WO2006137658A1 - New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory acitivity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same - Google Patents

New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory acitivity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same Download PDF

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WO2006137658A1
WO2006137658A1 PCT/KR2006/002325 KR2006002325W WO2006137658A1 WO 2006137658 A1 WO2006137658 A1 WO 2006137658A1 KR 2006002325 W KR2006002325 W KR 2006002325W WO 2006137658 A1 WO2006137658 A1 WO 2006137658A1
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thiazol
pyrimidin
fluorophenyl
amine
piperidin
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PCT/KR2006/002325
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French (fr)
Inventor
In Young Choi
Kwangjun Lee
Kyungjae Lee
Myeong Yun Chae
Hosoon Kim
Hwan Mook Kim
Song-Kyu Park
Kiho Lee
Sang Bae Han
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Dongbu Hitek Co., Ltd.
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Publication of WO2006137658A1 publication Critical patent/WO2006137658A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to new substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same.
  • TNF-ot tumor necrosis factor- ⁇
  • IL-I interleukin-1
  • Such substances are produced by a variety of cells, such as monocyte or macrophage, in response to the inflammation and the other cell stress. It has been known that the cytokines play a key role in the immune response or the inflammatory response if they exist with an optimal dose, whereas, they may be related to various inflammatory diseases if they are produced excessively.
  • the proinflammatory cytokines are regulated by p-38 MAP kinase that is one of the mitogen-activated protein (MAP) kinases (Seiji Miwatashi et al., J. Med. Chem. 48, 5966-5979, 2005).
  • MAP mitogen-activated protein
  • the protein kinase (PK) includes a Ser/Thr kinase that participates in the activation of its substrate by phosphorylation as an enzyme that participates in a variety of cell responses for the extra cellular signal (B. Stein et al., Ann. Rep. Med. Chem., 31, 289-298, 1996).
  • the MAPK of such PKs is activated in itself by a variety of signals including growth factor, cytokine, UV irradiation and stress inducer in general.
  • the p38 MAP kinase also known as a cycling sequence binding protein (CSBP) and a reacting kinase (RK)
  • CSBP cycling sequence binding protein
  • RK reacting kinase
  • LPS lipopolysaccarides
  • the p38 MAP kinase is considered as it plays a role in the cell response to the inflammatory stimuli, such as accumulation of leukocytes, activation of macrophages/monocytes, tissue resorption, pyrexia, acute phase reaction and neutrophilia.
  • Diseases associated with p38 MAP kinase include cancer, platelet aggregation induced by thrombin, immunodeficiency disease, autoimmune disease, necrocytosis, allergy, osteoporosis, degenerative disease, etc.
  • the p38 MAP kinase was activated in the cell stimulated by stress (e.g., LPS process, UV, isomycin or osmotic shock) and cytokines, such as TNF- ⁇ , IL-I, etc. Accordingly, if it would blockade the production of cytokines of TNF- ⁇ , 11-1, etc., it is possible to inhibit the activation of p38 MAP kinase.
  • stress e.g., LPS process, UV, isomycin or osmotic shock
  • cytokines such as TNF- ⁇ , IL-I, etc. Accordingly, if it would blockade the production of cytokines of TNF- ⁇ , 11-1, etc., it is possible to inhibit the activation of p38 MAP kinase.
  • Tumor necrosis factor- ⁇ is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator. Excessive or non-regulated production of TNF- ⁇ is associated with a variety diseases such as: rheumatic arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis diseases; sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, osseous resorption disease, reperfusion injury, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to influenza infection and secondary cachexia due to acquired immune deficiency syndrome (AIDS) , AIDS, AIDS-related complex (ARC) , keloid formation, wounded tissue formation, Crohn's disease, ulcerative colitis
  • AIDS acquired
  • IL-I Interleukin-1 is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator, like TNF- ⁇ . Moreover, it has been established that the numeric value of IL-I is increased also by the excessive or non-regulated production of TNF- ⁇ . Accordingly, TNF- ⁇ inhibitor reduces the numeric value of IL-I (European Cytokine Network 6, 225, 1995) and improves symptoms of disease due to the non-regulated synthesis of IL-I.
  • a variety of diseases exacerbated or induced by the excessive of non-regulated synthesis of IL-I include rheumatic arthritis, rheumatoid spondylitis, osteoarthritis, gout, traumatic arthritis, rubella arthritis, acute synovitis, sepsis, septic shock, endotoxin shock, gram- negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, osseous absorption disease, ischemic reperfusion injury, arteriosclerosis, traumatic brain injury, multiple sclerosis, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to infection or malignant tumor, secondary cachexia due to acquired immune deficiency syndrome (AIDS), AIDS, AIDS-related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colonitis
  • IL-I regulates various biological activities such as activation of T-helper cell, heat induction, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis and inhibition of plasma iron concentration (Rev. Infect. Disease, 6, 51(1984)).
  • virus sensitive to TNF inhibition e.g., HIV-I, HIV-2 and HIV-3
  • IL-I virus sensitive to TNF inhibition
  • 11-1 and TNF all induce the synthesis of collagenase to cause tissue destruction in joint ultimately (Lymphokine Cytokine Res. (11): 253-256, (1992)) and (Clin. Exp. Immunol. 989: 244-250, 1992).
  • IL- ⁇ IL-6 is another inflammatory cytokine associated with a variety of symptoms including inflammation.
  • IL-6 is a growth factor in various oncological diseases including multiple myeloma and related plasma cell dyscrasia.
  • IL-6 Diseases related to the excessive or non-regulated production of IL-6 include neurological disorders, such as AIDS dementia complex (ADC), Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus (SLE) , CNS trauma, and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15:307); and numerous diseases such as multiple myeloma, rheumatic arthritis, psoriasis and postmenopausal osteoporosis (Simpson, et al . , Protein Sci. 6, 929, 1997).
  • IL-8 IL-8 is a characterized chemotactic factor produced by- several cells such as monocyte, fibroblast, endothelial cell and keratinocyte.
  • the production of IL-8 induced by IL-I, TNF- ⁇ or lipopolysaccarides (LPS) in the endothelial cell releases histamine from basophile of normal and atopic subjects and further contributes to the induction of lysosomal enzyme release from neutrophil and the increase in vascular endothelial cell adhesion.
  • LPS lipopolysaccarides
  • IL-8 diseases mediated mainly by neutrophil, such as cerebral paralysis and myocardial infarction; heat injury, adult respiratory distress syndrome (ARDS) , multiple organ injury after trauma, acute glomerulonephritis, dermatosis accompanied by acute inflammatory disease, acute purulent meningitis, or other central nervous system (CNS) disorders, hemodialysis, granulocyte transfusion-related syndrome, necrotizing enterocolitis (NEC), etc.
  • neutrophil such as cerebral paralysis and myocardial infarction
  • ARDS adult respiratory distress syndrome
  • CNS central nervous system
  • hemodialysis hemodialysis
  • granulocyte transfusion-related syndrome necrotizing enterocolitis
  • GM-CSF graft versus host disease
  • IFN-Y is associated with collagen deposition that is one of the major histopathological characteristics of graft versus host disease (GVHD) and induces the activation of most peripheral T-cells prior to the progression of malfunctions of the central nervous system (CNS) in the diseases such as multiple sclerosis and AIDS dementia complex (ADC) (Martino et al., 1998, Ann Neurol. 43, 430) .
  • GVHD graft versus host disease
  • ADC AIDS dementia complex
  • Cyclooxygenase is generally classified into a constitutive expression of cyclooxygenase (COX-I) and an inducible expression of cyclooxygenase (COX-2) . It has been established that the expression of COX-2 is increased by cytokines. Accordingly, it is expected that a cytokine inhibitor may inhibit the expression of COX-2 (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888).
  • the COX inhibitor like non-steroidal anti-inflammatory drug (NSAID) well known as a drug that inhibits the cytokines such as IL-I and the like, will show efficacies for various diseases being under medical treatment.
  • NSAID non-steroidal anti-inflammatory drug
  • Anti-inflammatory agents of the initial stage served as tools to elucidate the role of p38 MAP kinase were pyridinyl imidazoles.
  • the first one is the bicyclic pyridinyl imidazole SKF-86002 developed by Lee, J. C. et al (Lee, J. C. et al., Int. J. Immunopharmacol . 10, 835-843, 1992). Since then, the structure-activity relationship
  • the new aryl-pyridinyl-heterocycle compounds were synthesized by replacing the imidazole pharmacophore with other heteroaryl pharmacophore.
  • the aryl-pyridinyl-heterocycle complexes include SB-242235 prepared by GlaxoSmithKline Inc., and RWJ-67657 provided by RW Johnson Pharmaceutical Research Institute (Badger, A. M. et . al., Arthritis Rheum. 43. 175-183, 2000; Wadsworth, S. A. et . al., J. Pharmacol. Exp. Ther. 291, 680- 687, 1999) .
  • Cirillo et al. prepared the non-aryl-pyridinyl compounds including triazanapthalenones, A/,W -diary1 ureas, -V,N-diaryl ureas, benzophenones, pyrazoleketones, indole amides, diamides, quinazolinones, pyrimido [4, 5-d] pyrimidinones and pyridyl- amino-quinazolines (Cirillo, P. F. et . al., Curr. Top. Med. Chem. 2, 1021-1035, 2002) .
  • non-aryl-pyridinyl compounds include VX-745 of Vertex Pharmaceutical Inc. classified as triazanapthalenones and BIRB-796 of Boehringer Ingelheim Pharmaceutical Inc. related to N,N r -diaryl ureas (Regan, J. et . al . , J. Med. Chem. 45, 2994-3008, 2002).
  • GlaxoSmithKline WO/2002/059083
  • Merck WO/2002/058695
  • the inventors of the present invention having executing researches aiming at selecting thiazole compounds as a pharmacophore to develop effective compounds that are useful in treating diseases mediated by proinflammatory cytokines such as TNF- ⁇ and IL-I and have excellent inhibitory activities of the proinflammatory cytokines, have confirmed that substituted 1,3-thiazole derivatives shows excellent immunosuppression or inflammation inhibitory activity, thus completing the present invention.
