KR20070052207A - Novel inhibitors of protein kinase - Google Patents

Abstract

The present invention relates to a compound of the formula below which inhibits the activity of VEGFR2 kinase (KDR), a method for its preparation, its use, and a pharmaceutical composition comprising the same in a pharmacologically effective amount. The compounds according to the invention show efficacy in the treatment and inhibition of diseases due to undesired KDR activity, for example diseases related to angiogenesis such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy and the like.

Wherein R ₁ , R ₂ , X and Y are as defined in the specification.

Description

NOVEL INHIBITORS OF PROTEIN KINASE

The present invention relates to a novel compound having an aminothiazole structure, and more particularly, to inhibit the novel VGF receptor2 kinase (VEGFR2 kinase or KDR, hereinafter referred to as "KDR") activity represented by the formula (1). Compounds, pharmaceutically acceptable salts thereof, and the like. The compounds according to the invention are useful for the treatment and inhibition of diseases due to undesired KDR activity, such as diseases related to angiogenesis such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy and the like.

Angiogenesis is a mechanism that creates new blood vessels, a pathway for supplying nutrients, oxygen, and metabolites for cell survival. In adults, only about 0.01% of blood vessel cells normally proliferate, resulting in various wounds in blood vessels. Is recovering (Carmeliet et al ., 2000, Nature 407 : 249-257).

However, fast-growing tissues such as solid tumours require more nutrients and oxygen, which in turn requires more new neovascularization. Indeed, solid tumors cannot grow beyond a certain size (100 to 200 μm in diameter) without new angiogenesis. This is because there is a limit on the distance that oxygen or nutrients can leave the blood vessels and reach the cells by diffusion (Carmeliet et al ., 2000, Nature 407 : 249-257).

Cancer cells away from blood vessels are placed in a hypoxia environment due to a lack of oxygen. Under these conditions, a variety of pro-angiogenic factors are secreted from cancer or stromal cells to induce neovascularization into solid cancer. Among the factors that induce such angiogenesis are Vascular Endothelial Growth Factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF). Angiogenesis is activated by these growth stimulating factors, resulting in active proliferation of cancer cells (Carmeliet P., 2000, Nature Medicine 6 : 389-395, Yancopoulos et. al ., 2000, Nature 407 : 242-248).

As angiogenesis-related diseases other than cancer, arthritis is an angiogenesis-related disease in which neocapillaries formed during the course of a chronic inflammatory disease invade joints and destroy cartilage. In addition, diabetic retinopathy is a disease caused by the capillary invasion of the retina's vitreous body, and its cause is known to cause the disease by releasing factors that stimulate angiogenesis from the ischemic retina. The eye is the tissue without the most blood vessels, and as soon as the blood vessels grow, they become blind. Thus, the fundamental treatment is only possible by preventing angiogenesis (Carmeliet P., 2000, Nature Medicine 6 : 389-395, Aiello LP, 2000, Nature Medicine 6 : 379-381).

Receptor Tyrosine Kinases (RTKs) such as VEGFR2 (KDR), FGFR1, and PDGFR-β, which are receptors for angiogenesis inducers, are attracting attention as targets for the development of anti-angiogenesis drugs. . Such inhibitors exhibit the effect of inhibiting the kinase activity of VEGFR2 (KDR) while simultaneously inhibiting the activity of other angiogenic RTK families. This complex inhibitory effect is known as one mechanism for amplifying neovascular suppression efficacy (Adams et al., 2002, Current Opinion in Chemical Biology, 6 : 486-492). Therefore, many studies have been conducted using compounds which can be used as agents for inhibiting and treating diseases related to angiogenesis such as cancer, rheumatoid arthritis, diabetic retinopathy and the like.

Representative examples of compounds that inhibit the kinase activity of KDR include 2-indolinone derivatives (WO 98/050356), quinazoline derivatives (EP 0566266 A1), triazole derivatives (WO 02/057240), diaminothiazole (WO 00/075120), benzothiazole derivatives (WO 01/057008) and the like, although these are not structurally related to the compounds according to the invention.

After further studies and various experiments, the inventors of the present application were able to synthesize a novel compound that inhibits the activity of KDR, and as a result of evaluating the inhibitory activity, the compound of Formula 1 was found to have undesirable KDR activity. It has been found that the present invention can be used for the treatment of diseases related to angiogenesis, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc., and has completed the present invention.

Accordingly, the present invention provides a compound of formula 1, or a pharmaceutically acceptable salt thereof.

(1)

(One)

Where

A) R ₁ is hydrogen or C ₁ -C ₁₀ alkyl,

B) A ₁ and A ₂ are each independently carbon or nitrogen,

C) R ₂ is hydrogen, halogen, cyano, -CF ₃ and Selected from the group consisting of C ₁ -C ₁₀ alkyl,

D) Ar ₁ is a 5 or 6 cyclic aromatic or heteroaromatic,

E) X is each independently selected from the group consisting of the following substituents,

I) hydrogen, halogen, cyano, hydroxy, -CF ₃ , optionally substituted C ₁ -C ₁₀ alkyl;

II) -OR ₃ , -SR ₃ , -NHR ₃ , -N (R ₃ ) ₂ , wherein R ₃ is hydrogen or optionally substituted C ₁ -C ₁₀ alkyl;

III) -C (= 0) R ₄ , -NR ₅ C (= 0) NR ₄ R ₆ , -NR ₅ C (= S) NR ₄ R ₆ ,

Where R ₄ Is

i) hydroxy;

ii) optionally substituted C ₁ -C ₁₀ alkyl;

iii) optionally substituted C ₁ -C ₁₀ alkoxy;

iv) -NR ₇ R ₈ or -N (-R ₇ ) OR ₈ , wherein R ₇ And R ₈ Are each independently hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted allyl, optionally substituted sulfone, or optionally substituted amine, and R ₇ And R ₈ Are interconnected to form a ring structure;

v)-(CH ₂ ) _n1 NR _9- (CH ₂ ) _n2 -NR ₇ R ₈ , wherein R ₇ And R ₈ Is as defined above, R ₉ is hydrogen or optionally substituted C ₁ -C ₁₀ alkyl, n ₁ Is 0 or an integer from 1 to 5, n ₂ Is an integer from 1 to 5;

R ₅ And R ₆ Are each independently hydrogen, hydroxy, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted allyl, optionally substituted sulfone alkyl, or optionally substituted amine;

R ₄ , R ₅ And two substituents selected from R ₆ may be connected to each other to form a ring structure;

F) n is 0 or an integer from 1 to 5,

G) E is oxygen or sulfur;

H) Ar ₂ is hydrogen or a 5- or 6-membered aromatic ring compound represented by the following formula (2),

(2)

(2)

here,

Q is selected from the group consisting of carbon, nitrogen, oxygen and sulfur,

l (L) is an integer from 3 to 4,

I) m is 0 or an integer from 1 to 4,

J) Y is each independently selected from the group consisting of the following substituents,

I) halogen, cyano, nitro, hydroxy, -CF ₃ and optionally substituted morpholine;

II) -R, -OR, -SR ', -NHR' and -NR'R ", wherein R, R 'and R" are hydrogen or optionally substituted C ₁ -C ₁₀ straight, branched or cyclic Saturated or unsaturated alkyl; And

III) substituents represented by the following general formulas (i to vi):

(i)

(i)

(ii)

(ii)

(iii)

(iii)

(iv)

(iv)

(v)

(v)

(vi)

(vi)

here,

n ₁ is 0 or an integer of 1 to 5;

J ₁ is selected from hydrogen, — (C═O) —, —N—, —O— and —S— or is a direct bond;

J ₂ and J ₃ are each independently selected from the group consisting of —N—, —O—, —CR′— and —S—, or a direct bond, wherein R ′ is as defined above;

J ₄ And J ₅ are each independently — (C═O) —, —NR′—, — (C═O) —NR′—, — (C═O) —NR′—R—, —O—, —S -NR '-(C = O)-,-(C = S)-,-(C = S) -NR'-,-(C = S) -NR'-R-, -NR'-(C = S)-and -SO _2- , wherein R and R 'are as defined above;

n ₂ and n ₆ Is 0 or an integer of 1 to 3;

n ₃ and n ₄ Are each independently selected from 0 or 1 to 3, and when 0 is nothing or a direct bond;

n ₅ Is selected from 0 or 1 to 3, and when 0 is nothing or a direct bond;

G and G 'are each independently hydrogen, -R', -CF ₃ ,-(C = O) R ', -OR', -CO ₂ R ', -SO ₂ R', -CONHR ', -CONRR' , -CONR'OR, -CN, halogen, -NH ₂ , -NRR ', -NHCOR', -NHCO ₂ R ', -C (R') OH, -C (R) OR ', -NR (C = O) R'OR "-, -C (= 0) ROR'-, optionally substituted C ₃ -C ₈ cycloalkyl or heterocycloalkyl, and optionally substituted 5- or 6-membered aromatic or heteroaromatic And R, R 'and R "are as defined above.

The terms used herein are briefly described.

The term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The pharmaceutical salt is a compound of the present invention, such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like, sulfonic acid, tartaric acid, formic acid, citric acid, acetic acid, trichloro It can be obtained by reaction with organic carboxylic acids such as roacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. In addition, the compounds of the present invention are reacted with a base, such as alkali metal salts such as ammonium salts, sodium or potassium salts, and alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, N-methyl-D-glu It may be obtained by forming salts of organic bases such as carmine, tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine.

Unless otherwise stated, the term "compound according to the present invention" or "compound of formula 1" is used in the concept including both the compound itself and its pharmaceutically acceptable salts.

Unless stated otherwise, the fact that a substituent is "optionally substituted" means that the substituent is alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, Hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, oxo, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thio Carbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, optionally substituted sulfonyl, C-carboxy, O-carboxy, isocyanato, thiocyanato, Isothiocyanato, nitro, cyryl, trihalomethanesulfonyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, morpholinyl, furyl, thiazolidine, isoxazole, azetidinyl, Dioxolane, pyrazinyl, thienyl, aziridine, oxazolidine, imidazole, piperidine-on-oxime, It is used as amino, and separately from the protected derivative thereof, and means to independently include the selected one or more groups when substituted by a substituted amino group, including - a no-and di. These substituents may also be optionally substituted.

The term "alkyl" refers to an aliphatic hydrocarbon group. The alkyl moiety can be a "saturated alkyl" group, meaning that it does not contain any alkenes or alkyne moieties. The alkyl moiety may be an "unsaturated alkyl" moiety, meaning that it contains at least one alkene or alkyne moiety. "Alkene" moiety means a group of at least two carbon atoms consisting of at least one carbon-carbon double bond, and "alkyne" is a moiety wherein at least two carbon atoms contain at least one carbon-carbon triple bond Means a group consisting of. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain or cyclic.

Lower alkyl having 1 to 10 carbon atoms in the present invention includes linear, branched, cyclic or partially cyclic. The partial cyclic alkyl group is a generic term for a substituent having any cyclic in any of the alkyl groups, for example, methylcyclopropylmethyl, cyclopropylvinyl, 2,2-dimethylcyclopropylmethyl and the like. The lower alkyl also includes a structure having 1 to 5 double bonds or triple bonds.

"Halogen" generically refers to -F, -Cl, -Br, -I.

Since the substituent X is bonded to the substituent Ar ₁ which is a 5- or 6-membered cyclic aromatic or heteroaromatic group, it may be one or two or more. When X is two or more, they may be the same substituents, or may be different substituents. For example, when Ar ₁ is phenyl and two substituents X are bonded thereto, one may be halogen and the other may be -C (= 0) R.

Meanwhile, in Chemical Formula 1, R ₁ Is preferably hydrogen or methyl, more preferably methyl.

A ₁ and A ₂ are preferably carbon.

R ₂ Is preferably hydrogen or halogen, more preferably hydrogen.

Ar ₁ Is preferably hexagonal cyclic aromatic or heteroaromatic, more preferably phenyl.

n is preferably 0 or an integer of 1 to 4, and more preferably 0 or an integer of 1 to 3.

E is preferably sulfur.

In the formula (2), Q is preferably carbon or nitrogen, and l (L) is preferably 3 or 4 and more preferably 4.

In Formula 1, R ₄ , R ₅ And when two substituents selected from R ₆ are interconnected to form a ring structure, R ₇ And when R ₈ is interconnected to form a ring structure, or is heterocycloalkyl, such ring structure is not particularly limited, and may form, for example, a triangular to octagonal cyclic ring, preferably Can be aziridine, pyrrolidine, piperazine, piperidine, morpholine

Representative compounds of the invention include the following compounds.

1. N ⁵ - (4-fluorophenyl) -N ⁵ - methyl -N ² - (6- methyl-pyridin-2-yl) thiazolo [5,4-b] pyridine-2,5-diamine

2. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -methanol

3. N ⁵ -Methyl-N ^2- (3-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine

4. N ⁵ -Methyl-N ^2- [3- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine

5. N ⁵ -Methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -phenyl-thiazolo [5,4-b] pyridine- 2,5-diamine

6. N ⁵ -Methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -phenyl-l-thiazolo [5,4-b] pyridine-2,5- Diamine

7. 4- {2- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1-carboxyl Acid methylamide

8. 4- {2- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1-carboxyl Acid Dimethylamide

9. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -methanol

10. 1- (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine -1-yl) -ethanone

11. N ² - (4- diethylamino-methyl-pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

12.N ⁵ -Methyl-N ^2- (4-pyrrolidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine

13.N ⁵ -Methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine

14.N ⁵ -Methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine

15. (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1 -Yl) -ethanol

16. (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1 -Yl) -acetic acid ethyl ester

17. (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1 -Yl) -acetic acid

18. N, N-dimethyl-2- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Monomethyl} -piperazin-1-yl) -acetamide

19. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid ethyl ester

20. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid

21. 1- (4-Methyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone

22. N- (2-Diethylamino-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine -4-yl} -acetamide

23. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -N- (2-mol Forin-4-yl-ethyl) -acetamide

24. N- (2-hydroxy-ethyl) -N-methyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -acetamide

25. N- (2-hydroxy-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-yl} -acetamide

26. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinonitrile

27. N ² - (5--diethylamino-methyl-pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

28.N ⁵ -Methyl-N ^2- (5-piperidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine

29. N ⁵ -Methyl-N ^2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine

30.N ⁵ -Methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine

31. 1- (4- {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -piperazine -1-yl) -ethanone

32.N ⁵ -Methyl-N ^2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine

33. 4- {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -piperazin-1- Carboxylic Acid Dimethylamide

34. ({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acetic acid methyl ester

35. 2-({6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acet amides

36. 2-({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -propionic acid Methyl ester

37. ({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acetic acid

38. 2-({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -propionic acid

39. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid methyl ester

40. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid

41. (4-Methyl-piperazin-1-yl)-{6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 3-day} -Methanone

42. N- (1-Methyl-piperidin-4-ylmethyl) -6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] Nicotinamide

43. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -morpholin-4-yl-meta Paddy field

44. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid ethyl ester

45. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid

46. 1- (4-Methyl-piperazin-1-yl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amino] -pyridin-3-yl} -ethanone

47. N- (1-Methyl-piperidin-4-ylmethyl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Ylamino] -pyridin-3-yl} -acetamide

48. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine

49. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5 , 4-b] pyridine-2,5-diamine

50. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -ethanone

51. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid tert-butyl ester

52. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid methylamide

53. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid dimethylamide

54. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -2-hydroxy-ethanone

55. N ⁵ - (4- ^{fluoro-phenyl) -N 2 - {4- [4-} (4- fluoro-phenyl) -piperazin-1-ylmethyl] pyrimidin-2-yl} -N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diamine

56. 1- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperidine-3-carboxylic acid diethylamide

57. 3-[(2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -Methyl-amino] -propionnitrile

58. N ⁵ - ^{(4-fluoro-phenyl) -N 2 - (4 - {} [(2- methoxy-ethyl) -methyl-amino] -methyl} -pyridin-2-yl) -N ⁵ - methyl -Thiazolo [5,4-b] pyridine-2,5-diamine

59. 2-[(2- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -Methyl-amino] -ethanol

60. N ² - [4- (2,6- Dimethyl-morpholine-4-ylmethyl) -pyridin-2-yl] -N ⁵ - (4-fluoro-phenyl) -N ^{5-methyl-thiazolo} [5,4-b] pyridine-2,5-diamine

61. 1- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperidine-4-carboxylic acid ethyl ester

62. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine

63. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -2-methoxy-ethanone

64. Cyclopropyl- [4- (2- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-4 -Ylmethyl) -piperazin-1-yl] -methanone

65. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -propan-1-one

66. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine

67. N ⁵ - (4- flow oro-phenyl) -N ⁵ - methyl -N ² - [5- (4- methyl-piperazin-1-ylmethyl) -pyridin-2-yl] - thiazolo [5 , 4-b] pyridine-2,5-diamine

68. 1- [4- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazin-1-yl] -ethanone

69. 1- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl)- Piperidine-4-ol

70. N ^2- [5- (4-ethyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ^5- (4-fluoro-phenyl) -N ⁵ -methyl-thiazolo [5 , 4-b] pyridine-2,5-diamine

71. N ² - [5- (3- dimethylamino-pyrrolidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ - (4-fluoro-phenyl) -N ^{5-methyl-thiazolo} [5,4-b] pyridine-2,5-diamine

72. 2-[(6- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl) -Amino] -butan-1-ol

73. N ^5- (4-Fluoro-phenyl) -N ^2- [5- (4-methanesulfonyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-thiazolo [5,4-b] pyridine-2,5-diamine

^{74. N 2 - {5- [4-} (2- fluoro-ethyl) -piperazin-1-ylmethyl] -pyridin-2-yl} -N ⁵ - (4-fluorophenyl) -N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diazine

75. N ^2- [5- (2,6-Dimethyl-morpholin-4-ylmethyl) -pyridin-2-yl] -N ^5- (4-fluoro-phenyl) -N ⁵ -methyl-thiazolo [5,4-b] pyridine-2,5-diamine

76. 1- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl)- Piperidine-4-carboxylic acid amide

77. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine

78.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thia Zolo [5,4-b] pyridine-2,5-diamine

79. 1- [4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 4-ylmethyl) -piperazin-1-yl] -ethanone

80. 4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazole [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazine-1-carboxylic acid dimethylamide

81.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine

82.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thia Zolo [5,4-b] pyridine-2,5-diamine

83. 1- [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 3-ylmethyl) -piperazin-1-yl] -ethanone

84. 2-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -tizolo [5,4-b] pyridin-2-ylamino} -pyridine-3- Monomethyl) -methyl-amino] -ethanol

85.N ^5- (2,4-Difluoro-phenyl) -N ^2- (5-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -pyridin-2-yl) -N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diamine

86. N ^5- (2,4-Difluoro-phenyl) -N ^2- [5- (2,6-dimethyl-morpholin-4-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl -Thiazolo [5,4-b] pyridine-2,5-diamine

87. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidin-4-ol

88. N ^5- (2,4-Difluoro-phenyl) -N ^2- [5- (3-dimethylamino-pyrrolidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl -Thiazolo [5,4-b] pyridine-2,5-diamine

89. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -pyrrolidine-2-carboxylic acid methyl ester

90. 4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazine-1-carboxylic acid methylamide

91. 4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazine-1-carboxylic acid dimethylamide

92. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidine-4-carboxylic acid methyl ester

93. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidine-4-carboxylic acid

94. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -pyrrolidine-2-carboxylic acid

95. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (5-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine

96. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- Morpholin-4-yl-methanone

97. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-Methyl-piperazin-1-yl) -methanone

98. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (1-methyl-py Ferridin-4-ylmethyl) -nicotinamide

99. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-hydroxy -Ethyl) -nicotinamide

100. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-hydroxy-piperidin-1-yl) -methanone

101. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-morpholin- 4-yl-ethyl) -nicotinamide

102. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-hydroxy- Ethyl) -N-methyl-nicotinamide

103. N- (2-Diethylamino-ethyl) -6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Monoamino} -nicotinamide

104. 4-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-3- Carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester

105. tert-Butyl [1- (6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine -3-carbonyl) -piperidin-4-yl] -carbamate

106. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N-piperidine-4- Mono-nicotinamide

107. (4-Amino-piperidin-1-yl)-(6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine -2-ylamino} -pyridin-3-yl) -methanone

108. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (1-methyl-pi Ferridin-4-yl) -nicotinamide

109. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-dimethylamino-piperidin-1-yl) -methanone

110. N ^5- (4-Chloro-2-fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4 -b] pyridine-2,5-diamine

111.N ^5- (4-Chloro-2-fluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-pyrazin-1-ylmethyl) -pyridin-2-yl]- Thiazolo [5,4-b] pyridine-2,5-diamine

112. 1- [4- (2- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine -4-ylmethyl) -piperazin-1-yl] -ethanone

113. N ^5- (4-Chlorophenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2 , 5-diamine

114. N ^5- (4-Chloro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5, 4-b] pyridine-2,5-diamine

115. 1- [4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl ) -Piperazin-1-yl] -ethanone

116. 4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -pipe Razine-1-carboxylic acid dimethylamide

117. 1- [4- (2- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 4-ylmethyl) -piperazin-1-yl] -ethanone

118. 6- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -nicotinic acid methyl ester

119. [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4 -Yl) -piperazin-1-yl] -acetic acid ethyl ester

120. 2- [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine -4-yl) -piperazin-1-yl] -ethanol

121. 2-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4 -Yl) -methyl-amino] -ethanol

122. N ⁵ - (2,4- difluoro-phenyl) -N ⁵ - methyl -N ² - [6- (2- morpholine-4-yl-ethylamino) -pyrimidin-4-yl] - Thiazolo [5,4-b] pyridine-2,5-diamine

123. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- {6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidine -4-yl} -thiazolo [5,4-b] pyridine-2,5-diamine

124. 2- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4- Monoamino) -ethanol

125. 2- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4- Yl) -piperidine-1-carboxylic acid ethyl ester

126. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-2- On

127. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -pyrrolidine-3 -All

128. (( S ) -1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Pyrrolidin-2-yl) -methanol

129. N ⁵ -Methyl-N ^2- [4- (4-methyl- [1,4] diazepane-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5 , 4-b] pyridine-2,5-diamine

130. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -On

131. ( R ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid methyl ester

132. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid methyl ester

133. ({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -acetic acid ethyl ester

134. 1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -cyclo Propane carboxylic acid methyl ester

135. 2-methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid methyl ester

136. 2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -propane -1,3-diol

137. ( S ) -2- (methyl- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl Methyl} -amino) -propionic acid methyl ester

138. 2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -ethanol

139. 1- (1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperi Din-4-yl) -ethanone

140. N ^2- [4- (4-methanesulfonyl-piperidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4 -b] pyridine-2,5-diamine

141. N ² - [4- (4- methanesulfonyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4- b] pyridine-2,5-diamine

^{142. N 2 - (4 - {} [2- (2,5- dimethyl-4-yl) -ethyl-amino] -methyl} -pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p -Tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

143. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazin-1- Carboxylic acid ethyl ester

144. 3-hydroxy-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -Amino) -propionic acid methyl ester

145. 3-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -propane -1,2-diol

146. [1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino)- Cyclopentyl] -methanol

147. 2-Methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propan-1-ol

148. N ^2- [4- (4-Isopropyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine

149. N ^2- [4- (4-cyclopropyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine

150.N ⁵ -Methyl-N ^2- (4-peperazin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine

151. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -On oxime

152. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -One O-methyl-oxime

153. N ⁵ -Methyl-N ^2- (4-pyrazol-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine

154. 2-hydroxy-1- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl Methyl} -piperazin-1-yl) -ethanone

155. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin- 4-ylmethyl} -piperazine-1- Carboxylic Acid Cyclopropylamide

