 g of the compound obtained in step 2) and 6.5 g of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine were dissolved in 100 ml of 2-propanol, and the temperature was raised to 100 ° C. and stirred for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0 ° C. and stirred for 2 hours. The resulting solid was washed with 2-propanol and filtered under reduced pressure, and the obtained solid was dried under reduced pressure to quantitatively obtain 12.5 g of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.56 ( m , 1H), 8.67 ( m , 2H), 8.05 ( m , 1H), 7.65 ( m , 2H), 7.34 ( m , 3H), 5.36 ( s , 2H).

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

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

¹ H-NMR (300 MHz, CDCl 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 ( s , 1H), 0.32 ( s , 9H).

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

After dissolving 1.8 g of the compound obtained in step 4) in 30 ml of tetrahydrofuran, 8.8 ml of a 1.0 M tetrabutylammonium fluoride-containing tetrahydrofuran solution was added and reacted at room temperature for 1 hour. Upon completion of the reaction, saturated aqueous ammonium chloride solution was added and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain 1.4 g (yield: 94%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.65 ( s , 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) 2-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) isoindolin Preparation of -1,3-dione

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

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.84 ( s , 1H), 8.61 ( s , 1H), 8.59 ( s , 1H), 8.56 ( d , 1H), 7.90 ( m , 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) 5- (3- (Aminomethyl) isoxazol-5-yl)- N Preparation of-(3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrimidin-4-amine

450 mg of the compound obtained in step 6) was dissolved in 10 ml of ethanol, and then 203 µl of hydrazine hydrate was added and stirred at 70 ° C. for 1 hour. When the reaction was completed, the resulting solid was cooled to 0 ℃ washed with chloroform, filtered off under reduced pressure and then distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 200 mg (yield: 59%) of the title compound.

¹ H-NMR (300 MHz, 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 ( d , 2H), 3.79 ( s , 2H).

Step 8) N Preparation of Preparation of ((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

Acrylic acid 148 was dissolved in dichloromethane 30 ㎎ ㎖ and N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride 492 ㎎, N --hydroxybenzotriazole ㎎ 69 and N, N - diisopropyl 895 μl of propylethylamine was added and stirred at room temperature for 10 minutes. Then, 700 mg of the compound obtained in step 7) was added thereto, and the resultant was stirred at room temperature for 3 hours. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 50: 1) to obtain 300 mg (yield: 38%) of the title compound.

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

MS (ESI ⁺ ): m / z = 463.1 [M + H] ⁺ .

Example 45: N Preparation of-((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

 Same as Example 44 above, except that 3-chloro-4- (3-fluorobenzyloxy) benzeneamine is used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in step 3). The process gave 6 mg (final step yield: 11%) of the title compound.

¹ H-NMR (300 MHz, CD ₃ OD) δ 8.57 ( m , 2H), 7.71 ( m , 1H), 7.40 ( m , 2H), 7.30 ( m , 2H), 7.11 ( m , 2H), 6.85 ( s , 1H), 6.30 ( m , 2H), 5.72 ( t , 1H), 5.19 ( s , 2H), 4.53 ( m , 2H);

MS (ESI ⁺ ): m / z = 480.4 [M + H] ⁺ .

Example 46: N Preparation of-(2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) ethyl) acrylamide

Use 3-chloro-4- (3-fluorobenzyloxy) benzeneamine instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine in step 3) and N- (2- 29 mg (final step yield: 51%) of the title compound were carried out in the same manner as in Example 44, except that N- (3-hydroxypropyl) phthalimide was used instead of hydroxyethyl) phthalimide. Got it.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.71 ( s , 1H), 8.60 ( s , 1H), 8.06 ( s , 1H), 7.77 ( m , 1H), 7.41 ( m , 4H), 7.22 ( m , 2H), 6.97 ( m , 2H), 6.55 ( s , 1H), 6.25 ( d , 1H), 6.08 ( m , 2H), 5.63 ( d , 1H), 5.16 ( s , 2H), 3.79 ( m , 2H ), 3.03 ( m , 2 H);

MS (ESI ⁺ ): m / z = 494.2 [M + H] ⁺ .

Example 47 1- (2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) pyrroli Preparation of din-1-yl) prop-2-en-1-one

Step 1) N Preparation of-(3-chloro-4- (3-fluorobenzyloxy) phenyl) -5-ethynylpyrimidin-4-amine

Step 5) was carried out in the same manner as in Example 44 using 3-chloro-4- (3-fluorobenzyloxy) benzeneamine instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine 184 mg of the title compound were obtained quantitatively.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.64 ( s , 1H), 8.44 ( s , 1H), 7.73 ( d , 1H), 7.40 ( m , 3H), 7.20 ( m , 3H), 6.94 ( m , 2H), 5.19 ( s , 2H), 3.66 ( d , 1H).