  • Still another object of the present invention is to provide a process for the preparation of the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof and intermediate compounds or pharmaceutically acceptable salts thereof.
  • Still another object of the present invention is to provide a pharmaceutical composition comprising the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof.
  • the present invention provides new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities, intermediate compounds or pharmaceutically acceptable salts thereof, a method for the preparation thereof and, further, a pharmaceutical composition comprising the substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof.
  • New substituted 1,3-thiazole derivatives of the present invention having excellent TNF- ⁇ inhibitory activity and inflammation inhibitory activity can be effectively used for preventing and treating TNF- ⁇ related diseases.
  • Fig. 1 is photographs of colons in a vehicle treatment group extracted by sacrificing rats having ulcers induced by TNBS (2, 4, ⁇ -trinitrobenzenesulfonic acid solution) that is an inflammatory intestinal disease induced substance
  • Fig. 2 is photographs of colons in a treatment group extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with prednisolone; and
  • Fig. 3 is photographs of colons extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with the compounds of Example 334 in accordance with the present invention. [Best Mode]
  • the present invention provides new substituted 1,3- thiazole derivatives expressed by Formula 1 below or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities:
  • Z denotes CH or N
  • Rl denotes a halogen atom, a haloalkyl of C 1 -C 4 , an alkyl of Ci ⁇ C4 or alkoxy of Ci-C 4 ;
  • R2 denotes H, a halogen atom, an alkyl of C 1 -C 4 , -NH-R4, an alkyl-S (O) n -phenyl of Ci-C 4 ,
  • X denotes CH, C-OH or N
  • Y denotes CH 2 , an alkyl of CH-Ci-C 4 , NH, an alkyl of N-Ci-C 4 , an alkyl of amino-Ci ⁇ C 4 of N-Ci-C 4 , an alkyl of N-CO-Ci-C 4 , a cycloalkyl of N-CO-C 3 -C 8 , an aryl of N-CO-C 5 -C 8 , an alkyl of amino-Ci ⁇ C 4 of N-CO-Ci-C 4 or an alkoxy of N-Co-N-Ci-C 4 ;
  • R3 denotes a halogen atom, -NH-R4, -NH-C0-R5, -N-(CO- R5) 2 or an alkyl of -S(O) n -Ci-C 4 ;
  • R4 denotes H, an alkyl of Ci-C 4 , a cycloalkyl of C 3 -C 8 , a cycloalkylalkyl of C 3 -C 8 , an aryl of C 5 -C 8 , CH(Ci-C 4 alkyl) - phenyl or amine;
  • R5 denotes an alkyl of Ci-C 4 , a cycloalkyl of C 3 -C 8 , an aryl of C 5 -C 8 or an alkoxy of Ci-C 4 ; m is 1 or 2; and n is 0, 1 or 2.
  • Z is CH or N;
  • Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 ;
  • R2 is H, Cl, ethyl, amino, NHNH 2 , methylamino, 6,N- dimethylnicotinilamino, 4- methylsulfanylphenyl, 4- methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidin-1- yl, 4-methyl-piperidin-l-yl, piperidin-4-yl, N-methyl piperidin-4-yl, N-ethyl- piperidin-4-yl, N-isopropyl- piperidin-4-yl, N-cyclopropylmethyl-piperidin-4-yl, N- dimethylaminoethyl- piperidin-4-yl, N-methylcarbonyl- piperidin-4-yl, N-cyclopropylcarbonyl-piperidin-4-yl, N- dimethylaminomethylcarbonyl-piperidin-4-yl, N- phenylcarbonyl-pipe
  • Rl denotes a halogen atom, a haloalkyl of Ci-C 4 , an alkyl of Ci-C 4 or alkoxy of Ci-C 4 ; and Hal denotes F, Cl or I.
  • Rl denotes a halogen atom, a haloalkyl of Ci-C 4 , an alkyl of Ci-C 4 or alkoxy of Ci-C 4 ; and Hal denotes F, Cl or I.
  • Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF 3 , 3-CH 3 or 4-OCH 3 ; and Hal is Cl.
  • the substituted 1,3-thiazol derivatives expressed by Formula 1 above and the intermediate compounds expressed by Formula 2 above can be used in the form of pharmaceutically acceptable salts, i.e., metal salts, salts of organic bases, salts of inorganic acids, salts of organic acids, salts of basic or acidic amino acids, etc.
  • metal salts are exemplified by alkali metal salts such as sodium salt, potassium salt, etc.; alkaline-earth metal salts such as calcium salt, magnesium salt, barium salt, etc.; and aluminum salts.
  • Suitable salts of organic bases are salts of trimethylamine, triethylamine, pyridine, picoline, 2,6- lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N- dibenzylethylenediamine, etc.
  • Appropriate salts of inorganic acids are salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Appropriate salts of organic acids are salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Suitable salts of basic amino acids are salts of arginine, lysine, ornithine and the like.
  • Appropriate salts of acidic amino acids are salts of aspartic acid, glutamic acid and the like.
  • inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline-earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and organic salts such as aluminum salt; and if the compounds have basic functional groups therein, such salts include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like) and salts of organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like) . Furthermore, the present invention provides a process formic acid, acetic acid, trifluoroacetic acid, phthal
  • step (1) (2) preparing a compound (V) by halogenating the compound (IV) obtained in step (1);
  • Rl, R2 and R4 are the same as defined in Formula 1; Hal' denotes a halogen atom; and L denotes a leaving group.
  • Compounds II, IE, VI and Vl may be used as they are if available commercially or be prepared according to the well- known method as it is or the similar process thereto.
  • Compound IV is prepared by treating compound II with base and reacting with compound HI.
  • Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound II, preferably, about 1.0 to 1.2 mol.
  • the "base” to be applied hereto includes, for example, alkyllithium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 60 ° C, desirably, in the range from -78 ° C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound V is prepared by treating compound IV with halogen or metal halide. This reaction may be carried out under the presence of a base or a basic salt, if necessary.
  • Hal or Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of halogen or metal halide to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 2.0 mol.
  • the "halogen” includes bromine, chloride, iodine and the like.
  • the "metal halide” includes copper halides such as copper ( II ) bromide, copper ( 13 ) chloride and the like.
  • the amount of base to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 3.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc.; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc .
  • reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound VII is prepared by reacting compound V with thioamide compound VI. This reaction may be carried out under the presence of a base, if necessary.
  • Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of thioamide compound VI to be applied hereto is about 0.5 to 6.0 mol for 1.0 mol of compound V, preferably, about 0.8 to 3.0 mol.
  • the amount of base to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound V, preferably, about 1.0 to 10.0 mol.
  • the "base” to be applied hereto includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc. ; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
  • basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.
  • aromatic amines such as pyridine, lutidine, etc.
  • tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyr
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -5 to 200 ° C, desirably, in the range from 5 to 150 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound I -a is prepared by reacting compound VI with amide compound Vi. This reaction may be carried out under the presence of a base, if necessary.
  • the amount of amide compound Vl to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
  • the amount of base to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 200 ° C, desirably, in the range from the room temperature to 170 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I -a is deprotected using acid or base.
  • the amount of acid or base to be applied hereto is about 0.1 to 50.0 mol for 1.0 mol of compound I -a, preferably, about 1.0 to 20.0 mol.
  • the “acid” to be applied hereto includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; Lewis acids such as boron trichloride, boron tribromide, trimethylsilyl halide, etc.; use of thiol or sulfide with Lewis acids; and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, etc.
  • the “base” to be applied hereto includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
  • metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.
  • basic salts such as sodium carbonate, potassium carbonate, etc.
  • metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.
  • organic salts such as triethylamine, imidazole, formamidine, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent alcohol, ether, aromatic hydrocarbon, halogenated hydrocarbon, aliphatic hydrocarbon, sulfoxide or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about 0 to 200 ° C, desirably, in the range from 20 to 120 ° C.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the deprotected compound of compound I -a can be methylated. This reaction may be carried out under the presence of a base, if necessary.
  • the amount of methylation agent to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 5.0 mol.
  • the "methylation agent” includes, for example, methyl halide, dimethylsulfate, reductive amination using formamide, etc.
  • the amount of base to be applied hereto is about 1.0 to 5.0 mol for 1.0 mol of the corresponding deprotected compound of compound I -a, preferably, about 1.0 to 2.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc. ; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
  • the methylated compound of compound I -a is prepared by reacting the deprotected compound of compound I -a with formaldehyde using a reducing agent under the presence of an alcohol solvent via the reductive amination.
  • the amount of formaldehyde to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol.
  • the reducing agent sodiumborohydride NaBH 4 , sodiumcyanoborohydride NaBH 3 CN or sodiumtriacetoxyborohydride NaB(OAc) 3 H is used.
  • the amount of the reducing agent to be applied hereto is about 1.0 mol to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol.
  • Reaction temperature is about -20 to 100 ° C, desirably, in the range of 0 ° C to the room temperature.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound X is prepared from compound IX via the process described in the references (Synthesis, 877-882, 1996, or Journal of Organic Chemistry, 61: 4810-4811, 1996) .
  • the amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound X, preferably, about 2.0 to 2.5 mol.
  • Compound X II is prepared by halogenating compound X I obtained in the above step in the same manner as step (2) of Scheme 1 above .
  • Hal denotes a halogen atom such as chlorine, bromine and iodine.
  • Thioamide compound VI may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto.
  • Compound XIV is prepared by deprotecting compound XlH using acid or base.
  • Compound I -b is prepared by reacting compound XIV with acylation agent XV under the presence of a base.
  • the amount of acylation agent XV to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound XIV, preferably, about 1.0 to 3.0 mol.
  • the amount of base to be applied hereto is about 0.1 to 3.0 mol for 1.0 mol of compound XIV, preferably, about 0.3 to 1.2 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 100 ° C, desirably, in the range from -78 to 70 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 20 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 3 below comprises the steps of: (1) treating a compound (XVI) with a base and reacting the base-treated compound with a compound (HI) to prepare a compound ( XVH) ;
  • Compound XVI may be prepared via the process described in the references such as Bioorganic & Medicinal Chemistry Letters, 13 (3) : 347-350, 2003; Organic Letters, 4(6): 979-981, 2002; or Zhurnal Organicheskoi Khimii, 12 (10) : 2063-6, 1976.
