KR20060079098A - Novel ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide derivatives - Google Patents

Abstract

The present invention provides a ([1,3] thiazolo [5,4- b ] pyridin-2-yl) -2-carboxamide structure that inhibits the activity of VEGFR2 kinase (KDR). The present invention relates to a compound of formula 1, a process for preparing the same, a use thereof, 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.

(1)

(One)

Wherein R ₁ , R ₂ , R ₃ And X is as defined in the specification.

Description

Novel ([1,3] thiazolo [5,4-k] pyridin-2-yl) -2-carboxamide derivatives {Novel ([1,3] Thiazolo [5,4-b] pyridin-2- yl) -2-carboxamide derivatives}

The present invention relates to a novel compound having a ([1,3] thiazolo [5,4- b ] pyridin-2-yl) -2-carboxamide structure, more particularly represented by Chemical Formula 1, Novel VEGF receptor2 kinase (VEGFR2 kinase or KDR, hereinafter referred to as "KDR") compounds, pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof, and the like are provided. 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. (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 m in diameter) without new angiogenesis. The reason for this is that there is a limit on the distance that oxygen or nutrients can leave the blood vessel and reach the cell 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).

Arthritis, an angiogenesis-related disease other than cancer, is angiogenesis-related disease in which neo-capillaries 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. Therefore, only by preventing angiogenesis, radical treatment is possible (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 on compounds that can be used as a therapeutic agent and a study on inhibiting angiogenesis-related diseases such as cancer, rheumatoid arthritis, diabetic retinopathy and the like using them.

Representative examples of compounds that inhibit the kinase activity of KDR include 2-indolinone derivatives (WO 9850356), quinazoline derivatives (EP 0566266 A1), triazole derivatives (WO 02057240), diaminothiazole (WO 0075120), benzo Thiazole derivatives (WO 0157008) and the like are known, but they are not structurally related to the compounds according to the invention.

After extensive research and numerous experiments, the present inventors have been able to synthesize novel compounds that inhibit KDR activity. As a result of evaluating the inhibitory activity, the compounds of Formula 1 may cause diseases due to undesirable KDR activity, eg For example, the inventors have found that the present invention can be used for the treatment of diseases related to angiogenesis, such as cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, and have completed the present invention.

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

(1)

(One)

Where

A) R ₁ is selected from the group consisting of the following substituents,

I) hydrogen;

II) optionally substituted straight chain, branched or cyclic saturated or unsaturated alkyl;

III) optionally substituted alkenyl;

IV) optionally substituted aryl;

V) optionally substituted heterocycle;

VI) perhaloalkyl;

Iii) a substituent of the formula -CY ₁ Y ₂ (Y ₃ ) nY ₄ ,

Wherein Y ₁ , Y ₂ are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and hetero aryl,

Y ₃ Is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

Y ₄ Is hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted Lower alkyl, optionally substituted aryl, and heteroaryl;

n is an integer from 0 to 3;

Iii) a substituent of the formula -NZ ₁ (Z ₂ ) n ₁ -Z ₃ ,

Where Z ₁ Is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and hetero aryl, or are linked together and are selected from cyclic saturated alkyl or cyclic saturated alkyl including N, O, S,

Z ₂ is selected from the group consisting of optionally substituted lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And

Z ₃ Is hydrogen and hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine , Aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl or heteroaryl;

n ₁ are each independently an integer of 0 to 3;

B) R ₂ is selected from cyclic alkyl, aryl, hetero aryl, or optionally substituted cyclic alkyl, aryl or hetero aryl;

C) R ₃ is selected from the group consisting of hydrogen, optionally substituted straight chain, branched or cyclic saturated or unsaturated alkyl; And

D) X is O, S or NR ' It is selected from the group consisting of wherein R 'is hydrogen or lower alkyl.

The terms used herein are briefly described.

Unless stated otherwise, "optionally substituted" is used to mean both substituted and unsubstituted, in which case the substituents are alkyl, cycloalkyl, Alkenyl, cyclo alkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl , N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, Isocyanato, thiocyanato, isothiocyanato, nitro, cyril, sulfonyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone (oxo-pyrrolidine), piperidine , Piperidinone (oxo-piperidine), piperazine, thiophene, morpholine, dioxolane, wool Amino, including no- and di-substituted amino groups, and those substituted with one or more groups selected individually and independently from protective derivatives thereof. In some cases, these may also be optionally substituted. In addition, the substituents may be bonded to each other to form a ring structure.

Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. And it means that the group may be substituted with one or more groups selected independently.

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 terms "hydrate", "solvate" and "isomer" also have the same meanings as above. 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, oxalic 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 compound of the present invention is reacted with a base, and salts 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, and N-methyl-D-glu It may be obtained by forming salts of organic bases such as carmine and tris (hydroxymethyl) methylamine, and amino acid salts such as arginine and lysine.

The term "hydrate" includes a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. Or salts thereof.

The term "solvate" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric amount of solvent bound by noncovalent intermolecular forces. Preferred solvents therein are volatile, nontoxic, and / or solvents suitable for administration to humans.

The term "isomer" means a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but which is optically or stereoscopically different.

The term "prodrug" refers to a substance that is transformed into a parent drug in vivo. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug. For example, prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to active chain carboxylic acids by metabolism in cells where water solubility is detrimental to mobility, but once water solubility is beneficial. Drug "). Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group which is converted by metabolism to reveal the active site.

Unless stated otherwise, the terms "compound according to the present invention" or "compound of formula 1" refer to all compounds, pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof. It is used as a concept to include.

The term "aryl" refers to an aryl group having at least one ring having a shared pi electron field and comprising a carbocyclic aryl (eg phenyl) and a heterocyclic aryl group (eg pyridine) Means. The term includes monocyclic or fused ring polycyclic (ie rings that divide adjacent pairs of carbon atoms) groups.

The term "heteroaryl" refers to an aryl group containing at least one heterocyclic ring.

The term "heterocycle" is a group in which ring carbon is substituted with oxygen, nitrogen, sulfur, etc., for example, furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imido Dazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyri Midine, pyrazine, piperazine, triazine, and the like, but are not limited to these.

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 an "alkyne" moiety means at least two carbon atoms having at least one carbon-carbon triple bond Means a group. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain or cyclic.

Alkyl groups may have from 1 to 20 carbon atoms. The alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms. The alkyl group may be lower alkyl having 1 to 6 carbon atoms. For example, C ₁ -C ₄ alkyl is one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t It is selected from the group consisting of -butyl.

Alkyl groups may be substituted or unsubstituted. If substituted, the substituents are cycloalkyl, cyclo alkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, merceto, alkylthio, arylthio, cyano, halogen, carbonyl, thio Carbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy , O-carboxy, acetyl, isocyanate, thiocyanato, isothiocyanato, nitro, cyryl, sulfonyl, pyrrolidinone, pyrrolidine, piperidine, piperazine, thiophene, morpholine And amino, including mono- and di-substituted amino groups, and substituted with one or more groups individually and independently selected from protective derivatives thereof. In some cases, these may also be optionally substituted.

Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. It is not limited only to these.

Substituent “R” as used herein, when described as such without designation of a number, is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted hetero A substituent selected from the group consisting of aryl (bonded via a ring carbon) and optionally substituted heteroalicyclic (bonded through a ring carbon).

"O-carboxy" group refers to a RC (= 0) O- group, wherein R is as defined herein.

A "C-carboxy" group refers to a -C (= 0) OR group, with R as defined herein. In the present specification, the expression “carboxy” without any limitation is interpreted to include both O-carboxy and C-carboxy.

An "acetyl" group refers to a -C (= 0) CH ₃ group.

Group refers to a Z ₃ CS (═O) ₂ — group, wherein Z is halogen.

"Cyano" group refers to a -CN group.

"Isocyanato" group refers to the -NCO group.

A "thiocyanato" group refers to a -CNS group.

"Isothiocyanato" group refers to a -NCS group.

"Sulfinyl" group refers to the group -S (= 0) -R, wherein R is as defined herein.

"S-sulfonamido" group means a -S (= 0) ₂ NR group, wherein R is as defined herein.

"N-sulfonamido" group refers to the RS (= 0) ₂ NH- group, wherein R is as defined herein.

Group refers to a Z ₃ CS (═O) ₂ NR— group, wherein Z and R are as defined herein.

"O-carbamyl" group refers to an -OC (= 0) -NR group, wherein R is as defined herein.

"N-carbamyl" group refers to the ROC (= 0) NH- group, with R as defined herein.

"O-thiocarbamyl" group refers to an -OC (= S) -NR group, wherein R is as defined herein.

"N-thiocarbamyl" group refers to the ROC (= S) NH- group, with R as defined herein.

A "C-amido" group refers to a -C (= 0) -NR ₂ group, where R is as defined herein.

"N-amido" group refers to the RC (= 0) NH- group, with R as defined herein.

The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced with halogen atoms.

Other terms may be interpreted as meanings commonly understood in the field to which the present invention belongs.

R ₁ is preferably selected from the following substituents I) -iii).

I) lower alkyl;

II) halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidi One or more selected from the group consisting of paddy, piperazine, thiophene, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Lower alkyl substituted with substituents;

III) cyclic alkyl or heterocycle;

IV) optionally substituted lower alkyl, halogen, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine , Pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Cyclic alkyl or heterocycle substituted with one or more substituents selected from the group consisting of;

V) alkenyl;

VI) optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, One selected from the group consisting of piperidine, piperidinone, piperazine, morpholin, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Alkenyl substituted with one or more substituents;

Iii) aryl or hetero aryl;

Iii) halogen, amide, carbonyl, carbamate, carboxy, lower alkyl, lower alkoxy, amine, lower alkylamine, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidi Aryl or hetero substituted with one or more substituents selected from the group consisting of paddy, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl Aryl;

Iii) a substituent of the formula -NZ ₁ (Z ₂ ) -Z ₃ ,

Where Z ₁ Is selected from hydrogen, optionally substituted lower alkyl,

Z ₂ is optionally substituted lower alkylene,

Z ₃ Is hydrogen and hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine , Aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl or heteroaryl.

R ₂ is preferably selected from the following substituents I) -IV).

Ⅰ) cyclic alkyl

II) halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, Cyclic alkyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl;

III) hetero aryl;

IV) halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, mol Aryl or hetero aryl substituted with one or more substituents selected from the group consisting of porin, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl.

R ₂ is more preferably halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, mol Aryl or hetero aryl substituted with one or more substituents selected from the group consisting of porin, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl, particularly preferably Is aryl substituted with halogen, lower alkyl, hydroxy.

R ₃ is preferably selected from the following substituents I) -III).

I) hydrogen;

II) lower alkyl;

III) consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkyl amino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amide oxime and trifluoromethyl Lower alkyl substituted with one or more substituents selected from the group.

R ₃ is more preferably hydrogen or lower alkyl.

X is preferably O or S, particularly preferably S.

Representative compounds of the invention include compounds as indicated below.

1. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopentanecarboxamide

2. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

3. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (thiophen-2-yl) acetamide

4. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -3-cyclopentylpropanamide

5. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (4-morpholinyl) acetamide

6. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (1-pyrrolidinyl) acetamide

7. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (diethylamino) acetamide

8. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acetamide

9. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2-methylpropanamide

10. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclobutane carboxamide

11. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (4-morpholino carbonyl) Pro Panama Id

12. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -2- (4-methyl-1-piperazinyl) acetoxy Tama Id

13. Ethyl 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylate

14. 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylic acid

15. N- [5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- (4- Morpholinyl) ethyl] urea

16. N - [5- (4- fluoro-2-hydroxymethyl-anilino [l, 3] thiazolo [5,4- b] pyridin-2-yl cyclopropane carboxyl amide

17. N- [5- (cyclohexylamino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

18. N - [5- (cyclopentylamino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide

19. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (diethylamino) prop Panama Id

20. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (1-piperidinyl) pro Panama Id

21. N - [5- (3- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide

22. N- [5- (2-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

23. N- [5- (2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

24. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

25. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (4-morpholinyl) acene Tamid

26. N - [5- (2- fluoro-4-methyl Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (4-morpholino carbonyl) Pro Panamide

27. N- [5- (2-fluoro-4-methoxyanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

28. 2-({[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxyl mountain

29. N- [5- (4-bromo-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

30. N- [5- (3-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

31. N - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide

32. N- [5- (2,4-difluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

33. N - [5- (2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -2 - [(4-methyl-1 Piperazinyl) carbonyl] cyclopropanecarboxamide

34. N ¹ - [2- (diethylamino) ethyl] - N ² - [5- (2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin- 2-yl] -1,2-cyclopropanedicarboxamide

35. (E) - N - [ 5- ( 2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-phenyl-2 Propenamid

36. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acrylamide

37. N ¹ - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] ^{pyridin-2-yl] - N 2 - [2- (} 4- Morpholinyl) ethyl] -1,2-cyclopropanedicarboxamide

38. N ¹ - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] ^{pyridin-2-yl] - N 2 - [2- (} 2- Pyridinyl) ethyl] -1,2-cyclopropanedicarboxamide

39. N- [5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acrylamide

40. N- [5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -3-methyl-3-butenamide

41. N - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-methyl-2-butene amide

42. N - [5- (4- chloro-2-fluoro not Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-butene amide

43. (E) - N - [ 5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -amide 2-butene

44. N- [5- (2,6-difluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

45. N - {5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} cyclopropane carboxamide

46. N- {5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} acrylamide

47. N- {5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

48. N- {5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} acrylamide

49. Ethyl 2- (4-chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) acetate

50. 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) acetic acid

51. 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) ethyl cyclopropanecarboxylate

52. N- {5- [4-Chloro (2-hydroxyethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

53. N- [5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

54. N- {5- [2,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

55. N - {5- [2,6- difluoro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} cyclopropane carboxamide

56. N- [5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide

57. N- {5- [2-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

58. N- {5- [3,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

59. N- {5- [methyl-4- (trifluoromethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

60. N- {5- [4-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

61. N- {5- [4-cyano (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

62. N- {5- [4-isopropyl (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide

63. N- {5- [2,3-dihydro-1 H -inden-5-yl (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclo Propanecarboxamide

64. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -pyrrole-2-car Copyamide

65. Ethyl 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzoate

66. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzoic acid

67. (E) - N - [ 5- (4- methyl bromide is not the parent-2fluoroanilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3 (4 -Piperidinyl) 2-propenamide

68. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1-ethyl-4 -Piperidinyl) -2-propenamide

69. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1-methyl- 4-piperidinyl) -2-propenamide

70. (E) - N - {5- [4-Chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (4-morpholino carbonyl ) -2-buteneamide

71. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] -N , N -dimethylbenzamide

72. 4 - [{2 - [(cyclopropylcarbonyl) amino] [1, 3] thiazolo [5,4- b] pyridin-5-yl} (methyl) amino] - N - [2- (dimethyl Amino) ethyl] benzamide

73. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -imidazole-4- Carboxamide

74. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] -N -methylbenzamide

75. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -imidazole-5- Carboxamide

76. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1 - (methylsulfonyl Ponyl) -4-piperidinyl) -2-propenamide

77. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzamide

78. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (1-piperidinyl ) -2-buteneamide

79. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (1,4- Oxa-8-azaspiro [4.5] de-8-sil) -2-buteneamide

80. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (dimethylamino) -2 Buteneamide

81. Ethyl 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] phenyl} acetate

82. 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] phenyl} acetic acid

83. N- {5- [4- [2- (dimethylamino) -2-oxoethyl] (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclo Propanecarboxamide

84. Ethyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} amino) -3 -Oxo-1-propenyl] -1-piperidinecarboxylate

85. Methyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} amino) -3 -Oxo-1-propenyl] -1-piperidinecarboxylate

86. (E) -3- (1- acetyl-4-piperidinyl) - N - {5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridine -2-yl} -2-propenamide

87. N- [5- (4-Chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- (4- Morpholinyl) ethyl] urea

88. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-ethyl-urea

89. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl}-3- (2-diethylamino- Ethyl) -urea

90. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-hydroxy-propyl ) -Urea

91. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholine-4 -Work-profile)-urea

92. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-methoxy-ethyl ) -Urea

93. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyrrolidine- 1-yl-ethyl) -urea

94. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea

95. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-dimethylamino-propyl ) -Urea

96. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-diethylamino- Profile) -urea

97. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1-methyl -Pyrrolidin-2-yl) -ethyl] -urea

98. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyridine-2- Yl-ethyl) -urea

99. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl}-3- (2-hydroxy-ethyl ) -Urea

100. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxy-1 -Methyl-ethyl) -urea

101. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxy-propyl ) -Urea

102. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-dimethylamino-ethyl ) -Urea

103. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclopentyl-urea

104. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclohexyl-urea

105. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-piperidine- 1-yl-ethyl) -urea

106. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (5-methyl-pyrazine- 2-ylmethyl) -urea

107. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyridine-4- Yl-ethyl) -urea

108. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-4-yl-urea

109. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1,5-dimethyl- 1H-pyrrole-3-ylmethyl) -urea

110. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-thiophen-3-ylmethyl Urea

111. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-furan-3-ylmethyl- Urea

112. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -1- (2-hydroxy-ethyl ) -1-methyl-urea

113. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-((R) -1- Hydroxymethyl-propyl) -urea

114. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-4-ylmethyl- Urea

115. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-3-ylmethyl- Urea

116. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-2-ylmethyl- Urea

117. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-3-yl-urea

118. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-2-yl-urea

119. 4- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido) -pi Ferridine-1-carboxylic acid tert-butyl ester

120. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclopropylmethyl-urea

121. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclohexylmethyl-urea

122. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-phenyl-urea

123. 1-Benzyl-3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -urea

124. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-phenethyl-urea

125. 4- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureidomethyl)- Piperidine-1-carboxylic acid tert-butyl ester

126. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-hydroxy-butyl ) -Urea

127. 3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureidomethyl)- Piperidine-1-carboxylic acid tert-butyl ester

128. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (3- Hydroxy-propoxy) -ethyl] -urea

129. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((R) -2 -Hydroxy-1-methyl-ethyl) -urea

130. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {2-[(2 -Hydroxy-ethyl) -methyl-amino] -ethyl} -urea

131. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Hydroxy-piperidin-1-yl) -ethyl] -urea

132. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3-[(2 -Hydroxy-ethyl) -methyl-amino] -propyl} -urea

133. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxy-piperidin-1-yl) -propyl] -urea

134. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3- [4- (2-hydroxy-ethyl) -piperidin-1-yl] -propyl} -urea

135. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-hydroxy-urea

136. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-methoxy-urea

137. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (carboxymethyloxy)- Urea

138. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido) -ethyl] -acet amides

139. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (methylamino) -urea

140. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxyethyl Amino) -urea

141. 1- (4-Aminomethyl-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Sun} -urea

142. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyridine-1 -Work-profile)-urea

143. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxymethyl-piperidin-1-yl) -propyl] -urea

144. {(S) -1- [3- (3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4

-b] pyridin-2-yl} -ureido) -propyl] -pyrrolidin-3-yl} -carbamic acid tert-butyl ester

145. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3,4-di Hydroxy-benzyl) -urea

146. 1- (4-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea

147. 1- (3-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea

148. 1- (2-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea

149. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (tetrahydro-furan- 2-ylmethyl) -urea

150. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-imidazole- 1-yl-propyl) -urea

151. 1- (4-Amino-cyclohexyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Sun} -urea

152. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-hydroxy- Cyclohexyl) -urea

153. (S) -1- [3- (3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Ureido) -propyl] -pyrrolidine-2-carboxylic acid tert-butyl ester

154. (R) -1- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Ureido) -propyl] -pyrrolidine-2-carboxylic acid tert-butyl ester

155. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Oxo-piperidin-1-yl) -propyl] -urea

156. 3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -1- (2-hydroxy- Ethyl) -1-methyl-urea

157. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-piperidine 4-yl-ethyl) -urea

158. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-4 -Work-urea

159. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-4- Ylmethyl-urea

160. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-3- Ylmethyl-urea

161. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-piperazin- 1-yl-propyl) -urea

162. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (S) -pyrroli Din-3-yl-urea

163. 1- [3-((S) -3-Amino-pyrrolidin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino ] -Thiazolo [5,4-b] pyridin-2-yl} -urea

164. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-methylamino- Ethyl) -urea

165. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxyimino-piperidin-1-yl) -propyl] -urea

166. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((R ) -2-hydroxymethyl-pyrrolidin-1-yl) -propyl] -urea

167. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((S ) -2-hydroxymethyl-pyrrolidin-1-yl) -propyl] -urea

168. 4- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido ) -Propyl] -pyrazine-1 -carboxylic acid ethyl ester

169. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methanesulfonyl-piperazin-1-yl) -propyl] -urea

170. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Ethanesulfonyl-piperazin-1-yl) -propyl] -urea

171. 1- [3- (4-acetyl-Piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea

172. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Cyclopropyl-piperazin-1-yl) -propyl] -urea

173. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3- [4- (2-Fluoro-ethyl) -piperazin-1-yl] -propyl} -urea

174. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Propionyl-piperazin-1-yl) -propyl] -urea

175. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Cyclopropionyl-piperazin-1-yl) -propyl] -urea

176. 1- [2- (4-Acetyl-piperazin-1-yl) -ethyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea

177. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1- Methyl-piperidin-4-yl) -ethyl] -urea

178. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1- Ethyl-piperidin-4-yl) -ethyl] -urea

179. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-4-yl) -urea

180. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-4-yl) -urea

181. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-4-ylmethyl) -urea

182. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-4-ylmethyl) -urea

183. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-3-ylmethyl) -urea

184. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-3-ylmethyl) -urea

185. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((S) -1 -Methyl-pyrrolidin-3-yl) -urea

186. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((S) -1 -Ethyl-pyrrolidin-3-yl) -urea

187. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((S ) -3-dimethylamino-pyrrolidin-1-yl) -propyl] -urea

188. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-dimethylamino- Cyclohexyl) -urea

189. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Ethyl-piperazin-1-yl) -propyl] -urea

190. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Isopropyl-piperazin-1-yl) -propyl] -urea

191. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Isobutyl-piperazin-1-yl) -propyl] -urea

192. 1- [3- (4-sec-Butyl-piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thia Zolo [5,4-b] pyridin-2-yl} -urea

193. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -3-oxo-propyl] -urea

194. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [4- (4- Methyl-piperazin-1-yl) -butyl] -urea

195. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Methyl-piperazin-1-yl) -ethyl] -urea

196. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-morpholin-4-yl-ethyl) -urea

197. 1-Ethyl-3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

198. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-morpholin-4-yl-propyl) -urea

199. 1- (2-Diethylamino-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

200. 1- [3- (4-Methyl-piperazin-1-yl) -propyl-3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea

201. 1- (3-hydroxy-propyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

202. 1- (3-Diethylamino-propyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

203. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-2-ylmethyl-urea

204. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-3-ylmethyl-urea

205. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-4-ylmethyl-urea

206. 1- (5-Methyl-pyrazin-2-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

207. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-2-yl-ethyl) -urea

208. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-4-yl-ethyl) -urea

209. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyrrolidin-1-yl-ethyl) -urea

210. 1- (1,5-dimethyl-1H-pyrrole-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea

211. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-3-yl-ethyl) -urea

212. 1- (4-hydroxy-butyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

213. 1- (2-hydroxy-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

214. 1-((R) -2-hydroxy-1-methyl-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea

215. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (2-oxo-pyrrolidin-1-yl ) -Propyl] -urea