Step 2) Tert-Butyl 2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) pyrrolidine Preparation of -1-carboxylate

After dissolving 500 mg of N -bok- L -prolinol in 25 ml of dichloromethane, 1.26 g of des-martin periodinan was added thereto, and the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, saturated aqueous 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 under reduced pressure and distilled under reduced pressure. The obtained solid was dissolved in 5 ml of pyridine, and then 517 mg of hydroxylamine hydrochloride was added and stirred at 65 ° C for 1 hour. After the reaction was completed, the mixture was distilled under reduced pressure, and ethyl acetate was added thereto and washed three times with water. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: hexane = 1: 1). 91 mg of the obtained solid was dissolved in 2 ml of tetrahydrofuran, 75 mg of N -chlorosuccinimide and 4 µl of pyridine were added thereto, followed by stirring at room temperature for 2 hours. Then, 100 mg of the compound obtained in step 1) and 47 μl of triethylamine were added thereto, followed by stirring at 65 ° C. for 3 hours. After the reaction was completed, the mixture was distilled under reduced pressure, and the obtained residue was separated by column chromatography (dichloromethane: ethyl acetate = 40: 1) to obtain 138 mg (yield: 86%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( s , 9H).

Step 3) N Preparation of-(3-chloro-4- (3-fluorobenzyloxy) phenyl) -5- (3- (pyrrolidin-2-yl) isoxazol-5-yl) pyrrolidin-4-amine

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

¹ H-NMR (300 MHz, 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) 1- (2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) pyrrolidine Preparation of -1-yl) prop-2-en-1-one

51 mg of the compound obtained in step 3) and 27 mg of sodium bicarbonate were dissolved in 2 ml of tetrahydrofuran and 0.5 ml of distilled water at 0 ° C., and 8.8 µl of acryloyl chloride was added thereto, followed by stirring at the same temperature for 1 hour. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added and extracted twice with chloroform. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (dichloromethane: ethyl acetate: methanol = 50: 150: 1) to obtain 20 mg (yield: 35%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( m , 1H), 5.77 ( m , 1H), 5.45 ( m , 1H), 5.15 ( s , 2H), 3.71 ( m , 3H), 2.26 ( m , 4H ).

Example 48: 1- (3- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperi Preparation of din-1-yl) prop-2-en-1-one

Except for using N -bok-piperidine-3-methanol in place of N -bok- L -prolinol in step 2), the same procedure as in Example 47 was carried out to give 15 mg of the title compound (final step yield). : 38%).

¹ H-NMR (300 MHz, 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: 1- (4- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperi Preparation of din-1-yl) prop-2-en-1-one

In the same manner as in Example 47, except that N -bok-4-piperidinemethanol was used instead of N -bok- L -prolinol in step 2), 7 mg of the title compound (final step yield: 21%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.65 ( d , 2H), 8.15 ( s , 1H), 7.74 ( s , 1H), 7.37 ( m , 2H), 7.21 ( m , 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 ( m , 1H), 3.09 ( m , 1H), 3.00 ( m , 1H), 2.02 ( m , 4H), 1.83 ( m , 3H).

Example 50: N Preparation of-((5- (4-1- (3-fluorobenzyl) -1H-indazol-5-ylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

Same as Example 44, except that 1- (3-fluoro-benzyl) -1H-indazol-5-ylamine is used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine The process was carried out to give 5 mg of the title compound (final step yield: 6%).

¹ H-NMR (300 MHz, 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 ( s , 2H).

Example 51: N Preparation of-((5- (4- (4-bromo-3-chloro-2-fluorophenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

The same process as in Example 44 was carried out except that 4-bromo-3-chloro-2-fluoroaniline was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine. 17 mg (final step yield: 38%) were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.78 ( m , 2H), 8.73 ( s , 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 (ESI ⁺ ): m / z = 452.07 [M + H] ⁺ .

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

70 mg of the title compound was carried out in the same manner as in Example 44, except that 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine ( R )-(+)-alpha-methylbenzylamine was used. (Final step yield: 31%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.59 ( s , 1H), 8.46 ( s , 1H), 7.40 to 7.27 ( m , 4H), 6.56 ( s , 1H), 6.41 to 6.35 ( m , 1H), 6.20 ~ 6.11 ( m , 2H), 5.76 ~ 5.72 ( m , 1H), 5.55 ~ 5.50 ( m , 1H), 4.68 ~ 4.66 ( d , 2H), 1.63 ~ 1.61 ( d , 3H).

Example 53: (E) - N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino Preparation of Boot-2-enamide

5 mg of the title compound (final step yield: 8) was carried out in the same manner as in Example 44, except that ( E ) -4- (dimethylamino) but-2-enoic acid was used instead of acrylic acid in step 8). %) Was obtained.

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

MS (ESI ⁺ ): m / z = 520.1 [M + H] ⁺ .

Example 54: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2-((dimethyl Preparation of amino) methyl) acrylamide

In the same manner as in Example 44, except that 2-((dimethylamino) methyl) acrylic acid was used instead of acrylic acid in step 8), 13 mg (the final step yield: 20%) of the title compound was obtained.