  • Compound XVH is prepared by reacting compound XVI with compound IH in the same manner as step (1) of Scheme 1 above.
  • Compound XVl may be prepared by halogenating compound XVK obtained in the above step in the same manner as step (2) of Scheme 1 above.
  • Rl is the same as defined in Formula 2; R2 is the same as defined in Formula 1; and Hal denotes Cl.
  • the base to be used in the chlorination of above (a) includes, besides LDA, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium bis (triraethylsilyl) amide and the like.
  • methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4- (trifluoromethyl) benzenesulfonyl chloride, sulfuryl chloride, etc. may be used, besides trifluoromethanesulfonyl .
  • the amount of chlorination agent to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XVII, preferably, about 1.0 to 2.0 mol.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 150 ° C, desirably, in the range from -78 ° C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the amount of TBAB applied thereto is about 0.01 to 5.0 mol for 1.0 raol of compound XVE, preferably, about 0.05 to 0.5 raol.
  • the amount of TMSCI to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVI, preferably, about 1.0 to 5.0 mol .
  • the amount of DMSO to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVH, preferably, about 1.0 to 5.0 mol .
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 50 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound XIX is prepared by reacting compound XVI obtained in the above step with thioamide compound VI in the same manner as step (3) of Scheme 1. According to International Publication No.
  • compound XIX is prepared in the yield of 24% by reacting compound XVl, of which Rl is 4-F and Hal is bromine, with thioamide compound VI, of which R2 is N-ethoxycarbonyl-piperydin-4-yl .
  • the yield of compound XIX is very low as about 7%.
  • Compound X X is prepared by treating compound XIX with organic peroxy acid.
  • the amount of organic peroxy acid to be applied hereto is about 0.8 to 10.0 mol for 1.0 mol of compound XIX, preferably, about 1.0 to 3.0 mol.
  • the "organic peroxy acid” includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc.
  • reaction temperature is generally about -20 to 130 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • compound X X is prepared by treating compound XlX with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
  • the amount of hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of .compound
  • alkyl hydroperoxide includes, for example, tert- butyl hydroperoxide, cumene hydroperoxide, etc.
  • the amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XK, preferably, about 0.8 to 5.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc.; and organic acids such as formic acid, acetic acid, etc.
  • the "metal oxide” includes, for example, vanadium oxide (V 2 O 5 ) , osmium tetroxide (OSO4) , tungsten oxide (WO 3 ) , selenium dioxide (SeO 2 ), chrome oxide (CrO 3 ), etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the deprotected compound of compound I -c can be methylated in the same manner as the methylation of Scheme 1.
  • the process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 4 below comprises the steps of: (1) preparing a compound (XXII) by reacting a compound ( XVHI) with a thiourea compound (XXI);
  • step (2) (2) preparing a compound (X XIH) by halogenating the compound (XXII) obtained in step (1) ;
  • Compound XXHI is prepared by halogenating compound X X ⁇ with tert-butyl nitrite and metal halide (Sandmeyer reaction) .
  • the halogenation reaction may be a general one.
  • Hal denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
  • the amount of tert-butyl nitrite to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
  • the amount of metal halide to be used is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
  • the "metal halide” includes copper halides such as copper ( II ) bromide, copper ( II ) chloride and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100°C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Compound XXV is prepared by reacting compound XXIH with compound XXIV. This reaction may be carried out under the presence of a base, if necessary.
  • Compound XXIV may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto.
  • the amount of compound XXIV to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXHI, preferably, about 1.0 to 10.0 mol.
  • the amount of base to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXIII, preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
  • reaction temperature is generally about -78 to 200 ° C, desirably, in the range from the room temperature to 170 "C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compounds XXVI and XXVE may be prepared according to steps (4) and (5) of Scheme 3, respectively.
  • compound XXV if Y is NH, compound X XVI may be prepared by protecting NH of compound XXV, and compounds X X IX and XXX may be prepared according to steps (4) and (5) of Scheme 3, respectively.
  • the deprotected compound may be methylated in the same manner as the methylation of Scheme 1.
  • Rl, R4 and Y are the same as defined in Formula 1; and Hal denotes a halogen atom.
  • Compound XXXVI is prepared by treating compound XXXIV with a base and reacting the base-treated compound with compound XXXV, if Y is an alkyl of N-C 1 --C 4 in compound XXXV.
  • compound X X XVII is prepared by deprotecting compound X X XVI, obtained in step (4) above, in the same manner as the deprotection of Scheme 1.
  • the amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXIV, preferably, about 1.0 to 1.2 mol.
  • the “base” includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -78 to 60 ° C, desirably, in the range from -78 °C to the room temperature.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
  • step (3) treating the compound (XXXX) obtained in step (2) with base, ZnCl 2 and reacting the base-treated compound with Pd (PPh 3 ) 4 and a compound (XXXXI).
  • a basic framework of Formula 1 may be prepared via Negishi type coupling reaction.
  • Compound XXXXI may be prepared via the process described in the reference (Tetrahedron, 45(3): 993, 1989).
  • Compound XIX is prepared treating compound XXXX with base, ZnCl 2 , and reacting the base-treated compound with Pd (PPh 3 ) 4 and compound XXXXI.
  • the amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
  • the amount of ZnCl 2 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
  • the amount of Pd(PPh 3 ) 4 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol.
  • the "base” includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
  • reaction temperature is generally about -78 to 200 ° C, desirably, in the range from -78 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • Thioamide compound VI is prepared according to Scheme 7 below.
  • R2 is the same as defined in Formula 1.
  • Thioamide compound VI may be prepared by treating compound XXXXII with hydrogen sulfide.
  • the amount of hydrogen sulfide to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound XXXXII.
  • the amount of base to be used is about 1.0 to 30.0 mol for 1.0 mol of compound X X X II , preferably, about 1.0 to 10.0 mol.
  • the “base” includes, for example, aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine, etc.; and ammonia. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, aromatic amine or a mixture of more than two of them may be used, for example.
  • aromatic amines such as pyridine, lutidine, etc.
  • tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexy
  • Reaction temperature is generally about -20 to 80 ° C, desirably, in the range from - 10 to 30 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound VI may be prepared by treating compound X X X X II with diethyl dithiophosphate under the presence of an acid.
  • the amount of diethyl dithiophosphate to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXII, preferably, about 1.0 to 3.0 mol.
  • the amount of acid to be used is about 1.0 to 30.0 mol for 1 . 0 mol of compound X X X II , preferably, about 1 . 0 to
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
  • reaction temperature is generally about -20 to 100 ° C, desirably, in the range from 0 to 50 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound VI may be prepared by treating compound XXXXIII with phosphorus pentasulfide or Lawesson' s reagent under the presence of a base.
  • the amount of phosphorus pentasulfide or Lawesson' s reagent to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXIII, preferably, about 0.5 to 3.0 mol.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • solvent halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
  • Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
  • Reaction temperature is generally about 0 to 150 ° C, desirably, in the range from the room temperature to 120 ° C.
  • the product (VI) may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I (including compounds I -a, I -b and I -c) is an acylamino compound
  • compound I is prepared by applying the corresponding amine compound directly to the well-known acylation reaction.
  • the compound, in which R2 is an acylamino having any substitution groups in compounds I is prepared by reacting the corresponding 2-thiazolamine compound with an acylation agent under the presence of any bases or acids.
  • the amount of acylation agent to be used is about 1.0 to 5.0 rtiol for 1.0 mol of the corresponding 2-thiazolamine, preferably, about 1.0 to 2.0 mol.
  • the "acylation agent” includes, for example, carboxylic acid corresponding to the target acyl group or its reactive derivative (e.g., acid halide, acid anhydride, ester, etc. ) .
  • the amount of base or acid to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of the corresponding 2- thiazolamine, preferably, about 1.0 to 2.0 mol.
  • the “base” includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc.
  • the “acid” includes, for example, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile, sulfoxide, aromatic amine or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 150 ° C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • compound I (including compounds I -a, I - b and I -c) is a sulfonyl or sulfinyl compound
  • compound I is prepared by applying the corresponding sulfide compound directly to the well-known oxidation reaction.
  • the compound, in which R2 is a methanesulfonylphenyl or methanesulfinylphenyl having any substitution groups in compounds I is prepared by treating the corresponding 2-methylsulfanyl thiazol compound with an organic peroxy acid.
  • the amount of organic peroxy acid to be used is about 0.8 to 10.0 mol for 1.0 mol of the corresponding 2- methylsulfanyl thiazol compound, preferably, about 1.0 to 3.0 mol .
  • the "organic peroxy acid” includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 "C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • compound I is prepared by treating 2- methylsulfanyl thiazol compound with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
  • the amount hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of the 2- methylsulfanyl thiazol compound, preferably, 1.0 to 3.0 mol.
  • alkyl hydroperoxide includes, for example, The “alkyl hydroperoxide” includes, for example, tert-butyl hydroperoxide, cumene hydroperoxide, etc.
  • the amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XIX, preferably, about 0.8 to 5.0 mol.
  • the "base” includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
  • the “acid” includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
  • the "metal oxide” includes, for example, vanadium oxide (V 2 O 5 ) , osmium tetroxide (OSO 4 ) , tungsten oxide (WO 3 ) , selenium dioxide (SeO 2 ) , chrome oxide (CrO 3 ) , etc.
  • this reaction be performed without solvent, or under the presence of an inert solvent.
  • an inert solvent there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
  • Reaction temperature is generally about -20 to 130 °C, desirably, in the range from 0 to 100 ° C.
  • Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
  • the product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
  • the starting material has amino, carboxy or hydroxy as substitution group, it is possible to introduce the protective group commonly used in peptide chemistry, etc. into such groups and to prepare a target compound by removing the protective group used, if necessary.
  • the protective group for amino to be used includes, for example, formyl or Ci ⁇ C 6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) phenylcarbonyl, Ci-C ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C 7 ⁇ Cio aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), trityl, phthaloyl, etc., which may have a substitution group, respectively.