216. 1- [2- (2-hydroxy-ethoxy) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] Urea

217. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-pyrrolidin-1-yl-propyl) -urea

218. 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea

219. 1- {3-[(2-hydroxy-ethyl) -methyl-amino] -propyl} -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea

220. 1- [3- (4-hydroxy-piperidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea

221. 1- [3-((R) -3-hydroxy-pyrrolidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4 -b] pyridin-2-yl] -urea

222. 1- [3- (4-hydroxymethyl-piperidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] Pyridin-2-yl] -urea

223. (R) -2- {3- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -ureidomethyl} -pyrrolidine-1 -Carboxylic acid tert-butyl ester

224. 1- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Work] -urea

225. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-4-yl-urea

226. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-4-ylmethyl-urea

227. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-3-ylmethyl-urea

228. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-piperidin-4-yl-ethyl) -urea

229. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-piperazin-1-yl-propyl) -urea

230. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (S) -pyrrolidin-3-yl-urea

231. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (R) -1-pyrrolidin-2-ylmethyl- Urea

232. 1- [2- (1-Methyl-piperidin-4-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea

233. 1- [2- (1-Ethyl-piperidin-4-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea

234. 1- (1-Methyl-piperidin-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea

235. 1- (1-Ethyl-piperidin-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea

236. 1- (1-Methyl-piperidin-4-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea

237. 1- (1-ethyl-piperidin-4-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] urea

238. 1- (1-Methyl-piperidin-4-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea

239. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Work] -urea

240. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea

241. 1-((S) -1-Methyl-pyrrolidin-3-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea

242. 1-((S) -1-Ethyl-pyrrolidin-3-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea

243. 1-((R) -1-furan-2-ylmethyl-pyrrolidin-2-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4- b] pyridin-2-yl] -urea

244. 1-[(R) -1- (1-Methyl-1H-pyrrole-2-ylmethyl) -pyrrolidin-2-ylmethyl] -3- [5- (methyl-p-tolyl-amino) -Thiazolo [5,4-b] pyridin-2-yl] urea

245. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl ) -Propyl] -urea

246. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl ) -Propyl] -urea

247. 1- [3- (4-Methanesulfonyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea

248. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea

249. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4 -Work-profile)-urea

250. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4 -Yl-ethyl) -urea

251. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl -Piperazin-1-yl) -ethyl] -urea

252. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperi Din-4-ylmethyl) -urea

253. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-iso Propyl-piperazin-1-yl) -propyl] -urea

254. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-ethyl -Piperazin-1-yl) -propyl] -urea

255. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methane Sulfonyl-piperazin-1-yl) -propyl] -urea

256. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-ethyl -Piperazin-1-yl) -ethyl] -urea

257. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea

258. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrazole-1 -Work-profile)-urea

259. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-propy O'Neill-piperazin-1-yl) -propyl] -urea

260. 1- [3- (4-Cyclopropanecarbonyl-piperazin-1-yl) -propyl] -3- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thia Zolo [5,4-b] pyridin-2-yl} -urea

261. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea

262. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea

263. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-methyl-piperazin-1-yl) -propyl ] -Urea

264. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-morpholin-4-yl-propyl) -urea

265. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-morpholin-4-yl-ethyl) -urea

266. 1- [3- (4-acetyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea

267. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl)- Profile]-Urea

268. 1- [3- (4-Cyclopropanecarbonyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea

269. 1- [3- (4-Methyl-piperazin-1-yl) -propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5, 4-b] pyridin-2-yl} -urea

270. 1- {5- [Methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4- Yl-ethyl) -urea

271. 1- {5- [Methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4- Th-propyl) -urea

272. 1- [3- (4-Ethyl-piperazin-1-yl-propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4 -b] pyridin-2-yl} -urea

273. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea

274. 1- [2- (4-Methyl-piperazin-1-yl) -ethyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -azino] -thiazolo [5,4-b] pyridin-2-yl} -urea

275. 1- (1-Methyl-piperidin-4-ylmethyl) -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] Pyridin-2-yl} -urea

276. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea

277. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- (3-morpholin-4-yl-propyl) -urea

278. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-methyl-piperazin-1-yl ) -Propyl] -urea

279. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [2- (4-methyl-piperazin-1-yl ) -Ethyl] -urea

280. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- (1-methyl-piperidin-4-ylmethyl) Urea

281. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-ethyl-piperazin-1-yl ) -Propyl] -urea

282. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-methanesulfonyl-piperazine-1 -Work) -propyl] -urea

283. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-isopropyl-piperazin-1- Th) -propyl] -urea

284. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [2- (4-ethyl-piperazin-1-yl ) -Ethyl] -urea

285. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-cyano-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea

286. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrazol-1-yl- Profile) -urea

287. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea

288. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea

289. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea

290. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl-piperazine -1-yl) -ethyl] -urea

291. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperidine-4 -Ylmethyl) -urea

292. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe) Razin-1-yl) -propyl] -urea

293. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea

294. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methanesulfonyl- Piperazin-1-yl) -propyl] -urea

295. 1- [2- (4-Ethyl-piperazin-1-yl) -ethyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea

296. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea

297. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea

298. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea

299. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperidine-4 -Ylmethyl) -urea

300. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea

301. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl-piperazine -1-yl) -ethyl] -urea

302. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- {5-[(2-fluoro-4-methoxy-phenyl) -ethyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -urea

303. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe Razin-1-yl) -propyl] -urea

304. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-metalsulfonyl- Piperazin-1-yl) -propyl] -urea

305. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -propyl] -urea

306. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-hydroxy- Profile) -urea

307. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholine- 4-yl-propyl) -urea

308. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-diethylamino -Propyl) -urea

309. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholine- 4-yl-ethyl) -urea

310. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrrolidine -1-yl-propyl) -urea

311. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Methyl-piperazin-1-yl) -ethyl] -urea

312. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea

313. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-ethyl-piperazine -1-yl) -propyl] -urea

314. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe Razin-1-yl) -propyl] -urea

315. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea

316. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea

317. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea

318. 1- [3- (4-acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-broro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea

319. 1- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea

320. 1- {5-[(2,6-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea

321. 1- {5-[(4-Chloro-3-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -propyl] -urea

322. 1- {5-[(2,3-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea

323. 1- {5-[(2-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea

324. 1- {5-[(2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea

325. 1- [3- (4-Methyl-piperazin-1-ylpropyl] -3- {5- [methyl- (2,3,4-trifluoro-phenyl) -amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea

The present invention also provides a method for preparing the compound of Formula 1. As can be seen in the preparations and examples to be described later, the preparation method of 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 one embodiment, the compound of Formula 1 is prepared by using 2-chloro-5-nitropyridine of Formula 2 as a starting material, and (i) introducing an NR ₂ R ₃ substituent in Formula 1, It can be produced by a method comprising the step of (ii) making a hetero pyridine, and (iii) introducing a carboxamide.

(2)

(2)

In one embodiment for the preparation of a compound in which X is S in Formula 1, the method of Formula 1,

a) reacting an amine with a compound of Formula 2 to prepare a compound of Formula 3;

(3)

(3)

Wherein R ₂ and R ₃ are the same as in formula (1).

b) preparing a compound of formula 4 by modifying the nitro group of the compound of formula 3 with an amine;

(4)

(4)

c) reacting bromine and thiocyanate to a compound of Formula 4 to prepare a compound of Formula 5; And

(5)

(5)

d) introducing a carboxamide to the compound of formula (5).

For reference, on the basis of the above, more specific reaction steps of the manufacturing method according to one embodiment are described below, but this is only for better understanding, and the scope of the present invention is not limited thereto. .

The following scheme shows the preparation of the compound of Formula 1.

In another embodiment, the method of formula 1

a) introducing bromoacetyl to a compound of Formula 5 to prepare Compound 6 below;

(6)

(6)

b) reacting the compound of Formula 6 with triethylphosphate to prepare Compound 7; And

(7)

(7)

c) reacting the compound of formula 7 with an aldehyde to produce a compound of formula 1 wherein R ₁ is an optionally substituted unsaturated alkyl substituent.

The following scheme shows that R ₁ is (4-piperidinyl) -2-propenamide in the compound of Formula 1 The manufacturing process of the phosphorus compound is shown.

The following scheme shows the preparation of a compound wherein R ₁ is -NZ ₁ (Z ₂ ) nZ ₃ in the compound of Formula 1.

Wherein R ₄ is the same as defined above and R ₅ Is the same as R _4, and Ra represents —Z ₁ (Z ₂ ) nZ ₃ .

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. Accordingly, the present invention provides a method of using the compound of formula 1 in the manufacture of a medicament for the treatment or prevention of such diseases. Examples of the diseases include, but are not limited to, cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic heart disease, atherosclerosis, Kaposi's sarcoma, and the like.

The invention also provides a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of the invention; 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.

The term “therapeutically effective amount” means that the amount of the compound administered to alleviate to some extent one or more symptoms of the disorder being treated. Thus, a pharmacologically effective amount can be obtained by (1) reversing the rate of progression of a disease or, in the case of cancer, reducing the size of a tumor; (2) the effect of inhibiting further progression of the disease to some extent and somewhat slowing in the case of cancer, or preferably stopping tumor metastasis; And / or (3) an amount having the effect of somewhat alleviating (preferably eliminating) one or more symptoms associated with the disease.

The term "carrier" is defined as a compound that facilitates the addition of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the incorporation of many organic compounds into organisms' cells or tissues.

The term "diluent" is defined as a compound that not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.

The term "physiologically acceptable" is defined as a carrier or diluent that does not impair the biological activity and the properties of the compound.

The compounds used herein may be administered to human patients as such or as pharmaceutical compositions in combination with other active ingredients or with a suitable carrier or excipient, such as in a combination therapy. Techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

a) Route of administration

Suitable routes of administration include, for example, oral, nasal, penetrating mucosal, or enteral administration; Parenteral delivery, including intramuscular, subcutaneous, intravenous, bone marrow injection, as well as intradiaphragmatic, direct intraventricular, intraperitoneal, or intraocular injection.

In addition, the compounds may also be administered in a local rather than systemic manner, for example by direct injection into solid tumors, often in immersion or sustained release formulations. Agents may also be administered as targeted drug delivery systems, eg, in liposomes coated with tumor-specific antibodies. Liposomes are targeted to and taken arbitrarily by the tumor.

b) Composition / Formulation

Pharmaceutical compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping and or lyophilizing processes. .

Thus, pharmaceutical compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.

For injection, the components of the invention may be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffalo. For mucosal permeation administration, noninvasive agents suitable for the barrier to pass through are used in the formulation. Such non-invasive agents are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. Such carriers allow the compounds of the present invention to be formulated into tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. Pharmaceutical preparations for oral use may be achieved by mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, treating the mixture of granules after permeation of appropriate adjuvants. A tablet or sugar core can be obtained. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone ( Cellulose-based materials such as PVP). If necessary, a disintergrating agent may be added, such as crosslinked polyvinyl pyrrolidone, butadiene, or salts thereof such as alginic acid or sodium alginate.

Sugar cores are supplied by appropriate coating. For this purpose, concentrated sugars, which optionally include arabide gum, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures Solutions can be used. Dyestuffs or pigments may be included in the tablets or sugars to characterize the identification of the active compound or to characterize other combinations thereof.

Pharmaceutical preparations that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycol or sorbitol, as well as pushable capsules made of gelatin. The push-fix capsule may contain the active ingredients, as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.

For buccal administration, the compositions may take the form of tablets or lozenges formulated according to conventional methods.

For administration by inhalation, the compounds of use according to the invention typically use a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Thus, it may be delivered in the form of aerosol injection provision from a pressurized pack or nebulisher. For use in inhalants or pulverulents, capsules and cartridges such as, for example, gelatin may be formulated comprising a powdered mixture of the compound and a suitable powder such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, eg, by large pill injection or continuous infusion. Injectable formulations may be presented in unit dose form, for example, as ampoules or multi-dos containers, with preservatives added. The compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants.

Liquid formulations for parenteral administration include liquid solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty acids such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, liposomes and the like. Liquid injection suspensions may include substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, dextran, and the like. In some cases, suspensions may contain components or stabilizers that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

The active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

The compounds may also be formulated in rectal dosage compositions, such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may be formulated as deposits. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular infusion. Thus, the compounds may, for example, be formulated with a suitable polymer or hydrophobic material (such as an emulsion in an acceptable oil), or with an ion exchange resin, or as a low soluble derivative, for example a low soluble salt. have.

The formulation carrier for the hydrophobic compound of the present invention is a cosolvent system composed of benzyl alcohol, nonpolar surfactant, water-miscible organic polymer, and liquid phase. The cosolvent may be a VPD cosolvent. VPD is a solution of benzyl alcohol 3% w / v, nonpolar surfactant Polysorbate 80 ^™ 85 w / v, and polyethylene glycol 300 65% w / v, made up to volume in anhydrous ethanol. VPD co-solvent system (VPD: D5W) consists of VPD diluted 1: 1 with 5% testrose in aqueous solution. This cosolvent system dissolves hydrophobic compounds well and provides itself with low toxicity upon systemic administration. Naturally, the proportion of cosolvent system may vary considerably without compromising its solubility and toxicological properties. Moreover, the identification of cosolvent components can be varied: for example, other low toxicity nonpolar surfactants can be used in place of Polysorbate 80 ^™ ; The fraction size of polyethylene glycol can vary; Other biocompatible polymers may replace polyethylene glycols such as, for example, polyvinyl pyrrolidone; And other parties and polysaccharides can replace dextrose.

In addition, other delivery systems for hydrophobic drug compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles for hydrophobic agents. Any organic solvent, such as dimethylsulfoxide, may be employed, usually at the expense of higher toxicity. In addition, the compound may be delivered using a sustained release system, such as a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic ingredient. Various sustained release materials have been developed and are known to those skilled in the art. Sustained release capsules can release the compound from 2 or 3 weeks to 100 days depending on its compound properties. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stability may be employed.

Many compounds of the present invention may also be provided as salts with pharmaceutically acceptable counterions. Pharmaceutically acceptable salts may be formed with many acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to dissolve better in aqueous or proton solutions than their corresponding acid free or base forms.

c) Effective amount

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.

A therapeutically effective amount for any compound used in the methods of the invention can be determined initially from cell culture assays. For example, the dose can be calculated in an animal model to obtain a range of circulating concentrations comprising an IC ₅₀ determined in cell culture. Such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficiency of the compounds described herein can be determined, for example, to determine LD ₅₀ (lethal dose for 50% of the population) and ED ₅₀ (dose with therapeutic effect for 50% of the population). Estimates can be made by surface pharmaceutical procedures in culture or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD ₅₀ and ED ₅₀ . Compounds showing high therapeutic indices are preferred. The data obtained from these cell culture assays can be used to estimate the range of doses used in humans. The dosage of such compounds is preferably in the range of circulating concentrations comprising ED ₅₀ in the absence or little toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact estimate, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (eg, Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 Reference). 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.

Dosages and intervals may be individually adjusted to provide plasma levels of the active site sufficient to maintain a kinase modulating effect or minimal effective concentration (MEC). The MEC depends on the individual compound, but can also be predicted from ex vivo data such as, for example, the concentration required to achieve 50-90% inhibition of kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC or biological quantification can be used to determine plasma concentration.

Dosage intervals may be determined using MEC values. Compounds should be administered using a dosing regimen that maintains blood serum levels above the MEC, such that 10-90%, preferably 30-90%, particularly preferably 50-90% at a time.

In the case of topical administration or selective uptake, the effective local concentration of the medicament may not be related to the plasma concentration.

Of course, the amount of composition to be administered will depend on the subject to be treated, on the weight of the subject, on the severity of pain, on the manner of administration and on the judgment of the physician.

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 these.

[ Production Example  One] N -(4- Chlorophenyl ) -5-nitro-2- Pyridineamine  Produce

5.00 g (31.5 mmol) of 2-chloro-5-nitropyridine was dissolved in 100 mL of dimethylsulfoxide, and 4.02 g (31.5 mmol) of 4-chloroaniline was added, followed by heating under reflux and stirring. After 5 hours, the temperature was lowered to room temperature, diluted with 500 mL of ethyl acetate, and washed with 300 mL of water and 300 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting impure compound was purified by column chromatography (dichloromethane) to give 5.43 g (21.7 mmol) of the title compound in a yield of 69%.

¹ H NMR (DMSO, ppm); δ 6.93 (1H, d), 7.33 (2H, d), 7.73 (2H, d), 7.91 (1H, d), 9.14 (1H, s)

ESI MS (m / e) = 250 [M + 1]

[ Production Example  2] N ² -(4- Chlorophenyl ) -2,5- Pyridinediamine  Produce

5.43 g (21.7 mmol) of the compound obtained in Preparation Example 1 were dissolved in 150 mL of ethyl acetate, and 9.79 g (43.4 mmol) of tin (II) chloride dihydrate was added thereto, followed by stirring at room temperature. After 5 hours, 500 mL of ethyl acetate was added thereto, diluted, and washed with 300 mL of 1N aqueous sodium hydroxide solution and 300 mL of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resulting impure compound was purified by column chromatography (hexane / ethyl acetate = 2/1, v / v) to give 2.53 g (11.5 mmol) of the title compound. Obtained at 53% yield.

¹ H NMR (DMSO, ppm); δ 6.93 (1H, d), 7.10 (2H, d), 7.57 (3H, m), 7.81 (1H, d)

ESI MS (m / e) = 220 [M + 1]

[ Production Example  3] N ⁶ -(4- Chlorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

2.53 g (11.5 mmol) of the compound obtained in Preparation Example 2 was dissolved in 100 mL of acetic acid, and 3.35 g (34.5 mmol) of potassium thiocyanate was added, followed by cooling to minus 20 degrees Celsius. Slowly stirring with a mechanical stirrer and slowly adding 1.84 g (11.5 mmol) of bromine, the temperature was gradually raised to room temperature over 2 hours and further stirred for 8 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, diluted with 300 mL of ethyl acetate, washed with 150 mL of water and 150 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resulting impure compound was purified by column chromatography (hexane / ethyl acetate = 1/1, v / v) to give 2.40 g (8.67 mmol) of the title compound. Obtained in 75% yield.

¹ H NMR (DMSO, ppm); δ 6.93 (1H, d), 7.33 (2H, d), 7.74 (2H, d), 7.90 (1H, d), 9.45 (1H, s)

ESI MS (m / e) = 277 [M + 1]

[ Production Example  4] N ⁶ - Cyclohexyl [1,3] tea Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 3.12 g (31.5 mmol) of hexylamine instead of 4-chloroaniline, and then 2.50 g (10.1 mmol) of the title compound was obtained in the same manner as in Preparation Example 2 and Preparation Example 3. Obtained at 32%.

¹ H NMR (DMSO, ppm); δ 1.01-1.84 (11H, m), 6.93 (1H, d), 7.91 (1H, d)

ESI MS (m / e) = 249 [M + 1]

[ Production Example  5] N ⁶ - Cyclopentyl [1,3] tea Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

The reaction was carried out using 2.68 g (31.5 mmol) of pentylamine in Preparation Example 1 instead of 4-chloroaniline, and then 3.30 g (14.1 mmol) of the title compound was obtained in the same manner as in Preparation Example 2 and Preparation Example 3. Obtained at 45%.

¹ H NMR (DMSO, ppm); δ 1.12-1.82 (9H, m), 6.93 (1H, d), 7.91 (1H, d)

ESI MS (m / e) = 235 [M + 1]

[ Production Example  6] N ⁶ -(3- Chlorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 4.02 g (31.5 mmol) of 3-chloroaniline instead of 4-chloroaniline, and then 3.44 g (12.4 mmol) of the title compound was washed in the same manner as in Preparation Example 2 and Preparation Example 3. The process yield was obtained at 39%.

¹ H NMR (DMSO, ppm); δ 6.30 (1H, dd), 6.95 (1H, d), 7.31 (1H, t), 7.58 (1H, dd), 7.89 (1H, t), 7.94 (1H, d)

ESI MS (m / e) = 277 [M + 1]

[ Production Example  7] N ⁶ -(2- Chlorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 4.02 g (31.5 mmol) of 2-chloroaniline instead of 4-chloroaniline, and then 3.11 g (11.2 mmol) of the title compound was washed in the same manner as in Preparation Example 2 and Preparation Example 3. The process yield was obtained at 36%.

¹ H NMR (DMSO, ppm); δ 7.04 (1H, t), 7.08 (1H, d), 7.32 (1H, t), 7.48 (1H, d), 7.92 (1H, d), 8.00 (1H, d), 8.61 (1H, s)

ESI MS (m / e) = 277 [M + 1]

[ Production Example  8] N ⁶ -(2- Fluorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

After reacting with 3.50 g (31.5 mmol) of 2-fluoroaniline instead of 4-chloroaniline in Preparation Example 1, 2.53 g (9.72 mmol) of the title compound were prepared in the same manner as in Preparation Example 2 and Preparation Example 3. Three process yields were obtained with 31%.

¹ H NMR (DMSO, ppm); δ 7.04 (1H, t), 7.08 (1H, d), 7.32 (1H, t), 7.48 (1H, d), 7.92 (1H, d), 8.00 (1H, d), 8.61 (1H, s)

ESI MS (m / e) = 261 [M + 1]

[ Production Example  9] N ⁶ -(2- Fluoro -4- Methylphenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 3.94 g (31.5 mmol) of 2-fluoro-4-methylaniline instead of 4-chloroaniline, followed by 2.85 g of the title compound in the same manner as in Preparation Example 2 and Preparation Example 3 10.4 mmol) was obtained in three procedures with 33% yield.

¹ H NMR (DMSO, ppm); δ 2.29 (3H, s), 6.61 (1H, s), 6.82 (1H, d), 6.96 (2H, m), 7.83 (1H, d), 7.99 (1H, t)

ESI MS (m / e) = 275 [M + 1]

[Production Example 10] N ⁶ -(2-fluoro-4-methoxyphenyl) [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 4.45 g (31.5 mmol) of 2-fluoro-4-methoxyaniline instead of 4-chloroaniline, and then 2.56 g of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. (8.82 mmol) was obtained in three steps yield 28%.

¹ H NMR (DMSO, ppm); δ 3.77 (3H, s), 6.79 (1H, dd), 6.87 (1H, d), 6.91 (1H, t), 7.75 (1H, t), 7.85 (1H, d), 8.65 (1H, s)

ESI MS (m / e) = 291 [M + 1]

[ Production Example  11] N ⁶ -(2- Fluorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 5.99 g (31.5 mmol) of 2-fluoro-4-bromoaniline instead of 4-chloroaniline, and then 2.88 g of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. (8.51 mmol) was obtained in three process yields of 27%.

¹ H NMR (DMSO, ppm); δ 7.14 (1H, d), 7.37 (1H, d), 7.55 (1H, d), 7.94 (1H, d), 8.25 (1H, t)

ESI MS (m / e) = 340 [M + 1]

[ Production Example  12] N ⁶ -(3- Fluoro -4- Methylphenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 3.94 g (31.5 mmol) of 3-fluoro-4-methylaniline instead of 4-chloroaniline, and then 2.85 g of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. 10.4 mmol) was obtained in three procedures with 33% yield.