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

MS (ESI ⁺ ): m / z = 520.1 [M + H] ⁺ .

Example 55: (E) - N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino Preparation of Boot-2-enamide

 The procedure of Example 53 was repeated except that 3-chloro-4- (3-fluorobenzyloxy) benzeneamine was used instead of 3-chloro-4- (pyridin-2-ylmethoxy) benzeneamine. 16 mg (final step yield: 30%) of the title compound were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.70 ( s , 1H), 8.60 ( s , 1H), 8.07 ( d , 1H), 7.73 ( d , 1H), 7.70 ( m , 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: (Z) - N- ((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) methyl) -4-hydroxybut-2- Preparation of Enamide

Step 1) ( Z )-4-( t -Butyldiphenylsilyloxy) but-2-en-1-ol

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

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.74 ( m , 4H), 7.46 ( m , 6H), 5.70 ( m , 2H), 4.30 ( d , 2H), 4.04 ( t , 2H), 1.71 ( t , 1H), 1.09 ( s , 9h).

Step 2) ( Z )-4-( t -Butyldiphenylsilyloxy) but-2-enoic acid

After 3.6 ml of oxalyl chloride was dissolved in 150 ml of dichloromethane and cooled to -78 ° C, a solution of 4.7 ml of dimethyl sulfoxide dissolved in 50 ml of dichloromethane was slowly added and stirred for 5 minutes. Then, a solution of 9 g of the compound obtained in step 1) in 50 ml of dichloromethane was slowly added at -78 ° C, stirred for 20 minutes, and 19.2 ml of trimethylamine was added thereto, and the temperature was raised to 0 ° C and stirred for 30 minutes. It was. Upon completion of the reaction, saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted twice with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. Diethyl ether was added to the obtained residue, and the produced solid was removed by filtration under reduced pressure, followed by distillation under reduced pressure. The obtained compound was dissolved in 80 ml of tetrahydrofuran and 80 ml of t -butanol, and a solution of 10 g of sodium dihydrogen phosphate dissolved in 40 ml of water at 0 ° C was added thereto, followed by stirring for 10 minutes. At the same temperature, 9.9 ml of dimethyl sulfoxide was added thereto, followed by stirring for 10 minutes. Then, 9.4 g of sodium chlorite was added and stirred for 1 hour. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added, acidified with 1 N aqueous hydrochloric acid solution (pH 3), and extracted twice with ethyl acetate. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (ethyl acetate: n -hexane = 1: 10) to obtain 6.9 g (yield: 73%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.66 ( m , 4H), 7.39 ( m , 6H), 6.58 ( m , 1H), 5.71 ( m , 1H), 4.78 ( m , 2H), 1.07 ( s , 9H).

Step 3) ( Z ) -4- (teryndin-5-yl) art-butyldiphenylsilyloxy)- N- Preparation of ((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) piaisoxazol-3-yl) methyl) but-2-enamide

45 mg (final step yield: 56%) of the title compound were obtained in the same manner as the Example 44, except that the compound obtained in step 2) was used instead of acrylic acid in step 8).

¹ H-NMR (300 MHz, CDCl 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 ( m , 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 ( s , 9H).

Step 4) (Z) - N- ((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) methyl) -4-hydroxybut-2- Preparation of Enamide

45 mg of the compound prepared in step 3) was dissolved in 2 ml of tetrahydrofuran, and 123 µl of 1.0 M tetrabutylammonium fluoride-containing tetrahydrofuran solution was added at 0 ° C. and reacted at room temperature for 1 hour. Upon completion of the reaction, saturated aqueous ammonium chloride solution was added and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 8 mg (yield: 26%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 , 2 H);

MS (ESI ⁺ ): m / z = 493.1 [M + H] ⁺ .

Example 57: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2-((diethyl Preparation of amino) methyl) acrylamide

Step 1) Preparation of 2-((diethylamino) 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. The mixture was heated to 75 ° C. and stirred for 2 hours, and then distilled under reduced pressure when the reaction was completed. The concentrated liquid residue was separated by column chromatography (chloroform: methanol = 2: 1) to obtain 500 mg (yield 33%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2-((diethyl Preparation of amino) methyl) acrylamide

5 mg (final step yield: 7%) of the title compound were obtained by the same process as Example 44, except that the compound prepared in step 1) was used instead of acrylic acid in step 8).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 10.29 ( s , 1H), 8.73 ( s , 1H), 8.62 ( m , 2H), 8.11 ( s , 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 ( s , 1H), 5.51 ( s , 1H), 5.33 ( s , 2H ), 4.66 ( d , 2H), 3.34 ( s , 2H), 2.58 ( q , 4H), 1.06 ( t , 6H);

MS (ESI ⁺ ): m / z = 548.2 [M + H] ⁺ .