156. (S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -py Lolidine-2-carboxylic acid

157. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid

158. ({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -acetic acid

159. ( R ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid

160. 1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -cyclo Propanecarboxylic acid

161. 2-Methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid

162. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid

163. 1-Methyl-4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -pipe Razin-2-one

164. (R) -N-methoxy-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4 -Ylmethyl} -amino) -propionamide

165. N-methoxy-2-methyl-2 - ({2- [5- (-p- tolyl-amino) thiazolo [5,4-b] pyridin-2-ylamino] -pyridin -4 -Ylmethyl} -amino) -propionamide

166. N ⁵ -Methyl-N ^2- (4-methylaminomethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

167. N ^2- (4-Aminomethyl-pyridin-2-yl) -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

168. 2-Methanesulfonyl-N- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} Acetamide

169. 2-hydroxy-N- {2- [5-methyl-p-tolyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl} -acet amides

170. 5-oxo-pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-ylmethyl} -amide

171. 1-Methanesulfonyl-piperidine-4-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-ylmethyl} -amide

172. 2-Dimethylamino-N- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Acetamide

173. N- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -3-piperidine -1-yl-propionamide

174. 1-Methyl-pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-ylmethyl} -amide

175. Pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl }-amides

176. N ² - [4- (1,1- ^dioxo-6 -1 - T Omo morpholin-4-ylmethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

177. N - {2- [5- (methyl -p- tolyl-amino) thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} - methanesulfonamide

178. 1-Cyclopropyl-3- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Urea

179. ( S ) -N-hydroxy-2- (methyl- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine -4-ylmethyl} -amino) -propionamide

180. N, N-dimethyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Acetamide

181. 1- (4-acetyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone

182. N-cyclopropyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acet amides

183. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperidine- 1-Day-Ethanon

184. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-pyrrolidine- 1-Day-Ethanon

185. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-morpholine-4 -Sun-Ethanon

186. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -acetamide

187. N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] Pyridin-2-ylarmano] -pyridin-4-yl} -acetamide

188. N-Methyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetamide

189. N- [2- (2,5-Dimethyl-oxazol-4-yl) -ethyl] -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4- b] pyridin-2-ylarmano] -pyridin-4-yl} -acetamide

190. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperazine-1 -Sun-Ethanon

191.N- (1-Hydroxymethyl-propyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine -4-yl} -acetamide

192. 1- (4-Ethyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone

193. 1- (4-Isopropyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -ethanone

194. 3-hydroxy-2- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl } -Acetylamino) -pyrionic acid methyl ester

195. 1-((S) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine -2-ylarmano] -pyridin-4-yl} -ethanone

196. 1-((R) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine -2-ylarmano] -pyridin-4-yl} -ethanone

197. N-[(R) -1- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine-4 -Yl} -acetyl) -pyrrolidin-3-yl] -acetamide

198. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -morpholin-4-yl-meta Paddy field

199. (4-Methyl-piperazin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine- 4-day} -Methanone

200. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -piperazin-1-yl-meta Paddy field

203- (3-hydroxy-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-yl} -piperazin-1-yl-methanone

202. (3-Dimethylamino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-yl} -methanone

203. N- [3- (4-Methyl-piperazin-1-yl) -propyl] -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Yl-amino] -isonicotinamide

204. N- [2- (4-acetyl-piperidin-1-yl) -ethyl] -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine -2-yl-amino] -isonicotinamide

205. N-(( R ) -1-hydroxymethyl-propyl) -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Isonicotinamide

206. (4-Amino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine -4-yl} -methanone

207. (4-Dimethylamino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano]- Pyridin-4-yl} -methanone

208. ((S) -3-Amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -methanone

209. N-((S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4-carbonyl } -Pyrrolidin-3-yl) -acetamide

210. ((R) -3-Amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -methanone

211.N-((R) -1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4-carbonyl } -Pyrrolidin-3-yl) -acetamide

212. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -ethanol

213. 1- [4- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl}- Ethyl) -piperazin-1-yl] -ethanone

214. 4- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -ethyl) Piperazine-2-one

215. ⁵ N-Methyl ^{-N 2 - {4- [2- (} 4- methyl-piperazin-1-yl) ethyl] pyridin-2-yl} -N ⁵ -p- tolyl-thiazolo [5, , 4-b] pyridine-2,5-diamine

216. ⁵ N-Methyl -N ² - [4- (2- morpholin-4-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine -2,5-diamine

217. ⁵ N-Methyl -N ² - [4- (2- pyrrolidin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine

218. ⁵ N-Methyl -N ² - [4- (2- piperazin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine -2,5-diamine

219. 2- [Methyl- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Ethyl) -amino] -ethanol

220. N ² - [4- (2- dimethylamino-ethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine

221. ⁵ N-Methyl -N ² - [4- (2- piperidin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine

222. ⁵ N-Methyl ^{-N 2 - {4- [2- (} 2- morpholin-4-yl-ethylamino) -ethyl] -pyridin-2-yl} -N ⁵ -p- tolyl-thiazolo [ 5,4-b] pyridine-2,5-diamine

223. 2-hydroxy-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-yl} -ethyl) -piperazin-1-yl] -ethanone

224. 2-hydroxy-2-methyl-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethyl) -piperazin-1-yl] propan-1-one

225. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid methyl ester

226. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid

227. 1- (4-acetyl-piperazin-1-yl) -3- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -propan-1-one

228. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-morpholine-4 -Yl-propane-1-one

229. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperazin-1 -Yl-propane-1-one

230. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propan-1-ol

231. 1- [4- (3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Propyl) -piperazin-1-yl] -ethanone

232. N ⁵ -Methyl-N ^2- {4- [3- (4-methyl-piperazin-1-yl) -propyl] -pyridin-2-yl} -N ⁵ -p-tolyl-thiazolo [5 , 4-b] pyridine-2,5-diamine

233. 4- (3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propyl)- Piperazine-1-carboxylic acid methylamide

234. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino}-methyl benzoate ester

235. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -benzoic acid

236. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N- Methoxy-benzamide

237. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5

, 4-b] -pyridin-5-yl} -methyl-amino) -2-chloro-N-methoxy-benzamide

238. 2-Chloro-N-methoxy-5- {methyl- [2- (4-morpholin-4-ylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridine-5 -Yl] -amino} -benzamide

239. 2-Chloro-N-methoxy-5- (methyl- {2- [4- (4-methyl-pyrazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4 -b] pyridin-5-yl} -amino) -benzamide

240. 3-[(2-amino-thiazolo [5,4-b] pyridin-5-yl) -methyl-amino] -N-methoxy-benzamide

241. 3-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -N-methoxy-benzamide

242. N-methoxy-3- {methyl- [2- (4-morpholin-4-ylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl]- Amino} -benzamide

243. N-methoxy-3- (methyl- {2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridine -5-yl} -amino) -benzamide

244. 3-{[2- (4-Dimethylaminomethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methoxy-benz amides

245. 3-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N, N-dimethyl- Benzamide

246. 3-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methyl-benzamide

247. 3-{[2- (4-Dimethylcarbamoylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methoxy- Benzamide

248. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-benzoic acid ethyl ester

249. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-N-methoxy-benzamide

250. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-N-methyl-benzamide

The present invention also provides a method for preparing the compound of Formula 1. As can be seen in the production examples and examples described below, the method for producing a compound according to the present invention can be prepared by a wide variety of methods. The following preparation methods are merely exemplary methods thereof, and of course, may be prepared by various methods based on the art of organic synthesis. Therefore, the scope of the present invention is not limited only to these.

In a first preparation, the compound of Formula 1 may be prepared by reacting a compound of Formula 3 with an aromatic ring compound of Formula 2 under a palladium catalyst. For example, the compound of Formula 3 may be prepared by combining the compound of Formula 3 and the compound of Formula 2-1 according to Scheme 1 below.

[Reaction Scheme 1]

Wherein dba represents dibenzylideneacetone and Xanphos is 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthine.

The compound of formula 3 having an aminothiazole structure can be synthesized by the method of Korean Patent Application No. 2004-117617, wherein Ar represents an aromatic compound as defined above. The contents of this application are incorporated into the contents of the present invention by reference.

In a second preparation example, the method for preparing a compound of Formula 1 is according to the following Scheme 2, by (a) combining the compound of Formula 3 and the compound of Formula 2-2 obtained in Scheme 3 under a palladium catalyst Synthesizing the compound of Formula 4, (b) iii) removing the protecting group (OTBDMS) of benzyl alcohol with ammonium fluoride (NH ₄ F), and ii) reacting with phosphorus oxychloride (POCl ₃ ) Synthesizing the compound, and (c) amidating the various amines to synthesize the compound of formula 1-2.

[Reaction Scheme 2]

Here, the compound of Chemical Formula 2-2 may be prepared by the method of Scheme 3 below.

[Reaction Scheme 3]

Referring to Scheme 3, (a) esterification with 2-chloro-isonicotinic acid of formula 2-2-1 as a starting material to make a compound of formula 2-2-2, and (b) lithium aluminum hydride Reduction with (LiAlH ₄ ) to form a compound of formula (2-2-3), and then (c) the protection reaction with an alkylsilyl compound to obtain a compound of formula (2-2).

In a third preparation, the method for preparing a compound of Formula 1 is according to Scheme 4 below: (a) reacting the compound of Formula 3 with methyl benzoate of Formula 2-3 under a palladium catalyst to obtain Formula 6, (b Hydrolyzing the compound of formula 6 with lithium hydroxide to obtain a compound of formula 7, and (c) amidating the compound of formula 7 with various amines to obtain a compound of formula 1-3. Can be configured.

[Reaction Scheme 4]

In a fourth preparation, the method for preparing a compound of Formula 1 is prepared according to Scheme 5 below: (a) Palladium acetate (Pd (Oac) ₂ ) and triphenylphosphine (PPh ₃ ) Reacting with carbon monoxide in the presence of to obtain a compound of formula 8, (b) hydrolyzing the compound of formula 8 with lithium hydroxide to obtain a compound of formula 9, and (c) phenylacetic acid of formula 9 to various amines And amidation reaction to obtain a compound of Formula 1-4.

[Reaction Scheme 5]

Those skilled in the art to which the present invention pertains can check the specific reaction conditions for the preparation of the compound according to the present invention through the preparation examples and examples which will be described later, and thus the detailed description thereof will be omitted. .

The compounds according to the invention are particularly effective for the treatment and prevention of diseases due to undesirable KDR activity, such as diseases associated with angiogenesis. Examples of such diseases include, but are not limited to, cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic heart disease, atherosclerosis, Kaposi's sarcoma, and the like. Accordingly, the present invention provides a method of treating and preventing a disease due to KDR activity using a compound of Formula 1.

The present invention also provides a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula 1; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof.

The term "pharmaceutical composition" means a mixture of a compound of the invention with other chemical components such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound into the organism. There are a variety of techniques for administering compounds, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions may also be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the dose range of the composition administered to the patient may be about 0.5 to 1000 mg / kg of the patient's body weight. Dosages may be given in a series of two or more, one at a time or in a day or more, depending on the extent required by the patient.

The present invention is explained in more detail by the following Preparation Examples, Examples and Experimental Examples, but the scope of the present invention is not limited in any way by this.

Example 1: N ⁵ -(4-fluorophenyl) -N ⁵ -Methyl-N ² Preparation of-(6-methyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

2.5 g (9.11 mmol) of N ^5- (4-fluorophenyl) -N ⁵ -methyl-thiazole [5,4-b] pyridine-2,5-diamine synthesized in Korean Patent Application No. 2004-117617; Dissolve 1.63 g (12.8 mmol) of 2-chloro-6-methylpyridine in 50 ml of toluene, 1.35 g (12.8 mmol) of sodium carbonate, 500 mg (0.547 mmol) of bis (dibenzylideneacetone) dipalladium, and 4,5- 470 mg (0.820 mmol) of bis (diphenylphosphino) -9,9-dimethylxanthine were added and stirred under reflux for 4 hours. After completion of the reaction, 40 ml of ethyl acetate was added, the solid was removed by filtration through celite, and the filtered solid was washed with 40 ml of water. Concentration and separation by column chromatography (eluent; ethyl acetate: normal hexane = 1: 2) gave 2.25 g (6.16 mmol, yield; 68%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 10.10 (1H, bs), 7.58 (1H, d), 7.46 (1H, t), 7.27 (2H, m), 7.13 (2H, t), 6.76 (1H, d), 6.65 (1H, d), 6.52 (1H, d), 3.51 (3H, s), 2.57 (3H, s)

FAB MS (m / e) = 366 [M + 1]

Production Example  1: 6- Chloropyridine -2- Carboxylic acid methyl  Preparation of ester

6.5 g (41.2 mmol) of 6-chloropyridine-2-carboxylic acid was dissolved in 100 ml of methanol, and 5 ml of a 2N methanolic acid hydrochloric acid solution was added thereto, followed by stirring under reflux for 15 hours. After completion of the reaction, the reaction mixture was concentrated, 100 ml of water was added thereto, and neutralized with 1N aqueous sodium hydroxide solution. Extracted twice with 70 ml of ethyl acetate and concentrated to give 6.69 g (39.1 mmol, yield; 95%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.71 (1H, d), 7.33 (1H, t), 7.14 (1H, d), 3.65 (3H, s)

FAB MS (m / e) = 172 [M + 1]

Production Example  2: (6- Chloropyridine 2-yl) -Methanol Preparation

6.67 g (39.0 mmol) of the compound obtained in Preparation Example 1 was dissolved in 90 ml of anhydrous tetrahydrofuran, and then cooled to -45 ° C. 40 ml of 1 mol lithium aluminum hydride tetrahydrofuran solution was added dropwise to this solution for 30 minutes. After stirring for 30 minutes, the temperature was raised to 0 ° C., and after stirring for 30 minutes, 15 ml of 1N aqueous sodium hydroxide solution was added dropwise. The solution was filtered through celite to remove solids and the filtered solution was concentrated to give 5.08 g (35.4 mmol, yield; 91%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.61 (1H, d), 7.30 (1H, t), 7.04 (1H, d), 3.72 (2H, s)

FAB MS (m / e) = 144 [M + 1]

Production Example  3: 2- ( tert -Butyl-dimethyl- Silanyloxymethyl ) -6- Chloro Preparation of Pyridine

After dissolving 5.0 g (35.0 mmol) of the compound obtained in Preparation Example 2 in 120 ml of dichloromethane, 4.76 g (69.9 mmol) of imidazole and 5.80 g (38.5 mmol) of t-butyldimethylsilyl chloride were added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, the mixture was washed with 100 ml of water, washed once more with 40 ml of saturated aqueous sodium hydrogen carbonate solution and concentrated to give 8.45 g (32.9 mmol, yield; 94%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.62 (1H, d), 7.31 (1H, t), 7.05 (1H, d), 4.68 (2H, s), 0.92 (9H, s), 0.10 (6H, s)

FAB MS (m / e) = 258 [M + 1]

Preparation Example 4 N ² -[3- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-yl] -N ⁵ -Methyl-N ⁵ -p-tolyl- Thiazolo [5,4-b] pyridine -2,5- Diamine  Produce

Preparation with N ₅ -methyl-N _5- (N ⁵ -methyl-N ⁵ ) -p-tolyl-thiazole [5,4-b] pyridine-2,5-diamine synthesized in Korean Patent Application No. 2004-117617 It reacted by the method of Example 1 using the compound obtained in Example 3, and obtained the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.31 (1H, d), 7.50 (1H, d), 7.41 (1H, d), 7.20 (4H, m), 6.86 (1H, t), 6.56 (1H, d), 4.87 (2H, bs), 3.82 (3H, s), 2.38 (3H, s), 0.93 (9H, s), 0.10 (6H, s)

FAB MS (m / e) = 492 [M + 1]

Example 2: Preparation of {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -methanol

1.8 g (3.67 mmol) of the compound obtained in Preparation Example 4 were dissolved in 30 ml of methanol, and 540 mg (14.7 mmol) of ammonium fluoride was added thereto, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the mixture was filtered and dried to obtain 1.09 g (2.90 mol, yield; 79%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.30 (1H, d), 7.52 (1H, d), 7.40 (1H, d), 7.20 (4H, m), 6.86 (1H, t), 6.56 (1H, d), 4.87 (2H, bs), 3.51 (3H, s), 2.38 (3H, s)

FAB MS (m / e) = 378 [M + 1]

Preparation Example 5 N ⁵ -(Chloromethyl-pyridin-2-yl) -N ⁵ -Methyl-N ⁵ -p-tolyl-thiazole [5,4-b] pyridine-2,5-di Ah Manufacture of private

0.95 g (2.52 mmol) of the compound obtained in Example 2 was dissolved in 50 ml of dichloromethane, 0.59 ml (7.56 mmol) of N, N-dimethylformamide and 0.69 ml (7.56 mmol) of phosphorus oxychloride were added thereto, followed by stirring at room temperature for 10 hours. It was. After completion of the reaction, the resultant was filtered, and the filtered solid was dissolved in 100 ml of water, and the solid formed by neutralization with sodium bicarbonate was filtered again to obtain 0.81 g (2.05 mmol, yield; 81%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.31 (1H, d), 7.51 (1H, d), 7.42 (1H, d), 7.21 (4H, m), 6.86 (1H, t), 6.56 (1H, d), 3.53 (2H, s), 3.51 (3H, s), 2.38 (3H, s)

FAB MS (m / e) = 396 [M + 1]

Example 3: N ⁵ -Methyl-N ² -(3-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ Preparation of -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

50 mg (0.127 mmol) of the compound obtained in Preparation Example 5 was dissolved in 0.8 ml of dimethyl sulfoxide, 0.044 ml (0.508 mmol) of morpholine was added thereto, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, 30 ml of water was added, and 20 ml of ethyl acetate was extracted twice, and concentrated. Separation by column chromatography (eluent; 10% methanol / dichloromethane) gave 45 mg (0.101 mmol, yield; 79%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.04 (1H, bs), 8.30 (1H, d), 7.57 (1H, d), 7.40 (1H, d), 7.20 (4H, m), 6.84 (1H, t), 6.56 (1H, d), 3.83 (4H, m), 3.65 (2H, s), 3.51 (3H, s), 2.55 (4H, bs), 2.37 (3H, s)

FAB MS (m / e) = 447 [M + 1]

Example 4: N ⁵ -Methyl-N ² -[3- (4-Methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ Preparation of -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

In Example 3, the reaction was carried out in the same manner as in Example 3, using N-methylpyrrazine instead of morpholine to obtain a target compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.06 (1H, bs), 8.30 (1H, d), 7.57 (1H, d), 7.40 (1H, d), 7.20 (4H, m), 6.84 (1H, t), 6.56 (1H, d), 3.65 (2H, s), 3.51 (3H, s), 2.61 (8H, bs), 2.38 (2H, bs), 2.37 (3H, s)

FAB MS (m / e) = 460 [M + 1]

Production Example  6: 4- ( tert -Butyl-dimethyl- Silanyloxymethyl )-2- Chloro Preparation of Pyridine

In Preparation Example 1, 6-chloroisonicotinic acid was used instead of 6-chloropyridine-2-carboxylic acid to react with the method of Preparation Example 1, and then sequentially by the methods of Preparation Example 2 and Preparation Example 3 to react the target compound. Got.

¹ H NMR (CDCl ₃ , ppm); δ 8.31 (1H, d), 7.30 (1H, s), 7.14 (1H, d), 4.71 (2H, s), 0.94 (9H, s), 0.11 (6H, s)

FAB MS (m / e) = 258 [M + 1]

Preparation Example 7 N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -Methyl-N ⁵ -Phenyl-thiazolo [5,4-b] pyridine-2,5-di Ah Manufacture of private

Example 1, using the compound obtained in Preparation Example 6 and N ⁵ -methyl-N ⁵ -phenyl-thiazolo [5,4-b] pyridine-2,5-diamine (Korean Patent Application No. 2004-117617) It reacted sequentially by the method of Example 2 and manufacture example 5, and obtained the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 7.62 (1H, s), 7.39 (2H, t), 7.28 (2H, d), 7.16 (1H, t), 7.05 (1H, s), 6.87 (1H, d), 6.57 (1H, d), 3.71 (2H, s), 3.40 (3H, s)

FAB MS (m / e) = 382 [M + 1]

Example 5: N ⁵ -Methyl-N ² -[4- (4-Methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ Preparation of -phenyl-thiazolo [5,4-b] pyridine-2,5-diamine

It reacted by the method of Example 3 using the compound obtained in manufacture example 7, and obtained the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.2 (1H, s), 8.20 (1H, d), 7.63 (1H, d), 7.40-7.37 (2H, m), 7.28-7.27 (2H, m), 7.17 (1H, t), 6.68 (1H , d), 6.59 (1H, d), 3.42 (3H, s), 3.34 (2H, s), 3.22-3.12 (4H, m), 2.36-2.21 (4H, m), 2.13 (3H, s)

FAB MS (m / e) = 446 [M + 1]

Example 6: N ⁵ -Methyl-N ² -(4-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ Preparation of -phenyl-l-thiazolo [5,4-b] pyridine-2,5-diamine

In Example 5, morpholine was used instead of N-methylpiperazine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 7.63 (1H, s), 7.39 (2H, t), 7.28 (2H, d), 7.18 (1H, t), 7.08 (1H, s), 6.89 (1H, d), 6.57 (1H, d), 3.58-3.56 (4H, m), 3.44 (2H, s), 3.40 (3H, s), 2.37-2.30 (4H, m)

FAB MS (m / e) = 433 [M + 1]

Production Example  8: piperazine-1- Carboxylic acid Methylamide  Produce

11 g (59 mmol) of N-butyloxycarbonylpiperazine was dissolved in 250 ml of anhydrous tetrahydrofuran, followed by 20.6 ml (118 mmol) of N, N-diisopropylethylamine and 13.1 g of 4-nitrophenylchloroformate ( 64.9 mmol) is added and stirred at room temperature for 1 hour. 177 ml of methylamine (2M tetrahydrofuran solution) was added to the solution, and the mixture was stirred under reflux for 30 hours. After completion of the reaction, the reaction solution was concentrated, 100 ml of water was added, 100 ml of extraction was performed twice with dichloromethane, and 30 ml of 4N hydrochloric acid / 1,4-dioxane solution was added thereto, followed by stirring at room temperature for 5 hours. The solid formed after completion of the reaction was filtered and dried to obtain 9.53 g (53 mmol, yield; 90%) in the form of the hydrochloride of the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.28 (1H, bs), 7.94 (1H, bs), 3.52 (4H, m), 3.01 (4H, m), 2.57 (3H, s)

FAB MS (m / e) = 144 [M + 1]

Example 7: 4- {2- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazin-1- Preparation of Carboxylic Acid Methylamide

The compound obtained in Preparation Example 7 and the compound obtained in Preparation Example 8 were reacted by the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.1 (1H, s), 8.21 (1H, d), 7.65 (1H, d), 7.40-7.37 (2H, m), 7.28-7.27 (2H, m), 7.15 (1H, t), 6.65 (1H , d), 6.57 (1H, d), 3.43 (3H, s), 3.34 (2H, s), 3.22-3.12 (4H, m), 2.46-2.31 (4H, m), 2.65 (3H, s)

FAB MS (m / e) = 489 [M + 1]

Production Example  9: piperazine-1- Carboxylic acid  Preparation of Dimethylamide

In Preparation Example 8, dimethylamine was used in place of methylamine to react with Preparation Example 8 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ9.93 (2H, bs), 3.58 (4H, bs), 3.22 (4H, bs), 2.84 (6H, s)

FAB MS (m / e) = 158 [M + 1]

Example 8: 4- {2- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazin-1- Preparation of Carboxylic Acid Dimethylamides

The target compound was obtained by reacting the compound obtained in Preparation Example 7 and the compound obtained in Preparation Example 9 by the method of Example 3.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.27 (1H, bs), 8.21 (1H, d), 7.62 (1H, d), 7.38 (2H, t), 7.27 (2H, d), 7.18 (1H, t), 7.08 (1H, s) , 6.90 (1H, d), 6.57 (1H, d), 3.47 (2H, s), 3.40 (3H, s), 3.10 (4H, s), 2.69 (6H, s), 2.36 (4H, s)

FAB MS (m / e) = 503 [M + 1]

Example 9: Preparation of {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -methanol

The compound obtained in Preparation Example 6 was used instead of the compound obtained in Preparation Example 3 to react with the method of Preparation Example 4, and subsequently with the method of Example 2 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.29 (1H, bs), 8.21 (1H, d), 7.62 (1H, d), 7.20 (4H, m), 7.12 (1H, bs), 6.89 (1H, d), 6.52 (1H, d) , 5.44 (1H, t), 4.52 (2H, d), 3.40 (3H, s), 2.33 (3H, s)

FAB MS (m / e) = 378 [M + 1]

Production Example  10: N ² -(4- Chloromethyl -Pyridin-2-yl)- N ⁵ - methyl - N ⁵ -p- Tolyl - Thiazolo [5,4-b] pyrid Dean-2,5- Diamine  Produce

The compound obtained in Example 9 was reacted by the method of Preparation Example 5 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.21 (1H, s), 8.24 (1H, d), 7.66 (1H, d), 7.24 (2H, d), 7.20 (2H, d), 7.11 (1H, s), 6.93 (1H, d), 6.54 (1H, d), 3.63 (2H, s), 3.41 (3H, s), 2.34 (3H, s)

FAB MS (m / e) = 396 [M + 1]

Example 10: 1- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Piperazin-1-yl) -ethanone

The target compound was obtained by the method of Example 3 using the compound obtained in Preparation Example 10.