¹ H NMR (DMSO, ppm); δ 2.17 (3H, s), 6.92 (1H, d), 7.23 (2H, q), 7.68 (1H, d), 7.91 (1H, d)

ESI MS (m / e) = 275 [M + 1]

[Production Example 13] N ⁶ -(4-chloro-2-fluorophenyl) [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 4.59 g (31.5 mmol) of 2-fluoro-4-chloroaniline instead of 4-chloroaniline, and then 2.79 g of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. 9.45 mmol) was obtained in three process yields of 30%.

¹ H NMR (DMSO, ppm); δ 7.14 (1H, d), 7.26 (1H, d), 7.45 (1H, dd), 7.94 (1H, d), 8.29 (1H, t)

ESI MS (m / e) = 295 [M + 1]

[ Production Example  14] N ⁶ -(2,4- Difluorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine My article

In Preparation Example 1, the reaction was carried out using 4.07 g (31.5 mmol) of 2 and 4-difluoroaniline instead of 4-chloroaniline, and then 2.63 g (9.45) of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. mmol) in three process yields 30%.

¹ H NMR (DMSO, ppm); δ 7.02 (1H, d), 7.08 (1H, t), 7.30 (1H, t), 7.91 (1H, d), 8.09 (1H, m)

ESI MS (m / e) = 279 [M + 1]

[ Production Example  15] N ⁶ -(2,6- Difluorophenyl ) [1,3] thiazolo [5,4- b ] Pyridine-2,5- Diamine My article

In Preparation Example 1, the reaction was carried out using 4.07 g (31.5 mmol) of 2,6-difluoroaniline instead of 4-chloroaniline, and then 2.19 g (7.88) of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. mmol) in three process yields of 25%.

¹ H NMR (DMSO, ppm); δ 6.53 (1H, d), 7.28 (2H, t), 7.47 (1H, m), 7.85 (1H, d)

ESI MS (m / e) = 279 [M + 1]

[ Production Example  16] ethyl 1- ( Chlorocarbonyl ) Of cyclopropanecarboxylate  Produce

5.00 g (26.9 mmol) of diethyl 1,1-cyclopropanedicarboxylate was dissolved in 100 mL of ethanol, and 1.51 g (26.9 mmol) of potassium hydroxide was added thereto, followed by stirring under reflux. After 4 hours, ethanol was removed by distillation under reduced pressure and 50 mL of 1N aqueous hydrochloric acid solution was added, followed by extraction with 100 mL (x3) of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 3.49 g (22.1 mmol) of carboxylic acid. The compound obtained without further purification was dissolved in 50 mL of chloroform, 5.26 g (44.2 mmol) of thionyl chloride were added, followed by stirring at room temperature. After 3 hours, the solvent and excess thionylchloride were removed by distillation under reduced pressure and 3.01 g (17.0 mmol) of the title compound were obtained in two procedures with 63% yield without further purification.

¹ H NMR (CDCl ₃ , ppm); δ 1.29 (3H, t), 1.79 (2H, m), 1.90 (2H, m), 4.24 (2H, q)

ESI MS (m / e) = 177 [M + 1]

[ Production Example  17] ethyl 2- ( Chlorocarbonyl ) Of cyclopropanecarboxylate  Produce

5.00 g (26.9 mmol) of diethyl 1,2-cyclopropanedicarboxylate was used instead of diethyl 1,1, -cyclopropanedicarboxylate in the same manner as in Production Example 16 3.18 g (18.0 mmol) of the title compound were obtained in a yield of 67%.

¹ H NMR (DMSO, ppm); δ 1.29 (3H, t), 1.40 (2H, m), 2.02 (1H, m), 2.50 (1H, m), 4.24 (2H, q)

ESI MS (m / e) = 177 [M + 1]

Production Example 18 2-({[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylic acid

58% of the title compound 4.01 g (9.86 mmol) was obtained in the same manner as in Example 30, except that 5.00 g (17.0 mmol) of the compound obtained in Preparation Example 13 were used instead of the compound obtained in Preparation Example 9. Obtained in the yield.

¹ H NMR (DMSO, ppm); δ 1.40 (2H, m), 2.02 (1H, m), 2.50 (1H, m), δ 7.14 (1H, d), 7.26 (1H, d), 7.45 (1H, dd), 7.94 (1H, d) , 8.29 (1H, t)

ESI MS (m / e) = 407 [M + 1]

[ Production Example  19] N -(4- Chlorophenyl )- N - methyl -5-nitro-2- Pyridineamine  Produce

5.00 g (20.0 mmol) of the compound obtained in Preparation Example 1 were dissolved in 50 mL of dimethylformamide, 1.20 g (60%, 30.0 mmol) of sodium hydride was added thereto, followed by stirring for 5 minutes, followed by 3.41 g (24.0 mmol) of iodomethane. It was added and stirred at room temperature. After 2 hours, excess sodium hydride was stopped with water, distilled under reduced pressure to remove the solvent, dissolved in 200 mL of ethyl acetate, and washed with 100 mL of water and 100 mL of saturated sodium chloride solution. The organic compound was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane / ethyl acetate = 2/1, v / v) to give 4.59 g (17.4 mmol) of the title compound in a yield of 87%. Got it.

¹ H NMR (DMSO, ppm); δ 3.51 (3H, s), 6.93 (1H, d), 7.33 (2H, d), 7.73 (2H, d), 7.91 (1H, d), 9.14 (1H, s)

ESI MS (m / e) = 264 [M + 1]

[ Production Example  20] N ⁶ -(4- Chlorophenyl )- N ⁶ - Methyl [1,3] ti Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

The reaction was carried out in the same manner as in Preparation Example 2, using 4.59 g (17.4 mmol) of the compound obtained in Preparation Example 19 instead of the compound obtained in Preparation Example 1, and then 2.58 g (8.87 mmol) of the title compound was prepared in the same manner as in Preparation Example 3. ) Was obtained with a yield of 51% in both procedures.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d)

ESI MS (m / e) = 291 [M + 1]

[Production Example 21] N ⁶ -(4-chloro-2-fluorophenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

5.00 g (34.4 mmol) of 2-fluoro-4-chloroaniline was used instead of 4-chloroaniline, and reaction was carried out in the same manner as in Preparation Example 1, followed by Preparation Example 19, Preparation Example 2 and Preparation Example 3 2.23 g (7.22 mmol) of the title compound were obtained by four procedures in 21% yield.

¹ H NMR (MeOD, ppm); δ 3.29 (3H, s), 6.52 (1H, d), 7.29 (1H, d), 7.34 (1H, dd), 7.38 (1H, t), 7.73 (1H, d)

ESI MS (m / e) = 309 [M + 1]

[Production Example 22] N ⁶ -(2,4-difluorophenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (38.7 mmol) of 2,4-difluoroaniline instead of 4-chloroaniline, and then the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. 2.41 g (8.25 mmol) was obtained in four procedures with a yield of 24%.

¹ H NMR (DMSO, ppm); δ 3.37 (3H, s), 6.46 (1H, d), 7.20-7.58 (3H, m), 7.80 (1H, d)

ESI MS (m / e) = 293 [M + 1]

[Manufacture example 23] N ⁶ -(2,6-difluorophenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (38.7 mmol) of 2,6-difluoroaniline instead of 4-chloroaniline, and then the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2 and Preparation Example 3. 2.41 g (8.25 mmol) was obtained in four procedures with a yield of 24%.

¹ H NMR (DMSO, ppm); δ 3.37 (3H, s), 6.54 (1H, d), 7.25-7.49 (3H, m), 7.85 (1H, d)

ESI MS (m / e) = 293 [M + 1]

[Manufacture example 24] N ⁶ -(4-bromo-2-fluorophenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (26.3 mmol) of 2-fluoro-4-bromoaniline instead of 4-chloroaniline, and then the title was obtained in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. 2.04 g (5.79 mmol) of the compound was obtained in a four step yield of 22%.

¹ H NMR (CDCl ₃ , ppm); δ 3.46 (3H, s), 6.43 (1H, dd), 7.22 (1H, t), 7.33-7.39 (2H, m), 7.64 (1H, d)

ESI MS (m / e) = 354 [M + 1]

[ Production Example  25] N ⁶ -(2- Methoxyphenyl )- N ⁶ - Methyl [1,3] ti Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was performed using 5.00 g (40.6 mmol) of 2-anisidine instead of 4-chloroaniline, and then 3.60 g (12.6) of the title compound was obtained in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. mmol) was obtained in four steps with a yield of 31%.

¹ H NMR (CDCl ₃ , ppm); δ 3.46 (3H, s), 3.77 (3H, s), 6.27 (1H, d), 7.02 (1H, d), 7.25 (1H, d), 7.31 (1H, td), 7.54 (1H, d)

ESI MS (m / e) = 287 [M + 1]

Production Example 26 N ⁶ -(3,4-difluorophenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was performed using 5.00 g (38.7 mmol) of 3,4-difluoroaniline instead of 4-chloroaniline, and then the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. 2.41 g (8.25 mmol) was obtained in four procedures with a yield of 24%.

¹ H NMR (DMSO, ppm); δ 3.37 (3H, s), 6.70 (1H, d), 7.19 (1H, m), 7.48 (2H, m), 7.80 (1H, d)

ESI MS (m / e) = 293 [M + 1]

[Production Example 27] N ⁶ -methyl- N ⁶ -[4- (trifluoromethyl) phenyl] [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (31.0 mmol) of 4-trifluoroaniline instead of 4-chloroaniline, and then 1.91 g of the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2 and Preparation Example 3. (5.90 mmol) was obtained in four steps 19% yield.

¹ H NMR (DMSO, ppm); δ 3.37 (3H, s), 7.01 (1H, d), 7.45 (1H, d), 7.70 (1H, d), 7.90 (1H, d)

ESI MS (m / e) = 325 [M + 1]

[ Production Example  28] N ⁶ -(4- Methoxyphenyl )- N ⁶ - Methyl [1,3] ti Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 5.00 g (40.6 mmol) of 4-anisidine instead of 4-chloroaniline, and then 3.60 g (12.6) of the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. mmol) was obtained in four steps with a yield of 31%.

¹ H NMR (CDCl ₃ , ppm); δ 3.46 (3H, s), 3.82 (3H, s), 6.43 (1H, d), 6.95 (2H, d), 7.18 (2H, d), 7.54 (1H, d)

ESI MS (m / e) = 287 [M + 1]

[Manufacture example 29] N ⁶ -(4-isopropylphenyl)- N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Production of pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (37.0 mmol) of 4-isopropylaniline instead of 4-chloroaniline, followed by 2.98 g of the title compound in the same manner as in Preparation Example 19, Preparation Example 2 and Preparation Example 3 ( 9.99 mmol) was obtained in four steps with a yield of 27%.

¹ H NMR (CDCl ₃ , ppm); δ 1.28 (6H, d), 2.94 (1H, m), 3.51 (3H, s), 6.56 (1H, d), 7.19 (2H, d), 7.27 (2H, d), 7.55 (1H, d)

ESI MS (m / e) = 299 [M + 1]

Production Example 30 N ⁶ -(2,3-dihydro-1 H Inden-5-day) N ⁶ -Methyl [1,3] thiazolo [5,4- b ] Preparation of Pyridine-2,5-diamine

In Preparation Example 1, the reaction was carried out using 5.00 g (37.5 mmol) of 4-isopropylaniline instead of 4-chloroaniline, followed by the same method as Preparation Example 19, Preparation Example 2 and Preparation Example 1. 6.01 mmol) was obtained in four procedures with a yield of 16%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (1H, m), 1.10 (1H, m), 2.93 (4H, t), 3.50 (3H, s), 6.53 (1H, d), 7.12 (1H, s), 7.26 (2H, m), 7.54 (1 H, d)

ESI MS (m / e) = 297 [M + 1]

Preparation Example 31 Ethyl 2- {4- [2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl] (methyl) amino} phenyl} acetate

In Preparation Example 1, the reaction was carried out using 5.00 g (27.9 mmol) of ethyl 4-aminophenyl acetate instead of 4-chloroaniline, and then 1.72 g of the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2 and Preparation Example 3. (5.02 mmol) was obtained in four procedures with a yield of 18%.

¹ H NMR (CDCl ₃ , ppm); δ 1.40 (3H, t), 2.92 (2H, s), 3.60 (3H, s), 4.38 (2H, q), 6.93 (1H, d), 7.42 (2H, d), 7.90 (2H, d), 8.11 (1 H, d)

ESI MS (m / e) = 343 [M + 1]

[ Production Example  32] N ⁶ -(4- Chlorophenyl )- N ⁶ - Ethyl [1,3] tea Azolo [5,4- b ] Pyridine-2,5- Diamine  Produce

In Preparation Example 1, the reaction was carried out using 5.00 g (32.1 mmol) of N-ethyl-4-chloroaniline instead of 4-chloroaniline, and then 2.64 g (8.67) of the title compound was prepared in the same manner as in Preparation Example 2 and Preparation Example 3. mmol) was obtained in three procedures with a yield of 27%.

¹ H NMR (DMSO, ppm); δ 1.03 (3H, t), 3.63 (2H, q), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d)

ESI MS (m / e) = 305 [M + 1]

[ Production Example  33] ethyl 2- [4-chloro (5-nitro-2- Pyridinyl ) Anilino ] Production of Acetate

6.04 g (18.0 mmol) of the title compound were obtained in the same manner as 4.01 g (24.0 mmol) of ethyl α-bromoacetate instead of iodomethane in Preparation Example 19.

¹ H NMR (DMSO, ppm); δ 1.03 (3H, t), 4.11 (2H, q), 4.62 (2H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 9.11 (1 H, s)

ESI MS (m / e) = 336 [M + 1]

Preparation 34 Ethyl 2-[(2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl) -4-chloroanilino] acetate

Instead of the compound obtained in Preparation Example 1, the reaction was carried out in the same manner as in Preparation Example 2, using 6.04 g (18.0 mmol) of the compound obtained in Preparation Example 33, followed by 3.98 g (11.0) of the title compound in the same manner as in Preparation Example 3. mmol) was obtained in two procedures with a yield of 61%.

¹ H NMR (DMSO, ppm); δ 1.03 (3H, t), 4.11 (2H, q), 4.62 (2H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d)

ESI MS (m / e) = 363 [M + 1]

Production Example 35 2-[(2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl) -4-chloroanilino] -1-ethanol

3.98 g (11.0 mmol) of the compound obtained in Preparation Example 34 were dissolved in 100 mL of tetrahydrofuran, and 417 mg (11.0 mmol) of lithium aluminum hydride was added at 0 ° C, followed by stirring at room temperature. After 1 hour, the reaction solution was cooled to 0 ° C., and the reaction was terminated with 0.42 mL of water, 0.42 mL of 15% sodium hydroxide, and 1.26 mL of water to remove solid impurities. The obtained organic layer was removed by distillation under reduced pressure to obtain 3.18 g (9.90 mmol) of the title compound in a yield of 90% without further purification.

¹ H NMR (DMSO, ppm); δ 4.21 (2H, t), 4.29 (2H, t), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d)

ESI MS (m / e) = 321 [M + 1]

[ Production Example  36] 4-[(5-nitro-2- Pyridinyl ) Amino] Benzonitrile  Produce

5.00 g (31.5 mmol) of 2-chloro-5-nitropyridine was dissolved in 100 mL of tetrahydrofuran, 2.52 g (60%, 63.0 mmol) of sodium hydride was slowly added at 0 ° C, stirred for 5 minutes, and then 4-cyanoaniline 5.59 g (47.3 mmol) was added and heated to reflux and stirred. After 4 hours, the reaction solution was cooled to room temperature and water was added to stop the activity of excess sodium hydride, diluted with 200 mL of ethyl acetate, and washed with 100 mL of water and 100 mL of saturated sodium chloride solution. The organic compound was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting impure compound was purified by column chromatography (hexane / ethyl acetate = 2/2, v / v) to give 4.77 g (19.8 mmol) of the title compound. Obtained in% yield.

¹ H NMR (DMSO, ppm); δ 7.12 (1H, d), 7.29 (2H, d), 7.70 (2H, d), 7.94 (1H, d), 9.14 (1H, s)

ESI MS (m / e) = 255 [M + 1]

Preparation Example 37 4-[(2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl) (methyl) amino] benzonitrile

The reaction was carried out in the same manner as in Preparation Example 19 using 4.77 g (19.8 mmol) of the compound obtained in Preparation Example 36 instead of the compound obtained in Preparation Example 1, and the title compound 1.45 in the same manner as in Preparation Example 2 and Preparation Example 3 g (5.15 mmol) was obtained in three procedures with a yield of 26%.

¹ H NMR (DMSO, ppm); δ 3.47 (3H, s), 7.12 (1H, d), 7.29 (2H, d), 7.70 (2H, d), 7.94 (1H, d)

ESI MS (m / e) = 282 [M + 1]

Preparation Example 38 Ethyl 4-[(2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl) (methyl) amino] benzoate

After reacting with 7.81 g (47.3 mmol) of ethyl 4-aminobenzoate in Preparation Example 36 instead of 4-cyanoaniline, 1.14 g of the title compound was prepared in the same manner as in Preparation Example 19, Preparation Example 2, and Preparation Example 3. 3.47 mmol) was obtained in four steps 11% yield.

¹ H NMR (CDCl ₃ , ppm); δ 1.40 (3H, t), 3.60 (3H, s), 4.38 (2H, q), 6.93 (1H, d), 7.28 (2H, d), 7.70 (2H, d), 8.03 (1H, d)

ESI MS (m / e) = 329 [M + 1]

Preparation Example 39 Diethyl 2-{[5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} -2-oxoethylphosphonate

5.00 g (14.2 mmol) of the compound obtained in Preparation 24 were dissolved in 100 mL of dichloromethane, 2.87 g (28.4 mmol) of triethylamine was added, and 4.30 g (21.3 mmol) of 2-broto acetylbroide was added thereto at room temperature. Stirred. After 2 hours, the solvent was removed by distillation under reduced pressure, dissolved in 150 mL of ethyl acetate, washed with 50 mL of saturated ammonium chloride solution and 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained compound was dissolved in 100 mL of toluene, and 4.72 g (28.4 mmol) of triethylphosphate was added thereto, and the mixture was heated to reflux and stirred. After 8 hours, the solvent was removed by distillation under reduced pressure and purified by column chromatography (dichloromethane / methanol = 95/5, v / v) to give 5.96 g (11.2 mmol) of the title compound in a two-yield 79% yield.

¹ H NMR (CDCl ₃ , ppm); δ 1.36 (6H, t), 3.20 (2H, d), 3.41 (3H, s), 4.24 (4H, q), 6.39 (1H, d), 7.13-7.35 (3H, m), 7.57 (1H, d ), 11.13 (1H, broad singlet)

ESI MS (m / e) = 532 [M + 1]

[Manufacture example 40] t -Butyl 4-(( E ) -3-{[5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} -3-oxo-1- (propenyl) -1-piperidinecarboxylate

5.96 g (11.2 mmol) of the compound obtained in Preparation Example 39 were dissolved in 100 mL of tetrahydrofuran, and 3.58 g (16.8 mmol) of 4-formyl-piperidine-1-carboxylic acid t-butyl ester and 2.56 g (16.8 mmol) of DBU were used. mmol) was added and stirred at room temperature. After 5 hours, the mixture was diluted with 100 mL of ethyl acetate, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting impure compound was purified by column chromatography (hexane / ethyl acetate = 1/1, v / v) to give 5.75 g (9.74 mmol) of the title compound in a yield of 87%.

¹ H NMR (CDCl ₃ , ppm); δ 1.30 (2H, qd), 1.46 (9H, s), 1.68 (2H, d), 2.27 (1H, m), 2.73 (2H, t), 3.49 (3H, s), 4.12 (2H, q), 5.94 (1H, d), 6.45 (1H, d), 7.09 (1H, q), 7.39 (1H, t), 7.38 (2H, t), 7.65 (1H, d)

ESI MS (m / e) = 591 [M + 1]

[Manufacture example 41] ( E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -3- (4-piperidinyl) -2-propenamide

5.00 g (17.2 mmol) of the compound obtained in Preparation Example 20 was used instead of the compound obtained in Preparation Example 24, and the reaction was carried out in the same manner as in Preparation Example 39, and the same procedure as in Preparation Example 39, Preparation Example 40, and Example 69 3.53 g (8.26 mmol) of the title compound were obtained in four steps with a yield of 48%.

¹ H NMR (CDCl ₃ , ppm); δ 1.47 (2H, qd), 1.68 (2H, d), 1.90 (2H, t), 1.94 (2H, d), 2.11 (1H, m), 3.46 (3H, s), 6.43 (1H, dd), 5.93 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.21 (2H, d), 7.36 (2H, d), 7.61 (1H, d)

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

[ Production Example  42] Tert -Butyl 4-fluor-2- Of hydroxyphenylcarbamate  Produce

3.8 g (30.0 mmol) of 2-amino-5-chlorophenol was dissolved in 150 mL of dichloromethane, and 6.5 g (30.0 mmol) of di-tert-butyl dicarbonate were added and stirred at room temperature. After 12 hours, 200 ml of dichloromethane was added, washed with 200 ml of saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained compound was purified by column chromatography (ethyl acetate / hexane = 1/6, v / v) to obtain 4.26 g (18.75 mmol) of the title compound in a yield of 63%.

¹ H NMR (DMSO, ppm); δ 1.44 (9H, s), 6.57-6.62 (3H, m), 7.48 (1H, br s), 7.23 (3H, m), 7.86 (1H, s), 10.17 (1H, br s)

[ Production Example  43] 5-fluor-2- ( Methylamino Production of Phenol

3.3 g (15.0 mmol) of the compound obtained in Preparation Example 42 was dissolved in 60 mL of tetrahydrofuran, 1.1 g (29.4 mmol) of lithium aluminum hydride was added thereto, and the mixture was heated to reflux and stirred. After 12 hours, the reaction was cooled to room temperature, water and 10% aqueous sodium hydroxide solution were added thereto, and the resulting solid was filtered off. The filtrate was eluted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained compound was purified by column chromatography (ethyl acetate / hexane = 1/3, v / v) to obtain 0.87 g (0.62 mmol) of the title compound in a yield of 42%.

¹ H NMR (DMSO, ppm); δ 2.63 (3H, s), 6.33 (1H, m), 6.45 (2H, m), 7.86 (1H, s)

[Preparation Example 44] 5-fluoro -2 [methyl (5-nitro-2-pyridinyl) amino] phenol Preparation of

0.85 g (5.4 mmol) of 2-chloro-5-nitropyridine was dissolved in 30 mL of dimethylsulfoxide, and 0.80 g (5.7 mmol) of the compound obtained in Preparation Example 43 was added thereto, followed by heating under reflux and stirring. After 5 hours, the temperature was lowered to room temperature and 500 mL of ethyl acetate was added, followed by washing with 300 mL of water and 300 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The obtained compound was purified by column chromatography (ethyl acetate / hexane = 1/4, v / v) to obtain 0.38 g (1.44 mmol) of the title compound. Obtained in% yield.