Example 58: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) methyl) -2- (pyrrolidine- Preparation of 1-ylmethyl) acrylamide

Except for using pyrrolidine in place of diethylamine in step 1), the same process as in Example 57 was carried out to obtain 30 mg of the title compound (final step yield: 45%).

¹ H-NMR (300 MHz, CDCl 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 ( s , 2H), 4.66 ( d , 2H), 3.35 ( s , 2H), 2.50 ( m , 4H), 1.75 ( m , 4H);

MS (ESI ⁺ ): m / z = 546.2 [M + H] ⁺ .

Example 59: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- (morpholino Preparation of Methyl) acrylamide

Except for using morpholine instead of diethylamine in step 1), the same process as in Example 57 was performed, to obtain 7 mg of the title compound (final step yield: 10%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.74 ( s , 1H), 8.70 ( s , 1H), 8.60 ( s , 1H), 8.58 ( s , 1H), 8.05 ( s , 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: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2-((4- Preparation of Methylpiperazin-1-yl) methyl) acrylamide

20 mg (final step yield: 29%) of the title compound were obtained in the same manner as in Example 57, except that 1-methylpiperazine was used instead of diethylamine in step 1).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 9.85 ( s , 1H), 8.70 ( s , 1H), 8.61 ( s , 1H), 8.58 ( s , 1H), 8.07 ( s , 1H), 7.74 ( m , 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 (ESI ⁺ ): m / z = 575.3 [M + H] ⁺ .

Example 61: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- (hydroxymethyl Production of Acrylamide

Step 1) 2-(( t Butyldimethylsilyloxy) methyl) N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

The same process as in Example 44, except that 2-(( t -butyldimethylsilyloxy) methyl) acrylic acid prepared according to the method described in WO 2008150118 is used instead of acrylic acid in step 8). To give 87 mg (59% final step yield) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( s , 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) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- (hydroxymethyl Production of Acrylamide

80 mg of the compound prepared in step 1) was dissolved in 2 ml of tetrahydrofuran, and 264 µl of 1.0 M tetrabutylammonium fluoride-containing tetrahydrofuran solution was added at 0 ° C. and reacted at room temperature for 1 hour. Upon completion of the reaction, saturated aqueous ammonium chloride solution was added and extracted twice with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 40 mg (yield: 61%) of the title compound.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.64 ( s , 1H), 8.57 ( s , 1H), 8.55 ( s , 1H), 7.79 ( m , 1H), 7.73 ( m , 2H), 7.38 ( m , 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 , 2 H);

MS (ESI ⁺ ): m / z = 493.0 [M + H] ⁺ .

Example 62: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- (methylsulfonyl Preparation of Methyl) 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 mixture was distilled under reduced pressure and filtered by column chromatography (chloroform: methanol = 5: 1). Dissolving the compound 25 ㎎ obtained in Step 7) of the resulting solid 12 ㎎ as in Example 44 in tetrahydrofuran ㎖ 2 and N - (3- dimethylaminopropyl) - N '- ethylcarbodiimide hydrochloride 18 ㎎ and pyridine 2 Μl was added and stirred at room temperature for 1 hour. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with chloroform. The separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 4 mg (yield: 12%) of the title compound.

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

MS (ESI ⁺ ): m / z = 555.1 [M + H] ⁺ .

Example 63: 2- (aminomethyl)- N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

Step 1) 2- (Azaidomethyl)- N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

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

¹ H-NMR (300 MHz, CDCl 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) 2- (aminomethyl)- N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

390 mg of the compound prepared in step 1) was dissolved in 4 ml of tetrahydrofuran, 626 mg of triphenylphosphine and 300 µl of water were added, followed by reaction at 60 ° C. for 3 hours. When the reaction was completed, the residue was distilled under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 8: 1) to obtain 130 mg (yield: 35%) of the title compound.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.06 ( m , 1H), 8.85 ( m , 1H), 8.64 ( s , 1H), 8.62 ( s , 1H), 8.58 ( m , 1H), 7.87 ( t , 1H), 7.72 ( d , 1H), 7.56 ( d , 1H), 7.46 ( m , 1H), 7.35 ( m , 1H), 7.21 ( d , 1H), 6.96 ( s , 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: 2- (acetamidomethyl)- N Preparation of-((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide

50 mg of the compound prepared in Example 63 was dissolved in 3 ml of tetrahydrofuran, and 30 µl of triethylamine and 20 µl of acetic anhydride were added at 0 ° C., followed by reaction at room temperature for 1 hour. When the reaction was completed, the residue was distilled under reduced pressure and the obtained residue was separated by column chromatography (ethyl acetate: dichloromethane: methanol = 5: 5: 1) to obtain 20 mg (yield: 37%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 534.3 [M + H] ⁺ .