  • formyl or Ci ⁇ C 6 alkyl-carbonyl e.g., acetyl, propionyl, etc.
  • phenylcarbonyl Ci-C ⁇ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.)
  • phenyloxycarbonyl C 7
  • substitution group includes, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl-carbonyl e.g., acetyl, propionyl, valeryl, etc.
  • nitro etc.
  • the protective group for carboxy to be used includes, for example, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., which may have a substitution group, respectively.
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.
  • phenyl, trityl, silyl, etc. which may have a substitution group, respectively.
  • substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, tert-butyl, etc.), C 6 -Ci O aryl (e.g., phenyl, naphthyl, etc.) and the like, and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl-carbonyl e.g., acetyl, propionyl, valeryl, etc.
  • nitro Ci-C 6 alkyl (e.g., methyl, ethyl, propyl,
  • the protective group for hydroxy to be used may include, for example, Ci-C 6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7 -Cn aralkyl (e.g., benzyl, etc.), formyl, Ci-C 6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), phenyloxycarbonyl, C 7 -Cn aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl, etc., which may have a substitution group, respectively.
  • Ci-C 6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc
  • substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C 6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C 7 -Cn aralkyl (e.g., benzyl, etc.), C 6 -CiO aryl (e.g., phenyl, naphthyl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3.
  • halogen atom e.g., fluorine, chlorine, bromine, iodine, etc.
  • Ci-C 6 alkyl e.g., methyl, ethyl, tert-butyl, etc.
  • C 7 -Cn aralkyl e.g., benzyl, etc.
  • C 6 -CiO aryl e.g., phenyl
  • the protective groups may be removed according to the well-known method as it is or the similar process thereto, for example, the methods of treating or reducing with acid, base, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc., may be used.
  • compound I may be synthesized by carrying out the well-known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain extension and substitution group exchange reactions solely or in association with at least two of them.
  • these reactions those disclosed in the reference (Shinjikkenkagakukoza 14, Vo. 15, 1997, Maruzen Press) are used.
  • a target product is prepared in the form of glass via the above reactions, the product can be converted into salts according to an ordinary method, whereas, if a target product is prepared as a salt, it can be converted into the form of glass or other salts according to an ordinary method.
  • Compound ( I ) prepared like that may be isolated and purified readily from the resulting solution via the well- known methods such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.
  • compound I is in the form of racemates thereof, they can be resolved into S- or R- enantiomers via any optical resolutions.
  • compound I may be hydrated or dehydrated.
  • Compound I may be labeled with isotopes (e.g., 3 H, 14 C, 35 S, etc.) .
  • Prodrug of compound I is referred to such compounds that are converted into compound I by enzymes, gastric acids, etc. under physiological conditions, that is, the prodrug includes compounds converted into compound I via enzymatic oxidation, reduction, hydrolysis, etc. and compounds converted into compound I via hydrolysis by gastric acids, etc.
  • the prodrug of compound I includes: compounds that the amino group of compound I is changed into acyl, alkyl, or phosphoryl group (e.g., compounds that the amino group of compound I is changed into eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl or tert-butyl group) ; compounds that the hydroxy group of compound I is changed into acyl, alkyl, phosphoryl or boryl group (e.g., compounds that the hydroxy group of compound I is changed into acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl group) ; compounds that the carboxyl group of compound I is changed into ester or
  • the prodrugs of compound I may be the compounds that are converted into compound I under the physiological conditions disclosed in the reference (Iyakuhin no kaihatsu, Hirokawashoten, pressed in 1990, Vol. 7, Melecular Design: 163-198) .
  • the present invention provides a pharmaceutical composition comprising substituted 1,3- thiazol derivatives or pharmaceutically acceptable salts for preventing and treating TNF- ⁇ related diseases.
  • the compound of the present invention shows a very low toxicity in a concentration of 3 ⁇ M, whereas, shows a noticeable toxicity in a concentration of 10 ⁇ M for the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, and exhibits little toxicity for the murine macrophage-derived cell line, RAW264.7.
  • the compound of the present invention strongly inhibits the production of TNF- ⁇ by the human macrophage-derived cancer cell line, THP-I cell, the murine macrophage-derived cancer cell line, RAW264.7, the murine marrow cell-derived macrophage and macrophages in vivo.
  • the compound of the present invention inhibits the inflammatory reactions in vivo.
  • the compound of the present invention having excellent TNF- ⁇ inhibitory activity and inflammation inhibitory activity can be effectively used as a safe drug based on such activities.
  • the pharmaceutical composition comprising compound I of the present invention can be applied to mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as an agent for the prevention or treatment of a variety of TNF- ⁇ related diseases such as arthritides (e.g., rheumatic arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, etc.), inflammatory intestinal diseases (e.g., Crohn's disease, ulcerative colonitis, etc.), inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc.), cachexias (e.g., cachexia due to infection, cancer cachexia, cachexia due to infection
  • composition comprising compound I of the present invention having a low toxicity can be administrated as it is, or by mixing compound I with pharmaceutically acceptable carriers according to the well-known methods generally used in preparing pharmaceutical formulations, safely by oral and parenteral (e.g., local, rectal or intravenous, etc.) administrations.
  • pharmaceutical formulations include tablets (e.g., sugar coating tablet, film coating tablet, etc.), powders, granules, capsules (including soft capsules) , solutions, injections, suppositories, sustained-release forms, etc.
  • the content of compound I in accordance with the present invention may be within 0.01 to 100 weight% based on the total weight of the preparation.
  • the pharmaceutically acceptable carrier that may be used in preparing the formulations in accordance with the present invention includes various organics or carrier-free as pharmaceutical materials, for example, excipients, lubricants, bonding agents and disintergrants in solid preparations, and solvents, solubilizers, suspending agents, isotonic agents, buffering agents and soothing agents in liquid preparations.
  • optimum quantity of additives such as general preservatives, oxidation inhibitors, colorants, sweeteners, absorbents, humectants, etc., may be appropriately used, if necessary.
  • the excipient includes, for example, lactose, sucrose,
  • the lubricant includes, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
  • the bonding agent includes, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, gelatin, methyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.
  • the solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame seed oil, corn oil, olive oil, etc.
  • the solubilizer includes, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
  • the suspending agent includes surfactants, such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc., and hydrophilic polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, etc.
  • surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc.
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose
  • the isotonic agent includes, for example, glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol, etc.
  • the buffering agent includes buffer solutions such as phosphate, acetate, carbonate, citrate, etc.
  • the soothing agent includes, for example, benzyl alcohol, etc.
  • the preservative includes, for example, p- hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
  • the oxidation inhibitor includes, for example, sulfate, ascorbic acid, ⁇ -tocopherol, etc.
  • room temperature indicates the temperatures generally in the range from 10 ° C to 35 ° C;
  • % denotes the percentage by weight, unless otherwise indicated; and
  • yield represents mol/mol% .
  • Example 5 4 - [ 4 - ( 4 -fluorophenyl ) -2 - ( 4 - methyl su If any lphenyl) thiazol-5-yl]pyridin-2-ylamine (5) Trifluoroacetic acid (20 mL) was added to ⁇ 4- [4- (4- Fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5- yl]pyridin-2-yl ⁇ carbaraic acid tert-butyl ester (1.12 g, 2.23 mmol) and the mixture was stirred at room temperature for 1 hour.
  • Examples 33 to 38 In the same process as Example 32 , compounds 33 to 38 were synthesized. The structure and 1 H-NMR data of them were shown in the following Table 3.
  • Example 39 4- [4- (4-fluorophenyl) -2-piperidin-l- ylthiazol-5- ⁇ l] -2-methylsulfanylpyrimidine (39)
  • Example 63 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl]piperazine-l- carboxylic acid tert-butyl ester (63) 4- [4- (4-Fluorophenyl) -2-piperazin-l-yl-thiazol-5-yl] - 2-methylsulfanylpyrimidine (1.95 g, 5.03 mmol) , di-tert- butyl dicarbonate (1.1 g, 5.03 mmol), and triethylamine (0.51 g, 5.03 mmol) were dissolved in tetrahydrofurane (70 mL) and the mixture was stirred at room temperature for 1 hour.
  • Example 122 ⁇ 4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl]pyrimidin-2-yl ⁇ cycloh ⁇ xylamine (122)
  • Examples 123 to 277 In the same process as Example 122, compounds 123 to 277 were synthesized. The structure and 1 H-NMR data of them were shown in the following Table 8. [Table 8]
  • Example 306 4- [5- (2-cyclopropylaminopyrimidin-4-yl) - 4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester (306)
  • a solution of cyclopropyl- ⁇ 4- [4- (4- fluorophenyl) thiazol-5-yl] pyrimidin- 2-yl ⁇ amine 150 rag, 0.48 mmol) in anhydrous tetrahydrofurane 4 mL) was cooled to - 40 ° C and a 1.6M n-butyllithium-hexane solution 0.6 mL, 0.96 ramol) was added thereto dropwise while stirring.
  • Example 334 cydopropyl- ⁇ 4- [4- (4 -fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl]p ⁇ rimidin-2-yl ⁇ amine (334)
  • Example 369 cyclopropyl- ⁇ 4- [4- (4-fluorophenyl) -2- piperazin-l-yl-thiazol-5-yl]pyrimidin-2-yl ⁇ amine (369)
  • Trifluoroacetic acid (5 mL) was added to a solution of 4- [5- (2-Cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester (352 mg, 0.67 ramol) in methylene chloride (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated sodium bicarbonate was added to the residue and the mixture was extracted with methylene chloride. The extract was washed with water, dried over MgSCU and the solvent was evaporated to give the title compound (254 mg, 0.60 mmol, yield 89%). The structure and 1 H-NMR data of compound 369 were shown in the following Table 12.
  • Example 428 4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] -2- methylsulfanylpyrimidine (428)
  • Example 485 compound 486 was synthesized using 2-iodopropane instead of iodoethane.
  • the structure and 1 H-NMR data of compound 486 were shown in the following Table 14.