¹ H NMR (CDCl ₃ , ppm); δ 10.28 (1H, bs), 8.30 (1H, d), 7.57 (1H, d), 7.19 (4H, m), 6.95 (1H, s), 6.87 (1H, d), 6.56 (1H, d), 3.68 (2H, m), 3.51 (3H, s), 3.45 (2H, s), 3.36 (2H, m), 2.38 (7H, m), 2.07 (3H, s).

FAB MS (m / e) = 488 [M + 1]

Table 1 below shows examples of synthesizing desired compounds by the method of Example 3 using the compound obtained in Preparation Example 10.

TABLE 1

Example 17: (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine Preparation of -1-yl) -acetic acid

450 mg (0.847 mmol) of the compound obtained in Example 16 was dissolved in 30 ml of tetrahydrofuran and 10 ml of methanol was added thereto. Then, 106 mg (2.54 mmol) of lithium hydroxide monohydrate was dissolved in 10 ml of water and added at room temperature. Stir for 3 hours. After completion of the reaction, the resultant was concentrated, 20 ml of water was added thereto, and the solid formed by neutralization with 1N aqueous hydrochloric acid solution was filtered and dried to obtain 400 mg (0.796 mmol, yield; 94%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.2 (1H, s), 8.25 (1H, d), 7.64 (1H, d), 7.26 (2H, d), 7.21 (2H, d), 7.11 (1H, s), 6.93 (1H, d), 6.54 (1H, d), 3.53 (4H, s), 3.49 (2H, s), 3.41 (3H, s), 2.66 (4H, s), 2.46 (2H, s), 2.34 (3H, s)

FAB MS (m / e) = 504 [M + 1]

Example 18 N, N-dimethyl-2- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- Preparation of 4-ylmethyl} -piperazin-1-yl) -acetamide

50 mg (0.0994 mmol) of the compound obtained in Example 17 was dissolved in 3 ml of N, N-dimethylformamide, followed by 0.065 ml (0.129 mmol) of dimethylamine (2M tetrahydrofuran solution) and 22.8 mg of 1-hydroxybenzotriazole. (0.170 mmol) and 28.6 mg (0.149 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added and stirred at room temperature for 2 hours. After completion of the reaction, the resultant was concentrated, dissolved in 30 ml of ethyl acetate, washed with 20 ml of saturated sodium hydrogen carbonate, concentrated and separated by column chromatography to obtain 43 mg (0.0811 mmol, yield; 82%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.24 (1H, d), 7.64 (1H, d), 7.22 (2H, d), 7.19 (2H, d), 7.11 (1H, s), 6.92 (1H, d), 6.54 (1H, d), 3.53 (4H, s), 3.49 (2H, s), 3.41 (3H, s), 2.66 (4H, s), 2.55 (6H, s), 2.46 (2H, s), 2.34 (3H, s)

FAB MS (m / e) = 531 [M + 1]

Production Example  11: 2- Chloro -4- Chloromethyl Preparation of Pyridine

2-Chloro-4-hydroxymethylpyridine obtained by reacting by the method of Preparation Example 1 using 6-chloroisonicotinic acid instead of 6-chloropyridine-2-carboxylic acid, and subsequently by the method of Preparation Example 2. 20.0 g (140 mmol) was reacted by the method of Preparation Example 1 to obtain 17.5 g (109 mmol, yield; 78%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.34 (1H, d), 7.29 (1H, s), 7.16 (1H, d), 3.82 (3H, s)

FAB MS (m / e) = 162 [M + 1]

Production Example  12: (2- Chloro Preparation of -pyridin-4-yl) -acetic acid ethyl ester

Dissolve 19.5 g (121 mmol) of the compound obtained in Preparation Example 11 in 400 ml of ethanol, and then add 950 mg (6.05 mmol) of palladium acetate, 3.17 g (12.1 mmol) of triphenylphosphine, and 50.2 g (363 mmol) of calcium carbonate. Stirred under 1 atm of carbon monoxide conditions. After completion of the reaction, the mixture was filtered through celite, concentrated and separated by column chromatography to obtain the title compound 19.0 g (95.5 mmol, yield, 79%).

¹ H NMR (CDCl ₃ , ppm); δ 8.34 (1H, d), 7.29 (1H, s), 7.16 (1H, d), 4.18 (2H, q), 3.61 (3H, s), 1.27 (3H, t)

FAB MS (m / e) = 200 [M + 1]

Example 19 Preparation of {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid ethyl ester

The compound obtained in Preparation Example 12 was reacted with N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine in the method of Example 1 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.21 (1H, d), 7.64 (1H, d), 7.22 (2H, d), 7.19 (2H, d), 6.97 (1H, s), 6.85 (1H, d), 6.53 (1H, d), 3.52 (2H, s), 3.11 (2H, q), 2.34 (3H, s), 2.19 (3H, s), 1.23 (3H, t)

FAB MS (m / e) = 434 [M + 1]

Example 20 Preparation of {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid

The compound obtained in Example 19 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.23 (1H, d), 7.62 (1H, d), 7.20 (2H, d), 7.19 (2H, d), 6.97 (1H, s), 6.84 (1H, d), 6.51 (1H, d), 3.50 (2H, s), 2.34 (3H, s), 2.19 (3H, s)

FAB MS (m / e) = 406 [M + 1]

Example 21 1- (4-Methyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Preparation of Ilamino] -pyridin-4-yl} -ethanone

The target compound was obtained by reacting the compound obtained in Example 20 with the method of Example 18 using N-methylpiperazine.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.24 (1H, d), 7.64 (1H, d), 7.21 (2H, d), 7.19 (2H, d), 6.98 (1H, s), 6.86 (1H, d), 6.52 (1H, d), 3.89 (3H, s), 3.50 (2H, s), 3.40 (4H, s), 2.34 (3H, s), 2.30 (4H, s), 2.19 (3H, s)

FAB MS (m / e) = 488 [M + 1]

Example 22 N- (2-diethylamino-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] Preparation of -pyridin-4-yl} -acetamide

Reaction was carried out in the same manner as in Example 21 using 3-diethylaminoethylamine instead of N-methylpiperazine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.12 (1H, d), 7.76 (1H, d), 7.26 (2H, d), 7.23 (2H, d), 7.03 (1H, s), 6.89 (1H, d), 6.52 (1H, d), 3.89 (3H, s), 3.50 (2H, s), 3.32-3.21 (4H, m), 2.97 (2H, m), 2.74 (2H, t), 2.33 (3H, s) , 1.18 (3H, t), 1.01 (3H, t)

FAB MS (m / e) = 504 [M + 1]

Example 23: 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -N- (2 Preparation of -morpholin-4-yl-ethyl) -acetamide

In Example 21, using the 2-morpholinoethylamine instead of N-methyl piperazine in the method of Example 21 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.2 (1H, s), 8.23 (1H, d), 7.64 (1H, d), 7.26 (2H, d), 7.19 (2H, s), 7.01 (1H, s), 6.90 (1H, d), 6.54 (1H, d), 3.57 (4H, s), 3.40 (2H, s), 2.97 (2H, m), 2.74 (2H, t), 2.39 (4H, s), 2.3 (3H, s)

FAB MS (m / e) = 518 [M + 1]

Example 24 N- (2-hydroxy-ethyl) -N-methyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Preparation of Ilamino] -pyridin-4-yl} -acetamide

In Example 21, 1-methyl-2-hydroxyethylamine was used instead of N-methylpiperazine to react in the same manner as in Example 21 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.3 (1H, s), 8.23 (1H, d), 7.62 (1H, d), 7.27 (2H, d), 7.20 (2H, d), 6.98 (1H, s), 6.85 (1H, d), 6.55 (1H, s), 4.82 (1H, t), 3.79-3.57 (4H, m), 3.40 (2H, s), 3.27 (3H, s), 2.88 (3H, s), 2.34 (3H, s)

FAB MS (m / e) = 463 [M + 1]

Example 25 N- (2-hydroxy-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] Preparation of -pyridin-4-yl} -acetamide

In Example 21, the reaction of Example 21 was carried out using 2-hydroxyethylamine instead of N-methylpiperazine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.23 (1H, d), 7.64 (1H, d), 7.27 (2H, d), 7.19 (2H, d), 7.03 (1H, s), 6.91 (1H, d), 6.52 (1H, d), 4.72 (1H, t), 3.70-3.65 (2H, m), 3.40 (2H, s), 3.28 (3H, s), 3.16 (2H, t), 2.34 (3H, s)

FAB MS (m / e) = 518 [M + 1]

Example 26 Preparation of 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinonitrile

N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine was reacted with 2-chloro-5-cyanopyridine by the method of Example 1 to obtain the target compound. Got it.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.94 (1H, bs), 8.79 (1H, s), 8.11 (1H, d), 7.70 (1H, d), 7.23 (5H, m), 6.53 (1H, d), 3.41 (3H, s) , 2.37 (3H, s)

FAB MS (m / e) = 373 [M + 1]

Production Example  13: 5- ( tert -Butyl-dimethyl- Silanyloxymethyl )-2- Chloro Preparation of Pyridine

In Preparation Example 6, 6-chloronicotinic acid was used instead of 6-chloroisonicotinic acid to react in the same manner as in Preparation Example 6 to obtain a target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.32 (1H, s), 7.62 (1H, d), 7.28 (1H, d), 4.72 (2H, s), 0.92 (9H, s), 0.10 (6H, s)

FAB MS (m / e) = 258 [M + 1]

Preparation Example 14 N ² -(5-chloromethyl-pyridin-2-yl) -N ⁵ -Methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine  Produce

Using the compound obtained in Preparation Example 13, the reaction was carried out by the method of Preparation Example 7 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.30 (1H, bs), 7.57 (1H, d), 7.23 (5H, m), 7.00 (1H, d), 6.45 (1H, d), 3.57 (2H, s), 3.51 (3H, s), 2.42 (3H, s)

FAB MS (m / e) = 396 [M + 1]

Example 27: N ² -(5-diethylaminomethyl-pyridin-2-yl) -N ⁵ -Methyl-N ⁵ Preparation of -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Preparation Example 14 was reacted by the method of Example 3 using diethylamine to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.30 (1H, bs), 7.57 (1H, d), 7.23 (5H, m), 7.00 (1H, d), 6.46 (1H, d), 3.51 (3H, s), 3.45 (2H, bs), 2.59 (4H, m), 2.42 (3H, s), 1.11 (6H, m)

FAB MS (m / e) = 433 [M + 1]

Table 2 below is an example in which the desired compound was synthesized by reacting by the method of Example 27 using the compound obtained in Preparation Example 14.

TABLE 2

Example 37: ({6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acetic acid Manufacture

The compound obtained in Example 34 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.17 (1H, s), 7.65 (1H, m), 7.57 (1H, d), 7.15 (4H, m), 7.05 (1H, m), 6.47 (1H, d), 3.59 (2H, s) , 3.36 (3H, s), 2.78 (2H, s), 2.29 (3H, s)

FAB MS (m / e) = 435 [M + 1]

Example 38: 2-({6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) Preparation of Propionic Acid

The compound obtained in Example 36 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 7.96 (1H, s), 7.32 (1H, d), 7.21 (1H, d), 7.09 (2H, d), 7.01 (2H, d), 6.62 (1H, d), 6.43 (1H, d) , 3.47 (1H, q), 3.33 (5H, s), 2.24 (3H, s), 1.03 (3H, d)

FAB MS (m / e) = 449 [M + 1]

Example 39 Preparation of 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid methyl ester

N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine was reacted with methyl 6-chloronicotinate by the method of Example 1 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 10.59 (1H, bs), 9.01 (1H, s), 8.13 (1H, d), 7.54 (1H, d), 7.20 (4H, m), 6.95 (1H, d), 6.55 (1H, d) , 3.93 (3H, s), 3.51 (3H, s), 2.38 (3H, s)

FAB MS (m / e) = 406 [M + 1]

Example 40 Preparation of 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid

The compound obtained in Example 39 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.32 (1H, s), 7.75 (1H, d), 7.61 (1H, d), 7.23 (2H, d), 7.18 (2H, d), 7.11 (1H, d), 6.59 (1H, d), 3.31 (3H, s), 2.21 (3H, s)

FAB MS (m / e) = 392 [M + 1]

Example 41: (4-Methyl-piperazin-1-yl)-{6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Preparation of Pyridin-3-yl} -Methanone

The compound obtained in Example 40 was reacted with N-methylpiperazine by the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.32 (1H, s), 7.75 (1H, d), 7.61 (1H, d), 7.23 (2H, d), 7.18 (2H, d), 7.11 (1H, d), 6.59 (1H, d), 3.50 (4H, bs), 3.38 (3H, s), 3.31 (3H, s), 2.32 (4H, bs), 2.20 (3H, s)

FAB MS (m / e) = 474 [M + 1]

Example 42 N- (1-methyl-piperidin-4-ylmethyl) -6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Preparation of Amino] -nicotinamide

The compound obtained in Example 40 was reacted with 1-methyl-4- (aminomethyl) piperidine in the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.2 (1H, s), 8.76 (1H, s), 8.46 (1H, d), 8.10 (1H, d), 7.63 (1H, d), 7.29 (2H, d), 7.17 (2H, d), 7.11 (1H, d), 6.50 (1H, d), 5.77 (1H, t), 3.31 (3H, s), 2.97 (2H, t), 2.85 (2H, t), 2.34 (3H, s), 2.23 (3H, s), 1.97 (2H, t), 1.63-1.60 (2H, m), 1.39-1.35 (1H, m), 1.19-1.14 (2H, m)

FAB MS (m / e) = 502 [M + 1]

Example 43 {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -morpholin-4-yl Preparation of Methanone

The compound obtained in Example 40 was reacted with morpholine in the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.57 (1H, s), 8.41 (1H, s), 7.83 (1H, d), 7.68 (1H, d), 7.27 (2H, d), 7.22 (2H, d), 7.18 (1H, d), 6.53 (1H, d), 3.64 (4H, s), 3.41 (3H, s), 3.32 (4H, s), 2.34 (3H, s)

FAB MS (m / e) = 461 [M + 1]

Production Example  15: 2- Chloro -5- Chloromethyl Preparation of Pyridine

In Preparation Example 11, 6-chloronicotinic acid was used instead of 6-chloronicotinic acid to react in the same manner as in Preparation Example 11, to obtain a target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.32 (1H, s), 7.61 (1H, d), 7.33 (1H, d), 3.89 (2H, s)

FAB MS (m / e) = 162 [M + 1]

Production Example  16: (6- Chloro Preparation of -pyridin-3-yl) -acetic acid ethyl ester

The target compound was obtained by reacting by the method of Preparation Example 12 using the compound obtained in Preparation Example 15.

¹ H NMR (CDCl ₃ , ppm); δ 8.30 (1H, s), 7.62 (1H, d), 7.30 (1H, d), 4.16 (2H, q), 3.60 (2H, s), 1.26 (3H, t)

FAB MS (m / e) = 200 [M + 1]

Example 44 Preparation of {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid ethyl ester

The compound obtained in Production Example 16 was reacted with N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine in the method of Example 1 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ9.90 (1H, bs), 8.26 (1H, s), 7.56 (2H, s), 7.19 (4H, m), 6.96 (1H, d), 6.57 (1H, d), 4.16 (2H, q) , 3.57 (2H, s), 3.50 (3H, s), 2.38 (3H, s), 1.26 (3H, t)

FAB MS (m / e) = 434 [M + 1]

Example 45 Preparation of {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid

The compound obtained in Example 44 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.10 (1H, s), 7.63 (2H, t), 7.20 (4H, m), 7.10 (1H, d), 6.51 (1H, d), 3.58 (2H, s), 2.32 (3H, s)

FAB MS (m / e) = 406 [M + 1]

Example 46: 1- (4-Methyl-piperazin-1-yl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Preparation of Ilamino] -pyridin-3-yl} -ethanone

The compound obtained in Example 45 was reacted with N-methylpiperazine in the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.21 (1H, d), 7.61 (1H, d), 7.40 (2H, d), 7.28 (2H, d), 7.17 (1H, t), 7.07 (1H, s), 6.89 (1H, d), 6.59 (1H, d), 6.38 (1H, d), 3.43 (2H, s), 3.40 (3H, s), 3.26 (4H, s), 2.46 (3H, s), 2.43 (3H, s), 2.30 (4H, s)

FAB MS (m / e) = 488 [M + 1]

Example 47 N- (1-methyl-piperidin-4-ylmethyl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- Preparation of 2-ylamino] -pyridin-3-yl} -acetamide

The compound obtained in Example 45 was reacted with 1-methyl-4- (aminomethyl) piperidine in the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.18 (1H, s), 8.08 (1H, t), 7.69-7.66 (2H, m), 7.27 (2H, d), 7.21 (2H, d), 7.08 (1H, d ), 6.52 (1H, d), 3.43 (2H, s), 3.31 (3H, s), 2.97 (2H, t), 2.85 (2H, t), 2.34 (3H, s), 2.23 (3H, s) , 1.97 (2H, t), 1.63-1.60 (2H, m), 1.39-1.35 (1H, m), 1.19-1.14 (2H, m)

FAB MS (m / e) = 516 [M + 1]

Preparation Example 17 N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -(4-fluoro-phenyl) -N ⁵ -Methyl-thiazolo [ 5,4-b] pyridine -2,5- Diamine  Produce

In Production Example 7 N ⁵ - (4-fluoro-phenyl) ^{-N-methyl-5-phenyl-thiazolo} [5,4-b] pyridine-2,5-diamine instead of N ⁵ -methyl -N ⁵ thiazolo It reacted by the method of Preparation Example 7 using [5,4-b] pyridine-2,5-diamine, and obtained the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.29 (1H, d), 7.57 (1H, d), 7.23 (2H, m), 7.07 (3H, m), 6.88 (1H, d), 6.49 (1H, d), 4.53 (2H, s), 3.48 (3H, s)

FAB MS (m / e) = 400 [M + 1]

Example 48: N ⁵ -(4-fluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 17 and the morpholine were reacted by the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.64 (1H, bs), 8.28 (1H, d), 7.47 (1H, d), 7.23 (2H, m), 7.08 (2H, t), 6.98 (1H, s), 6.93 (1H, d), 6.50 (1H, d), 3.70 (4H, t), 3.49 (3H, s), 3.47 (2H, s), 2.45 (4H, s)

FAB MS (m / e) = 400 [M + 1]

Table 3 below shows examples of synthesizing desired compounds by the method of Example 48 using the compound obtained in Preparation Example 17.

TABLE 3

Example 62: N ⁵ -(4-fluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(4-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

250 mg (0.455 mmol) of the compound obtained in Example 51 were dissolved in 3 ml of dichloromethane, 1 ml of 4N hydrochloric acid (1,4-dioxane) solution was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, 10 ml of water was added thereto, and the solid formed by neutralization with saturated sodium bicarbonate was filtered to obtain 194 mg (0.432 mmol, yield; 95%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.23 (1H, d), 7.64 (1H, d), 7.34 (2H, t), 7.28 (2H, t), 7.01 (1H, s), 6.92 (1H, t), 6.54 (1H, d), 3.40 (2H, s), 3.31 (3H, s), 2.88 (2H, t), 2,50-2.41 (7H, m)

FAB MS (m / e) = 450 [M + 1]

Example 63: 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-4 Preparation of -ylmethyl) -piperazin-1-yl] -2-methoxy-ethanone

The compound obtained in Example 62 was reacted with the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.27 (1H, s), 8.21 (1H, d), 7.61 (1H, d), 7.31 (2H, q), 7.23 (2H, t), 7.08 (1H, s), 6.90 (1H, d), 6.49 (1H, d), 4.04 (2H, s), 3.48 (2H, s), 3.44 (4H, s), 3.37 (3H, s), 3.24 (3H, s), 2.33 (4H, s)

FAB MS (m / e) = 522 [M + 1]

Example 64 cyclopropyl- [4- (2- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- Preparation of 4-ylmethyl) -piperazin-1-yl] -methanone

The compound obtained in Example 62 was reacted with cyclopropylcarboxylic acid by the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.22 (1H, d), 7.36 (2H, t), 7.24 (2H, t), 7.12 (1H, s), 6.95 (1H, d), 6.51 (1H, d), 3.79 (2H, bs), 3.40 (2H, s), 3.37 (2H, bs), 3.30 (3H, s), 2.43 (2H, bs), 2.36 (2H, bs), 1.98-1.94 (1H, m) , 0.73-0.69 (4H, m)

FAB MS (m / e) = 518 [M + 1]

Example 65 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-4 Preparation of -ylmethyl) -piperazin-1-yl] -propan-1-one

The compound obtained in Example 62 was reacted with propionic acid by the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.25 (1H, d), 7.67 (1H, d), 7.37 (2H, t), 7.26 (2H, t), 7.11 (1H, s), 6.69 (1H, d), 6.51 (1H, d), 3.50 (2H, s), 3.46 (4H, bs), 3.32 (3H, s), 2.39 (2H, bs), 2,34-2.27 (4H, m), 0.97 (3H, t)

FAB MS (m / e) = 506 [M + 1]

Preparation Example 18 N ² -(5-chloromethyl-pyridin-2-yl) -N ⁵ -(4-fluoro-phenyl) -N ⁵ -Methyl-thiazolo [ 5,4-b] pyridine -2,5- Diamine  Produce

In Production Example 7 N ⁵ - (4-fluoro-phenyl) ^{-N-methyl-5-phenyl-thiazolo} [5,4-b] pyridine-2,5-diamine instead of N ⁵ -methyl -N ⁵ thiazolo The target compound was obtained by using [5,4-b] pyridine-2,5-diamine and reacting by the method of Preparation Example 7 using the compound obtained in Preparation Example 13 instead of the compound obtained in Preparation Example 6.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.45 (1 H, s). 8.01 (1H, s), 7.85 (1H, d), 7.64 (1H, bs), 7.23 (2H, m), 7.16 (2H, t), 6.52 (1H, d), 4.61 (2H, s), 3.49 (3H, s)

FAB MS (m / e) = 400 [M + 1]

Example 66: N ⁵ -(4-fluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 18 was reacted with morpholine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.12 (1H, bs), 8.26 (1H, s), 7.57 (1H, d), 7.55 (1H, d), 7.23 (2H, m), 7.09 (2H, t), 6.97 (1H, d), 6.49 (1H, d), 3.69 (4H, t), 3.49 (3H, s), 3.43 (2H, s), 2.45 (4H, s)

FAB MS (m / e) = 451 [M + 1]

Table 4 below shows examples of synthesizing desired compounds by the method of Example 66 using the compound obtained in Preparation Example 18.