Example 65: N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- (methylsulfonami Preparation of Domethyl) acrylamide

30 mg of the compound prepared in Example 63 was dissolved in 3 ml of tetrahydrofuran, 25 μl of triethylamine and 7 μl of methanesulfonyl chloride were added at 0 ° C., and the mixture was reacted at 0 ° C. for 1 hour. When the reaction was completed, the residue was distilled under reduced pressure, and the obtained residue was separated by column chromatography (ethyl acetate: dichloromethane: methanol = 5: 5: 1) to obtain 10 mg (yield: 29%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 ( s , 1H), 5.29 ( s , 2H), 4.65 ( d , 2H), 3.99 ( s , 2H), 2.96 ( s , 3H );

MS (ESI ⁺ ): m / z = 570.3 [M + H] ⁺ .

Example 66: N Preparation of-(3- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) phenyl) acrylamide

Step 1) 5- (3-Aminophenyl)- N Preparation of-(3-chloro-4- (pyridin-2-ylmethoxy) phenyl) pyrimidin-4-amine

300 mg of the compound prepared 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 and reacted at 70 ° C. for 2 hours. . When the reaction was completed, the residue was distilled under reduced pressure, and the obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 120 mg (yield: 44%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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) N Preparation of-(3- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) phenyl) acrylamide

51 mg of the compound obtained in step 1) and 32 mg of sodium bicarbonate were dissolved in 2 ml of tetrahydrofuran and 0.5 ml of distilled water at 0 ° C., and 10 µl of acryloyl chloride was added thereto, followed by stirring at the same temperature for 30 minutes. Upon completion of the reaction, saturated aqueous sodium bicarbonate solution was added and extracted twice with chloroform. The separated organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure. The obtained residue was separated by column chromatography (chloroform: methanol = 15: 1) to obtain 12 mg (yield: 21%) of the title compound.

¹ H-NMR (300 MHz, CDCl 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 (ESI ⁺ ): m / z = 458.1 [M + H] ⁺ .

Example 67: N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl)- N Preparation of -methylacrylamide

In the same manner as in Example 47, except that t -butyl 2-hydroxyethyl (methyl) carbamate was used instead of N -bok- L -prolinol in step 2), 10 mg (final) of the title compound was obtained. Step yield: 50%).

¹ H-NMR (300 MHz, CDCl 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 ( m , 1H), 5.78 ( m , 1H), 5.15 ( s , 2H), 4.71 ( s , 2H ), 3.16 ( s , 2H), 1.23 ( s , 3H).

The structural formulas of the compounds obtained in Examples 1 to 67 are shown in Table 1 below.

Formulation example  One

According to a conventional method, a single tablet for oral administration containing the compounds prepared in Examples 1 to 67 as active compounds was prepared using the components shown in Table 2 in the corresponding amounts, respectively.

Formulation Example 2

According to a conventional method, hard gelatine capsules for oral administration containing the compounds prepared in Examples 1 to 67 as active compounds were prepared using the components shown in Table 3 in the corresponding amounts, respectively.

Formulation Example 3

According to a conventional method, the injectable preparations containing the compounds prepared in Examples 1 to 67 above as active compounds, respectively, were prepared using the components shown in Table 4 in the corresponding amounts. However, when the salt of the compound of formula (1) is used as the active compound, the pH is not controlled.

Formulation example  4

According to a conventional method, the injectable preparations containing the compounds prepared in Examples 1 to 67 above as active compounds, respectively, were used in the corresponding amounts of the ingredients in Table 5 below.

Test Example

For the compounds obtained in Examples 1 to 67, the effect of inhibiting cancer cell growth and the activity inhibitory effect of EGFR ^wt enzyme and EGFR ^T790M mutant enzyme was confirmed as follows.

1) Cancer cell growth inhibition test

Cancer cell growth inhibition test of compounds of the present invention in A431 (ATCC CRL-1555) overexpressed EGFR (Erb-B1) and SK-Br3 (ATCC HTB-30) overexpressed Erb-B2 breast cancer cell lines Was carried out as follows. As culture medium, DMEM (Dulbecco's Modified Eagle's Medium) medium containing 4.5 g / L glucose, 1.5 g / L sodium carbonate and 10% FBS (fetal bovine serum) was used.

The cancer cell lines stored in the liquid nitrogen tank were taken out and rapidly dissolved at 37 캜, and then centrifuged to remove the frozen storage medium. The recovered cell pellets were mixed well in the culture medium and placed in a culture flask, and then cultured for 2 to 3 days under 37 ° C. and 5% carbon dioxide conditions. Thereafter, the medium was removed from the flask, washed with Dulbecco's Phosphate Buffered Saline (DPBS), and cells were recovered using trypsin-EDTA solution, for A431 to 1 × 10 ⁵ cells / ml, and SK- For Br3 it was diluted with culture medium to 2 × 10 ⁵ cells / ml. The diluted cells were dispensed in a 96-well plate 100 μl per well and incubated for 1 day at 37 ℃, 5% carbon dioxide conditions.