  • compound 492 was synthesized using l- ⁇ 4- [5- (2-cyclopropylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-l-yl ⁇ -2- dimethylaminoethanone instead of cyclopropyl- ⁇ 4- [5- (2- cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2- yl] piperidin-1-yl ⁇ methanone .
  • the structure and 1 H-NMR data of compound 492 were shown in the following Table 15.
  • Example 499 N- ⁇ 4- [4- (4-Fluorophenyl) -2- (4- methanesulfinylphenyl) thiazol-5-yl]pyridin-2-yl ⁇ propionamide 499)
  • a solution of N- ⁇ 4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl ⁇ propionamide 300 mg, 0.66 mmol
  • methylenechloride 100 mL
  • 65% ra-chloroperoxybenzoic acid 212 mg, 0.80 mmol
  • Example 500 N- ⁇ 4- [4- (4-Fluorophenyl) -2- (4- methanesulfonylphenyl) thiazol-5-yl]pyridin-2-yl ⁇ propionamide (500)
  • Example 501 N- ⁇ 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl]pyrimidin-2-yl ⁇ propionamide (501)
  • a solution of 4- [4- (4-fluorophenyl) -5- (2- propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester (56 mg, 0.12 mmol) in chloroform(3 mL) was admixed with iodotrimethylsilane (140 mg, 0.52 mmol) and the mixture was stirred at 60 ° C for 5 hours.
  • Example 504 N- [4- (3-chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide (504)
  • a solution of 6-methylnicotinic acid (310 mg, 4.44 mmol) in benzene (5 mL) was cooled to 0 " C and a solution of oxalyl chloride (378 mL, 4.44 mmol) in benzene (2 mL) was added thereto while stirring. After completion of addition, N,N-dimethylformamide (25 mL) was added thereto.
  • the reaction mixture was admixed with 4- (3-Chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (1.03 g, 3.07 mmol) and 4- (dimethylamino) pyridine (126 mg, 1.03 mmol) and the mixture was stirred at 80 ° C for overnight.
  • the reaction mixture was cooled to room temperature, saturated sodium bicarbonate (200 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO 4 and the solvent was evaporated.
  • the reaction mixture was admixed with ⁇ 4- [4- (3-chlorophenyl) -2- methylaminothiazol-5-yl]pyrimidine-2-yl ⁇ - (1- (S) - phenylethyl) amine (300 mg, 0.71 mmol) and 4- (dimethylamino) pyridine (28 mg, 0.23 mmol) and the mixture was stirred at 80 ° C for overnight.
  • the reaction mixture was cooled to room temperature, saturated sodium bicarbonate (100 mL) was added, and extracted with ethyl acetate. The extract was washed with water, dried over MgSU 4 and the solvent was evaporated.
  • Example 507 2-chloro-l- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (507) (Compound of Formula 2)
  • a solution of 1- (4-fluorophenyl) -2- (2-methylthio-4- pyrimidyl) ethanone (131 mg, 0.5 itimol) in anhydrous tetrahydrofurane (3 mL) was cooled to -78 ° C and a 1.8M lithium diisopropylamide-hexane solution (306 mL, 0.55 mmol) was added thereto dropwise while stirring.
  • Trimethylchlorosilane (11.7 g, 107.5 ramol) was added to a solution of tetrabutylammoniumbromide (2 g, 10.7 mmol) in tetrahydrofurane (650 mL) and the mixture was stirred for 30min. The mixture cooled to 0 ° C , 1- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (9.4 g, 35.8 mmol) and dimethylsulfoxide (2.9 g, 37.6 mmol) were added thereto, and stirred at room temperature for 2 hours.
  • Cell lines used in the present experiment were the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, which were purchased from American Type Culture Collection.
  • Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . Cells were added in a 96-well plate in an appropriate concentration (IXlO 6 cells/ml) and cultured under the conditions of 5%, CO 2 and 37 ° C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 ⁇ M thereto. After adding such samples, the culturing further proceeded for 48 hours. Then, 5% trichloroacetic acid was added thereto to fix the cells on the bottom of the culture vessel. Proteins of the fixed cells were dyed with a sulforhodamine B (SRB) solution to measure absorbance at 595 nm. With the increase of living cells the level of absorbance also increased and the results were shown as rates of living cells to the control group (100%) in Tables 19 to 23 below.
  • SRB sulforhodamine B
  • the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention showed very low toxicities in a concentration of 3 ⁇ M, whereas, showed noticeable toxicities in a concentration of 10 ⁇ M.
  • MTT [3- (4, 5-dimethylthiazolyl-2) -2, 5- diphenyltetrazolium bromide] has been widely used in measuring the number of living cells, since it is a colorless reagent, whereas, changed into colored formazan when it is decomposed by living cells.
  • the cell line applied to the present experiment was the murine macrophage-derived cancer cell line, RAW264.7, purchased from American Type Culture Collection. Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added in a 96-well plate in an appropriate concentration (IXlO 6 cells/ml) and cultured under the conditions of 5%, CO2 and 37 ° C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 ⁇ M thereto. After adding such samples, the culturing further proceeded for 24 hours. Then, the MTT was added thereto and, after the lapse of 4 hours, the amount of formazan produced by living cells was measured at 595 nm. The results were shown as rates to the control group (100%l in Table 24 below.
  • the compounds in accordance with Examples 115 and 126 of the present invention showed little toxicities up to the concentration of 10 ⁇ M, whereas, the compounds of Examples 334 and 429 exhibited low toxicities in the concentration of 10 ⁇ M.
  • the concentrations of the compounds in accordance with the present invention were less than 1 ⁇ M in order to identify the effects of immunosuppression in such concentrations that there is no cell toxicity.
  • TNF- ⁇ production inhibitory effects of the compounds in accordance with the present invention on the human macrophage-derived cancer cell line, THP-I cells was carried out.
  • the cell line applied to the present experiment was the human macrophage-derived cancer cell line, THP-I cells, purchased from American Type Culture Collection.
  • TNF- ⁇ was induced by using lipopolysaccharide (final concentration: 1 mg/ml) (Sigma, USA) and the compounds prepared in Examples 115, 126, 334 and 429 were added thereto in concentrations of 0.0003-1 ⁇ M. After 24 hours, the culture solutions were collected and the amount of TNF- ⁇ existing in the cell culture solutions were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 25 below.
  • Example 429 As shown in Table 24 above, it was seen that the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention inhibited the production of TNF- ⁇ of THP-I cells concentration-dependently. Particularly, the compound of Example 429 showed the most excellent inhibitory effect with 0.28 nM of 50% inhibitory concentration (IC 50 ) and the compounds of Examples 334, 126 and 115 exhibited 1 nM, 1.5 nm, and 0.48 nm of 50% inhibitory concentration (IC50), respectively.
  • IC 50 50% inhibitory concentration
  • TNF- ⁇ induced by LPS in the experimental groups were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) , based on the amount of 100% TNF- ⁇ induced by treating only LPS existing in the cell culture solution. The results were depicted in Tables 26 to 30 below.

Abstract

Disclosed relates to new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The compound of the present invention having excellent TNF-α inhibitory activity and inflammation inhibitory activity can be effectively used in the prevention and treatment of TNF-α related diseases.

Description

[DESCRIPTION]
[invention Title]
NEW SUBSTITUTED 1,3-THIAZOLE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVING IMMUNOSUPPRESSION AND INFLAMMATION INHIBITORY ACTIVITY,
INTERMEDIATE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS
THEREOF, A PROCESS FOR THE PREPARATION THEREOF, AND
PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
[Technical Field]
The present invention relates to new substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same.
[Background Art] As biological substances that play an important role in immune response and inflammatory response, proinflammatory cytokines, such as tumor necrosis factor-α (TNF-ot), interleukin-1 (IL-I), etc., have been known.
Such substances are produced by a variety of cells, such as monocyte or macrophage, in response to the inflammation and the other cell stress. It has been known that the cytokines play a key role in the immune response or the inflammatory response if they exist with an optimal dose, whereas, they may be related to various inflammatory diseases if they are produced excessively.
The proinflammatory cytokines, such as the TNF-α, 11-1, etc., are regulated by p-38 MAP kinase that is one of the mitogen-activated protein (MAP) kinases (Seiji Miwatashi et al., J. Med. Chem. 48, 5966-5979, 2005). As well known, the protein kinase (PK) includes a Ser/Thr kinase that participates in the activation of its substrate by phosphorylation as an enzyme that participates in a variety of cell responses for the extra cellular signal (B. Stein et al., Ann. Rep. Med. Chem., 31, 289-298, 1996). The MAPK of such PKs is activated in itself by a variety of signals including growth factor, cytokine, UV irradiation and stress inducer in general.
Especially, the p38 MAP kinase, also known as a cycling sequence binding protein (CSBP) and a reacting kinase (RK) , was isolated and sequentialized after inducing a murine pre-B cell, transformed by lipopolysaccarides (LPS) receptor CD14, with LPS and the cDNA that codes the p38 MAP kinase of human and mouse was isolated and sequentialized. The p38 MAP kinase is considered as it plays a role in the cell response to the inflammatory stimuli, such as accumulation of leukocytes, activation of macrophages/monocytes, tissue resorption, pyrexia, acute phase reaction and neutrophilia. Diseases associated with p38 MAP kinase include cancer, platelet aggregation induced by thrombin, immunodeficiency disease, autoimmune disease, necrocytosis, allergy, osteoporosis, degenerative disease, etc.
Moreover, it was observed that the p38 MAP kinase was activated in the cell stimulated by stress (e.g., LPS process, UV, isomycin or osmotic shock) and cytokines, such as TNF-α, IL-I, etc. Accordingly, if it would blockade the production of cytokines of TNF-α, 11-1, etc., it is possible to inhibit the activation of p38 MAP kinase. That is, it is possible to treat the diseases that the cytokines intermediate or the diseases that are associated with p38 MAP kinase by blockading the production of other proinflammatory cytokines, e.g., IL-6 or IL06, produced by the stimuli of IL-I and TNF-α.
Hereinafter, the diseases associated with the excessive production of TNF-α, IL-I, IL-6 and IL-8 will now be described in more detail.