TABLE 4

Preparation Example 19 N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-thiazolo [ 5,4-b] pyridine -2,5- Diamine  Produce

N ⁵ in Preparative Example ^7-methyl-5 -N-phenyl-thiazolo [5,4-b] pyridine-2,5-diamine instead of N ⁵ -methyl -N ⁵ - (4-fluorophenyl) thiazolo [ 5,4-b] pyridine-2,5-diamine was reacted in the same manner as in Preparation Example 7 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.35 (1H, d), 7.61 (1H, d), 7.20 (1H, m), 7.20 (1H, s), 7.03 (1H, d), 6.96 (2H, m), 6.39 (1H, d), 4.52 (2H, s), 3.45 (3H, s)

FAB MS (m / e) = 418 [M + 1]

Example 77: N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Preparation Example 19 was reacted by the method of Example 3 using morpholine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.19 (1H, bs), 8.27 (1H, d), 7.60 (1H, d), 7.31 (1H, m), 6.91 (4H, m), 6.35 (1H, d), 3.69 (4H, t), 3.45 (5H, s), 2.44 (4H, s)

FAB MS (m / e) = 469 [M + 1]

Example 78: N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-[4- (4-Methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5,4-b] pyridine-2,5-diamine

In Example 77, 1-methylpiperazine was used instead of morpholine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.09 (1H, bs), 8.26 (1H, d), 7.60 (1H, d), 7.31 (1H, m), 6.90 (4H, m), 6.36 (1H, d), 3.46 (2H, s), 3.45 (3H, s), 2.61 (4H, s), 2.48 (4H, bs), 2.28 (3H, s)

FAB MS (m / e) = 482 [M + 1]

Example 79: 1- [4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino}- Preparation of Pyridin-4-ylmethyl) -piperazin-1-yl] -ethanone

In Example 77, 1-acetylpiperazine was used instead of morpholine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.09 (1H, bs), 8.28 (1H, d), 7.61 (1H, d), 7.31 (1H, m), 6.93 (3H, m), 6.90 (1H, d), 6.35 (1H, d), 3.61 (2H, t), 3.47 (2H, s), 3.45 (3H, s), 3.42 (2H, t), 2.42 (4H, s), 2.08 (3H, s)

FAB MS (m / e) = 510 [M + 1]

Example 80: 4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazole [5,4-b] pyridin-2-ylamino} -pyridine-4 Preparation of -ylmethyl) -piperazine-1-carboxylic Acid Dimethylamide

In Example 77, 1- (dimethylamino) carbonylpiperazine was used instead of morpholine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.27 (1H, s), 8.19 (1H, s), 7.65 (1H, d), 7.49 (1H, q), 7.39 (1H, t), 7.16 (1H, t), 7.08 (1H, s), 6.89 (1H, d), 6.39 (1H, d), 3.46 (2H, s), 3.10 (4H, s), 2.69 (6H, s), 2.51 (3H, s), 2.36 (4H, s)

FAB MS (m / e) = 539 [M + 1]

Preparation Example 20 N ² -(5-chloromethyl-pyridin-2-yl) -N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-thiazolo [ 5,4-b] pyridine -2,5- Diamine  Produce

N ⁵ in Preparative Example ^7-methyl-5 -N-phenyl-thiazolo [5,4-b] pyridine-2,5-diamine instead of N ⁵ -methyl -N ⁵ - (2,4-difluoro-phenyl) Using the thiazolo [5,4-b] pyridine-2,5-diamine and the compound obtained in Preparation Example 13 instead of the compound obtained in Preparation Example 6, the reaction was carried out in the same manner as in Preparation Example 7 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.38 (1H, s), 7.73 (1H, d), 7.59 (1H, d), 7.29 (1H, m), 7.17 (1H, d), 6.95 (2H, m), 6.39 (1H, d), 4.59 (2H, s), 3.45 (3H, s)

FAB MS (m / e) = 418 [M + 1]

Example 81: N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The target compound was obtained by reacting the compound obtained in Production Example 20 with morpholine by the method of Example 3.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.18 (1H, bs), 8.26 (1H, s), 7.59 (2H, t), 7.30 (1H, m), 6.94 (3H, t), 6.36 (1H, d), 3.70 (4H, s), 3.45 (5H, s), 2.45 (4H, s)

FAB MS (m / e) = 469 [M + 1]

Table 5 below shows examples of synthesizing desired compounds by the method of Example 81 using the compound obtained in Preparation Example 20.

TABLE 5

Example 93: 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-3 Preparation of -ylmethyl) -piperidine-4-carboxylic acid

The compound obtained in Example 92 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.02 (1H, bs), 7.44 (3H, bs), 7.24 (1H, bs), 7.07 (1H, bs), 6.92 (1H, bs), 6.30 (1H, bs), 3.27 (9H, bs), 2.69 (2H, bs), 1.83 (2H, t), 1.47 (2H, bs)

FAB MS (m / e) = 511 [M + 1]

Example 94: 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-3 Preparation of -ylmethyl) -pyrrolidine-2-carboxylic acid

The compound obtained in Example 89 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.56 (1H, s), 8.24 (1H, s), 7.66 (1H, d), 7.58 (1H, d), 7.32-7.28 (2H, m), 6.94-6.91 (3H, m), 6.37 (1H) , d), 3.83 (1H, d), 3.52 (1H, d), 3.45 (3H, s), 3.25 (1H, t), 3.07-3.04 (1H, m), 2.41-2.39 (1H, m), 2.19-2.15 (1H, m), 1.98-1.82 (2H, m)

FAB MS (m / e) = 497 [M + 1]

Preparation 21: 4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl army No} -pyridine-3- Methyl ) -Piperazine-1- Carboxylic acid tert Of butyl ester Produce

The target compound was obtained by reacting the compound obtained in Preparation Example 20 with N-butoxycarbonylpiperazine by the method of Example 81.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.24 (1H, s), 7.59 (2H, d), 7.30 (1H, q), 6.93 (3H, m), 6.33 (1H, d), 3.45 (5H, s), 2.87 (4H, s), 2.41 (4H, s), 1.54 (9H, s)

FAB MS (m / e) = 568 [M + 1]

Example 95: N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(5-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

400 mg (0.705 mmol) of the compound obtained in Preparation Example 21 were reacted by the method of Example 62, to obtain 306 mg (0.656 mmol, yield; 93%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.25 (1H, s), 7.59 (2H, d), 7.31 (1H, q), 6.94 (3H, m), 6.35 (1H, d), 3.45 (5H, s), 2.87 (4H, s), 2.41 (4H, s)

FAB MS (m / e) = 468 [M + 1]

Preparation Example 22 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -nicotinic acid methyl  Preparation of ester

N ⁵ -Methyl-N ^5- (2,4-difluorophenyl) -thiazolo [5,4-b] pyridine-2,5-diamine by the method of Example 1 with methyl 6-chloronicotinate Reaction gave the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 7.83 (1H, d), 7.78 (1H, d), 7.56-7.53 (1H, m), 7.45-7.40 (1H, m), 7.21-7.17 (2H, m), 6.45 (1H, d), 3.67 (3H, s), 3.32 (3H, s)

FAB MS (m / e) = 428 [M + 1]

Preparation Example 23 Preparation of 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -nicotinic acid

The compound obtained in Preparation Example 22 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 7.83 (1H, d), 7.78 (1H, d), 7.56-7.53 (1H, m), 7.45-7.40 (1H, m), 7.21-7.17 (2H, m), 6.45 (1H, d), 3.32 (3H, s)

FAB MS (m / e) = 414 [M + 1]

Example 96: (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Preparation of) -morpholin-4-yl-methanone

The target compound was obtained by reacting the compound obtained in Preparation Example 23 with the method of Example 18 using morpholine.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.40 (1H, d), 7.84 (1H, d), 7.77 (1H, d), 7.56-7.53 (1H, m), 7.45-7.40 (1H, m), 7.21-7.17 (2H, m), 6.47 (1H, d), 3.63 (4H, bs), 3.32 (3H, s), 3.25 (4H, bs)

FAB MS (m / e) = 483 [M + 1]

Table 6 below shows examples of synthesizing desired compounds by the method of Example 96 using the compound obtained in Preparation Example 23.

TABLE 6

Example 106 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N-piperidine- Preparation of 4-yl-nicotinamide

The compound obtained in Example 104 was reacted by the method of Example 62 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.08 (1H, s), 8.31 (1H, d), 8.14 (1H, d), 7.74 (2H, d), 7.56-7.53 (1H, m), 7.45-7.41 (1H , m), 7.23-7.16 (2H, m), 6.47 (1H, d), 3.82-3.79 (2H, m), 3.31 (3H, s), 2.83 (2H, d), 2.03 (2H, t), 1.81-1.78 (2H, m), 1.64-1.56 (2H, m)

FAB MS (m / e) = 496 [M + 1]

Example 107: (4-Amino-piperidin-1-yl)-(6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b ] Preparation of Pyridin-2-ylamino} -pyridin-3-yl) -methanone

The compound obtained in Example 105 was reacted by the method of Example 62 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.37 (1H, s), 7.81 (1H, d), 7.72 (1H, d), 7.57-7.53 (1H, m), 7.46-7.43 (1H, m), 7.23-7.19 (2H, m), 6.43 (1H, d), 3.81-3.82 (1H, m), 3.32 (3H, s), 2.98-2.85 (4H, m), 1.82-1.80 (2H, m), 1.46-1.39 (2H, m)

FAB MS (m / e) = 496 [M + 1]

Example 108: 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (1-methyl Preparation of -piperidin-4-yl) -nicotinamide

25 mg (0.050 mmol) of the compound obtained in Example 106 was dissolved in 1 ml of methanol and 2 ml of N, N-dimethylformamide, followed by 0.019 ml (0.25 mmol) of formalin and 53 mg (0.25 mmol) of sodium triacetoxyborohydride. Was added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, 10 ml of water was added, 20 ml of ethyl acetate was extracted twice, and concentrated again, and then separated by column chromatography to obtain 20 mg (0.039 mmol, yield; 79%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.80 (1H, s), 8.32 (1H, d), 8.15 (1H, d), 7.77 (1H, d), 7.57-7.51 (1H, m), 7.45-7.40 (1H , m), 7.23-7.16 (2H, m), 6.47 (1H, d), 3.19-3.14 (1H, m), 2.83 (2H, d), 2.21 (3H, s), 2.01 (2H, t), 1.81-1.56 (4H, m)

FAB MS (m / e) = 510 [M + 1]

Example 109: (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Preparation of)-(4-dimethylamino-piperidin-1-yl) -methanone

The compound obtained in Example 107 was reacted by the method of Example 108 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.38 (1H, s), 7.82 (1H, d), 7.73 (1H, d), 7.57-7.53 (1H, m), 7.46-7.43 (1H, m), 7.23-7.19 (2H, m), 6.45 (1H, d), 3.81-3.82 (1H, m), 3.32 (3H, s), 2.98-2.85 (4H, m), 2.27 (6H, s), 1.82-1.80 (2H , m), 1.46-1.39 (2H, m)

FAB MS (m / e) = 524 [M + 1]

Preparation Example 24 N ⁵ -(4-chloro-2-fluoro-phenyl) -N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -Methyl-tee Azolo [5,4-b] pyridine -2,5- Diamine  Produce

N ⁵ -methyl-N ⁵ -phenyl-thiazolo [5,4-b] pyridine-2,5-diamine in Preparation Example 7 instead of N ⁵ -methyl-N ^5- (4-chloro-2-fluoro) phenyl -Tiazolo [5,4-b] pyridine-2,5-diamine was reacted by the method of Preparation Example 7 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.26 (1H, s), 8.24 (1H, d), 7.73 (1H, d), 7.54- 7.46 (2H, m), 7.35 (1H, d), 7.10 (1H, s), 6.94 (1H, d ), 6.54 (1H, d), 3.53 (2H, s), 3.37 (3H, s)

FAB MS (m / e) = 434 [M + 1]

Example 110: N ⁵ -(4-chloro-2-fluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-(4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 24 was reacted with morpholine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.25 (1H, d), 7.74 (1H, d), 7.60 (1H, d), 7.52 (1H, t), 7.38 (1H, d), 7.13 (1H, s), 6.96 (1H, d), 6.55 (1H, d), 3.62 (4H, bs), 3.49 (2H, s), 3.31 (3H, s), 2.40 (4H, bs)

FAB MS (m / e) = 485 [M + 1]

Example 111 N ⁵ -(4-chloro-2-fluoro-phenyl) -N ⁵ -Methyl-N ² Preparation of-[4- (4-Methyl-pyrerazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 24 was reacted with 1-methylpiperazine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.24 (1H, d), 7.74 (1H, d), 7.60 (1H, d), 7.52 (1H, t), 7.38 (1H, d), 7.13 (1H, s), 6.96 (1H, d), 6.55 (1H, d), 3.50 (2H, s), 3.42 (4H, bs), 3.37 (3H, s), 2.45 (4H, bs), 2.19 (3H, s)

FAB MS (m / e) = 498 [M + 1]

Example 112: 1- [4- (2- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} Preparation of Pyridin-4-ylmethyl) -piperazin-1-yl] -ethanone

The compound obtained in Production Example 24 was reacted with 1-tetylpiperazine with the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.27 (1H, s), 8.25 (1H, d), 7.74 (1H, d), 7.54- 7.46 (2H, m), 7.36 (1H, d), 7.11 (1H, s), 6.95 (1H, d ), 6.54 (1H, d), 3.51 (2H, s), 3.46 (4H, bs), 3.37 (3H, s), 2.40 (2H, bs), 2.34 (2H, bs), 2.00 (3H, s)

FAB MS (m / e) = 526 [M + 1]

Preparation Example 25 N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -(4-chloro-phenyl) -N ⁵ Preparation of -methyl-thiazolo [5,4-b] pyridine-2,5-diamine

In Production Example 7 N ^5-methyl-5 -N-phenyl-thiazolo [5,4-b] pyridine-2,5-diamine instead of N ⁵ - methyl -N ⁵ - (4- chlorophenyl) thiazolo [5, , 4-b] pyridine-2,5-diamine was reacted by the method of Preparation Example 7 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.21 (1H, d), 7.72 (1H, d), 7.44 (2H, d), 7.32 (2H, d), 7.11 (1H, s), 6.94 (1H, d), 6.72 (1H, d), 3.51 (2H, s), 3.31 (3H, s)

FAB MS (m / e) = 416 [M + 1]

Example 113: N ⁵ -(4-chlorophenyl) -N ⁵ -Methyl-N ² Preparation of-(4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Preparation Example 25 was reacted with morpholine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.26 (1H, d), 7.72 (1H, d), 7.46 (2H, d), 7.34 (2H, d), 7.12 (1H, s), 6.95 (1H, d), 6.74 (1H, d), 3.51 (2H, s), 3.40 (3H, s), 3.29 (4H, bs), 2.61 (4H, bs)

FAB MS (m / e) = 467 [M + 1]

Example 114: N ⁵ -(4-chloro-phenyl) -N ⁵ -Methyl-N ² Preparation of-[4- (4-Methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 25 was reacted with 1-methylpiperazine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.26 (1H, d), 7.73 (1H, d), 7.46 (2H, d), 7.34 (2H, d), 7.14 (1H, s), 6.97 (1H, d), 6.74 (1H, d), 3.63 (4H, bs), 3.42 (2H, s), 3.31 (3H, s), 2.62 (3H, s), 2.41 (4H, bs)

FAB MS (m / e) = 480 [M + 1]

Example 115: 1- [4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-4- Preparation of Ilmethyl) -piperazin-1-yl] -ethanone

The compound obtained in Production Example 25 was reacted with 1-acetylpiperazine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.35 (1H, s), 8.21 (1H, d), 7.73 (1H, d), 7.43 (2H, d), 7.34 (2H, d), 7.13 (1H, s), 6.96 (1H, d), 6.72 (1H, d), 3.52 (2H, s), 3.50-3.46 (4H, m), 3.31 (3H, s), 2.42 (2H, bs), 2.35 (2H, bs), 2.05 (3H, s)

FAB MS (m / e) = 508 [M + 1]

Example 116 4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) Preparation of Piperazine-1-carboxylic Acid Dimethylamide

The compound obtained in Production Example 25 was reacted with 1- (dithylaminocarbonyl) perazine with the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.22 (1H, d), 7.72 (1H, d), 7.43 (2H, d), 7.32 (2H, d), 7.11 (1H, s), 6.94 (1H, d), 6.72 (1H, d), 3.52 (2H, s), 3.50-3.46 (4H, m), 3.32 (3H, s), 2.65 (6H, s), 2.41 (2H, bs), 2.32 (2H, bs)

FAB MS (m / e) = 537 [M + 1]

Preparation Example 26 N ² -(4-chloromethyl-pyridin-2-yl) -N ⁵ -(3,4-difluoro-phenyl) -N ⁵ -Methyl-thiazolo [ 5,4-b] pyridine -2,5- Diamine  Produce

Phenyl -N ⁵ --methyl-thiazol [5,4-b] pyridine-2,5-diamine instead of N ⁵ - (3,4- difluorophenyl) -N ⁵ - ^N-methyl-5 in Preparative Example 7 It reacted by the method of manufacture example 7 using thiazole [5, 4-b] pyridine-2, 5- diamine, and obtained the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.33 (1H, s), 8.21 (1H, s), 7.68 (1H, d), 7.42-7.38 (2H, m), 7.12-7.09 (2H, m), 6.91 (1H, d), 6.61 (1H , d), 3.53 (2H, s), 3.42 (3H, s)

FAB MS (m / e) = 418 [M + 1]

Example 117: 1- [4- (2- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino}- Preparation of Pyridin-4-ylmethyl) -piperazin-1-yl] -ethanone

The compound obtained in Production Example 26 was reacted with 1-acetylferrazine in the method of Example 3 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.33 (1H, s), 8.22 (1H, s), 7.69 (1H, d), 7.42-7.38 (2H, m), 7.12-7.09 (2H, m), 6.90 (1H, d), 6.69 (1H , d), 3.48 (2H, s), 3.42 (3H, s), 3.29 (4H, bs), 2.37 (2H, bs), 2.30 (2H, bs), 1.95 (3H, s)

FAB MS (m / e) = 510 [M + 1]

Example 118: Preparation of 6- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -nicotinic acid methyl ester

Example 1 using N ^5- (3,4-difluorophenyl) -N ⁵ -methyl-thiazolo [5,4-b] pyridine-2,5-diamine and methyl 6-chloronicotinate Reaction was carried out to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.21 (1H, s), 7.68 (1H, d), 7.42-7.38 (2H, m), 7.12-7.09 (2H, m), 6.90 (1H, d), 6.69 (1H , d), 3.67 (3H, s), 3.35 (3H, s)

FAB MS (m / e) = 428 [M + 1]

Preparation Example 27 N ² -(6-chloro-pyrimidin-4-yl) -N ⁵ -(2,4-difluoro-phenyl) -N ⁵ -Methyl-thiazolo- [5,4-b] pyridine-2,5- Diamine  Produce

Example 1 using N ^5- (2,4-difluorophenyl) -N ⁵ -methyl-thiazole [5,4-b] pyridine-2,5-diamine and 4,6-dichloropyrimidine Reaction was carried out to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 10.4 (1H, bs), 8.41 (1H, s), 7.63 (1H, d), 7.31 (1H, m), 6.99 (2H, m), 6.34 (1H, d), 6.17 (1H, s), 3.45 (3H, s)

FAB MS (m / e) = 405 [M + 1]

Example 119: [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine Preparation of -4-yl) -piperazin-1-yl] -acetic acid ethyl ester

80 mg (0.198 mmol) of the compound obtained in Preparation Example 27 was dissolved in 5 ml of 1,4-dioxane, and 170 mg (0.990 mmol) of 1- (ethoxycarbonylmethyl) piperazine was added thereto, followed by stirring at reflux for 4 hours. After completion of the reaction, 50 ml of water was added to the resulting solid, which was filtered and dried to obtain 98 mg (0.182 mmol, yield; 92%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ10.4 (1H, bs), 8.42 (1H, s), 7.64 (1H, d), 7.30 (1H, m), 6.99 (2H, m), 6.34 (1H, d), 6.17 (1H, s) , 4.20 (2H, m), 3.60 (4H, m), 3.45 (3H, s), 3.23 (2H, s), 2.60 (6H, m), 1.27 (3H, m)

FAB MS (m / e) = 541 [M + 1]

Example 120: 2- [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino}- Preparation of Pyrimidin-4-yl) -piperazin-1-yl] -ethanol

80 mg (0.148 mmol) of the compound obtained in Example 119 was dissolved in 20 ml of anhydrous tetrahydrofuran, cooled to −40 ° C., and 0.15 ml of 1N lithium aluminum hydride solution was added dropwise for 10 minutes. After 30 minutes of further stirring, the temperature was raised to 0 ° C., and 1N caustic soda solution was added to the resulting solid and filtered through Celite. The filtered solution was concentrated and separated by tube chromatography to give 64 mg (0.129 mmol, yield; 87%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 10.3 (1H, bs), 8.43 (1H, s), 7.64 (1H, d), 7.32 (1H, m), 6.98 (2H, m), 6.34 (1H, d), 6.19 (1H, s), 3.67 (2H, m), 3.56 (4H, m), 3.45 (3H, s), 2.60 (2H, m), 2.55 (4H, m)

FAB MS (m / e) = 499 [M + 1]

Table 7 below is an example in which the compound obtained in Preparation 27 was reacted by the method of Example 119 to synthesize predetermined target compounds.

TABLE 7

Example 126: 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine- Preparation of 2-one

The compound obtained in Production Example 10 was reacted by the method of Example 3, to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.29 (1H, bs), 7.52 (1H, d), 7.20 (4H, m), 7.01 (1H, s), 6.91 (1H, d), 6.55 (1H, d), 6.05 (1H, s), 3.56 (2H, s), 3.49 (3H, s), 3.37 (2H, m), 3.20 (2H, s), 2.65 (2H, m), 2.37 (3H, s)

FAB MS (m / e) = 460 [M + 1]

Table 8 below is an example in which the compound obtained in Preparation Example 10 was reacted by the method of Example 3 to synthesize predetermined target compounds.

TABLE 8

Example 151: 1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine 4-one oxime

100 mg (0.218 mmol) of the compound obtained in Example 130 was dissolved in 10 ml of ethanol, and 18 mg (0.30 mmol) of hydroxylamine and 26 mg (0.3 mmol) of potassium acetate were added and refluxed for 4 hours. After completion of the reaction, it was concentrated, 20 ml of water was added, and 20 ml of ethyl acetate was extracted twice and concentrated. Separation by column chromatography gave 87 mg (0.183 mmol, yield; 84%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.27 (1H, d), 7.51 (1H, d), 7.15-7.21 (4H, m), 6.93 (1H, s), 6.83 (1H, d), 6.53 (1H, d), 3.56 (2H, s ), 3.49 (3H, s), 2.75 (2H, t), 2.61 (4H, q), 2.48 (2H, t), 2.37 (3H, s)

FAB MS (m / e) = 474 [M + 1] ⁺

Example 152: 1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine 4-one O-methyl-oxime

The target compound was obtained in the same manner as in Example 151, except that methoxylamine was used instead of hydroxylamine.