¹ H NMR (DMSO, ppm); δ 3.39 (3H, s), 6.17 (1H, m), 6.76-6.82 (2H, m), 7.31 (1H, m), 8.12 (1Hm), 9.03 (1H, m), 10.44 (1H, br s)

ESI MS (m / e) = 264 [M + 1]

[ Production Example  45] 2- [(5-amino-2- Pyridinyl ) ( methyl ) Amino] -5- Fluorophenolic  Produce

0.34 g (1.3 mmol) of the compound obtained in Preparation 44 was dissolved in 25 mL of ethyl acetate, and 2.33 g (10.3 mmol) of tin (II) chloride dihydrate was added thereto, followed by stirring at room temperature. After 5 hours, 100 mL of ethyl acetate was added and washed with 80 mL of 1N sodium hydroxide solution and 1000 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The obtained compound was purified by column chromatography (ethyl acetate / dichloromethane = 2/1, v / v) to give 0.18 g (0.77 mmol) of the title compound. Obtained in 59% yield.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 6.32 (1H, m), 6.82-6.79 (2H, m), 7.35 (1H, m), 7.54 (2H, br s), 8.12 (1H, m), 9.03 (1H, m), 9.97 (1h, br)

ESI MS (m / e) = 234 [M + 1]

Preparation Example 46 2- [(2-amino [1,3] thiazolo [5,4- b ] Pyridin-5-yl) (methyl) amino] -5-fluorophenol

0.27 g (1.20 mmol) of the compound obtained in Preparation 45 was dissolved in 25 mL of acetic acid, and 0.90 g (9.30 mmol) of potassium thiocyanate was added, followed by cooling to minus 20 degrees. Bromine 0.19 g (1.20 mmol) was slowly added with a mechanical stirrer, and the temperature was slowly raised to room temperature over 2 hours, followed by further stirring for 8 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, 100 mL of ethyl acetate was added, and the mixture was washed with 50 mL of water and 50 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The obtained compound was purified by column chromatography (ethyl acetate / hexane = 2/3, v / v) to give 0.15 g (0.52 mmol) of the title compound. Obtained in% yield.

¹ H NMR (DMSO, ppm); δ 3.25 (3H, s), 5.76 (1H, s), 6.15 (1H, d), 6.67 (2H, m), 7.36 (2H, s), 7.37 (1H, d), 9.03 (1H, m), 9.97 (1 H, s)

ESI MS (m / e) = 291 [M + 1]

Production Example 47 2-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] -5-fluorophenyl Of cyclopropanecarboxylate  Produce

40 mg (0.14 mmol) of the compound obtained in Preparation 46 was dissolved in 3 mL of tetrahydrofuran, and 63 mg (0.62 mmol) of triethylamine and 43 mg (0.41 mmol) of cyclopropanecarbonyl chloride were added, followed by stirring at room temperature. After 30 minutes, 5 mL of methanol was added and stirred for 1 hour. After the reaction was completed, the solvent was removed by distillation under reduced pressure, 10 mL of ethyl acetate was added thereto, and washed with 10 mL of water and 10 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The obtained compound was purified by column chromatography (ethyl acetate / hexane = 1/2, v / v) to give 56 mg (0.13 mmol) of the title compound. Obtained in 95% yield.

¹ H NMR (DMSO, ppm); δ 0.91 (4H, m), 1.10 (4H, m), 1.93-1.99 (2H, m), 3.28 (3H, s), 6.06 (1H, d), 6.68 (1H, d), 6.74 (1H, s ), 7.01 (1H, d), 7.62 (1H, d), 9.55 (1H, br s)

ESI MS (m / e) = 427 [M + 1]

Example 1 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopentanecarboxamide

5.00 g (18.1 mmol) of the compound obtained in Preparation Example 3 were dissolved in 150 mL of dichloromethane, and 2.75 g (27.2 mmol) of triethylamine and 2.88 g (21.7 mmol) of cyclopentanecarbonyl chloride were added, followed by stirring at room temperature. After 2 hours, the mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 98/2, v / v) to give 5.74 g (15.4 mmol) of the title compound in a yield of 85%.

¹ H NMR (DMSO, ppm); δ 1.24-1.92 (8H, m), 2.95 (1H, m), 6.93 (1H, d), 7.33 (2H, d), 7.74 (2H, d), 7.90 (1H, d), 9.45 (1H, s )

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

Example 2 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

5.68 g (16.5 mmol) of the title compound were obtained in 91% yield in the same manner using 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride in Example 1.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.99 (1H, m), 6.93 (1H, d), 7.33 (2H, d), 7.73 (2H, d), 7.91 (1H, d), 9.42 (1H, s)

ESI MS (m / e) = 345 [M + 1]

Example 3 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (thiophen-2-yl) acetamide

6.62 g (16.5 mmol) of the title compound were obtained in the same manner using 3.49 g (21.7 mmol) of 2-thiophenacetyl chloride instead of cyclopentanecarbonyl chloride in Example 1.

¹ H NMR (DMSO, ppm); δ 4.06 (2H, s), 6.94 (1H, d), 7.01 (2H, m), 7.33 (2H, d), 7.43 (1H, d), 7.74 (2H, d), 7.94 (1H, d), 9.46 (1H, s), 12.47 (1H, s)

ESI MS (m / e) = 401 [M + 1]

Example 4 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3-cyclopentylpropanamide

6.32 g (15.8 mmol) of the title compound were obtained in 87% yield in the same manner using 3.49 g (21.7 mmol) of 3-cyclopentylpropionyl chloride instead of cyclopentanecarbonyl chloride in Example 1.

¹ H NMR (DMSO, ppm); δ 1.12 (2H, m), 1.48-1.97 (11H, m), 6.93 (1H, d), 7.33 (2H, d), 7.74 (2H, d), 7.91 (1H, d), 9.42 (1H, s ), 12.15 (1H, s)

ESI MS (m / e) = 401 [M + 1]

Example 5 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (4-morpholinyl) acetamide

5.00 g (18.1 mmol) of the compound obtained in Preparation Example 3 were dissolved in 150 mL of dichloromethane, and 2.75 g (27.2 mmol) of triethylamine and 5.48 g (27.2 mmol) of 2-bromoacetyl bromide were added and stirred at room temperature. After 1 hour, 100 mL of dichloromethane was added thereto, diluted, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The compound obtained by removing the solvent by distillation under reduced pressure was dissolved in 15 mL of morpholine and stirred at room temperature for 2 hours. The reaction solution was dissolved in 50 mL of water, extracted with 100 mL (x3) of ethyl acetate, and then the organic layer was washed with 100 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting impure compound was removed by distillation under reduced pressure. The resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) to give 4.68 g (11.6 mmol) of the title compound in a yield of 64%.

¹ H NMR (CDCl ₃ , ppm); δ 2.65 (4H, t), 3.29 (2H, s), 3.80 (4H, t), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 10.24 (1H, s)

ESI MS (m / e) = 404 [M + 1]

Example 6 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (1-pyrrolidinyl) acetamide

In Example 5 3.37 g (8.69 mmol) of the title compound were obtained in 48% yield in the same manner using 15 mL of pyrrolidine instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 1.88 (4H, br m), 2.73 (4H, br m), 3.42 (2H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d )

ESI MS (m / e) = 388 [M + 1]

Example 7 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (diethylamino) acetamide

In Example 5 3.39 g (8.69 mmol) of the title compound were obtained in 48% yield in the same manner using 15 mL of diethylamine instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 1.11 (6H, t), 2.68 (4H, q), 3.29 (2H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d)

ESI MS (m / e) = 390 [M + 1]

Example 8 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] acetamide Preparation

In Example 1 5.54 g (17.4 mmol) of the title compound were obtained in 96% yield in the same manner using 1.70 g (21.7 mmol) of acetyl chloride instead of cyclopentanecarbonyl chloride.

¹ H NMR (DMSO, ppm); δ 2.19 (3H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 9.44 (1H, s), 12.19 (1H, s)

ESI MS (m / e) = 319 [M + 1]

Example 9 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2-methylpropanamide

In Example 1 5.52 g (15.9 mmol) of the title compound were obtained in 88% yield in the same manner using 2.31 g (21.7 mmol) of isobutyryl chloride instead of cyclopentanecarbonyl chloride.

¹ H NMR (CDCl ₃ , ppm); δ 1.27 (6H, m), 2.71 (1H, m), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d)

ESI MS (m / e) = 347 [M + 1]

Example 10 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclobutanecarboxamide

In Example 1 5.26 g (14.7 mmol) of the title compound were obtained in 81% yield in the same manner using 2.57 g (21.7 mmol) of cyclobutanecarbonyl chloride instead of cyclopentanecarbonyl chloride.

¹ H NMR (CDCl ₃ , ppm); δ 2.05 (2H, m), 2.26 (2H, m), 2.44 (2H, m), 3.26 (1H, m), 6.66 (1H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 9.21 (1H, s)

ESI MS (m / e) = 359 [M + 1]

Example 11 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl] -3- (4-morpholinyl) propanamide

5.00 g (18.1 mmol) of the compound obtained in Preparation Example 3 were dissolved in 150 mL of dichloromethane, and 2.75 g (27.2 mmol) of triethylamine and 4.66 g (27.2 mmol) of 2-bromopropionic chloride were added and stirred at room temperature. After 1 hour, 100 mL of dichloromethane was added thereto, diluted, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The compound obtained by removing the solvent by distillation under reduced pressure was dissolved in 15 mL of morpholine and stirred at room temperature for 2 hours. The reaction solution was dissolved in 50 mL of water, extracted with 100 mL (x3) of ethyl acetate, and then the organic layer was washed with 100 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) under reduced pressure distillation to give 4.85 g (11.6 mmol) of the title compound in a yield of 64%.

¹ H NMR (DMSO, ppm); δ 2.41 (4H, brs), 2.65 (4H, brs), 3.57 (4H, t), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 9.44 (1 H, s), 12.28 (1 H, s)

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

Example 12 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (4-methyl-1-piperazinyl) acetamide

In Example 5, 3.32 g (7.96 mmol) of the title compound were obtained in 44% yield in the same manner using 15 mL of N-methylpiperazine instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 2.30 (3H, br s), 2.65 (4H, br m), 2.88 (4H, br m), 3.29 (2H, s), 3.80 (4H, t), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 10.24 (1H, s)

ESI MS (m / e) = 417 [M + 1]

Example 13 Ethyl 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} carbonyl) cyclopentanecarboxylate

5.66 g (13.6 mmol) of the title compound were obtained in 75% yield in the same manner using 3.83 g (21.7 mmol) of the compound obtained in Preparation Example 16 instead of cyclopentanecarbonyl chloride in Example 1.

¹ H NMR (CDCl ₃ , ppm); δ 1.29 (3H, t), 1.79 (2H, m), 1.90 (2H, m), 4.24 (2H, q), 6.55 (1H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 12.15 (1H, s)

ESI MS (m / e) = 417 [M + 1]

Example 14 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} carbonyl) cyclopentanecarboxylic acid

5.66 g (13.6 mmol) of the compound obtained in Example 13 were dissolved in 100 mL of a tetrahydrofuran: methanol: water = 3: 1: 1 solution, and 856 mg (20.4 mmol) of lithium hydroxide monohydrate was added thereto, followed by stirring at room temperature. After 4 hours, the mixture was neutralized with 1N aqueous hydrochloric acid, extracted with 100 mL (x3) of ethyl acetate, washed with 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and 3.60 g (9.25 mmol) of the title compound were obtained in a yield of 68% without further purification.

¹ H NMR (DMSO, ppm); δ 1.55 (4H, br s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d), 9.40 (1H, s), 12.48 (1H, s)

ESI MS (m / e) = 389 [M + 1]

Example 15 N- [5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- Preparation of (4-morpholinyl) ethyl] urea

10.0 g (32.4 mmol) of the compound obtained in Preparation Example 21 was dissolved in 200 mL of tetrahydrofuran, and 6.6 g (32.4 mmol) of 4-nitrophenyl-chloroformate and 5.2 g (64.8 mmol) of pyridine were added thereto, followed by stirring at room temperature. After 2 hours, the solvent was removed by distillation under reduced pressure, and the obtained solid compound was washed with ether to give 4-nitrophenyl 5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4- b] 15.0 g of pyridine-2-ylcarbamate was obtained. 2.0 g (4.2 mmol) of this compound was dissolved in 50 mL of tetrahydrofuran, 1.1 g (8.4 mmol) of 4- (2-aminoethyl) morpholine and 1.3 g (64.8 mmol) of triethylamine were added thereto, and the mixture was heated to reflux and stirred. . After 1 hour, the mixture was diluted with 200 ml of ethyl acetate, washed with 100 ml of saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) to obtain 1.5 g of the title compound in a yield of 79%.

¹ H NMR (CDCl ₃ , ppm); δ 2.54 (4H, br), 2.60 (2H, m), 3.44 (3H, s), 3.47 (2H, m), 3.75 (4H, br), 6.40 (1H, d), 7.23 (3H, m), 7.79 (1 H, d)

ESI MS (m / e) = 465 [M + 1]

Example 16 N -[5- (4-Fluoro-2-hydroxymethylanilino [1,3] thiazolo [5,4- b ] Pyridin-2-yl Of cyclopropanecarboxamide  Produce

56 mg (0.13 mmol) of the compound obtained in Preparation 47 was dissolved in methanol / water (2 mL / 2 mL, v / v), and 17 mg (0.39 mmol) of lithium hydroxide monohydrate was added thereto, followed by stirring at room temperature. After 1 hour, the reaction was neutralized with 1-normal hydrochloric acid solution, and then the solvent was removed by distillation under reduced pressure. 10 mL of ethyl acetate was added and washed with 10 mL of water and 10 mL of saturated aqueous sodium chloride solution. The organic compound was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resulting impure compound was purified by column chromatography (ethyl acetate / hexane = 1/1, v / v) to obtain 39 mg (0.09 mmol) of the title compound. Obtained in 83% yield.

¹ H NMR (DMSO, ppm); δ 0.91 (2H, m), 1.10 (2H, m), 1.93 (1H, m), 3.28 (3H, s), 6.02 (1H, d), 6.65 (1H, d), 6.64 (1H, s), 7.05 (1H, d), 7.66 (1H, d), 9.52 (1H, br s), 12.32 (1H, br s)

ESI MS (m / e) = 359 [M + 1]

Example 17 N -[5- (cyclohexylamino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1 except that 4.50 g (18.1 mmol) of the compound obtained in Preparation Example 4 were used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. In the same manner as in 4.47 g (14.1 mmol) of the title compound were obtained in a yield of 78%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.01-1.84 (11H, m), 1.99 (1H, m), 6.93 (1H, d), 7.91 (1H, d)

ESI MS (m / e) = 317 [M + 1]

Example 18 N -[5- (cyclopentylamino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1 except that 4.24 g (18.1 mmol) of the compound obtained in Preparation Example 5 were used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. In the same manner as in 4.71 g (15.6 mmol) of the title compound were obtained in a yield of 86%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.12-1.82 (9H, m), 1.99 (1H, m), 6.93 (1H, d), 7.91 (1H, d)

ESI MS (m / e) = 303 [M + 1]

Example 19 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3- (diethylamino) propanamide

In Example 11 2.71 g (6.70 mmol) of the title compound were obtained in 37% yield in the same manner using 15 mL of diethylamine instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 1.18 (6H, t), 2.60 (2H, t), 2.74 (4H, q), 2.83 (2H, t), 6.63 (1H, s), 6.85 (1H, d), 7.30 (2H, d), 7.43 (2H, d), 7.84 (1H, d)

ESI MS (m / e) = 404 [M + 1]

Example 20 N -[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl] -3- (1-piperidinyl) propanamide

In Example 11 3.16 g (7.60 mmol) of the title compound were obtained in 42% yield in the same manner using 15 mL of piperidine instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 1.57 (2H, br s), 1.78 (4H, m), 2.63 (5H, m), 2.96 (2H, t), 6.58 (1H, s), 6.85 (1H, d), 7.30 (2H, d) , 7.43 (2H, d), 7.84 (1H, d)

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

Example 21 N -[5- (3-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1, except that 5.01 g (18.1 mmol) of the compound obtained in Preparation Example 6 was used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. In the same manner as in, 5.38 g (15.6 mmol) of the title compound were obtained in a yield of 86%.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 2.00 (1H, m), 6.30 (1H, dd), 6.95 (1H, d), 7.31 (1H, t), 7.58 (1H, dd), 7.89 (1H, t), 7.94 (1H, d), 9.51 (1H, s), 12.51 (1H, s)

ESI MS (m / e) = 345 [M + 1]

Example 22 N -[5- (2-chloroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1 except that 5.01 g (18.1 mmol) of the compound obtained in Preparation Example 7 was used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. In the same manner as in 5.00 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 2.00 (1H, m), 7.04 (1H, t), 7.08 (1H, d), 7.32 (1H, t), 7.48 (1H, d), 7.92 (1H, d), 8.00 (1H, d), 8.61 (1H, s), 12.54 (1H, s)

ESI MS (m / e) = 345 [M + 1]

Example 23 N -[5- (2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1, except that 4.71 g (18.1 mmol) of the compound obtained in Preparation Example 8 was used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. 5.17 g (15.7 mmol) of the title compound were obtained in the same manner as in 87% yield.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 2.00 (1H, m), 7.04 (1H, t), 7.08 (1H, d), 7.32 (1H, t), 7.48 (1H, d), 7.92 (1H, d), 8.00 (1H, d), 8.61 (1H, s), 12.54 (1H, s)

ESI MS (m / e) = 329 [M + 1]

Example 24 N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

Example 1, except that 4.71 g (18.1 mmol) of the compound obtained in Preparation Example 9 was used instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride was used instead of the cyclopentanecarbonyl chloride. In the same manner as in, 5.08 g (14.8 mmol) of the title compound were obtained in a yield of 82%.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 2.00 (1H, m), 2.29 (3H, s), 6.61 (1H, s), 6.82 (1H, d), 6.96 (2H, m), 7.83 (1H, d), 7.99 (1 H, t)

ESI MS (m / e) = 343 [M + 1]

Example 25 N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2- (4-morpholinyl) acetamide

Using 3.71 g (18.1 mmol) of the compound obtained in Preparation Example 9 instead of the compound obtained in Preparation Example 3, 3.71 g (9.23 mmol) of the title compound was obtained in a yield of 51% by the same method as in Example 5.

¹ H NMR (CDCl ₃ , ppm); δ 2.34 (3H, s), 2.66 (4H, t), 3.28 (2H, s), 3.80 (4H, t), 6.61 (1H, s), 6.82 (1H, d), 6.96 (2H, m), 7.83 (1 H, d), 7.99 (1 H, t)

ESI MS (m / e) = 402 [M + 1]

Example 26 N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl] -3- (4-morpholinyl) propanamide

In the same manner as in Example 11, using 4.71 g (18.1 mmol) of the compound obtained in Preparation Example 9 instead of the compound obtained in Preparation Example 3, 3.16 g (7.60 mmol) of the title compound was obtained in a yield of 42%.

¹ H NMR (CDCl ₃ , ppm); δ 2.34 (3H, s), 2.66 (6H, m), 2.82 (2H, t), 3.92 (4H, t), 6.61 (1H, s), 6.82 (1H, d), 6.96 (2H, m), 7.83 (1 H, d), 7.99 (1 H, t)

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

Example 27 N -[5- (2-fluoro-4-methoxyanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 4.71 g (18.1 mmol) of the compound obtained in Preparation Example 8 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride was used. 5.17 g (15.7 mmol) of the title compound were obtained in 87% yield.

¹ H NMR (DMSO, ppm); δ 0.93 (4H, m), 1.97 (1H, m), 3.77 (3H, s), 6.79 (1H, dd), 6.87 (1H, d), 6.91 (1H, t), 7.75 (1H, t), 7.85 (1 H, d), 8.65 (1 H, s), 12.42 (1 H, s)

ESI MS (m / e) = 359 [M + 1]

Example 28 2-({[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylic acid

The same method as in Example 1, using 4.71 g (18.1 mmol) of the compound obtained in Preparation Example 9 instead of the compound obtained in Preparation Example 3 and 3.83 g (21.7 mmol) of the compound obtained in Preparation Example 17 instead of the cyclopentanecarbonyl chloride. The reaction was carried out in the same manner as in Example 14 to obtain 3.01 g (7.78 mmol) of the title compound in a two-yield 43% yield.

¹ H NMR (DMSO, ppm); δ 1.40 (2H, m), 2.02 (1H, m), 2.29 (3H, s), 2.50 (1H, m), 6.82 (1H, d), 6.96 (2H, m), 7.83 (1H, d), 7.99 (1 H, t), 8.82 (1 H, s), 12.50 (1 H, s)

ESI MS (m / e) = 387 [M + 1]

Example 29 N -[5- (4-bromo-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 6.14 g (18.1 mmol) of the compound obtained in Preparation Example 11 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 6.39 g (15.7 mmol) of the title compound were obtained in 87% yield.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.98 (1H, m), 7.14 (1H, d), 7.37 (1H, d), 7.55 (1H, d), 7.94 (1H, d), 8.25 (1H, t), 9.08 (1 H, s), 12.53 (1 H, s)

ESI MS (m / e) = 408 [M + 1]

Example 30 N -[5- (3-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

4.97 g (18.1 mmol) of the compound obtained in Preparation Example 12, instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used in the same manner as in Example 1. 4.96 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.99 (1H, m), 2.17 (3H, s), 6.92 (1H, d), 7.23 (2H, q), 7.68 (1H, d), 7.91 (1H, d), 9.41 (1H, s), 12.49 (1H, s)

ESI MS (m / e) = 343 [M + 1]

Example 31 N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 5.33 g (18.1 mmol) of the compound obtained in Preparation Example 13 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.32 g (14.7 mmol) of the title compound were obtained in 81% yield.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.99 (1H, m), 7.14 (1H, d), 7.26 (1H, d), 7.45 (1H, dd), 7.94 (1H, d), 8.29 (1H, t), 9.08 (1 H, s), 12.53 (1 H, s)

ESI MS (m / e) = 363 [M + 1]

Example 32 N -[5- (2,4-difluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 5.04 g (18.1 mmol) of the compound obtained in Preparation Example 14 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride was used. 5.45 g (15.7 mmol) of the title compound were obtained in 87% yield.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.99 (1H, m), 7.02 (1H, d), 7.08 (1H, t), 7.30 (1H, t), 7.91 (1H, d), 8.09 (1H, m), 8.91 (1 H, s), 12.48 (1 H, s)

ESI MS (m / e) = 347 [M + 1]

Example 33 N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2-[(4-methyl-1-piperazinyl) carbonyl] cyclopropanecarboxamide

3.01 g (7.78 mmol) of the compound obtained in Example 28 was dissolved in 50 mL of dichloromethane, and 2.78 g (23.3 mmol) of thionyl chloride were added and stirred at room temperature. After 1 hour, the mixture was distilled under reduced pressure to remove the solvent and remaining thionyl chloride, which was then dissolved in 100 mL of dichloromethane. Then, 1.56 g (15.6 mmol) of N-methylpiperazine and 1.58 g (15.6 mmol) of triethylamine were added thereto. Stirred at. After 2 hours, the mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 95/5, v / v) to give 2.66 g (5.68 mmol) of the title compound in a yield of 73%.

¹ H NMR (CDCl ₃ , ppm); δ 1.40 (2H, m), 2.10-2.48 (6H, m), 2.29 (3H, s), 3.75 (4H, m), 6.58 (1H, s), 6.82 (1H, d), 6.96 (2H, m ), 7.83 (1H, d), 7.99 (1H, t), 10.85 (1H, s)

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

Example 34 N ^One -[2- (diethylamino) ethyl]- N ² -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -1,2-cyclopropanedicarboxamide

In Example 33 2.49 g (5.14 mmol) of the title compound were obtained in 66% yield in the same manner using 1.81 g (15.6 mmol) of N, N-diethylethylenediamine instead of N-methylpiperidine.