The compounds prepared in Examples 1 to 67 were dissolved in 99.5% DMSO (cell culture grade) to 25 mM, respectively. If the test material was not dissolved in DMSO, 1% hydrochloric acid solution was added to dissolve it. In order to completely dissolve the test substance, it was stored for 30 minutes in a water bath at about 40 ℃ water bath. Each compound-containing DMSO solution was diluted to a final concentration of 100 μM in a culture medium and then diluted stepwise by 10 times to prepare a solution diluted to 10 ^-6 μM (the final DMSO concentration was 1% or less) .

After removing the culture solution from the cultured 96-well plate, 100 μl of the test solution of each compound prepared as described above was added to each well and incubated for 72 hours under 37 ° C. and 5% carbon dioxide conditions. After removing the medium, 50 μl of 10% trichloroacetic acid was added and reacted at 4 ° C. for 1 hour to fix the cells on the plate bottom. After removing 10% trichloroacetic acid solution from each well and drying well, 100 μl of a 0.4% SRB (sulforhodamine-B) dye solution dissolved in 1% acetic acid was added and reacted at room temperature for 10 minutes. After the dye solution was removed, the dye on the plate was completely removed by using water, and then dried well, where 1% acetic acid was used if not completely removed with water. 150 μl of 10 mM trisma base was added to each well, and the absorbance at 540 nm was measured with a microplate reader.

Based on the measured values, IC ₅₀ of each compound at the time and then in a final cell density value of the well not treated with the test material obtained by subtracting the initial cell density values hayeoteul the value as 100% cell growth by 50% inhibitory concentrations The value was calculated. In addition, experiments were performed in the same manner as above using gefitinib (EGFR inhibitor) and lapatinib (EGFR and Erb-B2 double inhibitor) as a comparative group, and IC ₅₀ values were calculated. IC ₅₀ calculation and analysis of the results of each compound using Microsoft Excel, the results are shown in Table 6 below.

IC ₅₀ (nM) Example A431 SK-Br3 Example A431 SK-Br3 Example A431 SK-Br3 One 10.8 0.7 24 351.6 4.9 47 131 12 2 129.6 31.4 25 326.4 7 48 1044 56 3 190.3 2.4 26 67.8 6.1 49 3082 379 4 29 2.6 27 423.5 4.6 50 > 1000 > 1000 5 > 1000 > 1000 28 8.4 125.1 51 65 515 6 136.7 25.5 29 65.1 3.3 52 > 1000 > 1000 7 - - 30 282 93 53 5 101 8 - - 31 91.2 29.5 54 One 35 9 59 3.9 32 52 34 55 111 30 10 113.2 18.2 33 26 4.2 56 618 103 11 105.1 6.5 34 88 62 57 391 10 12 183.5 1.9 35 105.3 9.7 58 266 5.4 13 59.7 3.1 36 313 9.7 59 182 13 14 78.5 1.0 37 - - 60 309 28 15 28.7 4.7 38 14.2 3 61 > 1000 380 16 74.7 0.5 39 119.2 9.7 62 289 6.8 17 39.3 6.0 40 > 1000 > 1000 63 > 1000 > 1000 18 35.8 1.7 41 436.8 455.4 64 > 1000 473 19 67.9 2.4 42 98.6 68.5 65 > 1000 335 20 159 45.4 43 > 1000 845.4 66 593 6.1 21 825.9 137.4 44 2 122 67 68.7 6.8 22 290.9 120.3 45 79 9 Gefitinib 28 206 23 64 1.1 46 504 77 Lapatinib 80 40

As shown in Table 6 above, most of the compounds of formula 1 of the present invention are currently commercially available gefitinib (EGFR inhibitor) or lapatinib for the growth of A431 cell line overexpressing EGFR or SK-Br3 cell line overexpressing Erb-B2. (EGFR and Erb-B2 double inhibitor) showed more than equivalent effect and effectively inhibited.

2) EGFR ^wt  Enzyme Inhibition Test

10 μl of EGF receptor (EGFR type 1 kinase, obtained from Upstate, concentration: 10 ng / μl) in each well of a 96-well plate, and then in Examples 1 to 67. After diluting the prepared compounds step by step to each concentration was added 10 μl per well and incubated for 10 minutes at room temperature. Then, 10 μl (concentration: 10 ng / ml) and 10 μl (concentration: 50 uM) of poly (Glu, Tyr) 4: 1 (Sigma) as a substrate of the kinase were added to each well and incubated at room temperature for 1 hour. Kinase reactions were performed. Thereafter, 10 µl of 100 mM EDTA was added to each well to terminate the kinase reaction, and then slowly mixed in a stirrer for 5 minutes, and 10 µl of 10 × anti-phosphotyrosine antibody (panvera). 10 μl of 10 × PTK (protein tyrosine kinase) green tracer (Panvera) and 30 μl of FP (fluorescence polarization) dilution buffer were added and cancer-cultured at room temperature for 30 minutes. After incubation, the polarization (FP) value of each well was measured using a VICTORIII fluorescence meter (Perkin Elmer, Inc.) (excitation filter: 488 nm and emission filter: 535 nm), based on the EGFR inhibitor The IC ₅₀ value was calculated by calculating the concentration at which 50% inhibition of the kinase activity of each compound was obtained when the measured polarization value (mP) was maximized and 100% inhibition was minimum (0%). Was calculated. In addition, experiments were performed in the same manner as above using gefitinib (EGFR inhibitor) and lapatinib (EGFR and Erb-B2 double inhibitor) as a comparative group, and IC ₅₀ values were calculated. IC ₅₀ calculation and analysis of the results of each compound using Microsoft Excel, the results are shown in Table 7 below.