¹ H NMR (CDCl ₃ , ppm); δ 8.27 (1H, d), 7.54 (1H, d), 7.16-7.22 (4H, m), 6.98 (1H, s), 6.91 (1H, d), 6.54 (1H, d), 3.72 (3H, s ), 3.49 (3H, s), 3.48 (2H, s), 2.55 (4H, m), 2.48 (2H, m), 2.37 (3H, s), 2.32 (2H, m)

FAB MS (m / e) = 488 [M + 1] ⁺

Example 153: N ⁵ -Methyl-N ² -(4-pyrazol-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

34 mg (0.505 mmol) of pyrazole was dissolved in 10 ml of tetrahydrofuran and 20 mg (60%, 0.505 mmol) of sodium hydride were added and stirred for 10 minutes. 100 mg (0.252 mmol) of the compound obtained in Preparation Example 10 were added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, 20 ml of water was added, extracted with 20 ml of ethyl acetate, and concentrated. Separation by column chromatography gave 80 mg of the target compound (0.186 mmol, yield; 74%).

¹ H NMR (CDCl ₃ , ppm); δ 8.25 (1H, d), 7.56 (1H, s), 7.50 (1H, d), 7.42 (1H, s), 7.15-7.22 (4H, m), 6.69 (1H, s), 6.65 (1H, d ), 6.53 (1H, d), 6.31 (1H, s), 3.47 (5H, s), 2.37 (3H, s)

FAB MS (m / e) = 428 [M + 1] ⁺

Example 154: 2-hydroxy-1- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4 -Ylmethyl} -piperazin-1-yl) -ethanone

The target compound was obtained by reacting the compound obtained in Example 150 with the method of Example 18 using 1-hydroxyacetic acid.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.21 (1H, d), 7.58 (1H, d), 7.15-7.22 (4H, m), 7.08 (1H, s), 6.90 (1H, d), 6.48 (1H, d), 4.49 (1H, t ), 4.04 (2H, d), 3.47 (4H, d), 3.36 (3H, s), 3.13 (2H, d), 2.46 (4H, s), 2.29 (3H, s)

FAB MS (m / e) = 504 [M + 1] ⁺

Example 155: 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine- 1-carboxylic acid cyclopropylamide

200 mg (0.505 mmol) of the compound obtained in Example 150 were taken up in 20 ml of dichloromethane, and 0.18 ml (1.01 mmol) of N, N-diisopropylethylamine were added and cooled to 0 ° C. Triphosgene 75 mg (0.253 mmol) was added thereto, stirred for 30 minutes, and then 0.14 ml (2.02 mmol) of cyclopropylamine was added thereto, and the mixture was heated to room temperature and stirred for 30 minutes. After completion of the reaction, the mixture was concentrated, 30 ml of water was added thereto, and 30 ml of ethyl acetate was extracted twice, and the organic layer was concentrated. Separation by column chromatography gave 170 mg (0.321 mmol, yield; 64%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.58 (1H, s), 8.27 (1H, d), 7.53 (1H, d), 7.16-7.22 (4H, m), 6.97 (1H, s), 6.90 (1H, d), 6.54 (1H, d ), 4.65 (1H, s), 3.49 (3H, s), 3.47 (2H, s), 3.34 (4H, t), 2.64 (1H, m), 2.42 (4H, m), 2.37 (3H, s) , 0.70 (2H, m), 0.46 (2H, m)

FAB MS (m / e) = 529 [M + 1] ⁺

Preparation Example 28: (S) -1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Methyl }- Pyrrolidine -2- Carboxylic acid methyl  ester

The compound obtained in Production Example 10 and (S) -pyrrolidine-2-carboxylic acid methyl ester were reacted by the method of Example 3 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 9.01 (1H, s), 8.27 (1H, d), 7.54 (1H, d), 7.15-7.22 (4H, m), 6.95 (1H, s), 6.91 (1H, d), 6.54 (1H, d ), 3.89 (1H, d), 3.66 (3H, s), 3.48 (4H, m), 3.29 (1H, m), 3.02 (1H, m), 2.36 (3H, s), 2.13 (1H, m) , 1.97 (1H, m), 1.89 (1H, m), 1.87 (1H, m)

FAB MS (m / e) = 489 [M + 1] ⁺

Example 156: (S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -Pyrrolidine-2-carboxylic acid

The compound obtained in Preparation Example 28 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 7.94 (1H, d), 7.09 (1H, d), 7.00-7.10 (4H, m), 6.58 (1H, s), 6.48 (1H, s), 6.43 (1H, d), 3.98 (1H, d ), 3.29 (3H, s), 3.08 (1H, m), 2.78 (2H, m), 2.24 (3H, s), 2.06 (1H, m), 1.55-1.82 (4H, m)

FAB MS (m / e) = 475 [M + 1] ⁺

Table 9 shows the examples synthesized by hydrolysis by the method of Example 17.

TABLE 9

Example 163: 1-methyl-4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} Piperazine-2-one

145 mg (0.315 mmol) of the compound obtained in Example 126 was dissolved in 10 ml of N, N-dimethylformamide, cooled to 0 ° C., and 14 mg (0.345 mmol) of sodium hydride were added thereto and stirred for 5 minutes. 21 uL (0.345 mmol) of methane iodide was added to the reaction solution, and the mixture was stirred for 1 hour. After completion of the reaction, 1 ml of water was added and concentrated. 20 ml of water were added, extracted twice with 20 ml of ethyl acetate and concentrated. Separation by column chromatography gave 110 mg (0.233 mmol) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.29 (1H, d), 7.53 (1H, d), 7.16-7.22 (4H, m), 6.98 (1H, s), 6.90 (1H, d), 6.54 (1H, d), 3.51 (2H, s ), 3.49 (3H, s), 3.27 (2H, t), 3.18 (2H, s), 2.95 (3H, s), 2.65 (2H, t), 2.37 (3H, s)

FAB MS (m / e) = 474 [M + 1] ⁺

Example 164: (R) -N-methoxy-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine -4-ylmethyl} -amino) -propionamide

The target compound was obtained by reacting the compound obtained in Example 159 with the method of Example 18 using methoxylamine.

¹ H NMR (CDCl ₃ , ppm); δ 9.31 (1H, s), 8.28 (1H, s), 7.54 (1H, d), 7.16-7.22 (4H, m), 7.04 (1H, s), 6.84 (1H, s), 6.54 (1H, d ), 3.75 (5H, s), 3.49 (3H, s), 3.24 (1H, m), 2.34 (3H, s), 1.35 (3H, d)

FAB MS (m / e) = 478 [M + 1] ⁺

Example 165 N-methoxy-2-methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine -4-ylmethyl} -amino) -propionamide

The target compound was obtained by reacting the compound obtained in Example 161 with the method of Example 18 using methoxylamine.

¹ H NMR (CDCl ₃ , ppm); δ 10.69 (1H, s), 9.52 (1H, s), 8.28 (1H, s), 7.54 (1H, d), 7.15-7.21 (4H, m), 7.00 (1H, s), 6.82 (1H, s ), 6.52 (1H, d), 3.70 (3H, s), 3.61 (2H, s), 3.48 (3H, s), 2.36 (3H, s), 1.35 (6H, s)

FAB MS (m / e) = 492 [M + 1] ⁺

Example: 166 N ⁵ -Methyl-N ² -(4-methylaminomethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Production Example 10 was reacted with methylamine in the method of Example 3 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.27 (1H, d), 7.53 (1H, d), 7.16-7.21 (4H, m), 6.96 (1H, s), 6.87 (1H, d), 6.54 (1H, d), 3.75 (2H, s ), 3.49 (3H, s), 2.46 (3H, s), 2.37 (3H, s)

FAB MS (m / e) = 391 [M + 1] ⁺

Example 167: N ² -(4-aminomethyl-pyridin-2-yl) -N ⁵ -Methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

2.5 g (6.31 mmol) of the compound obtained in Preparation Example 10 was dissolved in 20 ml of dimethyl sulfoxide, and then 1.64 g (25.2 mmol) of sodium azide was added thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction, 300 ml of water was added, and the resulting solid was filtered and dried to yield 2.16 g (5.36 mmol) of an intermediate in the form of azide. This intermediate was dissolved in 150 ml of methanol, 300 mg of 10% palladium / carbon was added, and a reduction reaction was carried out in the presence of hydrogen at atmospheric pressure. After completion of the reaction, the solids were filtered through a cellite, the filtrate was concentrated, and 20 ml of diethyl ether and 50 ml of normal hexane were added thereto, followed by stirring for 20 minutes, followed by filtration and drying, to obtain 1.90 g (5.05 mmol, yield; 89) of the target compound. %) Was obtained.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.22 (1H, d), 7.63 (1H, d), 7.16-7.21 (4H, m), 7.11 (1H, s), 6.97 (1H, d), 6.54 (1H, d), 3.74 (2H, s ), 3.41 (3H, s), 2.34 (3H, s)

FAB MS (m / e) = 377 [M + 1] ⁺

Example 168 2-methanesulfonyl-N- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl Methyl} -acetamide

110 mg (0.292 mmol) of the compound obtained in Example 167 was dissolved in 5 ml of dichloromethane, and then 0.13 ml (0.73 mmol) of N, N-diisopropylethylamine was added, and 50 mg (0.321 mmol) of methanesulfonyl-acetyl chloride was added. ) Was added and stirred for 30 minutes. After completion of the reaction, 20 ml of water was added, followed by extraction with 20 ml of dichloromethane. Concentration and separation by column chromatography gave 126 mg (0.254 mmol) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.93 (1H, t), 8.21 (1H, d), 7.58 (1H, d), 7.15-7.22 (4H, m), 6.98 (1H, s), 6.86 (1H, d ), 6.48 (1H, d), 4.30 (2H, d), 4.13 (2H, s), 3.36 (3H, s), 3.10 (3H, s), 2.29 (3H, s)

FAB MS (m / e) = 497 [M + 1] ⁺

Table 10 below shows examples of synthesizing desired compounds by reacting by the method of Example 167 using the compound obtained in Example 167.

TABLE 10

Preparation Example 29 2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Methyl } Cabamo )- Pyrrolidine -One- Carboxylic acid  Thi-butyl ester

250 mg (0.664 mmol) of the compound obtained in Example 167 and pyrrolidin-1,2-dicarboxylic acid 1-tert-butyl ester were reacted by the method of Example 18 to obtain 323 mg (0.564 mmol, Yield: 85%).

¹ H NMR (CDCl ₃ , ppm); δ 8.33 (1H, d), 7.68 (1H, t), 7.56 (1H, d), 7.20-7.26 (4H, m), 6.98 (1H, s), 6.87 (1H, d), 6.58 (1H, d ), 4.50 (2H, s), 3.54 (3H, s), 3.04 (2H, m), 2.41 (3H, s), 1.69-2.31 (2H, m), 1.83 (2H, m), 1.4 (9H, s)

FAB MS (m / e) = 574 [M + 1] ⁺

Example 175 Pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Monomethyl} -amide

Using the compound obtained in Preparation Example 29, the reaction was carried out by the method of Example 62 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.61 (1H, s), 8.30 (1H, d), 7.68 (1H, t), 7.21-7.27 (4H, m), 7.12 (1H, s), 6.69 (1H, d), 6.54 (1H, d ), 4.28 (2H, m), 3.42 (3H, s), 3.32 (2H, m), 2.43 (1H, m), 2.34 (3H, s), 2.03 (1H, m), 1.93 (2H, m)

FAB MS (m / e) = 474 [M + 1] ⁺

Example 176: N ² -[4- (1,1-dioxo-1) ⁶ -Thiomorpholin-4-ylmethyl) -pyridin-2-yl] -N ⁵ -Methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

After dissolving 134 mg (0.355 mmol) of the compound obtained in Example 167 in 20 ml of methanol, 62 uL (0.374 mmol) of divinyl sulfone was added and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated, 30 ml of water was added thereto, and 20 ml of ethyl acetate was extracted twice. Separation by column chromatography gave 147 mg (0.298 mmol, yield; 84%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 9.02 (1H, s), 8.30 (1H, d), 7.54 (1H, d), 7.16-7.22 (4H, m), 7.04 (1H, s), 6.88 (1H, d), 6.55 (1H, d ), 3.62 (2H, s), 3.50 (3H, s), 3.05 (4H, d), 3.00 (4H, d), 2.37 (3H, s)

FAB MS (m / e) = 495 [M + 1] ⁺

Example 177: N -{2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -methanesulfonamide

The target compound was obtained in the same manner as in Example 168, except that methanesulfonyl chloride was used instead of methanesulfonyl-acetyl chloride.

¹ H NMR (CDCl ₃ , ppm); δ 8.29 (1H, s), 7.50 (1H, d), 7.15-7.21 (4H, m), 7.12 (1H, s), 6.89 (1H, d), 6.52 (1H, d), 3.49 (2H, s ), 3.48 (3H, s), 2.98 (3H, s), 2.37 (3H, s)

FAB MS (m / e) = 455 [M + 1] ⁺

Example 178: 1-cyclopropyl-3- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl } -Urea

135 mg (0.359 mmol) of the compound obtained in Example 167 were dissolved in 20 ml of dichloromethane, and 0.13 ml (0.72 mmol) of N, N-diisopropylethylamine was added thereto and cooled to 0 ° C. 53 mg (0.18 mmol) of triphosgene was added to the reaction solution, and the mixture was stirred for 1 hour. 75 uL (1.08 mmol) of cyclopropyl amine was added to the reaction solution, and the mixture was stirred for 1 hour. After completion of the reaction, it was washed with 20 ml of water and the organic layer was concentrated. Isolation by column chromatography gave 124 mg (0.269 mmol, yield; 75%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.27 (1H, d), 7.44 (1H, d), 7.15-7.21 (4H, m), 7.04 (1H, s), 6.81 (1H, d), 6.52 (1H, d), 5.54 (1H, t ), 4.42 (2H, d), 3.48 (3H, s), 2.46 (1H, m), 2.36 (3H, s), 0.76 (2H, m), 0.62 (2H, m)

FAB MS (m / e) = 460 [M + 1] ⁺

Example 179: ( S ) -N-hydroxy-2- (methyl- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl Methyl} -amino) -propionamide

The compound obtained in Example 162 was reacted by the method of Example 164 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.21 (1H, s), 10.44 (1H, s), 8.80 (1H, s), 8.19 (1H, d), 7.58 (1H, d), 7.15-7.22 (4H, m), 7.04 (1H, s ), 6.94 (1H, d), 6.47 (1H, d), 3.46-3.66 (2H, m), 3.36 (3H, s), 3.30 (1H, q), 2.29 (3H, s), 2.12 (3H, s), 1.15 (3H, d)

FAB MS (m / e) = 492 [M + 1] ⁺

Example 180 N, N-dimethyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl } -Acetamide

Reaction was carried out in the same manner as in Example 18 using the compound obtained in Example 20 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.23 (1H, d), 7.63 (1H, d), 7.23 (4H, m), 6.98 (1H, s), 6.84 (1H, d), 6.53 (1H, d), 3.73 (2H, s), 3.03 (3H, s), 2.86 (3H, s), 2.33 (3H, s)

FAB MS (m / e) = 433 [M + 1] ⁺

Example 181 1- (4-acetyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Ylamino] -pyridin-4-yl} -ethanone

Reaction was carried out in the same manner as in Example 18 using the compound obtained in Example 20 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.29 (1H, bs), 8.19 (1H, d), 7.58 (1H, d), 7.19 (4H, m), 6.93 (1H, s), 6.49 (1H, d), 6.48 (1H, d), 3.76 (2H, m), 3.48-3.36 (8H, m), 3.30 (3H, s), 2.29 (3H, s), 1.98 (3H, s)

FAB MS (m / e) = 516 [M + 1] ⁺

Table 11 below shows examples of synthesizing desired compounds by reacting by the method of Example 18 using the compound obtained in Example 20.

TABLE 11

Preparation 30: [(S) -1- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4 -Yl} -acetyl)- Pyrrolidine -3 days]- Carbamic acid tert -Butyl ester

The compound obtained in Example 20 was reacted with (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester by the method of Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.41 (1H, s), 8.42 (1H, br), 8.23 (1H, d), 7.62 (1H, d), 7.22 (2H, d), 7.16 (2H, d), 7.05 (1H, s), 6.90 (1H, d), 6.51 (1H, d), 3.73-3.70 (1H, m), 3.68 (2H, s), 3.52-3.40 (4H, m), 3.37 (3H, s), 2.27 (3H, s), 2.27-1.98 (2H, m), 1.34 (9H, s)

FAB MS (m / e) = 574 [M + 1] ⁺

Example 195 1-((S) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b ] Pyridin-2-ylarmano] -pyridin-4-yl} -ethanone

The compound obtained in Preparation Example 30 was reacted by the method of Example 62, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.34 (1H, s), 8.33 (2H, br), 8.22 (1H, d), 7.65 (1H, d), 7.23 (2H, d), 7.18 (2H, d), 7.06 (1H, s), 6.90 (1H, d), 6.51 (1H, d), 3.73-3.70 (1H, m), 3.68 (2H, s), 3.52-3.40 (4H, m), 3.34 (3H, s), 2.29 (3H, s), 2.27-1.98 (2H, m)

FAB MS (m / e) = 474 [M + 1] ⁺

Preparation 31: [(R) -1- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4 -Yl} -acetyl)- Pyrrolidine -3 days]- Carbamic acid tert -Butyl ester

The compound obtained in Example 20 was reacted with (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester in the same manner as in Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.36 (1H, s), 8.43 (1H, s), 8.23 (1H, d), 7.66 (1H, d), 7.22 (2H, d), 7.18 (2H, d), 7.06 (1H, s), 6.94 (1H, d), 6.52 (1H, d), 3.81-3.74 (1H, m), 3.70 (2H, s), 3.53-3.42 (4H, m), 3.34 (3H, s), 2.28 (3H, s), 2.23-1.92 (2H, m), 1.32 (9H, s)

FAB MS (m / e) = 574 [M + 1] ⁺

Example 196 1-((R) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b ] Pyridin-2-ylarmano] -pyridin-4-yl} -ethanone

The compound obtained in Preparation Example 30 was reacted by the method of Example 62, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.33 (2H, br), 8.22 (1H, d), 7.67 (1H, d), 7.23 (2H, d), 7.18 (2H, d), 7.09 (1H, s), 6.93 (1H, d), 6.52 (1H, d), 3.82-3.75 (1H, m), 3.71 (2H, s), 3.53-3.41 (4H, m), 3.37 (3H, s), 2.29 (3H, s), 2.23-1.87 (2H, m)

FAB MS (m / e) = 474 [M + 1] ⁺

Example 197 N-[(R) -1- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine -4-yl} -acetyl) -pyrrolidin-3-yl] -acetamide

The compound obtained in Example 196 was dissolved in 10 ml of dichloromethane, and cooled to 0 ° C. after adding N, N-diisopropylamine. Acetic anhydride was added thereto, stirred for 30 minutes, washed with water, and the organic layer was concentrated. Separation by column chromatography gave the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.26 (1H, s), 8.19 (1H, s), 8.10 (1H, d), 7.59 (1H, d), 7.19 (2H, d), 7.16 (2H, d), 6.94 (1H, s), 6.80 (1H, d), 6.47 (1H, d), 4.23-4.15 (1H, m), 3.61 (2H, s), 3.58-3.41 (2H, m), 3.32 (3H, s), 3.20-3.11 ( 2H, m), 2.28 (3H, s), 2.05-1.97 (1H, m), 1.79 (3H, s), 1.76-1.69 (1H, m)

FAB MS (m / e) = 516 [M + 1] ⁺

Preparation 32: 2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -isonicotinic acid methyl  ester

N ⁵ -methyl-N ^5- (4-methylphenyl) -thiazolo [5,4-b] pyridine-2,5-diamine was reacted with methyl 2-chloroisonicotinate by the method of Example 1 to obtain the target compound. Got it.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.10 (1H, d), 7.60 (1H, d), 7.17 (2H, d), 7.14 (2H, d), 6.93 (1H, s), 6.80 (1H, d), 6.47 (1H, d), 3.92 (3H, s), 3.34 (3H, s), 2.29 (3H, s)

FAB MS (m / e) = 406 [M + 1] ⁺

Production Example  33: 2- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2- Monoamino ]- Isoni Cortinic acid

The compound obtained in Preparation Example 32 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 13.57 (1H, s), 11.27 (1H, s), 8.11 (1H, d), 7.61 (1H, d), 7.16 (2H, d), 7.14 (2H, d), 6.92 (1H, s), 6.81 (1H, d), 6.46 (1H, d), 3.32 (3H, s), 2.28 (3H, s)

FAB MS (m / e) = 392 [M + 1] ⁺

Table 12 below shows examples of synthesizing desired compounds by reacting by the method of Example 18 using the compound obtained in Preparation Example 33.