¹ H NMR (CDCl ₃ , ppm); δ 1.40 (2H, m), 2.10-2.48 (9H, m), 2.29 (3H, s), 3.75 (4H, m), 6.78 (1H, s), 6.82 (1H, d), 6.96 (2H, m ), 7.83 (1H, d), 7.99 (1H, t)

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

Example 35 E )- N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3-phenyl-2-propenamide

5.27 g (18.1 mmol) of the compound obtained in Preparation Example 9, instead of the compound obtained in Preparation Example 3, and 3.62 g (21.7 mmol) of cinnamoyl chloride instead of cyclopentanecarbonyl chloride, were used in the same manner as in Example 1. (13.0 mmol) was obtained in a yield of 72%.

¹ H NMR (DMSO, ppm); δ 2.30 (3H, s), 7.01 (4H, m), 7.44 (1H, s), 7.45 (2H, d), 7.66 (2H, d), 7.77 (1H, d), 7.91 (1H, d), 7.97 (1 H, t), 8.85 (1 H, s)

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

Example 36 N -[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] acrylamide Preparation

4.75 g (18.1 mmol) of the compound obtained in Preparation Example 9, instead of the compound obtained in Preparation Example 3, and 1.96 g (21.7 mmol) of acryloyl chloride instead of cyclopentanecarbonyl chloride were used in the same manner as in Example 1. g (14.5 mmol) was obtained in a yield of 80%.

¹ H NMR (DMSO, ppm); δ 2.30 (3H, s), 5.94 (1H, d), 6.54 (2H, m), 6.98-7.10 (3H, m), 7.89-7.97 (2H, m), 8.84 (1H, s), 12.42 (1H , s)

ESI MS (m / e) = 329 [M + 1]

Example 37 N ^One -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl]- N ² Preparation of-[2- (4-morpholinyl) ethyl] -1,2-cyclopropanedicarboxamide

Example 35, using 3.17 g (7.78 mmol) of the compound obtained in Preparation Example 18 instead of the compound obtained in Example 28, and 2.03 g (15.6 mmol) of 4- (2-aminoethyl) morpholine instead of N-methylpiperazine In the same manner as in 2.46 g (4.74 mmol) of the title compound were obtained in a yield of 61%.

¹ H NMR (DMSO, ppm); δ 1.30 (2H, m), 2.28 (1H, m), 2.33 (7H, m), 3.20 (2H, m), 3.59 (4H, m), 7.14 (1H, d), 7.26 (1H, d), 7.45 (1H, dd), 7.94 (1H, d), 8.29 (1H, t), 9.08 (1H, s), 12.53 (1H, s)

ESI MS (m / e) = 519 [M + 1]

Example 38 N ^One -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl]- N ² Preparation of-[2- (2-pyridinyl) ethyl] -1,2-cyclopropanedicarboxamide

In Example 35, using 3.17 g (7.78 mmol) of the compound obtained in Preparation Example 18 instead of the compound obtained in Example 28, and 1.91 g (15.6 mmol) of 2- (2-aminoethyl) pyridine were used instead of N-methylpiperazine. In the same manner as 1.47 g (2.88 mmol) of the title compound were obtained in a yield of 37%.

¹ H NMR (DMSO, ppm); δ 1.30 (2H, m), 2.28 (1H, m), 2.33 (1H, m), 2.88 (2H, t), 3.46 (2H, t), 7.14 (1H, d), 7.26 (3H, m), 7.45 (1H, dd), 7.70 (1H, t), 7.94 (1H, d), 8.29 (1H, t), 8.42 (1H, d), 8.49 (1H, d), 9.08 (1H, s), 12.53 (1H, s)

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

Example 39 N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] acrylamide Preparation

5.06 g (18.1 mmol) of the compound obtained in Preparation Example 13, instead of the compound obtained in Preparation Example 3, and 1.96 g (21.7 mmol) of acryloyl chloride instead of cyclopentanecarbonyl chloride were used in the same manner as in Example 1. g (14.5 mmol) was obtained in a yield of 80%.

¹ H NMR (DMSO, ppm); δ 5.95 (1H, d), 6.43 (1H, d), 6.58 (1H, m), 7.16 (1H, d), 7.27 (1H, d), 7.46 (1H, d), 7.96 (1H, d), 8.31 (1H, t), 9.10 (1H, s), 12.48 (1H, s)

ESI MS (m / e) = 349 [M + 1]

Example 40 N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3-methyl-3-butenamide

In Example 1, using 5.33 g (18.1 mmol) of the compound obtained in Preparation Example 13 instead of the compound obtained in Preparation Example 3, and 2.57 g (21.7 mmol) of 3,3-dimethylacryloyl chloride instead of cyclopentanecarbonyl chloride were used. After the reaction was carried out in the same manner as in the following, HPLC (acetonitrile / water = 70/30, v / v) was taken out at 8.72 minutes of Retention Time to give 1.16 g (3.08 mmol) of the title compound in a yield of 17%. .

¹ H NMR (DMSO, ppm); δ 1.78 (3H, s), 3.22 (2H, s), 4.90 (2H, d), 7.14 (1H, d), 7.26 (1H, d), 7.45 (1H, dd), 7.94 (1H, d), 8.29 (1H, t), 9.08 (1H, s), 12.53 (1H, s)

ESI MS (m / e) = 377 [M + 1]

Example 41 N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3-methyl-2-butenamide

In Example 40 the compound as obtained by HPLC (acetonitrile / water = 70/30, v / v) Retention Time 10.14 min was taken to give 2.73 g (7.24 mmol) of the title compound in 40% yield.

¹ H NMR (DMSO, ppm); δ 1.92 (3H, s), 2.22 (3H, s), 6.03 (1H, s), 7.13 (1H, d), 7.25 (1H, d), 7.43 (1H, d), 7.92 (1H, d), 8.30 (1H, t), 9.06 (1H, s), 12.11 (1H, s)

ESI MS (m / e) = 377 [M + 1]

Example 42 N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -3-buteneamide

The reaction was carried out in the same manner as in Example 1, using 5.33 g (18.1 mmol) of the compound obtained in Preparation Example 13 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of crotonyl chloride instead of cyclopentanecarbonyl chloride. After doing so, the compound obtained in 7.30 minutes of HPLC (acetonitrile / water = 70/30, v / v) Retention Time was taken to give 788 mg (2.17 mmol) of the title compound in a yield of 12%.

¹ H NMR (DMSO, ppm); δ 3.30 (2H, d), 5.20 (2H, t), 5.98 (1H, m), 7.15 (1H, d), 7.25 (1H, d), 7.44 (1H, d), 7.94 (1H, d), 8.31 (1H, t), 9.07 (1H, s), 12.28 (1H, s)

ESI MS (m / e) = 363 [M + 1]

Example 43 E )- N -[5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] -2-butenamide Preparation

In Example 42 the compound as obtained by HPLC (acetonitrile / water = 70/30, v / v) Retention Time 7.62 minutes was taken to give 2.04 g (5.61 mmol) of the title compound in a yield of 31%.

¹ H NMR (DMSO, ppm); δ 1.91 (2H, d), 6.26 (1H, d), 6.99 (1H, q), 7.13 (1H, d), 7.26 (1H, d), 7.43 (1H, d), 7.94 (1H, d), 8.31 (1H, t), 9.07 (1H, s), 12.27 (1H, s)

ESI MS (m / e) = 363 [M + 1]

Example 44 N -[5- (2,6-difluoroanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 5.04 g (18.1 mmol) of the compound obtained in Preparation Example 15 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 4.70 g (15.7 mmol) of the title compound were obtained in 75% yield.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 6.53 (1H, d), 7.28 (2H, t), 7.47 (1H, m), 7.85 (1H, d), 9.03 (1H, s), 12.48 (1 H, s)

ESI MS (m / e) = 347 [M + 1]

[ Example  45] N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.13 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.42 (3H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 12.48 (1 H, s)

ESI MS (m / e) = 359 [M + 1]

Example 46 N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Production of Pyridin-2-yl} acrylamide

In the same manner as in Example 1, using 5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 instead of the compound obtained in Preparation Example 3, and 1.96 g (21.7 mmol) of acryloyl chloride instead of cyclopentanecarbonyl chloride were used. 5.24 g (15.2 mmol) of the compound were obtained in a yield of 84%.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 5.94 (1H, d), 6.50 (2H, qd), 6.71 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 12.48 (1 H, s)

ESI MS (m / e) = 345 [M + 1]

Example 47 N -{5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} Cyclolopane Carboxamide

In the same manner as in Example 1, using 5.52 g (18.1 mmol) of the compound obtained in Preparation Example 32 instead of the compound obtained in Preparation Example 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride was used. 5.33 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.03 (3H, t), 1.97 (1H, m), 3.63 (2H, q), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1 H, d), 12.48 (1 H, s)

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

Example 48 N -{5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] Production of Pyridin-2-yl} acrylamide

In the same manner as in Example 1, using 5.52 g (18.1 mmol) of the compound obtained in Preparation Example 32 instead of the compound obtained in Preparation Example 3 and 1.96 g (21.7 mmol) of acryloyl chloride instead of cyclopentanecarbonyl chloride were used. 3.90 g (10.9 mmol) of the compound of were obtained in a yield of 60%.

¹ H NMR (DMSO, ppm); δ 1.03 (3H, t), 3.63 (2H, q), 5.94 (1H, d), 6.50 (2H, qd), 6.71 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1 H, d), 12.48 (1 H, s)

ESI MS (m / e) = 359 [M + 1]

Example 49 Ethyl 2- (4-chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Preparation of Pyridine-5-yl} anilino) acetate

In the same manner as in Example 1, using 6.57 g (18.1 mmol) of the compound obtained in Preparation Example 34 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.77 g (13.4 mmol) of the title compound were obtained in a yield of 74%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.03 (3H, t), 1.97 (1H, m), 4.11 (2H, q), 4.62 (2H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 12.48 (1H, s)

ESI MS (m / e) = 431 [M + 1]

Example 50 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Preparation of pyridin-5-yl} anilino) acetic acid

5.77 g (13.4 mmol) of the compound obtained in Example 49 were dissolved in 100 mL of tetrahydrofuran / ethanol / water (3/1/1), and 1.12 g (26.8 mmol) of lithium hydroxide monohydrate was added thereto, followed by stirring at room temperature. After 8 hours, 1N aqueous hydrochloric acid solution was added to neutralize, extracted with 100 mL (x2) of ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and 3.67 g (9.11 mmol) of the title compound were obtained in a yield of 68% without further purification.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 4.62 (2H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 12.48 (1 H, s)

ESI MS (m / e) = 403 [M + 1]

Example 51 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} anilino) ethyl Of cyclopropanecarboxylate  Produce

5.81 g (18.1 mmol) of the compound obtained in Preparation 35 was dissolved in 150 mL of dichloromethane, and 5.49 g (54.3 mmol) of triethylamine and 6.01 g (45.3 mmol) of cyclopentanecarbonyl chloride were added, followed by stirring at room temperature. After 2 hours, the mixture was diluted with 200 mL of dichloromethane, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 98/2, v / v) to give 7.04 g (15.4 mmol) of the title compound in a yield of 85%.

¹ H NMR (DMSO, ppm); δ 0.68 (2H, m), 0.77 (2H, m), 0.94 (4H, m), 1.48 (1H, m), 1.97 (1H, m), 4.21 (2H, t), 4.29 (2H, t), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 12.48 (1H, s)

ESI MS (m / e) = 457 [M + 1]

Example 52 N -{5- [4-chloro (2-hydroxyethyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

7.04 g (15.4 mmol) of the compound obtained in Example 51 was dissolved in 150 mL of tetrahydrofuran / ethanol / water (3/1/1), and lithium hydroxide monohydrate 1.29 g (30.8 mmol) was added thereto, followed by stirring at room temperature. After 8 hours, 1N aqueous hydrochloric acid solution was added to neutralize, extracted with 100 mL (x2) of ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and 3.71 g (9.55 mmol) of the title compound were obtained in 62% yield without further purification.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.61 (2H, t), 3.97 (2H, t), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1 H, d), 12.48 (1 H, s)

ESI MS (m / e) = 389 [M + 1]

Example 53 N -[5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 5.59 g (18.1 mmol) of the compound obtained in Preparation Example 21 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.39 g (14.3 mmol) of the title compound were obtained in 79% yield.

¹ H NMR (MeOD, ppm); δ 0.97 (2H, m), 1.03 (2H, m), 1.90 (1H, m), 3.29 (3H, s), 6.52 (1H, d), 7.29 (1H, d), 7.34 (1H, dd), 7.38 (1 H, t), 7.73 (1 H, d)

ESI MS (m / e) = 377 [M + 1]

Example 54 N -{5- [2,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.29 g (18.1 mmol) of the compound obtained in Preparation Example 22 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.15 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.37 (3H, s), 6.46 (1H, d), 7.20-7.58 (3H, m), 7.80 (1H, d), 12.48 (1H, s )

ESI MS (m / e) = 361 [M + 1]

Example 55 N -{5- [2,6-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.29 g (18.1 mmol) of the compound obtained in Preparation Example 23 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.15 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.37 (3H, s), 6.54 (1H, d), 7.25-7.49 (3H, m), 7.85 (1H, d), 12.48 (1H, s )

ESI MS (m / e) = 361 [M + 1]

Example 56 N -[5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] Pyridin-2-yl] cyclopropanecarboxamide

In the same manner as in Example 1, using 6.39 g (18.1 mmol) of the compound obtained in Preparation Example 24 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.26 g (12.5 mmol) of the title compound were obtained in a yield of 69%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.63 (1H, m), 3.46 (3H, s), 6.43 (1H, dd), 7.22 (1H, t), 7.33-7.39 (2H, m ), 7.64 (1 H, d)

ESI MS (m / e) = 422 [M + 1]

Example 57 N -{5- [2-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.18 g (18.1 mmol) of the compound obtained in Preparation Example 25 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.84 g (16.5 mmol) of the title compound were obtained in 91% yield.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.63 (1H, m), 3.46 (3H, s), 3.77 (3H, s), 6.27 (1H, d), 7.02 (1H, d), 7.25 (1H, d), 7.31 (1H, td), 7.54 (1H, d)

ESI MS (m / e) = 355 [M + 1]

Example 58 N -{5- [3,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.29 g (18.1 mmol) of the compound obtained in Preparation Example 26 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.15 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.37 (3H, s), 6.70 (1H, d), 7.19 (1H, m), 7.48 (2H, m), 7.80 (1H, d), 12.48 (1 H, s)

ESI MS (m / e) = 361 [M + 1]

Example 59 N -{5- [methyl-4- (trifluoromethyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.87 g (18.1 mmol) of the compound obtained in Preparation Example 27 instead of the compound obtained in Preparation Example 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride was used. 5.33 g (13.6 mmol) of the title compound were obtained in 75% yield.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.37 (3H, s), 7.01 (1H, d), 7.45 (1H, d), 7.70 (1H, d), 7.90 (1H, d), 12.57 (1 H, s)

ESI MS (m / e) = 393 [M + 1]

Example 60 N -{5- [4-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.18 g (18.1 mmol) of the compound obtained in Preparation Example 28 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.84 g (16.5 mmol) of the title compound were obtained in 91% yield.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.63 (1H, m), 3.46 (3H, s), 3.82 (3H, s), 6.43 (1H, d), 6.95 (2H, d), 7.18 (2H, d), 7.54 (1H, d)

ESI MS (m / e) = 355 [M + 1]

Example 61 N -{5- [4-cyano (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.09 g (18.1 mmol) of the compound obtained in Preparation Example 37 and 2.27 g (21.7 mmol) of the cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.44 g (15.6 mmol) of the title compound were obtained in a yield of 86%.

¹ H NMR (DMSO, ppm); δ 0.94 (4H, m), 1.97 (1H, m), 3.47 (3H, s), 7.12 (1H, d), 7.29 (2H, d), 7.70 (2H, d), 7.94 (1H, d), 12.62 (1 H, s)

ESI MS (m / e) = 350 [M + 1]

Example 62 N -{5- [4-isopropyl (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.40 g (18.1 mmol) of the compound obtained in Preparation Example 29 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.31 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.28 (6H, d), 1.63 (1H, m), 2.94 (1H, m), 3.51 (3H, s), 6.56 (1H, d), 7.19 (2H, d), 7.27 (2H, d), 7.55 (1H, d)

ESI MS (m / e) = 367 [M + 1]

Example 63 N -{5- [2,3-dihydro-1 H -Inden-5-yl (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

In the same manner as in Example 1, using 5.36 g (18.1 mmol) of the compound obtained in Preparation Example 30 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride were used instead of the compound obtained in Preparation Example 3. 5.28 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (3H, m), 1.10 (1H, m), 1.22 (2H, m), 1.65 (1H, m), 2.93 (4H, t), 3.50 (3H, s), 6.53 (1H, d), 7.12 (1H, s), 7.26 (2H, m), 7.54 (1H, d)

ESI MS (m / e) = 365 [M + 1]

Example 64 N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} -1-methyl-1 H Preparation of Pyrrole-2-carboxamide

Example 1, using 5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 instead of the compound obtained in Preparation Example 3, and 3.12 g (21.7 mmol) of 1-methylpyrrole-2-carbonyl chloride instead of cyclopentanecarbonyl chloride were used. 5.69 g (14.3 mmol) of the title compound were obtained in the same manner as in the 79% yield.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 3.93 (3H, s), 6.15 (1H, s), 6.70 (1H, d), 7.16 (1H, s), 7.34 (2H, d), 7.40 (1H, s), 7.46 (2H, d), 7.79 (1H, d), 12.18 (1H, s)

ESI MS (m / e) = 398 [M + 1]

Example 65 Ethyl 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] benzoate

In the same manner as in Example 1, using 5.94 g (18.1 mmol) of the compound obtained in Preparation Example 38 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.75 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.40 (3H, t), 1.65 (1H, m), 3.60 (3H, s), 4.38 (2H, q), 6.93 (1H, d), 7.28 (2H, d), 7.70 (2H, d), 8.03 (1H, d)

ESI MS (m / e) = 397 [M + 1]

Example 66 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] benzoic acid

5.75 g (14.5 mmol) of the compound obtained in Example 65 was dissolved in 150 mL of ethanol / water (4/1), and 1.21 g (29.0 mmol) of lithium hydroxide monohydrate was added thereto, followed by stirring at room temperature. After 8 hours, 1N aqueous hydrochloric acid solution was added to neutralize and the resulting white solid was filtered off and washed with daethyl ether to give 3.84 g (10.4 mmol) of the title compound in 72% yield without further purification.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.91 (1H, m), 3.60 (3H, s), 6.93 (1H, d), 7.28 (2H, d), 7.70 (2H, d), 8.03 (1H, d)

ESI MS (m / e) = 369 [M + 1]

Example 67 E )- N -[5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl] -3- (4-piperidinyl) 2-propenamide

5.75 g (9.74 mmol) of the compound obtained in Preparation Example 40 were added to 100 mL of tetrahydrofuran, and 5 mL of 6N aqueous hydrochloric acid solution was added thereto, followed by heating under reflux and stirring. After 5 hours, the solvent was removed by distillation under reduced pressure and 4.77 g (9.06 mmol) of the title compound hydrogen chloride were obtained in 93% yield without further purification.

¹ H NMR (DMSO, ppm); δ 1.47 (2H, qd), 1.68 (2H, d), 1.90 (2H, t), 1.94 (2H, d), 2.11 (1H, m), 3.46 (3H, s), 6.43 (1H, dd), 5.93 (1H, d), 7.11 (1H, dd), 7.22 (1H, t), 7.33-7.39 (2H, m), 7.64 (1H, d)

ESI MS (m / e) = 491 [M + 1]

Example 68 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -3- (1-ethyl-4-piperidinyl) -2-propenamide

3.83 g (8.26 mmol) of the compound obtained in Preparation Example 41 were added to 100 mL of dichloroethane, and 2.09 g (20.7 mmol) of triethylamine was added thereto and stirred at room temperature. After 10 minutes, 1.09 g (24.8 mmol) of acetaldehyde and 6.97 g (33.0 mmol) of sodium triacetoxyborohydride were added, followed by stirring at room temperature. After 4 hours, 100 mL of saturated sodium hydrogen carbonate solution was added, extracted with 100 mL (x2) of dichloromethane, and the organic layer was washed with 100 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) to give 2.18 g (4.79 mmol) of the title compound in a yield of 58%.

¹ H NMR (CDCl ₃ , ppm); δ 1.08 (3H, t), 1.47 (2H, qd), 1.68 (2H, d), 1.90 (2H, t), 1.94 (2H, d), 2.11 (1H, m), 2.30 (2H, q), 3.46 (3H, s), 6.43 (1H, dd), 5.93 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.21 (2H, d), 7.36 (2H, d), 7.61 (1H, d)

ESI MS (m / e) = 456 [M + 1]

Example 69 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -3- (1-methyl-4-piperidinyl) -2-propenamide

In Example 68 1.86 g (4.21 mmol) of the title compound were obtained in 51% yield in the same manner using 2.12 g (35%, 24.8 mmol) of formaldehyde instead of acetaldehyde.

¹ H NMR (CDCl ₃ , ppm); δ 1.47 (2H, qd), 1.68 (2H, d), 1.90 (2H, t), 1.94 (2H, d), 2.11 (1H, m), 2.30 (3H, s), 3.46 (3H, s), 6.43 (1H, dd), 5.93 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.21 (2H, d), 7.36 (2H, d), 7.61 (1H, d)

ESI MS (m / e) = 442 [M + 1]

Example 70 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -4- (4-morpholinyl) -2-butenamide

4.48 g (27.2 mmol) of 4-bromochromonic acid was dissolved in 50 mL of dichloromethane, and 4.31 g (36.2 mmol) of thionyl chloride were added, followed by stirring at room temperature. After 2 hours, the solvent was distilled off under reduced pressure, and the obtained compound was added to 100 mL of dichloromethane containing 5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 and 3.66 g (36.2 mmol) of triethylamine, followed by stirring at room temperature. It was. After 30 minutes, 4.73 g (54.3 mmol) of morpholine was added to the reaction solution, followed by stirring at room temperature. After 2 hours, the mixture was diluted with 200 mL of dichloromethane, washed with 100 mL of saturated aqueous ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) to give 1.53 g (3.44 mmol) of the title compound in a yield of 19%.