2) Activity inhibition test of EGFR mutant enzyme (T790M)

The same procedure as in the EGFR activity inhibition test was conducted except that the EGFR variant receptor (EGFR T790M kinase, Upstate) was used instead of the EGFR enzyme. The results are shown in Table 7 below.

IC ₅₀ (nM) Example EGFR ^wt EGFR ^T790M Example EGFR ^wt EGFR ^T790M One 3.3 3.2 28 8.4 125.1 3 3.2 2.5 32 - 50.1 4 6.1 161 33 - 6.9 7 8.5 171.4 35 3.9 13.6 8 4.9 129.2 36 3.5 3.4 9 27.7 19 37 45.4 413.5 12 3.9 3.2 39 4.5 155.5 13 7.0 3.3 44 9.1 101 18 4.2 16 45 10.3 40.8 19 - 22.1 54 8.8 12.3 23 - 106.2 59 21.3 - Gefitinib 639 > 50,000 Lapatinib 21 > 5,000

As shown in Table 7, the compounds of the present invention effectively inhibited the activity of EGFR T790M mutant kinase as well as EGFR ^wt . Therefore, it can be seen that the pyrimidine compound of the present invention effectively inhibits the activity of epidermal growth factor receptor or its mutant kinase and effectively inhibits the growth of cancer cells overexpressed by the epidermal growth factor receptor.

Claims (6)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

In this formula,
X is

or

Wherein X ₁ is N, CH or CH ₂ , and X ₂ is N or CH;
Y is H, NH ₂ or N ( _C═O ) C _1-6 alkyl;
Z is halogen, C _1-6 alkyl, fluorobenzyloxy, pyridinylmethoxy, phenoxy, chlorophenoxy, dichlorophenoxy, fluorophenoxy, pyridinyloxy, methylpyridinyloxy, methylimidazole cycle Phenyl having 1 to 3 substituents selected from the group consisting of methyl, pyrazolyloxy and 1-methyl-3-trifluoromethyl pyrazolyloxy; Phenyl C _1-6 alkyl; Or fluorobenzylindazole;
n _a and n _b are each independently an integer from 0 to 3;
--- represents a bond that may exist when n _a and n _b are nonzero integers;
R is

or

ego; Wherein R _1, R ₂ and R ₃ are independently of each other hydrogen or C _1-3 alkyl substituted with substituent B; R ₄ is hydroxy or C _1-6 alkoxy; n _c is an integer from 1 to 6;
The substituent B is hydroxy, S- C _1-6 alkylsulfonyl, heterocycle, amino, or C _1-6 dialkyl, C- C _1-6 alkylcarbonyl or S- C _1-6 alkylsulfonyl Substituted amino;
The heterocycle is a C _5-12 monocyclic or bicyclic aromatic or nonaromatic compound comprising 1 to 4 members selected from the group consisting of N, O, S, SO and SO ₂ ;
The heterocycle is unsubstituted; Or halogen, hydroxy, amino, nitro, cyano, C _1-6 alkyl, trihalogenoC _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _It has a substituent selected from the group consisting of _1-6 monoalkylamino and C _1-6 dialkylamino. The method of claim 1,
In Formula 1,
X is