TABLE 12

Preparation 34: (1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine-4-carbonyl} -piperi Din-4-yl)- Carbamic acid tert -Butyl ester

The compound obtained in Preparation Example 33 was reacted with piperidin-4-yl-carbamic acid tert-butyl ester in the same manner as in Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.42 (1H, d), 8.34 (1H, s), 7.68 (1H, d), 7.26 (2H, d), 7.22 (2H, d), 7.11 (1H, s), 6.94 (1H, d), 6.55 (1H, d), 4.60-4.49 (2H, m), 3.57-3.50 (1H, m), 3.42 (3H, s), 3.38-3.31 (1H, m), 3.15- 2.91 (1H, m), 2.33 (3H, s), 2.03 (1H, m), 1.92 (1H, m), 1.60-1.42 (2H, m), 1.38 (9H, s)

FAB MS (m / e) = 574 [M + 1] ⁺

Example 206: (4-Amino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -Pyridin-4-yl} -methanone

The compound obtained in Preparation Example 34 was reacted by the method of Example 62, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.33 (1H, s), 8.42 (1H, d), 8.14 (2H, br), 7.69 (1H, d), 7.27 (2H, d), 7.22 (2H, d), 7.12 (1H, s), 6.94 (1H, d), 6.55 (1H, d), 4.60-4.49 (2H, m), 3.57-3.50 (1H, m), 3.41 (3H, s), 3.38-3.31 (1H, m), 3.15- 2.91 (1H, m), 2.34 (3H, s), 2.03 (1H, m), 1.92 (1H, m), 1.60-1.42 (2H, m)

FAB MS (m / e) = 474 [M + 1] ⁺

Example 207: (4-Dimethylamino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -methanone

97 mg (0.205 mmol) of the compound obtained in Example 206 were dissolved in 20 ml of dichloroethane, formalin 61 uL (0.819 mmol) was added thereto, and stirred at room temperature for 5 minutes, followed by 174 mg (0.819 mmol) of sodium triacetoxyborohydride. It was added and stirred at room temperature for 4 hours. After completion of the reaction, 20 ml of dichloromethane was added, washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution, and the organic layer was concentrated. Separation by column chromatography gave 90 mg (0.178 mmol, yield; 87%) of the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.39 (1H, d), 7.67 (1H, d), 7.27 (2H, d), 7.22 (2H, d), 7.10 (1H, s), 6.97 (1H, d), 6.55 (1H, d), 4.42 (2H, m), 3.50 (1H, m), 3.42 (3H, s), 3.05-2.84 (1H, m), 2.42 (1H, m), 2.34 (3H, s) , 2.22 (6H, s), 2.03 (1H, m), 1.92 (1H, m), 1.60-1.42 (2H, m)

FAB MS (m / e) = 502 [M + 1] ⁺

Preparation 35: ((S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine-4-carbonyl }- Pyrrolidine -3 days)- Carbamic acid tert -Butyl ester

The compound obtained in Preparation Example 33 was reacted with (S) -pyrrolidin-3-yl-carbamic acid tert-butyl ester in the same manner as in Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.47 (1H, s), 8.36 (1H, d), 7.69 (1H, d), 7.27 (2H, d), 7.21 (2H, d), 7.09 (1H, s), 6.93 (1H, d), 6.52 (1H, d), 3.82 (1H, m), 3.64-3.54 (2H, m), 3.36 (3H, s), 2.27 (3H, s), 2.21-2.13 (2H, m), 2.08-1.99 (2H, m), 1.34 (9H, s)

FAB MS (m / e) = 560 [M + 1] ⁺

Example 208: ((S) -3-Amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-ylamino] -pyridin-4-yl} -methanone

The compound obtained in Preparation Example 35 was reacted by the method of Example 62, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.33 (1H, s), 8.38 (1H, d), 8.15 (2H, br), 7.66 (1H, d), 7.27 (2H, d), 7.22 (2H, d), 7.11 (1H, s), 6.96 (1H, d), 6.54 (1H, d), 3.83 (1H, m), 3.64-3.56 (2H, m), 3.34 (3H, s), 2.28 (3H, s), 2.21-2.13 (2H, m), 2.08-1.99 (2H, m)

FAB MS (m / e) = 460 [M + 1] ⁺

Example 209: N-((S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Carbonyl} -pyrrolidin-3-yl) -acetamide

85 mg (0.185 mmol) of the compound obtained in Example 208 were dissolved in 10 ml of dichloromethane, and 80 uL (0.370 mmol) of N, N-diisopropylethylamine was added and cooled to 0 ° C. 17.5 uL (0.185 mmol) of acetic anhydride was added to the reaction solution, and the mixture was stirred for 1 hour. After completion of the reaction, washed with 10 ml of water and concentrated the organic layer. Separation by column chromatography gave 81 mg (0.161 mmol, yield; 87%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.40 (1H, s), 8.31 (1H, d), 7.67 (1H, d), 7.27 (2H, d), 7.21 (2H, d), 7.11 (1H, s), 6.96 (1H, d), 6.54 (1H, d), 3.83 (1H, m), 3.64-3.56 (2H, m), 3.37 (3H, s), 2.29 (3H, s), 2.21-2.13 (2H, m), 2.08-1.99 (2H, m), 1.89 (3H, s)

FAB MS (m / e) = 502 [M + 1] ⁺

Preparation 36: ((R) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine-4-carbonyl }- Pyrrolidine -3 days)- Carbamic acid tert -Butyl ester

The compound obtained in Production Example 33 was reacted with the (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester in the same manner as in Example 18 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.30 (1H, s), 8.61 (1H, s), 8.32 (1H, d), 7.65 (1H, d), 7.26 (2H, d), 7.20 (2H, d), 7.10 (1H, s), 6.96 (1H, d), 6.54 (1H, d), 3.82 (1H, m), 3.62-3.56 (2H, m), 3.37 (3H, s), 2.29 (3H, s), 2.21-2.13 (2H, m), 2.08-1.99 (2H, m), 1.82 (9H, s)

FAB MS (m / e) = 560 [M + 1] ⁺

Example 210: ((R) -3-amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Ylamino] -pyridin-4-yl} -methanone

The compound obtained in Preparation Example 36 was reacted by the method of Example 62, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); 11.27 (1H, s), 8.31 (1H, d), 8.29 (2H, br), 7.65 (1H, d), 7.27 (2H, d), 7.21 (2H, d), 7.12 (1H, s), 6.95 (1H, d), 6.52 (1H, d), 3.81 (1H, m), 3.62-3.57 (2H, m), 3.34 (3H, s), 2.27 (3H, s), 2.21-2.13 (2H, m ), 2.09-1.98 (2H, m)

FAB MS (m / e) = 460 [M + 1] ⁺

Example 211: N-((R) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Carbonyl} -pyrrolidin-3-yl) -acetamide

The compound obtained in Example 210 was reacted by the method of Example 209 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.34 (1H, s), 8.51 (1H, d), 8.32 (1H, s), 7.66 (1H, d), 7.28 (2H, d), 7.23 (2H, d), 7.11 (1H, s), 6.94 (1H, d), 6.51 (1H, d), 3.81 (1H, m), 3.63-3.56 (2H, m), 3.37 (3H, s), 2.29 (3H, s), 2.21-2.13 (2H, m), 2.11-1.99 (2H, m), 1.83 (3H, s)

FAB MS (m / e) = 502 [M + 1] ⁺

Example 212: 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -ethanol

The compound obtained in Example 19 was reacted by the method of Preparation Example 2 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 9.11 (1H, s), 8.26 (1H, d), 7.53 (1H, d), 7.16-7.22 (4H, m), 6.88 (1H, s), 6.81 (1H, d), 6.55 (1H, d ), 3.89 (2H, t), 3.49 (3H, s), 2.82 (2H, t), 2.37 (3H, s)

FAB MS (m / e) = 392 [M + 1] ⁺

Example 213: 1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl } -Ethyl) -piperazin-1-yl] -ethanone

150 mg (0.383 mmol) of the compound obtained in Example 212 are dissolved with 10 ml of dichloromethane, and 2.17 g (0.766 mmol, 15 wt% dichloromethane solution) of Dess-Martin reagent is added thereto. Stir for 2 hours at room temperature and add 5 ml of saturated aqueous sodium thiosulfate solution. Concentrate by extracting twice with 20 ml with dichloromethane. The obtained aldehyde was dissolved using 15 ml of dichloroethane, 98 mg (0.766 mmol) of acetylpiperazine and 162 mg (0.766 mmol) of sodium triacetoxyborohydride were added thereto, stirred at room temperature for 12 hours, and the reaction was terminated with methanol. do. After completion of the reaction, extracted with 30 ml of dichloromethane and concentrated. Separation by column chromatography gave 129 mg (0.257 mmol, yield; 67%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.95 (1H, s), 8.24 (1H, d), 7.53 (1H, d), 7.16-7.22 (4H, m), 6.85 (1H, s), 6.77 (1H, d), 6.54 (1H, d ), 3.62 (2H, m), 3.49 (3H, s), 3.44 (2H, m), 2.63 (2H, t), 2.61 (2H, t), 2.45 (4H, m), 2.37 (3H, s) , 2.09 (3H, s)

FAB MS (m / e) = 502 [M + 1] ⁺

Example 214: 4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -ethyl ) -Piperazine-2-one

In Example 213, the reaction was performed in the same manner using piperazine-2-one instead of N-acetylpiperazine to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 10.23 (1H, s), 8.22 (1H, d), 7.44 (1H, d), 7.15-7.20 (4H, m), 6.89 (1H, s), 6.74 (1H, d), 6.52 (1H, d ), 3.48 (3H, s), 3.33 (2H, t), 3.24 (2H, s), 2.72-2.78 (4H, m), 2.66 (2H, t), 2.36 (3H, s)

FAB MS (m / e) = 475 [M + 1] ⁺

Example 215: N ⁵ -Methyl-N ² -{4- [2- (4-Methyl-piperazin-1-yl) -ethyl] -pyridin-2-yl} -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

110 mg (0.226 mmol) of the compound obtained in Example 21 were dissolved in 20 ml of anhydrous tetrahydrofuran, 34 mg (0.902 mmol) of lithium aluminum hydride was added thereto, and the mixture was stirred under reflux for 6 hours. After completion of the reaction, the mixture was cooled to 0 ° C., 0.3 ml of water, 0.3 ml of 15% aqueous sodium hydroxide solution, and 0.9 ml of water were added thereto, and the mixture was slowly added thereto and stirred for 20 minutes. The solid was removed by filtration through celite, and the filtrate was concentrated and separated by column chromatography to obtain 65 mg (0.138 mmol, yield; 61%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.41 (1H, s), 8.23 (1H, d), 7.54 (1H, d), 7.15-7.20 (4H, m), 6.78 (1H, s), 6.74 (1H, d), 6.55 (1H, d ), 3.50 (3H, s), 2.54 (2H, t), 2.36 (3H, s), 2.28 (2H, t), 2.25 (3H, s), 2.24-2.62 (8H, m)

FAB MS (m / e) = 474 [M + 1] ⁺

Table 13 below shows examples of synthesizing desired compounds by reacting by the method of Example 215 using the compound obtained in the above examples.

TABLE 13

Example 223: 2-hydroxy-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -Pyridin-4-yl} -ethyl) -piperazin-1-yl] -ethanone

The target compound was obtained by reacting the compound obtained in Example 218 with the method of Example 18 using hydroxyacetic acid.

¹ H NMR (CDCl ₃ , ppm); δ 8.29 (1H, d), 7.58 (1H, d), 7.20-7.27 (4H, m), 6.93 (1H, s), 6.82 (1H, d), 6.58 (1H, d), 4.20 (2H, s ), 3.73 (2H, t), 3.54 (3H, s), 3.32 (2H, t), 2.79 (2H, t), 2.69 (2H, t), 2.54 (4H, t), 2.41 (3H, s)

FAB MS (m / e) = 518 [M + 1] ⁺

Example 224: 2-hydroxy-2-methyl-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Ylamino] -pyridin-4-yl} -ethyl) -piperazin-1-yl] propan-1-one

In Example 223, the reaction was carried out in the same manner using 2-hydroxy-2-methyl-propionic acid instead of hydroxyacetic acid to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.28 (1H, d), 7.57 (1H, d), 7.20-7.27 (4H, m), 6.92 (1H, s), 6.81 (1H, d), 6.57 (1H, d), 3.73 (4H, t ), 3.54 (3H, s), 2.84 (1H, d), 2.80 (2H, d), 2.66 (2H, t), 2.53 (4H, t), 2.40 (3H, s), 1.53 (6H, s)

FAB MS (m / e) = 546 [M + 1] ⁺

Example 225: 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid methyl ester

1.4 g (3.7 mmol) of the compound obtained in Example 9 were dissolved in 25 mL of dichloromethane, and 16 g (5.6 mmol, 15 wt% in dichloromethane) of Dess-Martin reagent was added thereto. After stirring for 2 hours at room temperature, 5 ml of saturated sodium thiosulfate aqueous solution was added, dichloromethane was extracted with 20 ml, and concentrated to obtain an aldehyde intermediate. Into a flame-dried round flask, 440 mg (11.1 mmol) of sodium hydride was added and 30 ml of anhydrous tetrahydrofuran was added. After the temperature was lowered to 0 ° C., 2.49 g (11.1 mmol) of triethyl phosphonoacetate was dissolved in 20 ml of anhydrous tetrahydrofuran. The temperature was raised to room temperature and stirred for 1 hour. The temperature was lowered to 0 ° C., and the aldehyde obtained above was dissolved in 20 ml of anhydrous tetrahydrofuran and slowly added for 30 minutes. The temperature is raised to room temperature and stirred for 12 hours. 5 ml of water is added to terminate the reaction and the solvent is removed under reduced pressure. Extracted 30 ml twice with ethyl acetate and concentrated. 40 ml of methanol was added to the obtained material, 10 mg of palladium / carbon was added thereto, and hydrogen gas was charged and stirred for 3 days. Celite is placed on the glass filter and the solution is filtered. The filtrate was concentrated, 30 ml of water was added, extracted twice with 30 ml of ethyl acetate and concentrated again. Separation by column chromatography gave 1.07 g (2.48 mmol, yield; 67%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 9.51 (1H, s), 8.25 (1H, d), 7.55 (1H, d), 7.16-7.22 (4H, m), 6.83 (1H, s), 6.77 (1H, d), 6.56 (1H, d ), 3.65 (3H, s), 3.50 (3H, s), 2.90 (2H, t), 2.62 (2H, t), 2.36 (3H, s)

FAB MS (m / e) = 434 [M + 1] ⁺

Example 226: 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid

The compound obtained in Example 225 was hydrolyzed by the method of Example 17 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.23 (1H, s), 8.12 (1H, d), 7.56 (1H, d), 7.16-7.22 (4H, m), 6.94 (1H, s), 6.81 (1H, d), 6.49 (1H, d ), 3.35 (3H, s), 2.74 (2H, t), 2.41 (2H, t), 2.30 (3H, s)

FAB MS (m / e) = 420 [M + 1] ⁺

Table 14 below shows examples of synthesizing desired compounds by reacting by the method of Example 18 using the compound obtained in Example 226.

TABLE 14

Example 230: 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propane-1- Come

The compound obtained in Example 225 was reacted by the method of Preparation Example 2 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.22 (1H, s), 7.52 (1H, d), 7.16-7.22 (4H, m), 6.89 (1H, s), 6.79 (1H, d), 6.54 (1H, d), 3.74 (2H, t ), 3.49 (3H, s), 2.68 (2H, t), 2.37 (3H, s), 1.92 (2H, m)

FAB MS (m / e) = 406 [M + 1] ⁺

Preparation Example 37 N ² -[4- (3-Chloro-propyl) -pyridin-2-yl] -N ⁵ -Methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine

The compound obtained in Example 230 was reacted by the method of Preparation Example 5 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.23 (1H, s), 7.51 (1H, d), 7.16-7.22 (4H, m), 7.11 (1H, d), 6.89 (1H, d), 6.53 (1H, d), 3.54 (2H, t ), 3.48 (3H, s), 2.81 (2H, t), 2.38 (3H, s), 2.10 (2H, m)

FAB MS (m / e) = 424 [M + 1] ⁺

Table 15 below shows examples of synthesizing desired compounds by reacting by the method of Example 3 using the compound obtained in Preparation Example 37.

TABLE 15

Production Example  38: 2- Chloro -5- [ methyl -(5-nitro-pyridin-2-yl) -amino] -benzoic acid methyl  ester

4.3 ml (60 mmol) of acetyl chloride was added to 200 ml of methanol and stirred at room temperature for 15 minutes, followed by 30 g (162 mmol) of 5-amino-2-chloro-benzoic acid methyl ester and 2-chloro-5-nitropyridine 23.9. g (150 mmol) was added and stirred under reflux for 20 hours. After completion of the reaction, the resultant was concentrated, 500 ml of water was added, the solid formed was filtered and dried to afford 40.2 g (130 mmol, yield; 87%) of 2-chloro-5- (5-nitro-pyridin-2-ylamino) -benzoic acid methyl ester. Got. Dissolve 40 g (130 mmol) of this intermediate in 150 ml of N, N-dimethylformamide, lower the temperature to 0 ° C, add 6.76 g (60%, 169 mmol) of sodium hydride, stir for 20 minutes, and then methyl iodine 10.5. ml (169 mmol) was added for 10 minutes and stirred for two hours. After completion of the reaction, 50 ml of water was added for 10 minutes, and then concentrated. 400 ml of water was added thereto, and the resulting solid was filtered and dried to afford 39.5 g (123 mmol, yield; 94%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.23 (1H, d), 7.81 (1H, s), 7.66 (1H, d), 7.43 (1H, s), 7.25 (1H, m), 6.52 (1H, s), 4.10 (3H, s), 3.41 (3H, s)

FAB MS (m / e) = 322 [M + 1] ⁺

Preparation 39: 5-[(2-amino-thiazolo [5,4-b] pyridin-5-yl) -methyl-amino] -2-chloro-benzoic acid methyl  ester

39.0 g (121 mmol) of the compound obtained in Preparation Example 38 was dissolved in 500 ml of ethyl acetate, and the temperature was reduced to 0 ° C. Then, 110 g (486 mmol) of dichlorotin dihydrate and 5 ml of concentrated hydrochloric acid solution were added, and the temperature was gradually decreased for 20 hours. It was stirred while raising to room temperature. After completion of the reaction, the temperature was lowered to 0 ° C. and neutralized with ammonia water. The solid produced at this time was filtered through celite and washed with 800 ml of ethyl acetate. The filtrate was concentrated and dissolved again using 300 ml of acetic acid. After the reaction solution was cooled to 0 ° C., 58.8 g (605 mmol) of potassium isothiocyanate was added thereto, and after stirring for 10 minutes, 9.3 ml of bromine was diluted with 100 ml of acetic acid and slowly added dropwise thereto for 4 hours. After completion of the dropwise addition, the temperature was slowly raised to room temperature and stirred for 20 hours. After completion of the reaction, the reaction solution was raised to 90 ℃ and filtered through celite to filter the solid formed during the reaction and washed with 150 ml of acetic acid. The filtrate was concentrated again, neutralized with saturated aqueous sodium hydrogen carbonate solution, and then extracted three times with 300 ml each with tetrahydrofuran. The organic layer was concentrated and separated by column chromatography to give 22.8 g (65.3 mmol, yield; 54%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 7.81 (1H, d), 7.66 (1H, d), 7.43 (1H, m), 7.25 (2H, m), 7.16 (1H, t), 6.52 (1H, d), 3.91 (3H, s), 3.51 (3H, s)

FAB MS (m / e) = 349 [M + 1] ⁺

Preparation Example 40: 5-({2- [4- (tert-butyl-dimethyl-silanyloxymethyl) -pyridin-2-ylamino] -thiazolo [ 5,4-b] pyridine -5 days}- methyl -Amino) -2- Chloro -Benzoic acid methyl  ester

15 g (43.1 mmol) of the compound obtained in Preparation Example 39 and 14.4 g (56.0 mmol) of 4- (tert-butyl-dimethyl-silanyloxymethyl) -2-chloro-pyridine were dissolved in 300 ml of toluene, followed by potassium carbonate 6.85. g (64.6 mmol), 2.37 g (2.59 mmol) of tris (dibenzylideneacetone) dipalladium and 2.24 g (3.86 mmol) of xantose were added thereto, stirred with blowing with nitrogen for 30 minutes, and then stirred under reflux for 8 hours. After completion of the reaction, the solid was filtered through celite, and then the filtrate was washed with 300 ml of water and the organic layer was concentrated. Separation by column chromatography gave 16.4 g (28.8 mmol, yield; 67%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.23 (1H, d), 7.72 (1H, d), 7.62 (1H, s), 7.50 (1H, d), 7.42 (1H, d), 7.09 (1H, s), 6.88 (1H, s), 6.81 (1H, s), 4.49 (2H, s), 3.80 (3H, s), 3.41 (3H, s), 0.92 (9H, s), 0.10 (6H, s)

FAB MS (m / e) = 570 [M + 1] ⁺

Example 234: 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino}- Benzoic acid methyl ester

After dissolving 10.5 g (18.4 mmol) of the compound obtained in Preparation Example 39 using 100 ml of methanol, 2.73 g (73.7 mmol) of ammonium fluoride was added thereto, and the mixture was stirred under reflux for 3 hours. After completion of the reaction, 400 ml of water was added to the resulting solid, which was filtered and dried to yield 7.81 g (17.1 mmol, yield; 93%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.38 (1H, s), 8.19 (1H, d), 7.73 (1H, d), 7.61 (1H, s), 7.51 (1H, d), 7.45 (1H, d), 7.09 (1H, s), 6.86 (1H, s), 6.81 (1H, s), 5.42 (1H, t), 4.49 (2H, d), 3.80 (3H, s), 3.41 (3H, s)

FAB MS (m / e) = 456 [M + 1] ⁺

Example 235: 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino}- Benzoic acid

7.6 g (16.7 mmol) of the compound obtained in Example 234 were dissolved in 150 ml of tetrahydrofuran and 50 ml of methanol, and 2.80 g (66.7 ml) of lithium hydride monohydrate was added to 50 ml of water and stirred at 50 ° C for 20 hours. It was. After completion of the reaction, the mixture was distilled under reduced pressure to remove tetrahydrofuran and methanol, which was then cooled to 0 ° C. and neutralized with a 2-normal hydrochloric acid aqueous solution. The resulting solid was filtered and dried to obtain 6.94 g (15.7 mmol, Yield; 94%) of the title compound. .

¹ H NMR (DMSO-d ₆ , ppm); δ 12.97 (1H, s), 11.32 (1H, s), 8.18 (1H, d), 7.72 (1H, d), 7.63 (1H, s), 7.51 (1H, d), 7.44 (1H, d), 7.09 (1H, s), 6.84 (1H, s), 6.79 (1H, s), 5.42 (1H, t), 4.49 (2H, d), 3.38 (3H, s)

FAB MS (m / e) = 442 [M + 1] ⁺

Example 236 2-chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino}- N-methoxy-benzamide

5.0 g (11.3 mmol) of the compound obtained in Example 235 were dissolved in 70 ml of N, N-dimethylformamide, 1.42 g (17.0 mmol) of methoxylamine hydrochloride, 3.05 g (22.6 mmol) of 1-hydroxybenzotriazole, N 3.68 g (19.2 mmol) of-(3-dimethylaminopropyl) -N'-ethylcarbodiimide and 2.36 ml (17.0 mmol) of triethylamine were added and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated, and 200 ml of water was added, and the resulting solid was filtered and dried to yield 4.87 g (10.3 mmol, yield; 92%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.27 (1H, s), 8.20 (1H, d), 7.72 (1H, d), 7.44 (1H, d), 7.33 (1H, d), 7.30 (1H, s), 7.08 (1H, s), 6.86 (1H, d), 6.78 (1H, d), 5.42 (1H, t), 4.49 (2H, d), 3.67 (3H, s), 3.40 (3H, s)

FAB MS (m / e) = 471 [M + 1] ⁺

Preparation 41: 2-Chloro-5-{[2- (4-chloromethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl]- methyl -Amino} -N- Methoxy - Benzamide

4.70 g (9.98 mmol) of the compound obtained in Example 236 are dissolved in 70 ml of dichloromethane, and 3.86 ml (49.9 mmol) of N, N-dimethylformamide and 4.57 ml (49.9 mmol) of phosphorus oxychloride are added thereto at room temperature for 15 hours. Stirred. After completion of the reaction, the reaction mixture was concentrated, 50 ml of diethyl ether was added, stirred for 10 minutes, and dried to obtain 4.10 g (8.38 mmol, yield; 84%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.21 (1H, d), 7.74 (1H, d), 7.47 (1H, d), 7.36 (1H, d), 7.31 (1H, s), 7.07 (1H, s), 6.84 (1H, d), 6.77 (1H, d), 3.88 (2H, s), 3.67 (3H, s), 3.40 (3H, s)

FAB MS (m / e) = 489 [M + 1] ⁺

Example 237: 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -Methyl-amino) -2-chloro-N-methoxy-benzamide

100 mg (0.204 mmol) of the compound obtained in Preparation Example 41 was dissolved in 1 ml of dimethyl sulfoxide, 105 mg (0.817 mmol) of N-acetylpiperazine was added thereto, and the resultant was stirred at room temperature for 5 hours. After completion of the reaction, 30 ml of water was added to the resulting solid, which was filtered and dried to yield 102 mg (0.175 mmol, yield; 86%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.28 (1H, s), 7.62 (1H, d), 7.46 (1H, s), 7.34 (1H, d), 7.30 (1H, d), 6.90-6.87 (2H, m ), 6.68 (1H, d), 3.93 (3H, s), 3.51 (5H, m), 3.42-3.36 (4H, m), 2.37 (4H, m), 2.03 (3H, s)

FAB MS (m / e) = 581 [M + 1] ⁺

Example 238: 2-Chloro-N-methoxy-5- {methyl- [2- (4-morpholin-4-ylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridine -5-yl] -amino} -benzamide

In Example 237, the reaction was carried out in the same manner using morpholine instead of N-acetylpiperazine to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.42 (1H, s), 8.21 (1H, d), 7.72 (1H, d), 7.45 (1H, d), 7.35 (1H, d), 7.30 (1H, s), 7.08 (1H, s), 6.90 (1H, d), 6.78 (1H, d), 3.67 (3H, s), 3.56 (2H, s), 3.44-3.40 (4H, m), 3.29 (3H, s), 2.35 (4H, m)

FAB MS (m / e) = 540 [M + 1] ⁺

Example 239 2-chloro-N-methoxy-5- (methyl- {2- [4- (4-methyl-pyrazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5 , 4-b] pyridin-5-yl} -amino) -benzamide

In Example 237, using the N-methyl piperazine instead of N-acetyl piperazine in the same manner to give the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.20 (1H, d), 7.71 (1H, d), 7.42 (1H, d), 7.34 (1H, d), 7.31 (1H, s), 7.06 (1H, s), 6.91 (1H, d), 6.75 (1H, d), 3.69 (2H, s), 3.43-3.38 (7H, m), 3.32 (3H, s), 2.45 (4H, m), 2.16 (3H, s)

FAB MS (m / e) = 553 [M + 1] ⁺

Production Example  42: 3-[(2-amino- Thiazolo [5,4-b] pyridine -5 days)- methyl -Amino] -benzoic acid ethyl ester

In Preparation Example 38, using 3-amino-benzoic acid ethyl ester instead of 5-amino-2-chloro-benzoic acid methyl ester, was reacted by the method of Preparation Example 38, followed by the method of Preparation Example 39, and the total yield was 46%. 14.6 g (44.5 mmol) of the title compound was obtained.