¹ H NMR (CDCl ₃ , ppm); δ 2.47 (4H, br s), 3.18 (2H, d), 3.51 (3H, s), 3.70 (4H, t), 6.18 (1H, d), 6.63 (1H, d), 7.13 (1H, m) , 7.23 (2H, d), 7.36 (2H, d), 7.61 (1H, d), 10.40 (1H, s)

ESI MS (m / e) = 444 [M + 1]

Example 71 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino]- N , N Preparation of -dimethylbenzamide

3.84 g (10.4 mmol) of the compound obtained in Example 66 was dissolved in 50 mL of dimethylformamide, 7.80 mL (2N, 15.6 mmol) of dimethylamine was added, and 2.99 g (15.6 mmol) of EDC and 2.11 g (15.6 mmol) of HOBT were added thereto. After stirring at room temperature. After 3 hours, the mixture was diluted with 150 mL of ethyl acetate, washed with 100 mL of saturated sodium chloride solution (x2), and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 95/5, v / v) to give 3.25 g (8.22 mmol) of the title compound in a yield of 79%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.23 (2H, m), 1.65 (1H, m), 3.10 (6H, br s), 3.56 (3H, s), 6.76 (1H, d), 7.29 (2H, d) , 7.48 (2H, d), 7.64 (1H, d), 11.10 (1H, s)

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

Example 72 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino]- N Preparation of-[2- (dimethylamino) ethyl] benzamide

In Example 71 2.83 g (6.45 mmol) of the title compound were obtained in 62% yield using the same method as 1.38 g (15.6 mmol) of N, N-dimethylethylenediamine instead of dimethylamine.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.23 (2H, m), 1.65 (1H, m), 2.34 (6H, s), 2.62 (2H, t), 3.56 (3H, s), 3.59 (2H, t), 6.83 (1H, d), 7.27 (2H, d), 7.66 (1H, d), 7.82 (2H, d)

ESI MS (m / e) = 439 [M + 1]

Example 73 N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} -1-methyl-1 H Preparation of -imidazole-4-carboxamide

2.74 g (21.7 mmol) of 1-methyl-imidazole-4-carboxylic acid obtained by the method described in Henry Rapoport, Synthesis , 1988 , 10 , 767-771 were dissolved in 50 mL of dichloromethane and 3.87 g (32.6) of thionyl chloride. mmol) was added and stirred at room temperature. After 1 hour, the compound obtained by removing the solvent by distillation under reduced pressure was used in place of cyclopentanecarbonyl chloride, and 5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 was used instead of the compound obtained in Preparation Example 3. This gave 3.47 g (8.69 mmol) of the title compound in a yield of 48%.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 3.76 (3H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 7.82 (1H, s), 8.06 (1H, s), 11.53 (1H, s)

ESI MS (m / e) = 399 [M + 1]

Example 74 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino]- N Preparation of Methylbenzamide

7.46 g (6.45 mmol) of the title compound were obtained in 62% yield in the same manner using 7.80 mL (2N, 15.6 mmol) of monomethylamine instead of dimethylamine in Example 71.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.99 (1H, m), 2.79 (3H, d), 3.48 (3H, s), 6.87 (1H, d), 7.35 (2H, d), 7.48 (2H, d), 7.85 (1 H, d), 8.37 (1 H, br s)

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

Example 75 N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} -1-methyl-1 H Preparation of -imidazole-5-carboxamide

5.26 g (18.1 mmol) of the compound obtained in Preparation Example 20 was used instead of the compound obtained in Preparation Example 3, and 3.12 g (21.7 mmol) of 1-methylimidazole-5-carbonyl chloride was used instead of cyclopentanecarbonyl chloride. In the same manner as in Example 1, 5.69 g (14.3 mmol) of the title compound were obtained in a yield of 79%.

¹ H NMR (DMSO, ppm); δ 3.42 (3H, s), 3.91 (3H, s), 6.70 (1H, d), 7.34 (2H, d), 7.46 (2H, d), 7.79 (1H, d), 8.13 (1H, s), 8.49 (1 H, s), 12.56 (1 H, s)

ESI MS (m / e) = 399 [M + 1]

Example 76 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -3- (1- (methylsulfonyl) -4-piperidinyl) -2-propenamide

3.83 g (8.26 mmol) of the compound obtained in Preparation Example 41 were added to 100 mL of dichloromethane, and 2.51 g (24.8 mmol) of triethylamine and 1.42 g (12.4 mmol) of methanesulfonyl chloride were added, followed by stirring at room temperature. After 1 hour, the mixture was diluted with 100 mL of dichloromethane, washed with 100 mL of saturated ammonium chloride solution and 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The resulting impure compound was purified by column chromatography (dichloromethane / methanol = 98/2, v / v) under reduced pressure distillation to give 3.34 g (6.61 mmol) of the title compound in a yield of 80%.

¹ H NMR (CDCl ₃ , ppm); δ 1.51 (2H, qd), 1.85 (2H, br d), 2.29 (1H, m), 2.72 (2H, td), 2.79 (3H, s), 3.51 (3H, s), 3.79 (2H, br d ), 5.97 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.22 (2H, d), 7.38 (2H, d), 7.61 (1H, d)

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

Example 77 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] benzamide

3.84 g (10.4 mmol) of the compound obtained in Example 66 was dissolved in 50 mL of tetrahydrofuran, 1.58 g (15.6 mmol) of triethylamine and 1.56 g (11.4 mmol) of isobutylchloroformate were added and stirred at room temperature. After 30 minutes, 6 mL of aqueous ammonia was added and stirred for 3 hours, after which the resulting solid was filtered and washed with diethyl ether to give 1.49 g (4.06 mmol) of the title compound in a yield of 39% without further purification.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.99 (1H, m), 3.48 (3H, s), 6.88 (1H, d), 7.34 (2H, d), 7.84 (1H, d), 7.89 (2H, d)

ESI MS (m / e) = 368 [M + 1]

Example 78 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -4- (1-piperidinyl) -2-butenamide

In Example 70, 4.62 g (54.3 mmol) of piperidine instead of morpholine were used to obtain 1.04 g (2.35 mmol) of the title compound in a yield of 13%.

¹ H NMR (CDCl ₃ , ppm); δ 0.84 (2H, m), 1.24 (4H, m), 2.55 (4H, m), 3.20 (2H, d), 3.50 (3H, s), 6.18 (1H, d), 6.63 (1H, d), 7.13 (1H, m), 7.23 (2H, d), 7.36 (2H, d), 7.61 (1H, d), 10.40 (1H, s)

ESI MS (m / e) = 442 [M + 1]

Example 79 ( E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} -4- (1,4-dioxa-8-azaspiro [4.5] de-8-sil) -2-buteneamide

In Example 70, 903 mg (1.81 mmol) of the title compound were obtained in a yield of 10% by the same method using 7.78 g (54.3 mmol) of 4-piperidine ethylene ketal instead of morpholine.

¹ H NMR (CDCl ₃ , ppm); δ 1.71 (4H, t), 2.54 (4H, br s), 3.18 (2H, d), 3.52 (3H, s), 3.94 (4H, s), 6.18 (1H, d), 6.63 (1H, d) , 7.13 (1H, m), 7.23 (2H, d), 7.36 (2H, d), 7.61 (1H, d), 10.40 (1H, s)

ESI MS (m / e) = 500 [M + 1]

Example 80 E )- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -4- (dimethylamino) -2-butenamide

727 mg (1.81 mmol) of the title compound were obtained in 10% yield in the same manner using 27.2 mL (2N, 54.3 mmol) of dimethylamine instead of morpholine in Example 70.

¹ H NMR (CDCl ₃ , ppm); δ 2.55 (6H, br s), 3.18 (2H, d), 3.52 (3H, s), 6.18 (1H, d), 6.63 (1H, d), 7.13 (1H, m), 7.23 (2H, d) , 7.36 (2H, d), 7.61 (1H, d), 10.40 (1H, s)

ESI MS (m / e) = 402 [M + 1]

Example 81 Ethyl 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] phenyl} acetate

In the same manner as in Example 1, using 6.20 g (18.1 mmol) of the compound obtained in Preparation Example 31 instead of the compound obtained in Preparation Example 3, and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride 5.95 g (14.5 mmol) of the title compound were obtained in a yield of 80%.

¹ H NMR (CDCl ₃ , ppm); δ 0.95 (2H, m), 1.22 (2H, m), 1.40 (3H, t), 1.65 (1H, m), 2.92 (2H, s), 3.60 (3H, s), 4.38 (2H, q), 6.93 (1H, d), 7.42 (2H, d), 7.90 (2H, d), 8.11 (1H, d)

ESI MS (m / e) = 411 [M + 1]

Example 82 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] Pyridin-5-yl} (methyl) amino] phenyl} acetic acid

In the same manner as in Example 66, using 5.95 g (14.5 mmol) of the compound obtained in Example 91 instead of the compound obtained in Example 65, 3.77 g (9.86 mmol) of the title compound was obtained in a yield of 68%.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.65 (1H, m), 2.80 (2H, s), 3.60 (3H, s), 6.93 (1H, d), 7.42 (2H, d), 7.90 (2H, d), 8.11 (1 H, d)

ESI MS (m / e) = 383 [M + 1]

Example 83 N -{5- [4- [2- (dimethylamino) -2-oxoethyl] (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} cyclopropanecarboxamide

Using 3.98 g (10.4 mmol) of the compound obtained in Example 82 instead of the compound obtained in Example 66, 2.64 g (6.45 mmol) of the title compound were obtained in a yield of 62% in the same manner as in Example 71.

¹ H NMR (DMSO, ppm); δ 0.95 (4H, m), 1.65 (1H, m), 2.80 (2H, s), 3.10 (6H, br s), 3.60 (3H, s), 6.93 (1H, d), 7.42 (2H, d) , 7.90 (2H, d), 8.11 (1H, d)

ESI MS (m / e) = 410 [M + 1]

Example 84 Ethyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} amino) -3-oxo-1-propenyl] -1-piperidinecarboxylate

3.76 g (7.52 mmol) of the title compound were obtained in 91% yield in the same manner using 1.35 g (12.4 mmol) of ethylchloroformate instead of methanesulfonyl chloride in Example 76.

¹ H NMR (CDCl ₃ , ppm); δ 1.25 (3H, t), 1.33 (2H, qd), 1.72 (2H, br d), 2.31 (1H, m), 2.79 (2H, br t), 3.51 (3H, s), 4.14 (2H, br s), 4.14 (2H, q), 5.97 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.22 (2H, d), 7.38 (2H, d), 7.61 (1H, d )

ESI MS (m / e) = 500 [M + 1]

Example 85 Methyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Pyridin-2-yl} amino) -3-oxo-1-propenyl] -1-piperidinecarboxylate

3.65 g (7.52 mmol) of the title compound were obtained in 91% yield in the same manner using 1.17 g (12.4 mmol) of methylchloroformate instead of methanesulfonyl chloride in Example 76.

¹ H NMR (CDCl ₃ , ppm); δ 1.33 (2H, qd), 1.72 (2H, br d), 2.31 (1H, m), 2.79 (2H, brt), 3.51 (3H, s), 3.71 (3H, s), 4.12 (2H, br s), 5.97 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.22 (2H, d), 7.38 (2H, d), 7.61 (1H, d)

ESI MS (m / e) = 486 [M + 1]

Example 86 E ) -3- (1-acetyl-4-piperidinyl)- N -{5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] Preparation of Pyridin-2-yl} -2-propenamide

In Example 76 2.27 g (6.20 mmol) of the title compound were obtained in the same manner using 1.27 g (12.4 mmol) of acetic anhydride instead of methanesulfonyl chloride in 75% yield.

¹ H NMR (CDCl ₃ , ppm); δ 1.38 (2H, qd), 1.82 (2H, brt), 2.12 (3H, s), 2.31 (1H, m), 2.63 (1H, br t), 3.11 (1H, td), 3.51 (3H, s ), 3.84 (1H, d), 4.64 (2H, d), 5.97 (1H, d), 6.61 (1H, d), 7.11 (1H, dd), 7.22 (2H, d), 7.38 (2H, d) , 7.61 (1 H, d)

ESI MS (m / e) = 470 [M + 1]

[ Production Example  48] 4- Nitrophenyl  5- (4- Chloro -2- Fluoromethylanilino ) [1,3] thiazolo [5,4-b] pyridine-2- Nilcarbamate

10.0 g (32.4 mmol) of the compound obtained in Preparation Example 21 was dissolved in 200 mL of tetrahydrofuran, and 6.6 g (32.4 mmol) of 4-nitrophenyl-chloroformate and 5.2 g (64.8 mmol) of pyridine were added thereto, followed by stirring at room temperature. After 2 hours, the solvent was removed by distillation under reduced pressure and the solid compound obtained was washed with ether to give 15.0 g of the title compound almost quantitatively. The obtained compound was unstable and proceeded to the next reaction without confirmation.

[ Example  87] N- [5- (4- Chloro -2- Fluoromethylanilino ) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- (4- Morpholinyl )ethyl] Urea

2.0 g (4.2 mmol) of the compound obtained in Preparation Example 42 were dissolved in 50 mL of tetrahydrofuran, 1.1 g (8.4 mmol) of 4- (2-aminoethyl) morpholine and 1.3 g (64.8 mmol) of triethylamine were added thereto, followed by heating. It was stirred at reflux. After 1 hour, the mixture was diluted with 200 ml of ethyl acetate, washed with 100 ml of saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the resulting impure compound was purified by column chromatography (dichloromethane / methanol = 9/1, v / v) to obtain 1.5 g of the title compound in a yield of 79%.

¹ H NMR (CDCl ₃ , ppm); δ 7.79 (1H, d), 7.23 (3H, m), 6.40 (1H, d), 3.75 (4H, br), 3.47 (2H, m), 3.44 (3H, s), 2.60 (2H, m), 2.54 (4 H, br)

ESI MS (m / e) = 465 [M + 1]

Table 1 below is an example synthesized by the method of Example 87 using the compound obtained in Preparation Example 48.

[ Production Example  49] 4- [2- (3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl-ureido) -Ethyl] -piperidine-1-carboxylic acid tert -Butyl ester

The compound obtained in Preparation Example 48 was reacted with 4- (2-amino-ethyl) -piperidine-1-carboxylic acid tert-butyl ester by the method of Example 87 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.51 (1H, d), 7.21 (3H, m), 6.38 (1H, d), 3.41 (3H, s), 3.40 (4H, m), 2.75 (2H, t), 2.03 (1H, m), 1.88 (2H, m), 1.45 (m, 2H), 1.33 (9H, s)

ESI MS (m / e) = 563 [M + 1]

[ Example  157] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- (2-piperidin-4-yl-ethyl)- Urea

500 mg (0.890 mmol) of the compound obtained in Preparation Example 49 were dissolved in 10 ml of dichloromethane, and 5 ml of 4 normal hydrochloric acid 1,4-dioxane solution was added thereto, followed by stirring for 2 hours. After completion of the reaction, concentrated, 30 ml of water was added, neutralized with saturated aqueous sodium hydrogen carbonate solution, filtered and dried to give 390 mg (0.844 mmol, yield; 95%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.50 (1H, d), 7.22 (3H, m), 6.39 (1H, d), 3.43 (3H, s), 3.40 (4H, m), 2.75 (2H, t), 2.03 (1H, m), 1.88 (2H, m), 1.45 (m, 2H)

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

[ Example  158] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3-piperidin-4-yl- Urea

The compound obtained in Example 119 was reacted by the method of Example 157 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.76 (1H, s), 8.68 (1H, s), 7.77 (1H, d), 7.60 (1H, d), 7.52-7.44 (2H, m), 7.36 (1H, d), 6.51 (1H, d ), 3.83 (1H, m), 3.36 (3H, s), 3.33 (2H, m), 3.02 (2H, m), 1.99 (2H, m), 1.66 (2H, m)

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

[ Example  159] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3-piperidine-4- Methyl - Urea

The compound obtained in Example 125 was reacted by the method of Example 157 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.69 (1H, s), 8.36 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.50 (1H, t), 7.39 (1H, d), 7.11 (1H, t), 6.51 (1H, d), 3.37 (3H, s), 3.28 (2H, m), 3.08 (2H, m), 2.86 (2H, m), 1.81 (3H, m), 1.33 (2H, m)

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

[ Example  160] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3-piperidine-3- Methyl - Urea

The compound obtained in Example 160 was reacted by the method of Example 157 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 8.86 (1H, s), 8.60 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.50 (1H, t), 7.39 (1H, d), 7.29 (1H, t), 6.51 (1H, d), 3.39 (3H, s), 3.20 (2H, m), 3.12 (2H, m), 2.67 (1H, m), 2.55 (1H, m), 1.99 (1H, m), 1.77 (2H, m), 1.60 (1H, m), 1.18 (1H, m)

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

Production Example 50 4- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl- Ureido) -propyl] -piperazine-1-carboxylic acid tert -Butyl ester

The compound obtained in Preparation Example 48 was reacted with 4- (3-amino-propyl) -pyrazine-1-carboxylic acid tert-butyl ester in the method of Example 87 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.35 (1H, d), 7.02 (3H, m), 6.49 (1H, d), 3.42 (3H, s), 3.30 (2H, m), 3.25 (4H, m), 2.65 (4H, m), 2.52 (2H, m), 1.75 (2H, m), 1.34 (9H, s)

ESI MS (m / e) = 578 [M + 1]

[ Example  161] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- (3-piperazin-1-yl-propyl)- Urea

The compound obtained in Preparation Example 50 was reacted by the method of Example 157, to obtain the target compound.

¹ H NMR (CD3OD, ppm); δ 7.36 (1H, d), 7.32 (3H, m), 6.48 (1H, d), 3.41 (3H, s), 3.31 (2H, m), 3.25 (4H, m), 2.65 (4H, m), 2.52 (2H, m), 1.75 (2H, m)

ESI MS (m / e) = 478 [M + 1]

Production Example 51 (S) -3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Ureido) -pyrrolidine-1-carboxylic acid tert -Butyl ester

The compound obtained in Preparation Example 48 was reacted with (S) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester in the method of Example 87 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.21 (1H, s), 9.01 (1H, s), 7.71 (1H, d), 7.52 (1H, d), 7.42 (2H, m), 7.31 (1H, d), 6.48 (1H, d), 3.32 (3H, s), 3.30 (1H, m), 3.22 (1H, m), 3.05 (1H, m), 2.12 (1H, m), 1.85 (2H, m), 1.39 (9H, s), 1.12 (1H, m)

ESI MS (m / e) = 521 [M + 1]

[ Example  162] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- (S)- Pyrrolidine -3 days- Urea

The compound obtained in Preparation Example 51 was reacted by the method of Example 157, to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 9.20 (1H, s), 9.01 (1H, s), 7.72 (1H, d), 7.53 (1H, d), 7.45 (2H, m), 7.31 (1H, d), 6.47 (1H, d), 3.39 (3H, s), 3.30 (1H, m), 3.22 (1H, m), 3.05 (1H, m), 2.12 (1H, m), 1.85 (2H, m), 1.12 (1H, m)

ESI MS (m / e) = 421 [M + 1]

[ Example  163] 1- [3-((S) -3-amino- Pyrrolidine -1-yl) -propyl] -3- {5-[(4- Chloro -2- Influenza Oro Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2 days}- Urea

The compound obtained in Example 144 was reacted by the method of Example 157 to obtain the target compound.

1 H NMR (DMSO-d ₆ , ppm); δ 8.52 (1H, s), 8.45 (1H, s), 7.68 (1H, d), 7.55 (1H, d), 7.50 (1H, t), 7.32 (1H, d), 7.01 (1H, t), 6.49 (1H, d), 4.00 (1H, m), 3.87 (2H, s), 3.75 (1H, m), 3.60 (2H, m), 3.31 (3H, s), 3.18 (4H, m), 3.06 (1H, m), 2.11 (1H, m), 1.98 (1H, m), 1.80 (2H, m)

ESI MS (m / e) = 478 [M + 1]

Production Example 52 [2- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -urei -Ethyl] -methyl-carboxylic acid tert -Butyl ester

The compound obtained in Preparation Example 48 was reacted with (2-amino-ethyl) -methyl-carbamic acid tert-butyl ester in the method of Example 87 to obtain the target compound.

1 H NMR (CD3OD, ppm); δ 7.83 (1H, d), 7.43 (3H, m), 6.65 (1H, d), 3.61 (2H, m), 3.41 (3H, s), 3.22 (2H, m), 2.77 (3H, s), 1.42 (9 H, s)

ESI MS (m / e) = 509 [M + 1]

[ Example  164] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- (2- Methylamino -ethyl)- Urea

The compound obtained in Preparation Example 52 was reacted by the method of Example 157, to obtain the target compound.

1 H NMR (CD3OD, ppm); δ 7.85 (1H, d), 7.43 (3H, m), 6.67 (1H, d), 3.61 (2H, m), 3.47 (3H, s), 3.22 (2H, m), 2.77 (3H, s)

ESI MS (m / e) = 409 [M + 1]

[ Example  165] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Hydroxyimino -Piperidin-1-yl) -propyl]- Urea

50 mg (0.102 mmol) of the compound obtained in Example 155 was dissolved in 10 ml of ethanol, and 35 mg (0.51 mmol) of hydroxylamine hydrochloride and 50 mg (0.51 mmol) of potassium acetate were added and refluxed for 2 hours. After completion of the reaction, the solid in the solution was filtered off and the filtrate was concentrated. Separation by column chromatography gave 48 mg ((0.095 mmol, yield; 93%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.57 (1H, s), 7.78 (1H, d), 7.67 (1H, d), 7.59 (1H, t), 7.31 (1H, d), 6.82 (1H, s, br), 6.55 (1H, d ), 3.60 (1H, s), 3.32 (3H, s), 3.19 (2H, t), 3.03 (2H, m), 2.52-2.15 (8H, m), 1.17 (2H, quin)

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

[ Example  166] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3-((R) -2- Hydroxymethyl - Pyrrolidine -1-yl) -propyl]- Urea

180 mg (0.32 mmol) of the compound obtained in Example 154 were dissolved in 15 ml of tetrahydrofuran and cooled to 0 ° C. 49 mg (1.28 mmol) of lithium aluminum hydride was added thereto, followed by stirring at room temperature for 2 hours. After completion of the reaction, 0.1 ml of water was added and the resulting solid was filtered through Celite. The filtrate was concentrated, 10 ml of diethyl ether was added thereto, stirred for 10 minutes, and filtered to obtain 133 mg (0.272 mmol, yield; 85%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.56 (1H, s), 7.67 (1H, d), 7.54 (1H, d), 7.47 (1H, t), 7.31 (1H, d), 6.73 (1H, s), 6.48 (1H, d), 4.38 (1H, s), 3.30 (3H, s), 3.12 (4H, m), 3.02 (H, m), 2.87 (1H, m), 2.32 (1H, m), 2.20 (1H, m), 2.01 (1H, m), 1.72 (1H, m), 1.54 (5H, m)

ESI MS (m / e) = 493 [M + 1]

[ Example  167] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3-((S) -2- Hydroxymethyl - Pyrrolidine -1-yl) -propyl]- Urea

Using the compound obtained in Example 153, the reaction was carried out by the method of Example 166 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.53 (1H, s), 7.48 (1H, d), 7.35 (1H, d), 7.27 (1H, t), 7.20 (1H, d), 6.26 (2H, m), 3.31 (3H, s), 3.17 (2H, m), 3.04 (3H, m), 2.71 (1H, m), 2.30 (1H, m), 2.18 (1H, m), 2.02 (1H, m), 1.82 (1H, m), 1.50 (5H, m)

ESI MS (m / e) = 493 [M + 1]

Example 168 4- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -Ureido) -propyl] -pyrazine-1 -carboxylic acid ethyl ester

50 mg (0.0907 mmol) of the compound obtained in Example 161 was dissolved in 10 ml of dichloromethane, and 29 μl (0.363 mmol) of pyridine was added, followed by 9.2 μl (0.118 mmol) of ethyl chloroformate, followed by stirring at room temperature for 2 hours. After completion of the reaction, washed twice with 10 ml of water, concentrated and separated by column chromatography to obtain 43 mg (0.0783 mmol, yield; 86%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.55 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.51 (1H, t), 7.37 (1H, d), 6.99 (1H, s), 6.52 (1H, d), 4.07 (2H, q), 3.60-3.41 (6H, m), 3.31 (3H, s), 3.23 (2H, m), 1.78 (4H, m), 1.41 (2H, m), 1.12 (3H, t)

ESI MS (m / e) = 550 [M + 1]

[ Example  169] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Methanesulfonyl Piperazin-1-yl) -propyl]- Urea