1. TNF-α
Tumor necrosis factor-α (TNF-α) is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator. Excessive or non-regulated production of TNF-α is associated with a variety diseases such as: rheumatic arthritis, rheumatoid spondylitis, osteoarthritis and other arthritis diseases; sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, osseous resorption disease, reperfusion injury, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to influenza infection and secondary cachexia due to acquired immune deficiency syndrome (AIDS) , AIDS, AIDS-related complex (ARC) , keloid formation, wounded tissue formation, Crohn's disease, ulcerative colitis, paralysis, non-insulin- dependent, non-insulin-dependent diabetes mellitus, multiple sclerosis and inflammatory bowel disease (IBD); viral infections, e.g., HIV, influenza virus and herpes simple virus type 1 (HSV-I) , herpes simple virus type 2 (HSV-2) , cytomegalovirus (CMV) , varicella-zoster virus (VZV) , Epstein-Barr virus, human herpes virus-6 (HHV-6) , human herpes virus-7 (HHV-7), human herpes virus-8 (HHV-8) and herpes virus including pseudorabies and rhiotracheitis .
2. IL-I Interleukin-1 (IL-I) is a cytokine produced mainly by activated monocyte and macrophage and is a strong proinflammatory mediator, like TNF-α. Moreover, it has been established that the numeric value of IL-I is increased also by the excessive or non-regulated production of TNF-α. Accordingly, TNF-α inhibitor reduces the numeric value of IL-I (European Cytokine Network 6, 225, 1995) and improves symptoms of disease due to the non-regulated synthesis of IL-I.
A variety of diseases exacerbated or induced by the excessive of non-regulated synthesis of IL-I include rheumatic arthritis, rheumatoid spondylitis, osteoarthritis, gout, traumatic arthritis, rubella arthritis, acute synovitis, sepsis, septic shock, endotoxin shock, gram- negative sepsis, toxic shock syndrome, adult respiratory distress syndrome (ARDS) , cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, osseous absorption disease, ischemic reperfusion injury, arteriosclerosis, traumatic brain injury, multiple sclerosis, graft versus host reaction, allograft rejection; myalgia and febricity due to infection, e.g., secondary cachexia due to infection or malignant tumor, secondary cachexia due to acquired immune deficiency syndrome (AIDS), AIDS, AIDS-related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colonitis, anaphylaxis, myodegeneration, Reuter' s syndrome, type 1 and type 2 diabetes, paralysis, etc.
Moreover, it has been reported that IL-I regulates various biological activities such as activation of T-helper cell, heat induction, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis and inhibition of plasma iron concentration (Rev. Infect. Disease, 6, 51(1984)). Furthermore, virus sensitive to TNF inhibition, e.g., HIV-I, HIV-2 and HIV-3, is affected by the production of IL-I. In rheumatic arthritis, 11-1 and TNF all induce the synthesis of collagenase to cause tissue destruction in joint ultimately (Lymphokine Cytokine Res. (11): 253-256, (1992)) and (Clin. Exp. Immunol. 989: 244-250, 1992).
3. IL-β IL-6 is another inflammatory cytokine associated with a variety of symptoms including inflammation. IL-6 is a growth factor in various oncological diseases including multiple myeloma and related plasma cell dyscrasia.
Diseases related to the excessive or non-regulated production of IL-6 include neurological disorders, such as AIDS dementia complex (ADC), Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus (SLE) , CNS trauma, and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15:307); and numerous diseases such as multiple myeloma, rheumatic arthritis, psoriasis and postmenopausal osteoporosis (Simpson, et al . , Protein Sci. 6, 929, 1997).
4. IL-8 IL-8 is a characterized chemotactic factor produced by- several cells such as monocyte, fibroblast, endothelial cell and keratinocyte. The production of IL-8 induced by IL-I, TNF-α or lipopolysaccarides (LPS) in the endothelial cell releases histamine from basophile of normal and atopic subjects and further contributes to the induction of lysosomal enzyme release from neutrophil and the increase in vascular endothelial cell adhesion.
Diseases associated with the excessive or non- regulated production of IL-8 include diseases mediated mainly by neutrophil, such as cerebral paralysis and myocardial infarction; heat injury, adult respiratory distress syndrome (ARDS) , multiple organ injury after trauma, acute glomerulonephritis, dermatosis accompanied by acute inflammatory disease, acute purulent meningitis, or other central nervous system (CNS) disorders, hemodialysis, granulocyte transfusion-related syndrome, necrotizing enterocolitis (NEC), etc.
5. The others Besides the cytokines, GM-CSF, IFN- Y and the like are associated with the immune and inflammatory response. GM- CSF affects hepatocyte proliferation and differentiation and regulates several other types of cells related to acute and chronic inflammations. IFN-Y is associated with collagen deposition that is one of the major histopathological characteristics of graft versus host disease (GVHD) and induces the activation of most peripheral T-cells prior to the progression of malfunctions of the central nervous system (CNS) in the diseases such as multiple sclerosis and AIDS dementia complex (ADC) (Martino et al., 1998, Ann Neurol. 43, 430) .
In addition, it has been observed that some proteins such as cyclooxygenase (COX) are present in vivo that participate in inflammation. Cyclooxygenase (COX) is generally classified into a constitutive expression of cyclooxygenase (COX-I) and an inducible expression of cyclooxygenase (COX-2) . It has been established that the expression of COX-2 is increased by cytokines. Accordingly, it is expected that a cytokine inhibitor may inhibit the expression of COX-2 (M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 1992, 89, 4888). Also, it is expected that the COX inhibitor, like non-steroidal anti-inflammatory drug (NSAID) well known as a drug that inhibits the cytokines such as IL-I and the like, will show efficacies for various diseases being under medical treatment. Up to the present, various studies aimed at developing p38 MAP kinase inhibitors for treating a variety of immune and inflammatory diseases by inhibiting the cytokines have continued to progress. Anti-inflammatory agents of the initial stage served as tools to elucidate the role of p38 MAP kinase were pyridinyl imidazoles. The first one is the bicyclic pyridinyl imidazole SKF-86002 developed by Lee, J. C. et al (Lee, J. C. et al., Int. J. Immunopharmacol . 10, 835-843, 1992). Since then, the structure-activity relationship
(SAR) for the inhibition of cytokine synthesis by bicyclic imidazoles was reported and subsequently various researches explored the imidazole compounds. For example, there was prepared SB-203580 by GlaxoSmithKline Inc (Badger, A. M. et. al., J. Pharmacol. Exp. Therap. 279, 1453-1461, 1996) and other 2, 3, 4-triaryl imidazole derivatives (Gallagher, T. F. et. al., Bioorg. Med. Chem. Lett. 5, 1171-1176, 1995).
Thereafter, the new aryl-pyridinyl-heterocycle compounds were synthesized by replacing the imidazole pharmacophore with other heteroaryl pharmacophore. For instance, the aryl-pyridinyl-heterocycle complexes include SB-242235 prepared by GlaxoSmithKline Inc., and RWJ-67657 provided by RW Johnson Pharmaceutical Research Institute (Badger, A. M. et . al., Arthritis Rheum. 43. 175-183, 2000; Wadsworth, S. A. et . al., J. Pharmacol. Exp. Ther. 291, 680- 687, 1999) .
Moreover, several structurally diverse and notable new p38 MAPK inhibitors were reported. Cirillo et al. prepared the non-aryl-pyridinyl compounds including triazanapthalenones, A/,W -diary1 ureas, -V,N-diaryl ureas, benzophenones, pyrazoleketones, indole amides, diamides, quinazolinones, pyrimido [4, 5-d] pyrimidinones and pyridyl- amino-quinazolines (Cirillo, P. F. et . al., Curr. Top. Med. Chem. 2, 1021-1035, 2002) . Such non-aryl-pyridinyl compounds include VX-745 of Vertex Pharmaceutical Inc. classified as triazanapthalenones and BIRB-796 of Boehringer Ingelheim Pharmaceutical Inc. related to N,Nr -diaryl ureas (Regan, J. et . al . , J. Med. Chem. 45, 2994-3008, 2002).
Recently, GlaxoSmithKline (WO/2002/059083) and Merck (WO/2002/058695) have published the compounds very closely related heteroaryl fused pyridinone structures.
In addition to the above described p38 MAPK inhibitors, there have been published numerous compounds containing pharmacophores with various structures, such as imidazole, oxazole, or pyrazole derivatives (WO/1993/014081, WO/1993/014082, WO/1995/002591, WO/1995/013067, WO/1995/031451, WO/1999/058523, WO/1998/056377, WO/1997/016442, WO/1999/057101, WO/2000/039116 and WO/2000/031063) , cycloalkenyl, pyrimidine and triazole compounds (WO/2000/025791, WO/1998/024782, WO/1999/001776, WO/2000/010563 and WO/2000/035911) and polycyclic compounds (WO/1999/064400, WO/1998/022457 , WO/2000/020402, WO/2000/012497, WO/1999/061426 and WO/1999/058502) .
As described above in detail, there have been numerous researches aimed at developing various compounds having effective ingredients useful in preventing and treating inflammatory diseases or immunologic diseases based on various pharmacophore compounds having inflammation inhibitory activity or immunosuppression activity. However, it is considered that there have been few studies performed by selecting thiazole as a pharmacophore up to now among the various compounds described above.
Accordingly, the inventors of the present invention having executing researches aiming at selecting thiazole compounds as a pharmacophore to develop effective compounds that are useful in treating diseases mediated by proinflammatory cytokines such as TNF-α and IL-I and have excellent inhibitory activities of the proinflammatory cytokines, have confirmed that substituted 1,3-thiazole derivatives shows excellent immunosuppression or inflammation inhibitory activity, thus completing the present invention.
[Disclosure] [Technical Problem] An object of the present invention is to provide new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities. Another object of the present invention is to provide intermediate compounds or pharmaceutically acceptable salts thereof.
Still another object of the present invention is to provide a process for the preparation of the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof and intermediate compounds or pharmaceutically acceptable salts thereof.
Still another object of the present invention is to provide a pharmaceutical composition comprising the substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof.