or

ego;
Y is H, NH ₂ or N (C═O) CH ₃ ;
R is

or

ego; At this time, R _1, R ₂ and R ₃ is independently of each other hydrogen, dimethylaminomethyl, diethylaminomethyl, hydroxymethyl, morpholinomethyl, pyrrolidin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, methylsulfonyl May be selected from the group consisting of methyl, aminomethyl, acetamidomethyl or methylsulfonamidomethyl; R ₄ is hydroxy or methoxy; n _c is an integer of 1 to 3, the compound or a pharmaceutically acceptable salt thereof. The method of claim 1,
A compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
1) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
2) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) -4,5-dihydrooxazole- 4-yl) methyl) acrylamide;
3) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 2-((dimethylamino) methyl) acrylamide;
4) (E) -N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl ) Methyl) -4- (dimethylamino) but-2-enamide;
5) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 2-hydroxyacetamide;
6) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 3-hydroxypropaneamide;
7) N -((2- (4-amino-6- (2-fluoro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) Acrylamide;
8) N -((2- (4-amino-6- (3-fluoro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) Acrylamide;
9) N -((2- (4-amino-6- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
10) N -((2- (4-amino-6- (3-chloro-4- (2,3-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;
11) N -((2- (4-amino-6- (3-chloro-4- (2,4-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;
12) N -((2- (4-amino-6- (3-chloro-4- (2,5-dichlorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl ) Acrylamide;
13) N -((2- (4-amino-6- (3-chloro-4-phenoxyphenylamino) 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-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
16) N -((2- (4-amino-6- (3-chloro-4- (3-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
17) N -((2- (4-amino-6- (3-chloro-4- (3-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
18) N -((2- (4-amino-6- (3-chloro-4- (pyridin-2-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
19) N -((2- (4-amino-6- (3-chloro-4- (pyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylic Amides;
20) N -((2- (4-amino-6- (3-chloro-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-hydroxypropaneamide;
22) N -((2- (4-amino-6- (3-chloro-4- (2-fluorophenoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 3-methoxypropaneamide;
23) N -((2- (4-amino-6- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) Methyl) acrylamide;
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-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazole- 4-yl) methyl) -4- (dimethylamino) but-2-enamide;
26) N -((2- (4-amino-6- (3-chloro-4- (6-methylpyridin-3-yloxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) Methyl) acrylamide;
27) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-imidazol-2-ylthio) phenylamino) pyrimidin-5-yl) oxazole -4-yl) methyl) acrylamide;
28) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-1H-pyrazol-5-yloxy) phenylamino) pyrimidin-5-yl) oxazole- 4-yl) methyl) acrylamide;
29) N -((2- (4-amino-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino) pyri) Midin-5-yl) oxazol-4-yl) methyl) acrylamide;
30) N -((2- (4-amino-6- (3,4-dichloro-2-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;
31) N -((2- (4-amino-6- (4-fluoro-3-methylphenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;
32) N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;
33) N -((2- (4-amino-6- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-((dimethyl Amino) 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-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) acrylamide;
36) N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -2-(( Dimethylamino) methyl) acrylamide;
37) N -((2- (4-acetamido-6- (3-chloro-4- (1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yloxy) phenylamino ) Pyrimidin-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 ) Acrylamide;
39) (E) -N -((2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl)- 4- (dimethylamino) but-2-enamide;
40) N -((2- (4- (3,4-dichloro-2-fluorophenylamino) pyrimidin-5-yl) oxazol-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-chloro-4-fluorophenylamino) pyridin-5-yl) oxazol-4-yl) methyl) -2-((dimethylamino) methyl) acrylic Amides;
43) (E) -N -((2- (4- (3-chloro-4-fluorophenylamino) pyrimidin-5-yl) oxazol-4-yl) methyl) -4- (dimethylamino ) But-2-enamide;
44) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;
45) N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;
46) N- (2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) ethyl) acrylamide;
47) 1- (2- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) pyrrolidine- 1-yl) prop-2-en-1-one;
48) 1- (3- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperidine- 1-yl) prop-2-en-1-one;
49) 1- (4- (5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) piperidine- 1-yl) prop-2-en-1-one;
50) N -((5- (4- (1- (3-fluorobenzyl) -1H-indazol-5-ylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylic Amides;
51) N -((5- (4- (4-bromo-3-chloro-2-fluorophenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;
52) (R) -N -((5- (4- (1-phenylethylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) acrylamide;
53) (E) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino) but-2-enamide;
54) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (Dimethylamino) methyl) acrylamide;
55) (E) -N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -4- (dimethylamino) but-2-enamide;
56) (Z) - N- ( (5- (4- (3- chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazole-3-yl) methyl) - 4-hydroxybut-2-enamide;
57) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (Diethylamino) methyl) acrylamide;
58) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyridin-5-yl) isoxazol-3-yl) methyl) -2- (pi Rollidin-1-ylmethyl) acrylamide;
59) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Morpholinomethyl) acrylamide;
60) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( (4-methylpiperazin-1-yl) methyl) acrylamide;
61) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Hydroxymethyl) acrylamide;
62) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Methylsulfonylmethyl) acrylamide;
63) 2- (aminomethyl) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl ) Methyl) acrylamide;
64) 2- (acetamidomethyl) -N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazole-3 -Yl) methyl) acrylamide;
65) N -((5- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -2- ( Methylsulfonamidomethyl) acrylamide;
66) N- (3- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) pyrimidin-5-yl) phenyl) acrylamide; And
67) N -((5- (4- (3-chloro-4- (3-fluorobenzyloxy) phenylamino) pyrimidin-5-yl) isoxazol-3-yl) methyl) -N -methyl Acrylamide. A pharmaceutical composition for inhibiting cancer cell growth, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. The method of claim 4,
The composition may comprise cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, anti-metabolic agents, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, bioreaction modifiers, anti-hormonal agents, anti-androgens and their A pharmaceutical composition for inhibiting cancer cell growth, further comprising an anticancer agent selected from the group consisting of a mixture. 5. The method of claim 4,
The cancer cell is characterized in that the epidermal growth factor receptor (EGFR) or is induced by a variant thereof, cancer cell growth inhibition pharmaceutical composition.