In Example 168, the reaction of Example 168 was carried out using methanesulfonyl chloride instead of ethyl chloroformate to obtain the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.52 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.51 (1H, t), 7.38 (1H, d), 6.99 (1H, s), 6.52 (1H, d), 3.55 (4H, m), 3.32 (3H, s), 3.22-3.10 (8H, m), 2.92 (3H, s), 1.73 (2H, m)

ESI MS (m / e) = 556 [M + 1]

[ Example  170] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Ethanesulfonyl Piperazin-1-yl) -propyl]- Urea

In Example 168, the reaction of Example 168 was carried out using ethanesulfonyl chloride instead of ethyl chloroformate to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.73 (1H, d), 7.60 (1H, d), 7.51 (1H, t), 7.38 (1H, d), 6.72 (1H, s), 6.50 (1H, d), 3.31 (3H, s), 3.20 (6H, m), 3.06 (2H, q), 2.44-2.38 (6H, m), 1.64 (2H, m), 1.21 (3H, t)

ESI MS (m / e) = 570 [M + 1]

[ Example  171] 1- [3- (4-acetyl-piperazin-1-yl) -propyl] -3- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2 days}- Urea

In Example 168, the reaction of Example 168 was carried out using acetyl chloride instead of ethyl chloroformate to obtain the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.52 (1H, s), 7.69 (1H, d), 7.51 (1H, d), 7.47 (1H, t), 7.36 (1H, d), 6.70 (1H, s), 6.48 (1H, d), 3.38 (6H, m), 3.30 (3H, s), 3.16 (4H, m), 2.40 (3H, s), 2.32 (2H, m), 1.61 (2H, m)

ESI MS (m / e) = 520 [M + 1]

[ Example  172] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Cyclopropyl Piperazin-1-yl) -propyl]- Urea

210 mg (0.440 mmol) of the compound obtained in Example 161 was dissolved in 20 ml of tetrahydro, followed by 0.186 ml (0.92 mmol) of (1-ethoxycyclopropoxy) trimethylsilane, 58 mg (0.092 mmol) of sodium cyanoborohydride. ), 0.2 ml of acetic acid and 0.2 ml of methanol were added, and the mixture was stirred under reflux for 3 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 and concentrated. Separation by column chromatography gave 123 mg (0.238 mmol, yield; 54%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.57 (1H, s), 7.74 (1H, d), 7.61 (1H, d), 7.52 (1H, t), 7.38 (1H, d), 6.72 (1H, s), 6.50 (1H, d), 3.31 (3H, s), 3.30 (1H, m), 3.15 (6H, m), 2.44-2.38 (6H, m), 1.64 (2H, m), 0.49 (2H, m), 0.31 (2H, m)

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

[ Example  173] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- {3- [4- (2- Fluoro -Ethyl) -piperazin-1-yl] -propyl}- Urea

70 mg (0.147 mmol) of the compound obtained in Example 161 were dissolved in 15 ml of 1,4-dioxane, 40 mg (0.294 mmol) of potassium carbonate and 37.3 mg (0.294 mmol) of 1-bromo-2-fluoroethane were added thereto. It was added and stirred at reflux for 5 hours. After completion of the reaction, the mixture was concentrated, 20 ml of water was added thereto, and 20 ml of ethyl acetate was extracted twice, and concentrated. Separation by column chromatography gave 49 mg (0.0941 mol, yield; 64%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.74 (1H, d), 7.60 (1H, d), 7.51 (1H, t), 7.38 (1H, d), 6.96 (1H, s), 6.52 (1H, d), 4.69 (1H, m), 4.62, 4.57, 4.33, 4.25, 3.41 (4H, m), 3.32 (3H, s), 3.21 (2H, m), 3.10 (4H, m), 1.81 (2H, m)

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

[ Example  174] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Propionyl Piperazin-1-yl) -propyl]- Urea

In Example 168, the reaction of Example 168 was carried out using propanoyl chloride instead of ethyl chloroformate to obtain the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.52 (1H, s), 7.69 (1H, d), 7.56 (1H, d), 7.47 (1H, t), 7.33 (1H, d), 6.70 (1H, s), 6.47 (1H, d), 3.41 (6H, m), 3.31 (3H, s), 3.17 (2H, q), 2.32-2.23 (6H, m), 1.60 (2H, m), 0.92 (3H, t)

ESI MS (m / e) = 534 [M + 1]

[ Example  175] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- Cyclopropionyl Piperazin-1-yl) -propyl]- Urea

In Example 168, the reaction of Example 168 was carried out using cyclopropylcarbonyl chloride instead of ethyl chloroformate to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.56 (1H, s), 7.69 (1H, d), 7.52 (1H, d), 7.40 (1H, t), 7.16 (1H, d), 6.61 (1H, s), 6.37 (1H, d), 3.41 (6H, m), 3.35 (1H, m), 3.31 (3H, s), 3.25 (2H, m), 2.41-2.33 (6H, m), 0.44 (2H, m), 0.32 (2H, m)

ESI MS (m / e) = 546 [M + 1]

[ Example  176] 1- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2 days}- Urea

Using the compound obtained in Example 157, the reaction was carried out by the method of Example 171 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.67 (1H, d), 7.50 (1H, d), 7.41 (1H, t), 7.16 (1H, d), 6.72 (1H, s), 6.38 (1H, d), 3.40 (6H, m), 3.31 (3H, s), 3.25 (2H, m), 2.42-2.33 (6H, m), 1.96 (3H, s)

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

[ Example  177] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [2- (1- methyl -Piperidin-4-yl) -ethyl]- Urea

73 mg (0.158 mmol) of the compound obtained in Example 157 were dissolved in 15 ml of dichloroethane, 47 μl (0.632 mmol) of formalin was added thereto, stirred for 5 minutes, and then 134 mg (0.632 mmol) of sodium triacetoxyborohydride were added thereto at room temperature. Stir for 2 hours. After completion of the reaction, the solution was washed twice with 10 ml of water and concentrated. Separation by column chromatography gave 56 mg (0.118 mmol, yield; 74%) of the title compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.52 (1H, d), 7.26 (3H, m), 6.41 (1H, d), 3.43 (3H, s), 3.40 (2H, m), 2.97 (2H, m), 2.35 (3H, s), 2.02 (2H, m), 1.76 (2H, m), 1.59 (2H, m), 1.43 (2H, m), 1.26 (1H, m)

ESI MS (m / e) = 477 [M + 1]

Table 2 below is an example synthesized using the reduction amination reaction of Example 177.

[ Production Example  53] 3- (3- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] Pyridin-2-yl- Ureido ) -Propionic acid

The compound obtained in Preparation Example 48 was reacted with 3-aminopropanoic acid by the method of Example 87 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.53 (1H, s), 7.68 (1H, d), 7.53 (1H, d), 7.46 (1H, t), 7.32 (1H, d), 6.81 (1H, t), 6.47 (1H, d), 3.40 (2H, m), 3.31 (3H, s), 2.30 (2H, t)

ESI MS (m / e) = 424 [M + 1]

[ Example  193] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- methyl Piperazin-1-yl) -3-oxo-propyl]- Urea

43 mg (0.100mm0l) of the compound obtained in Preparation Example 53 was dissolved in 10 ml of N, N-dimethylformamide, 17 µl (0.150 mmol) of N-methylpiperazine, 46 mg (0.340 mmol) of 1-hydroxybenzotriazole, 33 mg (0.170 mmol) of EDC were added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, it was concentrated, 20 ml of ethyl acetate was added, washed with 20 ml of saturated aqueous sodium hydrogen carbonate solution and concentrated. Separation by column chromatography gave 44 mg (0.0871 mmol, yield; 87%) of the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.55 (1H, s), 7.69 (1H, d), 7.55 (1H, d), 7.47 (1H, t), 7.33 (1H, d), 6.81 (1H, t), 6.47 (1H, d), 3.45 (4H, m), 3.40 (2H, m), 3.30 (3H, s), 3.27 (3H, s), 2.64 (4H, m), 2.30 (2H, t)

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

[ Example  194] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [4- (4- methyl -Piperazin-1-yl) -butyl]- Urea

The compound obtained in Preparation Example 48 was reacted with 4- (4-aminobutyl) -1-methylpiperazine in the method of Example 87 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.68 (1H, d), 7.53 (1H, d), 7.46 (1H, t), 7.32 (1H, d), 6.81 (1H, t), 6.47 (1H, d), 3.40 (4H, m), 3.43 (2H, t), 3.33 (3H, s), 3.29 (3H, s), 3.14 (2H, q), 2.46 (4H, m), 1.47 (4H, m)

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

[ Example  195] 1- {5-[(4- Chloro -2- Fluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [2- (4- methyl -Piperazin-1-yl) -ethyl]- Urea

The compound obtained in Preparation Example 48 was reacted with 1-methyl-4- (2-aminoethyl) pyrazine in the method of Example 87 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.55 (1H, s), 7.67 (1H, d), 7.51 (1H, d), 7.42 (1H, t), 7.30 (1H, d), 6.80 (1H, t), 6.47 (1H, d), 3.40 (4H, m), 3.43 (2H, q), 3.31 (3H, s), 3.26 (3H, s), 3.14 (2H, t), 2.44 (4H, m),

ESI MS (m / e) = 478 [M + 1]

Preparation 54 [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -carbamic acid 4

Nitro Phenyl  ester

Using N ⁵ -methyl-N ⁵ -p-tolyl-thiazole [5,4-b] pyridine-2,5-diamine synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 Reaction was performed by the method of Preparation Example 48 to obtain the target compound. Likewise unstable, the next reaction proceeded without confirmation.

[ Example  196] 1- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2-yl] -3- (2- Morality Lin-4-yl-ethyl)- Urea

Using the compound obtained in Preparation Example 54, the reaction was carried out by the method of Example 87 to obtain the target compound.

¹ H NMR (CDCl ₃ , ppm); δ 7.56 (1H, d), 7.22 (2H, d), 7.16 (2H, d), 6.54 (1H, d), 3.77 (4H, br), 3.50 (2H, t), 3.48 (3H, s), 2.61 (2H, t), 2.55 (4H, br), 2.38 (3H, s)

ESI MS (m / e) = 427 [M + 1]

Table 3 below is an example synthesized by the reaction of the method of Example 196 using the compound obtained in Preparation Example 54.

Production Example 55 4- {3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -ureido} -piperidine-1-car Acid tert -Butyl ester

The compound obtained in Production Example 54 was reacted with the method of Example 196 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.53 (1H, s), 7.63 (1H, d), 7.33 (2H, d), 7.17 (2H, d), 6.93 (1H, d), 6.48 (1H, d), 3.81 (2H, m), 3.70 (1H, m), 3.38 (3H, s), 2.91 (2H, m), 2.31 (3H, s), 1.80 (2H, m), 1.41 (9H, s), 1.31 (2H, m)

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

[ Example  225] 1- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2-yl] -3-piperidin-4-yl- Urea

The compound obtained in Preparation Example 55 was reacted by the method of Example 157 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.64 (1H, d), 7.25 (2H, d), 7.17 (2H, d), 6.93 (1H, d), 6.49 (1H, d), 3.82 (2H, m), 3.70 (1H, m), 3.38 (3H, s), 2.92 (2H, m), 2.32 (3H, s), 1.80 (2H, m), 1.31 (2H, m)

ESI MS (m / e) = 397 [M + 1]

Table 4 shows an example of reacting the compound obtained in Preparation Example 54 with an amine protected with a Boc group by the method of Example 196, followed by deprotection by the method of Example 157.

Table 5 below is an example of synthesizing the compounds obtained in the Examples of the above table by using a reduction amination reaction of Example 177.

[ Example  245] 1- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2-yl] -3- [3- (4- Propionyl Piperazin-1-yl) -propyl]- Urea

The compound obtained in Example 229 was reacted by the method of Example 168 using propanoyl chloride to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.55 (1H, s), 7.59 (1H, d), 7.23 (2H, d), 7.14 (2H, d), 6.70 (1H, s), 6.43 (1H, d), 3.42 (6H, m), 3.34 (3H, s), 3.11 (2H, q), 2.29-2.24 (9H, m), 1.62 (2H, m), 0.95 (3H, t)

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

[ Example  246] 1- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2-yl] -3- [3- (4- Propionyl Piperazin-1-yl) -propyl]- Urea

In Example 245, the reaction of Example 245 was carried out using cyclopropylcarbonyl chloride instead of propanoyl chloride to obtain the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.59 (1H, d), 7.23 (2H, d), 7.14 (2H, d), 6.70 (1H, s), 6.43 (1H, d), 3.42 (6H, m), 3.34 (3H, s), 2.29-2.24 (9H, m), 2.19 (1H, m), 1.62 (2H, m), 0.44 (2H, m), 0.32 (2H, m)

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

[ Example  247] 1- [3- (4- Methanesulfonyl -Piperazin-1-yl) -propyl] -3- [5- ( methyl -p- Tolyl -Amino)- Thiazolo [5,4-b] pyridine -2 days]- Urea

In Example 245, the reaction of Example 245 was carried out using methanesulfonyl chloride instead of propanoyl chloride to obtain the title compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.56 (1H, s), 7.63 (1H, d), 7.26 (2H, d), 7.19 (2H, d), 6.79 (1H, s), 6.50 (1H, d), 3.39 (3H, s), 3.21 (2H, m), 3.13 (4H, m), 2.88 (3H, s), 2.56-2.47 (6H, m), 2.34 (3H, s), 1.78 (2H, m)

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

Production Example 56 {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (2,4-difluorophenyl) -thiazole [5,4-b] pyridine-2 synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 The reaction product was carried out by the method of Preparation Example 48 using, 5-diamine to obtain the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Table 6 below is an example synthesized by the reaction of the method of Example 87 using the compound obtained in Preparation Example 56.

Preparation Example 57 [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -carbamic acid 4-nitro-phenyl ester

Preparation Example using N ⁵ -methyl-N ⁵ -phenyl-thiazole [5,4-b] pyridine-2,5-diamine synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 It reacted by the method of 48 and obtained the target compound. Likewise unstable, the next reaction proceeded without confirmation.

[Preparation Example 58] {5- [Methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (4-trifluoromethyl) phenyl-thiazole [5,4-b] pyridine-2, synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48; It reacted by the method of Preparation Example 48 using 5-diamine, and obtained the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Production Example 59 {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (4-cyanophenyl) -thiazole [5,4-b] pyridine-2,5- synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 It reacted by the method of Preparation Example 48 using diamine, and obtained the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Production Example 60 {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (4-fluorophenyl) -thiazole [5,4-b] pyridine-2,5- synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 It reacted by the method of Preparation Example 48 using diamine, and obtained the target compound. It was likewise unstable and the next reaction proceeded without confirmation.

Production Example 61 {5-[(2-Fluoro-4-methoxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (2-methoxy-4-methoxyphenyl) -thiazole [5,4-b] pyridine synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 It reacted by the method of Preparation Example 48 using -2,5-diamine, and obtained the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Production Example 62 {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (2-hydroxy-4-chlorophenyl) -thiazole [5,4-b] pyridine- synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 It reacted by the method of manufacture example 48 using 2, 5- diamine, and obtained the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Production Example 63 {5-[(4-Bromo-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -carbamic acid 4-nitro- Phenyl  ester

N ⁵ -methyl-N ^5- (2,4-difluorophenyl) -thiazole [5,4-b] pyridine-2 synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation Example 21 in Preparation Example 48 The reaction product was carried out by the method of Preparation Example 48 using, 5-diamine to obtain the target compound. Likewise unstable, the next reaction proceeded without confirmation.

Table 7 below is an example synthesized by the reaction of the method of Example 48 using the compound obtained in Preparation Example 57 to Preparation Example 63.

[ Example  319] 1- {5-[(3,4- Difluoro - Phenyl )- methyl -Amino]- Thiazolo [5,4-b] pyridine -2-yl} -3- [3- (4- methyl Piperazin-1-yl) -propyl]- Urea

N ⁵ -methyl-N ^5- (3,4-difluorophenyl-thiazole [5,4-b] pyridine-2, synthesized in Korean Patent Application No. 04117617 instead of the compound obtained in Preparation 21 in Preparation Example 48; Reaction with the method of Preparation Example 48 using 5-diamine gave the intermediate, which was reacted with N-methylpiperazine in the method of Example 87 to obtain the target compound.

¹ H NMR (DMSO-d ₆ , ppm); δ 10.54 (1H, s), 7.72 (1H, d), 7.50-7.42 (2H, m), 7.17 (1H, m), 6.74 (1H, s), 6.69 (1H, d), 3.41 (3H, s ), 3.31 (4H, m), 3.20 (2H, q), 2.32-2.29 (6H, m), 2.17 (3H, s), 1.62 (2H, quin)

ESI MS (m / e) = 476 [M + 1]

Table 8 below is an example synthesized by reacting various aminothiazole and N-methylpiperazine synthesized in Korean Patent Application No. 04117617 by the method of Example 319.

[ Experimental Example  1] several kinds RTK Receptor Tyrosine Kinase Activity inhibitory effect on

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 Reaction was performed for 20 minutes under the same conditions as KDR using ㎍ / ml Poly Glu: Tyr peptide (4: 1) (Sigma) and 5 ㎍ / 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- or bFGF-dependent Human Umbilical Vein Endothelial Cell (HUVEC) Growth Inhibitory Effect of the Compounds According to the Present Invention

HUVEC cells isolated from the placenta (5 × 10 ³ cells / well) 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. Thereafter, serum starvation was performed for 24 hours in M199 starvation medium (0.5% FBS). Thereafter, the starvation medium was changed to a working medium containing the compound diluted step by step, and treated with 10 ng / ml VEGF (R & D systems) or 5 ng / ml bFGF (Upstate) 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 with the concentration of a compound that inhibits 50% of total VEGF or bFGF-induced cell growth.

Experimental Example 3 PDGF-BB-dependent PASMC (Pulmonary Artery Smooth Muscle Cell) Growth Inhibitory Effect of the Compounds According to the Present Invention

PASMC cells (5 × 10 ³ cells / well: Clonetics) are seeded in 96-well culture vessels and cells in DMEM cell culture medium (Gibco BRL) (containing 10% FBS, 1X Penicillin / Sterptomycin and 0.5 mM Glutamine) for one day. 5% CO _{2 in the} incubator, incubated at 37 ℃ conditions. Thereafter, serum starvation was performed for 24 hours in DMEM starvation medium (0.1% FBS). Thereafter, the starvation medium was changed to a working medium containing the compounds diluted in stages, and treated with 20 ng / ml PDGF-BB (Upstate) 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 linear regression analysis as 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 PDGF-BB.

Experimental Example 4 Experiment of Inhibitory Effect of HUVEC Formation on Tube Formation of Compounds According to the Present Invention

Passage 5 HUVEC (human neovascular cells) in a cell culture incubator at 5% CO ₂ , 37 ° C. in a cell culture to fill 70-80% of the 100 mm culture vessel and then trypsinized, containing 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. Add. 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 5 SRB (Sulforhodamine B) Growth Inhibitory Effect of the Compounds According to the Present Invention on HCT116

Inoculate HCT116 cells (3 × 10 ³ cells / well: KCLB) into a 96-well culture vessel in a volume of 100 μl and use RPMI1640 culture medium (containing 5% FBS, 1X Penicillin / Streptomycin 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 then 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.

Representative compounds of Formula 1 and their enzyme activity inhibition capacity measured for KDR and HUVEC as shown in the IC ₅₀ value is summarized in Table 9 below.

To the results shown for some of the compounds of the HCT116 cells, and bFGF-dependent HUVEC cell growth inhibition capabilities of the formula (1) with IC ₅₀ values are disclosed in table 10.

From the above results, it can be confirmed that the compounds according to the present invention are very effective in inhibiting KDR activity and inhibiting the growth of HUVEC.

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 (14)

A compound of formula 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof.