¹ H NMR (DMSO-d ₆ , ppm); δ 7.46 (1H, d), 7.41-7.39 (2H, m), 7.32 (1H, s), 7.26 (1H, d), 6.62 (1H, d), 4.40 (2H, q), 3.51 (3H, s ), 1.37 (3H, t)

FAB MS (m / e) = 329 [M + 1] ⁺

Example 240: 3-[(2-amino-thiazolo [5,4-b] pyridin-5-yl) -methyl-amino] -N-methoxy-benzamide

3.5 g (10.7 mmol) of the compound obtained in Preparation Example 42 was hydrolyzed by the method of Example 235 to obtain an acid, and then reacted by the method of Example 236 to yield 2.67 g (8.10 mmol) of the target compound in a total yield of 76%. Got it.

¹ H NMR (DMSO-d ₆ , ppm); δ 7.48 (1H, d), 7.41-7.39 (2H, m), 7.31 (1H, s), 7.26 (1H, d), 6.62 (1H, d), 3.84 (3H, s), 3.41 (3H, s )

FAB MS (m / e) = 330 [M + 1] ⁺

Preparation Example 43 3-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl]- methyl -Amino} -benzoic acid ethyl ester

Using 9.5 g (28.9 mmol) of the compound obtained in Preparation Example 42, the reaction was carried out in the same manner as in Preparation Example 40 and Example 234 to obtain 7.2 g (16.5 mmol) of the target compound in a total yield of 57%.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.31 (1H, s), 8.21 (1H, d), 7.78 (1H, s), 7.71 (1H, d), 7.54-7.50 (2H, m), 7.05 (1H, s), 6.90 (1H, d ), 6.72 (1H, d), 5.42 (1H, t), 4.48 (2H, d), 3.43 (2H, q), 3.34 (3H, s), 1.45 (3H, t)

FAB MS (m / e) = 436 [M + 1] ⁺

Production Example  44: 3-{[2- (4- Chloromethyl Pyridine-2- Monoamino )- Thiazolo [5,4-b] pyridine -5 days]- methyl -Amino} -N- Methoxy - Benzamide

4.7 g (10.3 mmol) of the compound obtained in Preparation Example 43 was reacted sequentially in the same manner as in Example 235, Example 236, and Preparation 41 to obtain 3.32 g (7.30 mmol) of the title compound in a yield of 71% in total.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.34 (1H, s), 8.20 (1H, d), 7.77 (1H, s), 7.70 (1H, d), 7.54-7.50 (2H, m), 7.02 (1H, s), 6.90 (1H, d ), 6.71 (1H, d), 4.31 (2H, s), 3.47 (3H, s), 3.32 (3H, s)

FAB MS (m / e) = 455 [M + 1] ⁺

Table 16 below shows examples of synthesizing desired compounds by reacting by the method of Example 237 using the compound obtained in Preparation 44.

TABLE 16

Production Example  45: 3-{[2- (4- Hydroxymethyl Pyridine-2- Monoamino )- Thiazolo [5,4-b] pyridine -5 days]- methyl -Amino} -benzoic acid

3.2 g (7.34 mmol) of the compound obtained in Preparation Example 43 were hydrolyzed by the method of Example 235 to obtain 2.82 g (6.92 mmol, yield; 94%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 12.79 (1H, s), 11.34 (1H, s), 8.42 (1H, d), 8.17 (1H, d), 7.70 (1H, s), 7.65 (1H, d), 7.58 (1H, d), 7.45-7.42 (2H, m), 7.08 (1H, s), 6.86 (1H, d), 6.64 (1H, d), 5.42 (1H, t), 4.48 (2H, d), 3.42 (3H, s)

FAB MS (m / e) = 408 [M + 1] ⁺

Table 17 below shows examples of synthesizing desired compounds by reacting by the method of Example 236 using the compound obtained in Preparation Example 45.

TABLE 17

Preparation 46: (2- {5-[(3-methoxycarbamoyl-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl army No} -pyridin-4-yl) -acetic acid ethyl ester

2.3 g (6.98 mmol) of the compound obtained in Example 240 and 1.81 g (9.08 mmol) of (2-chloro-pyridin-4-yl) -acetic acid ethyl ester were dissolved in 80 ml of toluene, followed by 1.10 g (10.5 mmol) of potassium carbonate. 0.38 g (0.42 mmol) of tris (dibenzylideneacetone) dipalladium and 0.36 g (0.63 mmol) of xantose were added thereto, followed by stirring with nitrogen for 30 minutes, followed by stirring under reflux for 5 hours. After completion of the reaction, the solid was filtered through celite, and then the filtrate was washed with 60 ml of water and the organic layer was concentrated. Separation by column chromatography gave 1.65 g (3.35 mmol, yield; 48%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.32 (1H, s), 8.24 (1H, s), 7.82 (1H, d), 7.74 (1H, s), 7.52 (1H, d), 7.46 (1H, d), 6.97 (1H, s), 6.82 (1H, d), 6.67 (1H, d), 3.75 (3H, s), 3.69 (2H, s), 3.48 (2H, q), 3.40 (3H, s), 1.43 (3H, t)

FAB MS (m / e) = 493 [M + 1] ⁺

Example 247: 3-{[2- (4-dimethylcarbamoylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-meth Oxy-benzamide

1.10 g (2.23 mmol) of the compound obtained in Preparation Example 46 were hydrolyzed by the method of Example 235 to obtain 0.96 g (2.08 mmol, yield; 93%) of the intermediate in the acid form. 120 mg (0.258 mmol) and N, N-dimethylamine were reacted in the same manner as in Example 236 to obtain 110 mg (0.224 mmol, yield; 87%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 11.37 (1H, s), 8.25 (1H, s), 7.80 (1H, d), 7.70 (1H, s), 7.54 (1H, d), 7.48 (1H, d), 6.99 (1H, s), 6.87 (1H, d), 6.69 (1H, d), 3.75 (3H, s), 3.69 (2H, s), 3.40 (3H, s), 3.04 (3H, s), 2.87 (3H, s)

FAB MS (m / e) = 492 [M + 1] ⁺

Preparation 47: 5-[(2-Amino-thiazolo [5,4-b] pyridin-5-yl) -methyl-amino] -2-fluoro-benzoic acid ethyl ester

In the preparation 42, using the 5-amino-2-fluoro-benzoic acid ethyl ester instead of 3-amino-benzoic acid ethyl ester in the same manner as in Preparation 42, 8.7 g (25. 1 mmol) of the target compound in a yield of 48% in total )

¹ H NMR (DMSO-d ₆ , ppm); δ 7.82 (1H, d), 7.66 (1H, d), 7.43 (1H, m), 7.25 (2H, br), 7.16 (1H, t), 6.52 (1H, d), 4.40 (2H, q), 3.51 (3H, s), 1.37 (3H, t)

FAB MS (m / e) = 347 [M + 1] ⁺

Preparation 48: 5-{[2- (4-cyclomethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl]- methyl -Amino} -2- Fluoro -Benzoic acid ethyl ester

Using the compound 3.2 g (6.98 mmol) obtained in Preparation Example 47, the reaction was carried out in the same manner as in Preparation Example 39, Example 234, and Preparation Example 41 to obtain 1.58 g (3.35 mmol, total yield; 48%) of the title compound. .

¹ H NMR (CDCl ₃ , ppm); δ 8.71 (1H, br), 8.28 (1H, d), 7.82 (1H, dd), 7.61 (1H, d), 7.46 (1H, m), 7.15 (1H, t), 6.95 (1H, s), 6.91 (1H, d), 6.56 (1H, d), 5.11 (2H, s), 4.40 (2H, q), 1.39 (3H, t)

FAB MS (m / e) = 472 [M + 1] ⁺

Example 248: 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -Methyl-amino) -2-fluoro-benzoic acid ethyl ester

0.9 g (1.91 mmol) of the compound obtained in Preparation Example 48 were used to obtain 0.89 g (1.58 mmol, yield; 83%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 8.69 (1H, br), 8.30 (1H, d), 7.84 (1H, dd), 7.62 (1H, d), 7.45 (1H, m), 7.16 (1H, t), 6.99 (1H, s), 6.93 (1H, d), 6.57 (1H, d), 4.40 (2H, q), 3.63 (2H, m), 3.50 (5H, m), 3.46 (2H, m), 2.44 (4H, m), 2.10 (3H, s), 1.39 (3H, t)

FAB MS (m / e) = 564 [M + 1] ⁺

Production Example  49: 5-({2- [4- (4-acetyl-piperazine-1- Methyl ) -Pyridine-2- Monoamino ]- Thiazole in[ 5,4-b] pyridine -5 days}- methyl -Amino) -2- Fluoro -Benzoic acid

0.85 g (1.51 mmol) of the compound obtained in Example 248 was hydrolyzed in the same manner as in Example 235 to obtain 0.74 g (1.39 mmol, yield; 92%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.72 (1H, br), 8.31 (1H, d), 7.82 (1H, dd), 7.61 (1H, d), 7.46 (1H, m), 7.16 (1H, t), 6.99 (1H, s), 6.92 (1H, d), 6.57 (1H, d), 3.63 (2H, m), 3.50 (5H, m), 3.46 (2H, m), 2.44 (4H, m), 2.10 (3H, s)

FAB MS (m / e) = 536 [M + 1] ⁺

Example 249: 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -Methyl-amino) -2-fluoro-N-methoxy-benzamide

Using the compound obtained in Preparation Example 49, the reaction was carried out by the method of Example 236 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 11.00 (1H, br), 9.82 (1H, br), 8.30 (1H, d), 7.91 (1H, d), 7.62 (1H, d), 7.42 (1H, m), 7.14 (1H, t), 6.92 (1H, s), 6.88 (1H, d), 6.55 (1H, d), 3.92 (3H, m), 3.50 (5H, m), 3.41 (2H, s), 3.35 (2H, s), 2.37 (4H, m), 2.06 (3H, s)

FAB MS (m / e) = 565 [M + 1] ⁺

Example 250: 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -Methyl-amino) -2-fluoro-N-methyl-benzamide

In Example 249, the reaction of Example 249 was carried out using methylamine hydrochloride instead of methoxylamine hydrochloride to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 9.20 (1H, br), 8.30 (1H, d), 8.01 (1H, dd), 7.62 (1H, d), 7.38 (1H, m), 7.14 (1H, t), 6.97 (1H, s), 6.92 (1H, d), 6.81 (1H, m), 6.60 (1H, d), 3.60 (2H, m), 3.52 (3H, s), 3.48 (2H, m), 3.43 (2H, m), 3.05 (3H, s), 2.43 (4H, m), 2.06 (3H, s)

FAB MS (m / e) = 549 [M + 1] ⁺

Experimental Example  1: several kinds RTK ( Receptor Tyrosine Kinase Activity inhibitory efficacy test

In order to confirm the inhibitory effect of tyrosine kinase activity of the compounds according to the present invention, the following in vitro kinase activity inhibition was performed on five RTKs. First, only kinase domains of KDR, FLT-3, EGFR, FGFR1 and PDGFR-β in the form of GST fusion or His-tag were expressed and purified in insect cells (SF21).

For KDR, 20 mM Tris-HCl, pH 7.5, 10 mM MgCl ₂ , 1 mM MnCl _{2 ,} 2 mM DTT, 0.1 mM Sodium Orthovanadate, 10 μM ATP, 0.2 μCi [γ-P ³² ] -ATP, 69 μg Reaction was performed under the following conditions using / ml Poly Glu: Tyr peptide (4: 1) (Sigma) and 3 μg / ml of purified GST: KDR protein. The reaction volume of 20 μl was used to run the reaction at 30 ° C. for 10 minutes in the presence of 5% DMSO containing the concentrations of the designated compounds and then stopped with 10% phosphoric acid. Then, the reaction solution was transferred to an Immobilon-PVDF membrane (Milipore) in 96-well format, washed four times with 0.5% phosphoric acid, and the amount of radioactivity remaining on the membrane was quantified with Phosphorimager (Molecular Dynamics). The IC ₅₀ value was determined by the linear regression analysis of the average value of the experiment repeated three or more times with the concentration of compound that inhibits 50% of the total activity.

For FLT3, 20 mM Tris-HCl (pH 7.5), 3 mM MgCl ₂ , 7 mM MnCl _{2 ,} 2 mM DTT, 0.1 mM Sodium Orthovanadate (Sigma), 8 μM ATP, 0.2 μCi [γ-P ³² ] -ATP , 69 μg / ml Poly Glu: Tyr peptide (4: 1) (Sigma), and 8 μg / ml of purified His-Tag: FLT3 protein were used for 15 minutes under the same conditions as KDR.

For EGFR, 20 mM Tris-HCl (pH 7.4), 10 mM MgCl ₂ , 1 mM MnCl _{2 ,} 2 mM DTT, 0.1 mM Sodium Orthovanadate, 10 μM ATP, 0.2 μCi [γ-P ³² ] -ATP, 690 μg Reaction was performed for 20 minutes under the same conditions as KDR using / ml Poly Glu: Tyr peptide (4: 1) (Sigma) and 5 μg / ml of purified His-Tag: EGFR.

For FGFR1, 20 mM Tris-HCl (pH 7.5), 3 mM MgCl ₂ , 3 mM MnCl _{2 ,} 2 mM DTT, 10 μM Sodium Orthovanadate, 0.25 mg / ml PEG3350, 8 μM ATP, 0.2 μCi [γ-P ³² ] -ATP, 69 μM Poly Glu: Tyr peptide (4: 1) (Sigma) and 6.25 μg / ml of purified GST: FGFR1 protein were used for 10 minutes under the same conditions as KDR.

For PDGFRβ, 25 mM HEPES (pH 7.4), 150 mM NaCl, 10 mM MnCl _{2 ,} 2 mM DTT, 0.2 mM Sodium Orthovanadate, 2 μM ATP, 0.2 μCi [γ-P ³² ] -ATP, 690 μg / ml Poly Glu: Tyr peptide (4: 1) (Sigma) and 8 μg / ml of purified GST: PDGFRβ were used for 10 minutes under the same conditions as KDR.

Experimental Example 2: VEGF-dependent HUVECs (Human Umbilical Vein Endothelial) of Compounds According to the Present Invention Cell Growth Inhibition Effect Test

HUVEC cells (5 × 10 ³ cells / well) isolated from the placenta were inoculated in a 0.3% Gelatin-coated 96-well culture vessel and for one day M199 cell culture medium (Gibco BRL) (10% FBS, 30 μg / ml ECGS). , 50 μg / ml Heparin, 1 × Penicillin / Sterptomycin, and 0.5 mM Glutamine) were incubated at 37 ° C. in 5% CO ₂ in a cell culture. Then, serum starvation was performed for 24 hours in M199 starvation medium (0.5% FBS). The starvation medium was then changed to a working medium containing the diluted compounds in stages and treated with 10 ng / ml VEGF (R & D systems) after 2 hours. After incubation for two days, BrdU Cell Proliferation ELISA (Roche) was performed according to the manufacturer's instructions. The IC ₅₀ value was determined by the linear regression analysis of the average value of the experiment repeated three or more times at the concentration of the compound that inhibits 50% of the total cell growth induced by VEGF.

Experimental Example  3: of the compounds according to the invention HUVEC Tube formation inhibitory efficacy test

Passage 5 HUVEC (human neovascular cells) in a 100 mm culture vessel was incubated at 5% CO ₂ , 37 ° C in a cell culture incubator with trypsin and 0.2% BSA (Sigma) Neutralized with M199, inoculated in a 24 well culture vessel coated with 10 mg / ml Matrigel (R & D systems) with medium containing 4 × 10 ⁴ cells / well and compound diluted in stages, followed by 5% FBS Added. After 17 hours, the medium was carefully removed and fixed with 100 μl of 3.7% Paraformaldehyde / PBS, the screen was taken under a microscope and the length of the formed tube was quantified using KS Lite software.

Experimental Example 4: SRB (Sulforhodamine B) growth inhibitory effect test on HCT116 of the compounds according to the invention

Inoculate HCT116 cells (3 × 10 ³ cells / well: ATCC) into 96-well culture vessels in 100 μl volume and in RPMI1640 culture medium (containing 5% FBS, 1X Penicillin / Sterptomycin and 0.5 mM Glutamine: Gibco BRL) for one day. Was cultured in a 5% CO ₂ , 37 ℃ condition in the cell culture. The medium was then treated with the compounds diluted in stages. After incubation for 2 days, fixation was performed with 4% Formaldehyde (Sigma) for 3-4 hours. After washing 5 times with PBS, it was dried for 10 minutes in a 55 ℃ oven. 50 μl of 0.4% (w / v) SRB (Sigma) solution dissolved in 1% acetic acid was added to each well and left at room temperature for 30 minutes and washed with 1% acetic acid. It was then dried again in a 55 ° C. oven for 10 minutes. Dissolve on the shaker for 20 minutes with 100 mL of 10 mM Tris-HCl (pH 10.5) and measure the absorbance at 530 nm to quantify the amount of cells. The GI ₅₀ value was determined by the linear regression analysis of the average value of the experiment repeated three or more times at the concentration of the compound inhibiting 50% of total cell growth.

Experimental Example  5: of the compounds according to the invention in vivo  Cancer cell growth inhibitory effect test

Female BALB / c nude mice, 5-6 weeks old, were purchased from Harlan, USA, and housed in cages with a clean animal room HEPA filter for a week of acclimatization. Human tumor cells selected for the test were cultured according to each condition, and then cells of appropriate concentration (5-10 × 10 ⁶ cells / 100 uL) were inoculated subcutaneously into nude mice. For the regression model, the tumors were grown to 90-120 mm ³ and then orally administered once a day according to the test dose. The tumor size and body weight were measured every 3 days, and the clinical symptoms were observed and recorded 1-2 times daily. Tumor size was expressed as a volume value calculated by measuring the length, width and height of the tumor, respectively (width x length x height) π / 6. The test was run for 15-18 days.

Tumor growth inhibition effect was evaluated by the following two indicators (IR%: Inhibition Rate,% T / C).

IR% = (1-group mean tumor size / control group mean tumor size) X 100,

% T / C = {(average tumor size on specific day group-mean tumor size on start date) / (average tumor size on specific day-mean tumor size on start date)} X 100

Representative compounds of Formula 1 and their enzyme activity inhibition capacity measured for KDR and HUVEC as shown in the IC ₅₀ value are shown in Table 18 below.

TABLE 18

The results showing the growth inhibition of the HCT116 cells, bFGF-dependent HUVEC and PDGF-dependent PASMC of some compounds of Formula 1 as IC ₅₀ are shown in Table 19 below.

TABLE 19

Compounds of formula (1) using nude mouse in vivo Tumor cell growth inhibitory effect showed a significant growth inhibitory effect (IR> 50%).

From the above results, the compounds according to the present invention inhibit KDR activity, inhibit the growth of HUVEC, in It can be seen that it is very effective in inhibiting the growth of cancer cells in vivo .

Those skilled in the art to which the present invention pertains will be able to perform various applications and modifications within the scope of the present invention based on the above contents.

Claims (7)

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

(One) Where A) R ₁ is hydrogen or C ₁ -C ₁₀ alkyl, B) A ₁ and A ₂ are each independently carbon or nitrogen, C) R ₂ is selected from the group consisting of hydrogen, halogen, cyano, -CF ₃ and C ₁ -C ₁₀ alkyl, D) Ar ₁ is a 5 or 6 cyclic aromatic or heteroaromatic, E) X is each independently selected from the group consisting of the following substituents, I) hydrogen, halogen, cyano, hydroxy, -CF ₃ , optionally substituted C ₁ -C ₁₀ alkyl; II) -OR ₃ , -SR ₃ , -NHR ₃ , -N (R ₃ ) ₂ , wherein R ₃ is hydrogen or optionally substituted C ₁ -C ₁₀ alkyl; III) -C (= 0) R ₄ , -NR ₅ C (= 0) NR ₄ R ₆ , -NR ₅ C (= S) NR ₄ R ₆ , Where R ₄ Is i) hydroxy; ii) optionally substituted C ₁ -C ₁₀ alkyl; iii) optionally substituted C ₁ -C ₁₀ alkoxy; iv) -NR ₇ R ₈ or -N (-R ₇ ) OR ₈ , wherein R ₇ And R ₈ Are each independently hydrogen, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted allyl, optionally substituted sulfone, or optionally substituted amine, and R ₇ And R ₈ Are interconnected to form a ring structure; v)-(CH ₂ ) _n1 NR _9- (CH ₂ ) _n2 -NR ₇ R ₈ , wherein R ₇ And R ₈ Is as defined above, R ₉ is hydrogen or optionally substituted C ₁ -C ₁₀ alkyl, n ₁ Is 0 or an integer from 1 to 5, n ₂ Is an integer from 1 to 5; R ₅ And R ₆ Are each independently hydrogen, hydroxy, optionally substituted C ₁ -C ₁₀ alkyl, optionally substituted allyl, optionally substituted sulfone alkyl, or optionally substituted amine; R ₄ , R ₅ And two substituents selected from R ₆ may be connected to each other to form a ring structure; F) n is 0 or an integer from 1 to 5, G) E is oxygen or sulfur; H) Ar ₂ is hydrogen or a 5- or 6-membered aromatic ring compound represented by the following formula (2),

(2) here, Q is selected from the group consisting of carbon, nitrogen, oxygen and sulfur, l (L) is an integer from 3 to 4, I) m is 0 or an integer from 1 to 4, J) Y is each independently selected from the group consisting of the following substituents, I) halogen, cyano, nitro, hydroxy, -CF ₃ and optionally substituted morpholine; II) -R, -OR, -SR ', -NHR' and -NR'R ", wherein R, R 'and R" are each independently hydrogen, or optionally substituted C ₁ -C ₁₀ straight chain, branched Or cyclic saturated or unsaturated alkyl; And III) substituents represented by the following general formulas (i to vi):

(i)

(ii)

(iii)

(iv)

(v)