[Technical Solution]
To accomplish the above objects, the present invention provides new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities, intermediate compounds or pharmaceutically acceptable salts thereof, a method for the preparation thereof and, further, a pharmaceutical composition comprising the substituted 1,3- thiazole derivatives or pharmaceutically acceptable salts thereof.
[Advantageous Effects] New substituted 1,3-thiazole derivatives of the present invention having excellent TNF-α inhibitory activity and inflammation inhibitory activity can be effectively used for preventing and treating TNF-α related diseases.
[Description of Drawings]
Fig. 1 is photographs of colons in a vehicle treatment group extracted by sacrificing rats having ulcers induced by TNBS (2, 4, β-trinitrobenzenesulfonic acid solution) that is an inflammatory intestinal disease induced substance; Fig. 2 is photographs of colons in a treatment group extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with prednisolone; and
Fig. 3 is photographs of colons extracted by sacrificing rats having ulcers induced by TNBS, which is an inflammatory intestinal disease induced substance, and treated with the compounds of Example 334 in accordance with the present invention. [Best Mode]
The present invention provides new substituted 1,3- thiazole derivatives expressed by Formula 1 below or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activities:
Figure imgf000016_0001
wherein Z denotes CH or N;
Rl denotes a halogen atom, a haloalkyl of C1-C4, an alkyl of Ci~C4 or alkoxy of Ci-C4;
R2 denotes H, a halogen atom, an alkyl of C1-C4, -NH-R4, an alkyl-S (O)n-phenyl of Ci-C4,
Figure imgf000016_0002
in which X denotes CH, C-OH or N ; and Y denotes CH2 , an alkyl of CH-Ci-C4 , NH, an alkyl of N-Ci-C4, an alkyl of amino-Ci~C4 of N-Ci-C4, an alkyl of N-CO-Ci-C4, a cycloalkyl of N-CO-C3-C8, an aryl of N-CO-C5-C8, an alkyl of amino-Ci~C4 of N-CO-Ci-C4 or an alkoxy of N-Co-N-Ci-C4;
R3 denotes a halogen atom, -NH-R4, -NH-C0-R5, -N-(CO- R5)2 or an alkyl of -S(O)n-Ci-C4 ; R4 denotes H, an alkyl of Ci-C4, a cycloalkyl of C3-C8, a cycloalkylalkyl of C3-C8, an aryl of C5-C8, CH(Ci-C4 alkyl) - phenyl or amine;
R5 denotes an alkyl of Ci-C4, a cycloalkyl of C3-C8, an aryl of C5-C8 or an alkoxy of Ci-C4; m is 1 or 2; and n is 0, 1 or 2.
Preferably, in Formula 1 above, Z is CH or N; Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 or 4-OCH3;
R2 is H, Cl, ethyl, amino, NHNH2, methylamino, 6,N- dimethylnicotinilamino, 4- methylsulfanylphenyl, 4- methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidin-1- yl, 4-methyl-piperidin-l-yl, piperidin-4-yl, N-methyl piperidin-4-yl, N-ethyl- piperidin-4-yl, N-isopropyl- piperidin-4-yl, N-cyclopropylmethyl-piperidin-4-yl, N- dimethylaminoethyl- piperidin-4-yl, N-methylcarbonyl- piperidin-4-yl, N-cyclopropylcarbonyl-piperidin-4-yl, N- dimethylaminomethylcarbonyl-piperidin-4-yl, N- phenylcarbonyl-piperidin-4-yl, ethoxycarbonyl-piperidin-4-yl, N-butoxycarbonyl-piperidin-4-yl, piperazin-1-yl, N-methyl- piperazin-1-yl, N-bytoxycarbonyl-piperazin-1-yl, 4-methyl-4- oxypiperazin-1-yl, 4-hydroxy—piperidin-4-yl, N-methyl-4- hydroxy-piperidin-4-yl, N-butoxycarbonyl-4-hydroxy- piperidin-4-yl, 2, 5-diazabicyclo [2.2.1] -hept-2-yl, N-t- butoxycarbonyl-2, 5-diazabicyclo [2.2.1] -hept-2-yl, piperidin- 4-ylamino, N-t-butoxycarbonyl-piperidin-4-ylamino, piperidin-4-yloxy or N-t-butoxycarbonyl-piperidin-4-yloxy; and R3 is F, amino, cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylaraino, phenylamino, benzylamino, (S) -1-phenylethylamino, (R) -1-phenylethylamino, ethylcarbonylamino, N, N-diethylcarbonylamino, cyclohexylcarbonylamino, N,N-dicyclohexylcarbonylamino, phenylcarbonylamino, t-butoxycarbonylamino, methylsulfanyl, methanesulfinyl or methanesulfonyl .
In the above compounds of Formula 1, preferable compounds are as follows in detail:
1. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4- yl) thiazol-2-yl]methylamine
2. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4- yl) thiazol-2-yl] hydrazine 3. 4-[2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] -2- fluoropyridine
4. {4-[4-(4-fluorophenyl)-2-(4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl }carbamic acid tert-butyl ester 5. 4- [4- (4-fluorophenyl)-2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine
6. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
7. [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-yl]methylamine
8. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2- methylsulfanylpyrimidine
9. 4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine 10. 4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
11. 4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
12. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
13. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-ylamine
14. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-ylamine 15. 4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin- 4-yl) thiazol-2-ylamine
16. [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin- 4-yl) thiazol-2-yl]methylamine
17. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid tert-butyl ester
18. 4- [5- (2-aminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 19. 4- [4- (3-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
20. 4-[4-(2-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
21. 4-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
22. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
23. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 24. 4- [4- (4-methoxyphenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
25. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine 26. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
27. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
28. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
29. 2-methylsulfanyl-4-[4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
30. 2-methylsulfanyl-4-[4-(3-methylphenyl) thiazol-5- yl] pyrimidine 31. 4- [4- (4-methoxyphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
32. 4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
33. 4- [2-chloro-4- (3-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
34. 4- [2-chloro-4- (2-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
35. 4- [2-chloro-4- (3-chlorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine 36. 4- [2-chloro-4- (3-trifluoromethylphenyl) thiazol-5- yl] -2-methylsulfanylpyrimidine
37. 4- [2-chloro-4- (3-methylphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
38. 4- [2-chloro-4- (4-methoxyphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
39. 4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
40. 4- [4- (3-fluorophenyl) -2-piperidin~l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine 41. 4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
42. 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
43. 2-methylsulfanyl-4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
44. 2-methylsulfanyl-4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidine
45. 4- [4- (4-methoxyphenyl) -2-piperidin~l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine 46. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
47. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
48. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine 49. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
50. 4-[2-(4-methylpiperidin-l-yl)-4- (3- trifluoromethylphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
51. 4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine
52. 4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine 53. 4- [4- (4-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
54. 4- [4- (3-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
55. 4- [4- (2-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
56. 4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
57. 2-methylsulfanyl-4-[2-piperazin-l-yl-4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine 58. 2-methylsulfanyl-4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidine
59. 4- [4- (4-methoxyphenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
60. 2- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2, 5- diazabicyclo [2.2.1] heptane
61. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1- carboxylic acid tert-butyl ester 62. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1- carboxylic acid tert-butyl ester
63. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
64. 4-[4-(3-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
65. 4-[4-(2-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
66. 4-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester 67. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
68. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester 69. 4- [4- (4-methoxyphenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
70. 5-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyriraidin-4-yl) thiazol-2-yl] -2, 5- diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
71. 4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin- 4-yl) thiazol-2-ylamine 72. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2- methanesulfinylpyrimidine
73. 4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin- 4-yl) thiazol-2-ylamine
74. [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin- 4-yl) thiazol-2-yl Jmethylamine
75. 4- [4- (4-fluorophenyl) -5- (2- methanesulfonylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
76. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid tert-butyl ester
77. 4-[4-(3-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester 78. 4-[4-(2-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
79. 4-[4-(3-chlorophenyl)-5- (2- raethanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
80. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
81. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
82. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 83. 4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
84. 4- [4- (3-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
85. 4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
86. 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
87. 2-methanesulfinyl-4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine 88. 2-methanesulfinyl-4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidine
89. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- piperidin-l-yl-thiazol-5-yl] pyrimidine
90. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
91. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
92. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine 93. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
94. 2-methanesulfinyl-4- [2- (4-methylpiperidin-l-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine
95. 2-methanesulfinyl-4- [2- (4-methylpiperidin-l-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidine
96. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidine
97. 4- [4- (4-fluorophenyl) -2- (4-methyl-4-oxypiperazin- 1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine 98. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
99. 4- [4- (3-fluorophenyl) -5- (2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester 100 . 4- [ 4- ( 2-fluorophenyl ) -5- ( 2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
101. 4-[4-(3-chlorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
102. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester 103. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
104. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
105. 4-[4~(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1- carboxylic acid tert-butyl ester
106. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-ylamino] piperidine- 1-carboxylic acid tert-butyl ester
107. 5-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -2, 5- diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester 108. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2- raethanesulfinylpyrimidine
109. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine 110. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
111. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
112. 2-methanesulfinyl-4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
113. 2-methanesulfinyl-4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidine
114. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) thiazol- 5-yl] pyrimidine 115. {4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl] pyridin-2-yl } cyclohexylamine
116. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyridin-2-yl } cyclohexylamine
117. { 4- [4- (3-chlorophenyl) -2-hydrazinothiazol-5- yl] pyridin-2-yl} cyclohexylamine
118. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5- yl] pyridin-2-yl}- (1- (S) -phenylethyl) amine
119. cyclohexyl-{ 4- [4- (4-fluorophenyl) thiazol-5- yl] pyridin-2-yl }amine 120. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl}- (1- (S) -phenylethyl) amine
121. cyclohexyl-{ 4- [2-ethyl-4- (4-fluorophenyl) thiazol- 5-yl] pyridin-2-yl }amine
122. {4-[2-amino-4- (3-chlorophenyl) thiazol-5- yl] pyrimidin-2-yl }cyclohexylamine
123. { 4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyrimidin-2-yl } cyclopentylamine
124. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5- yl] pyrimidin-2-yl } - (1- (s) -phenylethyl) -amine 125. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyrimidin-2-yl } - (1- (s) -phenylethyl) amine
126. {4- [2-amino-4- (4-fluorophenyl) thiazol-5-yl] - pyrimidin-2-yl } - ( 1- ( s ) -phenylethyl ) amine
127. {4- [4- (4-fluorophenyl) -2-methylaminothiazol-5- yl] -pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
128. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
129. 4- [5- (2-cyclobutylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
130. 4- [5- (2-cycloheptylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 131. 4- [5- [2- (cyclopropylmethylamino) pyrimidin-4-yl] - 4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
132. 4- [5- (2-benzylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
133. 4- [4- (4-fluorophenyl) -5- (2-phenylaminopyrimidin- 4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
134. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
135. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
136. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
137. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 138. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
139. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 140. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl]piperidine-l-carboxylic acid tert- butyl ester
141. 4- [5- (2-cyclopentylaminopyriinidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert- butyl ester
142. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 143. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
144. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
145. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
146. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
147. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 148. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert- butyl ester
149. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
150. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
151. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
152. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 153. 4- [5- (2-cyclohexylaminopyriraidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
154. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
155. 4-{ 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid tert-butyl ester
156. 4-{4- (4-fluorophenyl) -5- [2- (1- (R) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
157. 4-{4- (3-fluorophenyl) -5- [2- (1- (s) - phenylethylaraino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester 158. 4-{4-(2-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
159. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperidine-l- carboxylic acid ethyl ester
160. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
161. 4-{5- [2- (1- (S) -phenylethylamino)pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl}piperidine-l-carboxylic acid ethyl ester