(One) Where A) R ₁ is selected from the group consisting of the following substituents, I) hydrogen; II) optionally substituted straight chain, branched or cyclic saturated or unsaturated alkyl; III) optionally substituted alkenyl; IV) optionally substituted aryl; V) optionally substituted heterocycle; VI) perhaloalkyl; Iii) a substituent of the formula -CY ₁ Y ₂ (Y ₃ ) nY ₄ , Wherein Y ₁ , Y ₂ are each independently selected from the group consisting of hydrogen, optionally substituted loweralkyl, aryl and hetero aryl, Y ₃ Is selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And Y ₄ Is hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted Lower alkyl, optionally substituted aryl, and heteroaryl; n is an integer from 0 to 3; Iii) a substituent of the formula -NZ ₁ (Z ₂ ) n ₁ -Z ₃ , Where Z ₁ Is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and hetero aryl, or are linked together and are selected from cyclic saturated alkyl or cyclic saturated alkyl including N, O, S, Z ₂ is selected from the group consisting of optionally substituted lower alkylene, lower alkenylene, lower alkynylene, aryl and heteroaryl; And Z ₃ Is hydrogen and hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine , Aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl or heteroaryl; n ₁ are each independently an integer of 0 to 3; B) R ₂ is selected from cyclic alkyl, aryl, hetero aryl, or optionally substituted cyclic alkyl, aryl or hetero aryl; C) R ₃ is selected from the group consisting of hydrogen, optionally substituted straight chain, branched or cyclic saturated or unsaturated alkyl; And D) X is O, S or NR ' It is selected from the group consisting of wherein R 'is hydrogen or lower alkyl. A compound according to claim ₁ , or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, characterized in that R ₁ is preferably selected from the following substituents I) -iii): I) lower alkyl; II) halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidi One or more selected from the group consisting of paddy, piperazine, thiophene, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Lower alkyl substituted with substituents; III) cyclic alkyl or heterocycle; IV) optionally substituted lower alkyl, halogen, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine , Pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Cyclic alkyl or heterocycle substituted with one or more substituents selected from the group consisting of; V) alkenyl; VI) optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, One selected from the group consisting of piperidine, piperidinone, piperazine, morpholin, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime, trifluoromethyl, aryl and heteroaryl Alkenyl substituted with one or more substituents; Iii) aryl or hetero aryl; Iii) halogen, amide, carbonyl, carbamate, carboxy, lower alkyl, lower alkoxy, amine, lower alkylamine, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidi Aryl or hetero substituted with one or more substituents selected from the group consisting of paddy, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl Aryl; Iii) a substituent of the formula -NZ ₁ (Z ₂ ) -Z ₃ , Where Z ₁ Is selected from hydrogen, optionally substituted lower alkyl, Z ₂ is optionally substituted lower alkylene, Z ₃ is hydrogen and hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, Morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl or heteroaryl. 3. The method of claim 2, wherein R ₁ of Z ₁ Is hydrogen, Z ₂ Is a alkylene having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, wherein R ₂ is selected from the following substituents I) -IV). Ⅰ) cyclic alkyl II) halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, Cyclic alkyl substituted with one or more substituents selected from the group consisting of cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl; III) hetero aryl; IV) halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, mol Aryl or hetero aryl substituted with one or more substituents selected from the group consisting of porin, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl. The compound of claim 4, wherein R ₂ is halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, pipepe. Being aryl or hetero aryl substituted with one or more substituents selected from the group consisting of lazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl A compound characterized by the above, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. 6. A compound according to claim 5, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, wherein R ₂ is aryl substituted with halogen. According to claim 1, wherein R ₃ Is selected from the following substituents I) -III), or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. Hydrogen; Lower alkyl; In the group consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkyl amino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amidoxime and trifluoromethyl Lower alkyl substituted with one or more substituents selected. 8. A compound according to claim 7, wherein R ₃ is hydrogen or lower alkyl, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. The compound of claim 1, wherein X is O or S, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. 10. The compound of claim 9, wherein X is S, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof. A compound according to claim 1, or a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof, characterized in that the following compounds. 1. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopentanecarboxamide 2. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 3. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (thiophen-2-yl) acetamide 4. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -3-cyclopentylpropanamide 5. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (4-morpholinyl) acetamide 6. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (1-pyrrolidinyl) acetamide 7. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (diethylamino) acetamide 8. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acetamide 9. N- [5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2-methylpropanamide 10. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclobutane carboxamide 11. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (4-morpholino carbonyl) Pro Panama Id 12. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -2- (4-methyl-1-piperazinyl) acetoxy Tama Id 13. Ethyl 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylate 14. 1-({[5- (4-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxylic acid 15. N- [5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- (4- Morpholinyl) ethyl] urea 16. N - [5- (4- fluoro-2-hydroxymethyl-anilino [l, 3] thiazolo [5,4- b] pyridin-2-yl cyclopropane carboxyl amide 17. N- [5- (cyclohexylamino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 18. N - [5- (cyclopentylamino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide 19. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (diethylamino) prop Panama Id 20. N - [5- (4- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (1-piperidinyl) pro Panama Id 21. N - [5- (3- chloro-anilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide 22. N- [5- (2-chloroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 23. N- [5- (2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 24. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 25. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -2- (4-morpholinyl) acene Tamid 26. N - [5- (2- fluoro-4-methyl Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3- (4-morpholino carbonyl) Pro Panamide 27. N- [5- (2-fluoro-4-methoxyanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 28. 2-({[5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] amino} carbonyl) cyclopropanecarboxyl mountain 29. N- [5- (4-bromo-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 30. N- [5- (3-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 31. N - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] cyclopropane carboxamide 32. N- [5- (2,4-difluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 33. N - [5- (2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -2 - [(4-methyl-1 Piperazinyl) carbonyl] cyclopropanecarboxamide 34. N ¹ - [2- (diethylamino) ethyl] - N ² - [5- (2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin- 2-yl] -1,2-cyclopropanedicarboxamide 35. (E) - N - [ 5- ( 2-fluoro-4 is not methyl Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-phenyl-2 Propenamid 36. N- [5- (2-fluoro-4-methylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acrylamide 37. N ¹ - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] ^{pyridin-2-yl] - N 2 - [2- (} 4- Morpholinyl) ethyl] -1,2-cyclopropanedicarboxamide 38. N ¹ - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] ^{pyridin-2-yl] - N 2 - [2- (} 2- Pyridinyl) ethyl] -1,2-cyclopropanedicarboxamide 39. N- [5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] acrylamide 40. N- [5- (4-chloro-2-fluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] -3-methyl-3-butenamide 41. N - [5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-methyl-2-butene amide 42. N - [5- (4- chloro-2-fluoro not Reno) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3-butene amide 43. (E) - N - [ 5- (4- chloro-2-fluoro-Reno not) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -amide 2-butene 44. N- [5- (2,6-difluoroanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 45. N - {5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} cyclopropane carboxamide 46. N- {5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} acrylamide 47. N- {5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 48. N- {5- [4-chloro (ethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} acrylamide 49. Ethyl 2- (4-chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) acetate 50. 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) acetic acid 51. 2- (4-Chloro {2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} anilino) ethyl cyclopropanecarboxylate 52. N- {5- [4-Chloro (2-hydroxyethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 53. N- [5- (4-chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 54. N- {5- [2,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 55. N - {5- [2,6- difluoro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} cyclopropane carboxamide 56. N- [5- (4-bromo-2-fluoromethylanilino) [1,3] thiazolo [5,4- b ] pyridin-2-yl] cyclopropanecarboxamide 57. N- {5- [2-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 58. N- {5- [3,4-difluoro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 59. N- {5- [methyl-4- (trifluoromethyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 60. N- {5- [4-methoxy (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 61. N- {5- [4-cyano (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 62. N- {5- [4-isopropyl (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclopropanecarboxamide 63. N- {5- [2,3-dihydro-1 H -inden-5-yl (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclo Propanecarboxamide 64. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -pyrrole-2-car Copyamide 65. Ethyl 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzoate 66. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzoic acid 67. (E) - N - [ 5- (4- methyl bromide is not the parent-2fluoroanilino) [1, 3] thiazolo [5,4- b] pyridin-2-yl] -3 (4 -Piperidinyl) 2-propenamide 68. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1-ethyl-4 -Piperidinyl) -2-propenamide 69. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1-methyl- 4-piperidinyl) -2-propenamide 70. (E) - N - {5- [4-Chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (4-morpholino carbonyl ) -2-buteneamide 71. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] -N , N -dimethylbenzamide 72. 4 - [{2 - [(cyclopropylcarbonyl) amino] [1, 3] thiazolo [5,4- b] pyridin-5-yl} (methyl) amino] - N - [2- (dimethyl Amino) ethyl] benzamide 73. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -imidazole-4- Carboxamide 74. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] -N -methylbenzamide 75. N- {5- [4-Chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} -1-methyl-1 H -imidazole-5- Carboxamide 76. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -3- (1 - (methylsulfonyl Ponyl) -4-piperidinyl) -2-propenamide 77. 4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] benzamide 78. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (1-piperidinyl ) -2-buteneamide 79. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (1,4- Oxa-8-azaspiro [4.5] de-8-sil) -2-buteneamide 80. (E) - N - { 5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridin-2-yl} -4- (dimethylamino) -2 Buteneamide 81. Ethyl 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] phenyl} acetate 82. 2- {4-[{2-[(cyclopropylcarbonyl) amino] [1,3] thiazolo [5,4- b ] pyridin-5-yl} (methyl) amino] phenyl} acetic acid 83. N- {5- [4- [2- (dimethylamino) -2-oxoethyl] (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} cyclo Propanecarboxamide 84. Ethyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} amino) -3 -Oxo-1-propenyl] -1-piperidinecarboxylate 85. Methyl 4-[( E ) -3-({5- [4-chloro (methyl) anilino] [1,3] thiazolo [5,4- b ] pyridin-2-yl} amino) -3 -Oxo-1-propenyl] -1-piperidinecarboxylate 86. (E) -3- (1- acetyl-4-piperidinyl) - N - {5- [4- chloro (methyl) anilino] [1, 3] thiazolo [5,4- b] pyridine -2-yl} -2-propenamide 87. N- [5- (4-Chloro-2-fluoromethylanilino) [1,3] thiazolo [5,4-b] pyridin-2-yl] -N '-[2- (4- Morpholinyl) ethyl] urea 88. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-ethyl-urea 89. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl}-3- (2-diethylamino- Ethyl) -urea 90. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-hydroxy-propyl ) -Urea 91. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholine-4 -Work-profile)-urea 92. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-methoxy-ethyl ) -Urea 93. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyrrolidine- 1-yl-ethyl) -urea 94. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea 95. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-dimethylamino-propyl ) -Urea 96. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-diethylamino- Profile) -urea 97. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1-methyl -Pyrrolidin-2-yl) -ethyl] -urea 98. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyridine-2- Yl-ethyl) -urea 99. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl}-3- (2-hydroxy-ethyl ) -Urea 100. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxy-1 -Methyl-ethyl) -urea 101. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxy-propyl ) -Urea 102. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-dimethylamino-ethyl ) -Urea 103. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclopentyl-urea 104. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclohexyl-urea 105. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-piperidine- 1-yl-ethyl) -urea 106. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (5-methyl-pyrazine- 2-ylmethyl) -urea 107. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-pyridine-4- Yl-ethyl) -urea 108. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-4-yl-urea 109. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1,5-dimethyl- 1H-pyrrole-3-ylmethyl) -urea 110. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-thiophen-3-ylmethyl Urea 111. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-furan-3-ylmethyl- Urea 112. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -1- (2-hydroxy-ethyl ) -1-methyl-urea 113. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-((R) -1- Hydroxymethyl-propyl) -urea 114. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-4-ylmethyl- Urea 115. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-3-ylmethyl- Urea 116. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-2-ylmethyl- Urea 117. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-3-yl-urea 118. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-pyridin-2-yl-urea 119. 4- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido) -pi Ferridine-1-carboxylic acid tert-butyl ester 120. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclopropylmethyl-urea 121. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-cyclohexylmethyl-urea 122. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-phenyl-urea 123. 1-Benzyl-3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -urea 124. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3-phenethyl-urea 125. 4- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureidomethyl)- Piperidine-1 -Carboxylic acid tert-butyl ester 126. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methylamino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-hydroxy-butyl ) -Urea 127. 3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureidomethyl)- Piperidine-1-carboxylic acid tert-butyl ester 128. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (3- Hydroxy-propoxy) -ethyl] -urea 129. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((R) -2 -Hydroxy-1-methyl-ethyl) -urea 130. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {2-[(2 -Hydroxy-ethyl) -methyl-amino] -ethyl} -urea 131. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Hydroxy-piperidin-1-yl) -ethyl] -urea 132. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3-[(2 -Hydroxy-ethyl) -methyl-amino] -propyl} -urea 133. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxy-piperidin-1-yl) -propyl] -urea 134. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3- [4- (2-hydroxy-ethyl) -piperidin-1-yl] -propyl} -urea 135. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-hydroxy-urea 136. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-methoxy-urea 137. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (carboxymethyloxy)- Urea 138. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido) -ethyl] -acet amides 139. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (methylamino) -urea 140. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-hydroxyethyl Amino) -urea 141. 1- (4-Aminomethyl-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Sun} -urea 142. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyridine-1 -Work-profile)-urea 143. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxymethyl-piperidin-1-yl) -propyl] -urea 144. {(S) -1- [3- (3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Il} -ureido) -propyl] -pyrrolidin-3-yl} -carbamic acid tert-butyl ester 145. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3,4-di Hydroxy-benzyl) -urea 146. 1- (4-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea 147. 1- (3-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea 148. 1- (2-Amino-benzyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Urea 149. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (tetrahydro-furan- 2-ylmethyl) -urea 150. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-imidazole- 1-yl-propyl) -urea 151. 1- (4-Amino-cyclohexyl) -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridine-2- Sun} -urea 152. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-hydroxy- Cyclohexyl) -urea 153. (S) -1- [3- (3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Ureido) -propyl] -pyrrolidine-2-carboxylic acid tert-butyl ester 154. (R) -1- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl } -Ureido) -propyl] -pyrrolidine-2-carboxylic acid tert-butyl ester 155. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Oxo-piperidin-1-yl) -propyl] -urea 156. 3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -1- (2-hydroxy- Ethyl) -1-methyl-urea 157. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-piperidine 4-yl-ethyl) -urea 158. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-4 -Work-urea 159. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-4- Ylmethyl-urea 160. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-piperidine-3- Ylmethyl-urea 161. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-piperazin- 1-yl-propyl) -urea 162. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (S) -pyrroli Din-3-yl-urea 163. 1- [3-((S) -3-Amino-pyrrolidin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino ] -Thiazolo [5,4-b] pyridin-2-yl} -urea 164. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-methylamino- Ethyl) -urea 165. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Hydroxyimino-piperidin-1-yl) -propyl] -urea 166. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((R ) -2-hydroxymethyl-pyrrolidin-1-yl) -propyl] -urea 167. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((S ) -2-hydroxymethyl-pyrrolidin-1-yl) -propyl] -urea 168. 4- [3- (3- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -ureido ) -Propyl] -pyrazine-1 -carboxylic acid ethyl ester 169. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methanesulfonyl-piperazin-1-yl) -propyl] -urea 170. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Ethanesulfonyl-piperazin-1-yl) -propyl] -urea 171. 1- [3- (4-acetyl-Piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea 172. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Cyclopropyl-piperazin-1-yl) -propyl] -urea 173. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- {3- [4- (2-Fluoro-ethyl) -piperazin-1-yl] -propyl} -urea 174. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Propionyl-piperazin-1-yl) -propyl] -urea 175. 1- {5-[(4-Cyclochloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4 -Propionyl-piperazin-1-yl) -propyl] -urea 176. 1- [2- (4-Acetyl-piperazin-1-yl) -ethyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea 177. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1- Methyl-piperidin-4-yl) -ethyl] -urea 178. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (1- Ethyl-piperidin-4-yl) -ethyl] -urea 179. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-4-yl) -urea 180. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-4-yl) -urea 181. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-4-ylmethyl) -urea 182. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-4-ylmethyl) -urea 183. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-pi Ferridin-3-ylmethyl) -urea 184. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-ethyl-pi Ferridin-3-ylmethyl) -urea 185. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((S) -1 -Methyl-pyrrolidin-3-yl) -urea 186. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3-((S) -1 -Ethyl-pyrrolidin-3-yl) -urea 187. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3-((S ) -3-dimethylamino-pyrrolidin-1-yl) -propyl] -urea 188. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (4-dimethylamino- Cyclohexyl) -urea 189. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Ethyl-piperazin-1-yl) -propyl] -urea 190. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Isopropyl-piperazin-1-yl) -propyl] -urea 191. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Isobutyl-piperazin-1-yl) -propyl] -urea 192. 1- [3- (4-sec-Butyl-piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-fluoro-phenyl) -methyl-amino] -thia Zolo [5,4-b] pyridin-2-yl} -urea 193. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -3-oxo-propyl] -urea 194. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [4- (4- Methyl-piperazin-1-yl) -butyl] -urea 195. 1- {5-[(4-Chloro-2-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Methyl-piperazin-1-yl) -ethyl] -urea 196. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-morpholin-4-yl-ethyl) -urea 197. 1-Ethyl-3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 198. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-morpholin-4-yl-propyl) -urea 199. 1- (2-Diethylamino-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 200. 1- [3- (4-Methyl-piperazin-1-yl) -propyl-3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea 201. 1- (3-hydroxy-propyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 202. 1- (3-Diethylamino-propyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 203. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-2-ylmethyl-urea 204. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-3-ylmethyl-urea 205. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-pyridin-4-ylmethyl-urea 206. 1- (5-Methyl-pyrazin-2-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 207. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-2-yl-ethyl) -urea 208. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-4-yl-ethyl) -urea 209. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyrrolidin-1-yl-ethyl) -urea 210. 1- (1,5-dimethyl-1H-pyrrole-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea 211. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-pyridin-3-yl-ethyl) -urea 212. 1- (4-hydroxy-butyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 213. 1- (2-hydroxy-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 214. 1-((R) -2-hydroxy-1-methyl-ethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea 215. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (2-oxo-pyrrolidin-1-yl ) -Propyl] -urea 216. 1- [2- (2-hydroxy-ethoxy) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] Urea 217. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-pyrrolidin-1-yl-propyl) -urea 218. 1- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea 219. 1- {3-[(2-hydroxy-ethyl) -methyl-amino] -propyl} -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea 220. 1- [3- (4-hydroxy-piperidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea 221. 1- [3-((R) -3-hydroxy-pyrrolidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4 -b] pyridin-2-yl] -urea 222. 1- [3- (4-hydroxymethyl-piperidin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] Pyridin-2-yl] -urea 223. (R) -2- {3- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -ureidomethyl} -pyrrolidine-1 -Carboxylic acid tert-butyl ester 224. 1- [2- (4-acetyl-piperazin-1-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Work] -urea 225. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-4-yl-urea 226. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-4-ylmethyl-urea 227. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3-piperidin-3-ylmethyl-urea 228. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-piperidin-4-yl-ethyl) -urea 229. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-piperazin-1-yl-propyl) -urea 230. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (S) -pyrrolidin-3-yl-urea 231. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (R) -1-pyrrolidin-2-ylmethyl- Urea 232. 1- [2- (1-Methyl-piperidin-4-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea 233. 1- [2- (1-Ethyl-piperidin-4-yl) -ethyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea 234. 1- (1-Methyl-piperidin-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea 235. 1- (1-Ethyl-piperidin-3-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea 236. 1- (1-Methyl-piperidin-4-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -urea 237. 1- (1-ethyl-piperidin-4-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] urea 238. 1- (1-Methyl-piperidin-4-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl]- Urea 239. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2 -Work] -urea 240. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea 241. 1-((S) -1-Methyl-pyrrolidin-3-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea 242. 1-((S) -1-Ethyl-pyrrolidin-3-yl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea 243. 1-((R) -1-furan-2-ylmethyl-pyrrolidin-2-ylmethyl) -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4- b] pyridin-2-yl] -urea 244. 1-[(R) -1- (1-Methyl-1H-pyrrole-2-ylmethyl) -pyrrolidin-2-ylmethyl] -3- [5- (methyl-p-tolyl-amino) -Thiazolo [5,4-b] pyridin-2-yl] urea 245. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl ) -Propyl] -urea 246. 1- [5- (Methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl ) -Propyl] -urea 247. 1- [3- (4-Methanesulfonyl-piperazin-1-yl) -propyl] -3- [5- (methyl-p-tolyl-amino) -thiazolo [5,4-b] pyridine 2-yl] -urea 248. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea 249. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholine-4 -Work-profile)-urea 250. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4 -Yl-ethyl) -urea 251. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl -Piperazin-1-yl) -ethyl] -urea 252. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperi Din-4-ylmethyl) -urea 253. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-iso Propyl-piperazin-1-yl) -propyl] -urea 254. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-ethyl -Piperazin-1-yl) -propyl] -urea 255. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methane Sulfonyl-piperazin-1-yl) -propyl] -urea 256. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-ethyl -Piperazin-1-yl) -ethyl] -urea 257. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea 258. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrazole-1 -Work-profile)-urea 259. 1- {5-[(2,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-propy O'Neill-piperazin-1-yl) -propyl] -urea 260. 1- [3- (4-Cyclopropanecarbonyl-piperazin-1-yl) -propyl] -3- {5-[(2,4-difluoro-phenyl) -methyl-amino] -thia Zolo [5,4-b] pyridin-2-yl} -urea 261. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea 262. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridine-2- Sun] -urea 263. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-methyl-piperazin-1-yl) -propyl ] -Urea 264. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (3-morpholin-4-yl-propyl) -urea 265. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- (2-morpholin-4-yl-ethyl) -urea 266. 1- [3- (4-acetyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl ] -Urea 267. 1- [5- (Methyl-phenyl-amino) -thiazolo [5,4-b] pyridin-2-yl] -3- [3- (4-propionyl-piperazin-1-yl)- Profile]-Urea 268. 1- [3- (4-Cyclopropanecarbonyl-piperazin-1-yl) -propyl] -3- [5- (methyl-phenyl-amino) -thiazolo [5,4-b] pyridine- 2-day] -urea 269. 1- [3- (4-Methyl-piperazin-1-yl) -propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5, 4-b] pyridin-2-yl} -urea 270. 1- {5- [Methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4- Yl-ethyl) -urea 271. 1- {5- [Methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4- Th-propyl) -urea 272. 1- [3- (4-Ethyl-piperazin-1-yl-propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4 -b] pyridin-2-yl} -urea 273. 1- [3- (4-Isopropyl-piperazin-1-yl) -propyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea 274. 1- [2- (4-Methyl-piperazin-1-yl) -ethyl] -3- {5- [methyl- (4-trifluoromethyl-phenyl) -azino] -thiazolo [5,4-b] pyridin-2-yl} -urea 275. 1- (1-Methyl-piperidin-4-ylmethyl) -3- {5- [methyl- (4-trifluoromethyl-phenyl) -amino] -thiazolo [5,4-b] Pyridin-2-yl} -urea 276. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea 277. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- (3-morpholin-4-yl-propyl) -urea 278. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-methyl-piperazin-1-yl ) -Propyl] -urea 279. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [2- (4-methyl-piperazin-1-yl ) -Ethyl] -urea 280. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- (1-methyl-piperidin-4-ylmethyl) Urea 281. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-ethyl-piperazin-1-yl ) -Propyl] -urea 282. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-methanesulfonyl-piperazine-1 -Work) -propyl] -urea 283. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [3- (4-isopropyl-piperazin-1- Th) -propyl] -urea 284. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo-b] pyridin-2-yl} -3- [2- (4-ethyl-piperazin-1-yl ) -Ethyl] -urea 285. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-cyano-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea 286. 1- {5-[(4-Cyano-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrazol-1-yl- Profile) -urea 287. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea 288. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea 289. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea 290. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl-piperazine -1-yl) -ethyl] -urea 291. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperidine-4 -Ylmethyl) -urea 292. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe) Razin-1-yl) -propyl] -urea 293. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea 294. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methanesulfonyl- Piperazin-1-yl) -propyl] -urea 295. 1- [2- (4-Ethyl-piperazin-1-yl) -ethyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea 296. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-fluoro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea 297. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea 298. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea 299. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (1-methyl-piperidine- 4-ylmethyl) -urea 300. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea 301. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4-methyl-piperazine -1-yl) -ethyl] -urea 302. 1- [3- (4-Ethyl-piperazin-1-yl) -propyl] -3- {5-[(2-fluoro-4-methoxy-phenyl) -ethyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -urea 303. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe Razin-1-yl) -propyl] -urea 304. 1- {5-[(4-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-metalsulfonyl- Piperazin-1-yl) -propyl] -urea 305. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -propyl] -urea 306. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-hydroxy- Profile) -urea 307. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholine- 4-yl-propyl) -urea 308. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-diethylamino -Propyl) -urea 309. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholine- 4-yl-ethyl) -urea 310. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-pyrrolidine -1-yl-propyl) -urea 311. 1- {5-[(4-Chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [2- (4- Methyl-piperazin-1-yl) -ethyl] -urea 312. 1- [3- (4-Acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-chloro-2-hydroxy-phenyl) -methyl-amino] -thiazolo [ 5,4-b] pyridin-2-yl} -urea 313. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-ethyl-piperazine -1-yl) -propyl] -urea 314. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-isopropyl-pipe Razin-1-yl) -propyl] -urea 315. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea 316. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (3-morpholin-4-yl- Profile) -urea 317. 1- {5-[(4-Bro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- (2-morpholin-4-yl- Ethyl) -urea 318. 1- [3- (4-acetyl-piperazin-1-yl) -propyl] -3- {5-[(4-broro-phenyl) -methyl-amino] -thiazolo [5,4- b] pyridin-2-yl} -urea 319. 1- {5-[(3,4-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea 320. 1- {5-[(2,6-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea 321. 1- {5-[(4-Chloro-3-fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4- Methyl-piperazin-1-yl) -propyl] -urea 322. 1- {5-[(2,3-Difluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl -Piperazin-1-yl) -propyl] -urea 323. 1- {5-[(2-Fluoro-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea 324. 1- {5-[(2-hydroxy-phenyl) -methyl-amino] -thiazolo [5,4-b] pyridin-2-yl} -3- [3- (4-methyl-piperazine -1-yl) -propyl] -urea 325. 1- [3- (4-Methyl-piperazin-1-ylpropyl] -3- {5- [methyl- (2,3,4-trifluoro-phenyl) -amino] -thiazolo [5 , 4-b] pyridin-2-yl} -urea A method of using the compound of formula 1 according to claim 1 in the preparation of a medicament for the treatment or prevention of a disease due to undesirable KDR activity using the compound according to claim 1. The method of claim 12, wherein the disease is cancer, psoriasis, rheumatoid arthritis, diabetic retinopathy, focal aneurysm, atherosclerosis, Kaposi's sarcoma, and the like. (a) a pharmacologically effective amount of a compound according to claim 1; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or combination thereof; Pharmaceutical composition comprising a.