(vi) here, n ₁ is 0 or an integer of 1 to 5; J ₁ is selected from hydrogen, — (C═O) —, —N—, —O— and —S— or is a direct bond; J ₂ and J ₃ are each independently selected from the group consisting of —N—, —O—, —CR′— and —S—, or a direct bond, wherein R ′ is as defined above; J ₄ And J ₅ are each independently — (C═O) —, —NR′—, — (C═O) —NR′—, — (C═O) —NR′—R—, —O—, —S -NR '-(C = O)-,-(C = S)-,-(C = S) -NR'-,-(C = S) -NR'-R-, -NR'-(C = S)-, and -SO _2- , wherein R and R 'are as defined above; n ₂ and n ₆ Is 0 or an integer of 1 to 3; n ₃ and n ₄ Are each independently selected from 0 or 1 to 3, and when 0 is nothing or a direct bond; n ₅ Is selected from 0 or 1 to 3, and when 0 is nothing or a direct bond; G and G 'are each independently hydrogen, -R', -CF ₃ ,-(C = O) R ', -OR', -CO ₂ R ', -SO ₂ R', -CONHR ', -CONRR' , -CONR'OR, -CN, halogen, -NH ₂ , -NRR ', -NHCOR', -NHCO ₂ R ', -C (R') OH, -C (R) OR ', -NR (C = O) R'OR "-, -C (= 0) ROR'-, optionally substituted C ₃ -C ₈ cycloalkyl or heterocycloalkyl, and optionally substituted 5- or 6-membered aromatic or heteroaromatic And R, R 'and R "are as defined above. The compound of claim 1, wherein R ₁ Is hydrogen or methyl, A ₁ and A ₂ are carbon, R ₂ Is hydrogen or halogen, Ar ₁ Is a hexagonal cyclic aromatic or heteroaromatic, n is 0 or an integer of 1 to 4, E is sulfur, Q is carbon or nitrogen, l (L) is 3 or 4, Or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ₁ Is methyl and R ₂ Is hydrogen, Ar ₁ Is phenyl, n is 0 or an integer of 1 to 3, and l (L) is 4, or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein R ₄ , R ₅ And when two substituents selected from R ₆ are interconnected to form a ring structure, R ₇ And when R ₈ is interconnected to form a ring structure, or is heterocycloalkyl, this ring structure is an optionally substituted aziridine, pyrrolidine, piperazine, piperidine or morpholine , Or a pharmaceutically acceptable salt thereof. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that 1. N ⁵ - (4-fluorophenyl) -N ⁵ - methyl -N ² - (6- methyl-pyridin-2-yl) thiazolo [5,4-b] pyridine-2,5-diamine 2. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -methanol 3. N ⁵ -Methyl-N ^2- (3-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine 4. N ⁵ -Methyl-N ^2- [3- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine 5. N ⁵ -Methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -phenyl-thiazolo [5,4-b] pyridine- 2,5-diamine 6. N ⁵ -Methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -phenyl-l-thiazolo [5,4-b] pyridine-2,5- Diamine 7. 4- {2- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1-carboxyl Acid methylamide 8. 4- {2- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1-carboxyl Acid Dimethylamide 9. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -methanol 10. 1- (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine -1-yl) -ethanone 11. N ² - (4- diethylamino-methyl-pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 12.N ⁵ -Methyl-N ^2- (4-pyrrolidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine 13.N ⁵ -Methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine 14.N ⁵ -Methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine 15.-(4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine- 1-yl) -ethanol 16. (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1 -Yl) -acetic acid ethyl ester 17. (4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-1 -Yl) -acetic acid 18. N, N-dimethyl-2- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4- Monomethyl} -piperazin-1-yl) -acetamide 19. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid ethyl ester 20. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetic acid 21. 1- (4-Methyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone 22. N- (2-Diethylamino-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-yl} -acetamide 23. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -N- (2-mol Forin-4-yl-ethyl) -acetamide 24. N- (2-hydroxy-ethyl) -N-methyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -acetamide 25. N- (2-hydroxy-ethyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-yl} -acetamide 26. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinonitrile 27. N ² - (5--diethylamino-methyl-pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 28.N ⁵ -Methyl-N ^2- (5-piperidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine 29. N ⁵ -Methyl-N ^2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine 30.N ⁵ -Methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine 31. 1- (4- {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -pipe Razin-1-yl) -ethanone 32.N ⁵ -Methyl-N ^2- (5-pyrrolidin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine 33. 4- {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -piperazin-1- Carboxylic Acid Dimethylamide 34. ({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acetic acid methyl ester 35. 2-({6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acet amides 36. 2-({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -propionic acid Methyl ester 37. ({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -acetic acid 38. 2-({6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-ylmethyl} -amino) -propionic acid 39. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid methyl ester 40. 6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -nicotinic acid 41. (4-Methyl-piperazin-1-yl)-{6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 3-day} -Methanone 42. N- (1-Methyl-piperidin-4-ylmethyl) -6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] Nicotinamide 43. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -morpholin-4-yl-meta Paddy field 44. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid ethyl ester 45. {6- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-3-yl} -acetic acid 46. 1- (4-Methyl-piperazin-1-yl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-3-yl} -ethanone 47. N- (1-Methyl-piperidin-4-ylmethyl) -2- {6- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Ylamino] -pyridin-3-yl} -acetamide 48. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine 49. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5 , 4-b] pyridine-2,5-diamine 50. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -ethanone 51. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid tert-butyl ester 52. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid methylamide 53. 4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperazine-1-carboxylic acid dimethylamide 54. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -2-hydroxy-ethanone 55. N ⁵ - ^{(4-fluoro-phenyl) -N 2 - {4- [4-} (4- fluoro-phenyl) -piperazin-1-ylmethyl] -pyridin-2-yl} -N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diamine 56. 1- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperidine-3-carboxylic acid diethylamide 57. 3-[(2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -Methyl-amino] -propionnitrile 58. N ⁵ - ^{(4-fluoro-phenyl) -N 2 - (4 - {} [(2- methoxy-ethyl) -methyl-amino] -methyl} -pyridin-2-yl) -N ⁵ - methyl -Thiazolo [5,4-b] pyridine-2,5-diamine 59. 2-[(2- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -Methyl-amino] -ethanol 60. N ² - [4- (2,6- Dimethyl-morpholine-4-ylmethyl) -pyridin-2-yl] -N ⁵ - (4-fluoro-phenyl) -N ^{5-methyl-thiazolo} [5,4-b] pyridine-2,5-diamine 61. 1- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl)- Piperidine-4-carboxylic acid ethyl ester 62. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine 63. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -2-methoxy-ethanone 64. Cyclopropyl- [4- (2- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-4- Ylmethyl) -piperazin-1-yl] -methanone 65. 1- [4- (2- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazin-1-yl] -propan-1-one 66. N ^5- (4-Fluoro-phenyl) -N ⁵ -methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine -2,5-diamine 67. N ⁵ - (4- flow oro-phenyl) -N ⁵ - methyl -N ² - [5- (4- methyl-piperazin-1-ylmethyl) -pyridin-2-yl] - thiazolo [5 , 4-b] pyridine-2,5-diamine 68. 1- [4- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazin-1-yl] -ethanone 69. 1- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl)- Piperidine-4-ol 70. N ^2- [5- (4-ethyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ^5- (4-fluoro-phenyl) -N ⁵ -methyl-thiazolo [5 , 4-b] pyridine-2,5-diamine 71. N ² - [5- (3- dimethylamino-pyrrolidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ - (4-fluoro-phenyl) -N ^{5-methyl-thiazolo} [5,4-b] pyridine-2,5-diamine 72. 2-[(6- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl) -Amino] -butan-1-ol 73. N ^5- (4-Fluoro-phenyl) -N ^2- [5- (4-methanesulfonyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-thiazolo [5,4-b] pyridine-2,5-diamine ^{74. N 2 - {5- [4-} (2- fluoro-ethyl) -piperazin-1-ylmethyl] -pyridin-2-yl} -N ⁵ - (4-fluorophenyl) -N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diazine 75. N ^2- [5- (2,6-Dimethyl-morpholin-4-ylmethyl) -pyridin-2-yl] -N ^5- (4-fluoro-phenyl) -N ⁵ -methyl-thiazolo [5,4-b] pyridine-2,5-diamine 76. 1- (6- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-ylmethyl)- Piperidine-4-carboxylic acid amide 77. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine 78.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thia Zolo [5,4-b] pyridine-2,5-diamine 79. 1- [4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 4-ylmethyl) -piperazin-1-yl] -ethanone 80. 4- (2- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazole [5,4-b] pyridin-2-ylamino} -pyridin-4-yl Methyl) -piperazine-1-carboxylic acid dimethylamide 81.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (5-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine 82.N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thia Zolo [5,4-b] pyridine-2,5-diamine 83. 1- [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 3-ylmethyl) -piperazin-1-yl] -ethanone 84. 2-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -tizolo [5,4-b] pyridin-2-ylamino} -pyridine-3- Monomethyl) -methyl-amino] -ethanol 85.N ^5- (2,4-Difluoro-phenyl) -N ^2- (5-{[(2-methoxy-ethyl) -methyl-amino] -methyl} -pyridin-2-yl)- N ⁵ -Methyl-thiazolo [5,4-b] pyridine-2,5-diamine 86. N ^5- (2,4-Difluoro-phenyl) -N ^2- [5- (2,6-dimethyl-morpholin-4-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl -Thiazolo [5,4-b] pyridine-2,5-diamine 87. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidin-4-ol 88. N ^5- (2,4-Difluoro-phenyl) -N ^2- [5- (3-dimethylamino-pyrrolidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl -Thiazolo [5,4-b] pyridine-2,5-diamine 89. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -pyrrolidine-2-carboxylic acid methyl ester 90. 4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazine-1-carboxylic acid methylamide 91. 4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperazine-1-carboxylic acid dimethylamide 92. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidine-4-carboxylic acid methyl ester 93. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl Methyl) -piperidine-4-carboxylic acid 94. 1- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl amino} -pyridin-3-yl Methyl) -pyrrolidine-2-carboxylic acid 95. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- (5-piperazin-1-ylmethyl-pyridin-2-yl) -thiazolo [5,4- b] pyridine-2,5-diamine 96. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- Morpholin-4-yl-methanone 97. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-Methyl-piperazin-1-yl) -methanone 98. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (1-methyl-py Ferridin-4-ylmethyl) -nicotinamide 99. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-hydroxy- Ethyl) -nicotinamide 100. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-hydroxy-piperidin-1-yl) -methanone 101. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-morpholin- 4-yl-ethyl) -nicotinamide 102. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (2-hydroxy- Ethyl) -N-methyl-nicotinamide 103. N- (2-Diethylamino-ethyl) -6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Monoamino} -nicotinamide 104. 4-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine-3- Carbonyl) -amino] -piperidine-1-carboxylic acid tert-butyl ester 105. tert-Butyl [1- (6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine -3-carbonyl) -piperidin-4-yl] -carbamate 106. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N-piperidine-4- Mono-nicotinamide 107. (4-Amino-piperidin-1-yl)-(6- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine -2-ylamino} -pyridin-3-yl) -methanone 108. 6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -N- (1-methyl-pi Ferridin-4-yl) -nicotinamide 109. (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-3-yl)- (4-dimethylamino-piperidin-1-yl) -methanone 110. N ^5- (4-Chloro-2-fluoro-phenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4 -b] pyridine-2,5-diamine 111.N ^5- (4-Chloro-2-fluoro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-pyrazin-1-ylmethyl) -pyridin-2-yl]- Thiazolo [5,4-b] pyridine-2,5-diamine 112. 1- [4- (2- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine -4-ylmethyl) -piperazin-1-yl] -ethanone 113. N ^5- (4-Chlorophenyl) -N ⁵ -methyl-N ^2- (4-morpholin-4-ylmethyl-pyridin-2-yl) -thiazolo [5,4-b] pyridine- 2,5-diamine 114. N ^5- (4-Chloro-phenyl) -N ⁵ -methyl-N ^2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-yl] -thiazolo [5, 4-b] pyridine-2,5-diamine 115. 1- [4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl ) -Piperazin-1-yl] -ethanone 116. 4- (2- {5-[(4-Chloro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl) -pipe Razine-1-carboxylic acid dimethylamide 117. 1- [4- (2- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridine- 4-ylmethyl) -piperazin-1-yl] -ethanone 118. 6- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -nicotinic acid methyl ester 119. [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4 -Yl) -piperazin-1-yl] -acetic acid ethyl ester 120. 2- [4- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine -4-yl) -piperazin-1-yl] -ethanol 121. 2-[(6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4 -Yl) -methyl-amino] -ethanol 122. N ⁵ - (2,4- difluoro-phenyl) -N ⁵ - methyl -N ² - [6- (2- morpholine-4-yl-ethylamino) -pyrimidin-4-yl] - Thiazolo [5,4-b] pyridine-2,5-diamine 123. N ^5- (2,4-Difluoro-phenyl) -N ⁵ -methyl-N ^2- {6- [3- (4-methyl-piperazin-1-yl) -propylamino] -pyrimidine -4-yl} -thiazolo [5,4-b] pyridine-2,5-diamine 124. 2- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4- Monoamino) -ethanol 125. 2- (6- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyrimidine-4- Yl) -piperidine-1-carboxylic acid ethyl ester 126. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazine-2- On 127. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -pyrrolidine-3 -All 128. (( S ) -1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Pyrrolidin-2-yl) -methanol 129. N ⁵ -Methyl-N ^2- [4- (4-methyl- [1,4] diazepane-1-ylmethyl) -pyridin-2-yl] -N ⁵ -p-tolyl-thiazolo [5 , 4-b] pyridine-2,5-diamine 130. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -On 131. ( R ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid methyl ester 132. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -Amino) -propionic acid methyl ester 133. ({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -acetic acid ethyl ester 134. 1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -cyclo Propane carboxylic acid methyl ester 135. 2-methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid methyl ester 136. 2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -propane -1,3-diol 137. ( S ) -2- (methyl- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl } -Amino) -propionic acid methyl ester 138. 2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -ethanol 139. 1- (1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperi Din-4-yl) -ethanone 140. N ^2- [4- (4-methanesulfonyl-piperidin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4 -b] pyridine-2,5-diamine 141. N ² - [4- (4- methanesulfonyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4- b] pyridine-2,5-diamine ^{142. N 2 - (4 - {} [2- (2,5- dimethyl-4-yl) -ethyl-amino] -methyl} -pyridin-2-yl) -N ⁵ - methyl -N ⁵ -p -Tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 143. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazin-1- Carboxylic acid ethyl ester 144. 3-hydroxy-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -Amino) -propionic acid methyl ester 145. 3-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -propane -1,2-diol 146. [1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino)- Cyclopentyl] -methanol 147. 2-Methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propan-1-ol 148. N ^2- [4- (4-Isopropyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine 149. N ^2- [4- (4-cyclopropyl-piperazin-1-ylmethyl) -pyridin-2-yl] -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b ] Pyridine-2,5-diamine 150.N ⁵ -Methyl-N ^2- (4-peperazin-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine 151. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -On oxime 152. 1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperidine-4 -One O-methyl-oxime 153. N ⁵ -Methyl-N ^2- (4-pyrazol-1-ylmethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5- Diamine 154. 2-hydroxy-1- (4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl Methyl} -piperazin-1-yl) -ethanone 155. 4- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -piperazin-1- Carboxylic Acid Cyclopropylamide 156. (S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -py Lolidine-2-carboxylic acid 157. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid 158. ({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -amino) -acetic acid 159. ( R ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid 160. 1-({2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin- 4-ylmethyl} -amino) -cyclo Propanecarboxylic acid 161. 2-Methyl-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid 162. ( S ) -2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Amino) -propionic acid 163. 1-Methyl-4- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -pipe Razin-2-one 164. (R) -N-methoxy-2-({2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4 -Ylmethyl} -amino) -propionamide 165. N-methoxy-2-methyl-2 - ({2- [5- (-p- tolyl-amino) thiazolo [5,4-b] pyridin-2-ylamino] -pyridin -4 -Ylmethyl} -amino) -propionamide 166. N ⁵ -Methyl-N ^2- (4-methylaminomethyl-pyridin-2-yl) -N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 167. N ^2- (4-Aminomethyl-pyridin-2-yl) -N ⁵ -methyl-N ⁵ -p-tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 168. 2-Methanesulfonyl-N- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} Acetamide 169. 2-hydroxy-N- {2- [5-methyl-p-tolyl-amino] -thiazolo [5,4-b] pyridin-2-ylamino} -pyridin-4-ylmethyl} -acet amides 170. 5-oxo-pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-ylmethyl} -amide 171. 1-Methanesulfonyl-piperidine-4-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-ylmethyl} -amide 172. 2-Dimethylamino-N- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Acetamide 173. N- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} -3-piperidine -1-yl-propionamide 174. 1-Methyl-pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-ylmethyl} -amide 175. Pyrrolidine-2-carboxylic acid {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl }-amides 176. N ² - [4- (1,1- ^dioxo-6 -1 - T Omo morpholin-4-ylmethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5-diamine 177. N - {2- [5- (methyl -p- tolyl-amino) thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl} - methanesulfonamide 178. 1-Cyclopropyl-3- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-ylmethyl}- Urea 179. ( S ) -N-hydroxy-2- (methyl- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine -4-ylmethyl} -amino) -propionamide 180. N, N-dimethyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Acetamide 181. 1- (4-acetyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone 182. N-cyclopropyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acet amides 183. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperidine- 1-Day-Ethanon 184. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-pyrrolidine- 1-Day-Ethanon 185. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-morpholine-4 -Sun-Ethanon 186. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -acetamide 187. N- [2- (4-acetyl-piperazin-1-yl) -ethyl] -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] Pyridin-2-ylarmano] -pyridin-4-yl} -acetamide 188. N-Methyl-2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -acetamide 189. N- [2- (2,5-Dimethyl-oxazol-4-yl) -ethyl] -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4 -b] pyridin-2-ylarmano] -pyridin-4-yl} -acetamide 190. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperazine-1 -Sun-Ethanon 191.N- (1-Hydroxymethyl-propyl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine -4-yl} -acetamide 192. 1- (4-Ethyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethanone 193. 1- (4-Isopropyl-piperazin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -ethanone 194. 3-hydroxy-2- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl } -Acetylamino) -pyrionic acid methyl ester 195. 1-((S) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine -2-ylarmano] -pyridin-4-yl} -ethanone 196. 1-((R) -3-Amino-pyrrolidin-1-yl) -2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine -2-ylarmano] -pyridin-4-yl} -ethanone 197. N-[(R) -1- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine-4 -Yl} -acetyl) -pyrrolidin-3-yl] -acetamide 198. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -morpholin-4-yl-meta Paddy field 199. (4-Methyl-piperazin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine- 4-day} -Methanone 200. {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -piperazin-1-yl-meta Paddy field 203- (3-hydroxy-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-yl} -piperazin-1-yl-methanone 202. (3-Dimethylamino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Pyridin-4-yl} -methanone 203. N- [3- (4-Methyl-piperazin-1-yl) -propyl] -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Yl-amino] -isonicotinamide 204. N- [2- (4-acetyl-piperidin-1-yl) -ethyl] -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-ylamino] -isonicotinamide 205. N-(( R ) -1-hydroxymethyl-propyl) -2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino]- Isonicotinamide 206. (4-Amino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridine -4-yl} -methanone 207. (4-Dimethylamino-piperidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano]- Pyridin-4-yl} -methanone 208. ((S) -3-Amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -methanone 209. N-((S) -1- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4-carbonyl } -Pyrrolidin-3-yl) -acetamide 210. ((R) -3-Amino-pyrrolidin-1-yl)-{2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl Amano] -pyridin-4-yl} -methanone 211.N-((R) -1- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine-4-carbonyl } -Pyrrolidin-3-yl) -acetamide 212. 2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl} -ethanol 213. 1- [4- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamano] -pyridin-4-yl}- Ethyl) -piperazin-1-yl] -ethanone 214. 4- (2- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -ethyl)- Piperazin-2-one 215. ⁵ N-Methyl ^{-N 2 - {4- [2- (} 4- methyl-piperazin-1-yl) ethyl] pyridin-2-yl} -N ⁵ -p- tolyl-thiazolo [5, , 4-b] pyridine-2,5-diamine 216. ⁵ N-Methyl -N ² - [4- (2- morpholin-4-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine -2,5-diamine 217. ⁵ N-Methyl -N ² - [4- (2- pyrrolidin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine 218. ⁵ N-Methyl -N ² - [4- (2- piperazin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl - [5,4-b] thiazole in Pyridine-2,5-diamine 219. 2- [Methyl- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Ethyl) -amino] -ethanol 220. N ² - [4- (2- dimethylamino-ethyl) -pyridin-2-yl] -N ⁵ - methyl -N ⁵ -p- tolyl-thiazolo [5,4-b] pyridine-2,5 -Diamine 221. ⁵ N-Methyl -N ² - [4- (2- piperidin-1-yl-ethyl) -pyridin-2-yl] -N ⁵ -p- tolyl-thiazolo [5,4-b] Pyridine-2,5-diamine 222. ⁵ N-Methyl ^{-N 2 - {4- [2- (} 2- morpholin-4-yl-ethylamino) -ethyl] -pyridin-2-yl} -N ⁵ -p- tolyl-thiazolo [ 5,4-b] pyridine-2,5-diamine 223. 2-hydroxy-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridine- 4-yl} -ethyl) -piperazin-1-yl] -ethanone 224. 2-hydroxy-2-methyl-1- [4- (2- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -ethyl) -piperazin-1-yl] propan-1-one 225. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid methyl ester 226. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propionic acid 227. 1- (4-acetyl-piperazin-1-yl) -3- {2- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino ] -Pyridin-4-yl} -propan-1-one 228. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-morpholine-4 -Yl-propane-1-one 229. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -1-piperazin-1 -Yl-propane-1-one 230. 3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propan-1-ol 231. 1- [4- (3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl}- Propyl) -piperazin-1-yl] -ethanone 232. N ⁵ -Methyl-N ^2- {4- [3- (4-methyl-piperazin-1-yl) -propyl] -pyridin-2-yl} -N ⁵ -p-tolyl-thiazolo [5 , 4-b] pyridine-2,5-diamine 233. 4- (3- {2- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-ylamino] -pyridin-4-yl} -propyl)- Piperazine-1-carboxylic acid methylamide 234. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino}-methyl benzoate ester 235. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -benzoic acid 236. 2-Chloro-5-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N- Methoxy-benzamide 237. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5 , 4-b] -pyridin-5-yl} -methyl-amino) -2-chloro-N-methoxy-benzamide 238. 2-Chloro-N-methoxy-5- {methyl- [2- (4-morpholin-4-ylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridine-5 -Yl] -amino} -benzamide 239. 2-Chloro-N-methoxy-5- (methyl- {2- [4- (4-methyl-pyrazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4 -b] pyridin-5-yl} -amino) -benzamide 240. 3-[(2-amino-thiazolo [5,4-b] pyridin-5-yl) -methyl-amino] -N-methoxy-benzamide 241. 3-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -N-methoxy-benzamide 242. N-methoxy-3- {methyl- [2- (4-morpholin-4-ylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl]- Amino} -benzamide 243. N-methoxy-3- (methyl- {2- [4- (4-methyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridine -5-yl} -amino) -benzamide 244. 3-{[2- (4-Dimethylaminomethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methoxy-benz amides 245. 3-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N, N-dimethyl- Benzamide 246. 3-{[2- (4-hydroxymethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methyl-benzamide 247. 3-{[2- (4-Dimethylcarbamoylmethyl-pyridin-2-ylamino) -thiazolo [5,4-b] pyridin-5-yl] -methyl-amino} -N-methoxy- Benzamide 248. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-benzoic acid ethyl ester 249. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-N-methoxy-benzamide 250. 5-({2- [4- (4-acetyl-piperazin-1-ylmethyl) -pyridin-2-ylamino] -thiazolo [5,4-b] pyridin-5-yl} -methyl -Amino) -2-fluoro-N-methyl-benzamide A pharmacologically effective amount of a compound according to claim 1 for treating and inhibiting diseases caused by undesirable KDR activity; And a pharmaceutically acceptable carrier, diluent, or excipient, or a combination thereof. 7. The composition of claim 6, wherein the disease is cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, focal anemia, atherosclerosis or Kaposi's sarcoma.