162. 4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester 163. cyclopropyl- { 4- [4- (4-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl]pyrimidin-2-yl} amine
164. cyclopropyl- { 4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl]pyrimidin-2-yl} amine
165. cyclopropyl- { 4- [4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine 166. { 4- [ 4- ( 3-chlorophenyl ) -2-piperidin-l-yl-thiazol- 5-yl ] pyrimidin-2-yl } cyclopropylainine
167. cyclopropyl-{ 4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 168. cyclopropyl-{4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
169. cyclopropyl-{4- [4- (4-methoxyphenyl) -2-piperidin- l-yl-thiazol-5-yl] pyrimidin-2-yl} amine
170. cyclopentyl- { 4- [4- (4-fluorophenyl) -2-piperidin-l- ylthiazol-5-yl] pyrimidin-2-yl} amine
171. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
172. cyclopentyl- { 4- [4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine 173. {4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopentylamine
174. cyclopentyl- { 4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
175. cyclopentyl-{4-[2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
176. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin- l-yl-thiazol-5-yl] pyrimidin-2-yl} amine
177. cyclohexyl-{ 4- [4- (4-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine 178. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
179. cyclohexyl-{ 4- [4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
180. {4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }cyclohexylamine
181. cyclohexyl-{ 4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
182. cyclohexyl-{4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 183. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
184. {4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
185. { 4- [4- (3-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
186. {4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }- (1- (s) -phenylethyl) amine
187. {4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine 188. (1- (S) -phenylethyl) -{4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
189. (1- (S) -phenylethyl) -{4- [2-piperidin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
190. { 4- [4- ( 4-methoxyphenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine 191. cyclopropyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] -pyrimidin-2-yl}amine
192. cyclopropyl-{4-[4- (3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine 193. cyclopropyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
194. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopropylamine
195. cyclopropyl- { 4- [2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}amine
196. cyclopropyl- {4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
197. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine 198. cyclopentyl-{4-[4- (4-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
199. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
200. cyclopentyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
201. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
202. cyclopentyl-{4- [2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine 203. cyclopentyl-{4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
204. cyclopentyl-{4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
205. cyclohexyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
206. cyclohexyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
207. cyclohexyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine 208. {4- [4- (3-Chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl }cyclohexylamine
209. cyclohexyl-{ 4- [2- (4-methylpiperidin-1-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
210. cyclohexyl-{4-[2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
211. cyclohexyl-{4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
212. {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine 213. {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
214. {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (s) -phenylethyl) amine
215. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine 216. {4- [2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) - phenylethyl) amine
217. {4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) - phenylethyl) amine
218. {4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
219. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
220. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester 221. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
222. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
223. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
224. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
225. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester 226. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
227. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
228. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
229. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
230. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester 231. 4- [5- (2-cyclopentylarainopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
232. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester 233. 4- [5- (2-cyclohexylarainopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
234. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
235. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester 236. 4- [4- (3-chlorophenyl) -5- (2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
237. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
238. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
239. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
240. 4- { 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyriraidin-4-yl] thiazol-2-yl }piperazine-l- carboxylic acid tert-butyl ester 241. 4-{4-(3-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperazine-l- carboxylic acid tert-butyl ester
242. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyriraidin-4-yl] thiazol-2-yl }piperazine-l- carboxylic acid tert-butyl ester
243. 4-{ 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperazine-1- carboxylic acid tert-butyl ester
244. 4- [5- [2- (1- (S) -phenylethylamino) pyriraidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
245. 4-{5-[2-(l-(S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl } -piperazine-1-carboxylic acid tert-butyl ester 246. 4-{4-(4-methoxyphenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}-piperazine-l- carboxylic acid tert-butyl ester
247. 5- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -2, 5-diazabicyclo [2.2.1] heptane-2- carboxylic acid tert-butyl ester
248. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl ester
249. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl ester
250. cyclopropyl- { 4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
251. cyclopropyl- {4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
252. cyclopropyl- {4- [4- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
253. { 4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } cyclopropylamine 254. cyclopropyl- {4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
255. cyclopropyl- { 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl} amine
256. cyclopropyl- { 4- [4- (4-Methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl} amine
257. cyclopentyl- { 4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl} amine
258. cyclopentyl- { 4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine 259. cyclopentyl- { 4- [4- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl} amine
260. { 4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } cyclopentylamine
261. cyclopentyl-{4-[4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 262. cyclopentyl- { 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl }amine
263. cyclopentyl- { 4- [4- (4-methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl } amine 264. cyclohexyl-{4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl }amine
265. cyclohexyl-{ 4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl }amine
266. cyclohexyl-{ 4- [4- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl }amine
267. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } cyclohexylamine
268. cyclohexyl-{4-[4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 269. cyclohexyl-{ 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl } amine
270. cyclohexyl-{ 4- [4- (4-methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl } amine
271. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2- yl }- (1- (S) -phenylethyl) amine
272. {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2■ yl}- (1- (S) -phenylethyl) amine
273. {4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2- yl } - (1- (S) -phenylethyl) amine 274. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } - ( 1- ( S) -phenylethyl) amine
275. (1- (S) -phenylethyl) -{4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
276. (1- (S) -phenylethyl) -{4- [4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
277. { 4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2- yl } - (1- (S) -phenylethyl) amine
278. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol 279. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
280. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
281. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
282. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
283. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
284. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
285. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol 286. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
287. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
288. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
289. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
290. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
291. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
292. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol 293. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
294. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
295. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
296. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
297. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol 298. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
299. 4-{4-(4-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) -pyrimidin-4-yl] thiazol-2-yl }-l- methylpiperidin-4-ol
300. 4-{ 4- (3-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }-l- methylpiperidin-4-ol
301. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
302. 4- {4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol 303. l-methyl-4-[5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
304. l-methyl-4-{5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol- 2-yl } -piperidin-4-ol
305. 4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
306. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- ( 4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
307. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester 308. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
309. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
310. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester
311. 4- [5- (2-cyclopropylarainopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
312. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- raethoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester 313. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
314. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester 315. 4- [5- (2-cyclopentylarainopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
316. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -A- hydroxypiperidine-1-carboxylic acid tert-butyl ester
317. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -A- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester 318. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
319. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -A- (4- methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
320. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
321. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -A- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
322. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -A- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester 323. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
324. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester
325. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
326. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
327. 4-{4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }-4- hydroxypiperidine-1-carboxylic acid tert-butyl ester 328. 4-{4-(3-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
329. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylaraino) pyrimidin-4-yl] thiazol-2-yl} -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
330. 4-{ 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl ] thiazol-2-yl} -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
331. 4-hydroxy-4- [5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester
332. 4-hydroxy-4-{5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol- 2-yl }piperidine-l-carboxylic acid tert-butyl ester
333. 4-hydroxy-4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid tert-butyl ester
334. cyclopropyl- { 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl]pyrimidin-2-yl} amine
335. cyclobutyl-{ 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl]pyrimidin-2-yl} amine
336. cycloheptyl-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine 337. cyclopropylmethyl-{4- [4- (4-fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl }amine
338. benzyl- { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl] pyrimidin-2-yl} amine
339. {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl }phenylamine
340. cyclopropyl- { 4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
341. cyclopropyl- { 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine 342. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl]pyrimidin-2-yl}cyclopropylamine
343. cyclopropyl-{4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyriraidin-2-yl} amine
344. cyclopropyl-{4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
345. cyclopropyl-{ 4- [4- (4-methoxyphenyl) -2-piperidin- 4-yl-thiazol-5-yl] pyrimidin-2-yl } amine
346. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine 347. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
348. cyclopentyl-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl} amine
349. cyclopentyl- { 4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
350. cyclopentyl- { 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
351. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopentylamine 352. cyclopentyl- { 4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
353. cyclopentyl- { 4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
354. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin- 4-yl-thiazol-5-yl] pyrimidin-2-yl } amine 355. cyclohexyl-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] -pyrimidin-2-yl } amine
356. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine 357. cyclohexyl-{ 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl} amine
358. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclohexylamine
359. cyclohexyl-{4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
360. cyclohexyl-{ 4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
361. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine 362. {4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine
363. { 4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl J-(I-(S) -phenylethyl) amine
364. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
365. (1- (S) -phenylethyl) -{4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
366. (1- (S) -phenylethyl) -{4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine 367. {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol- 5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
368. {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl]pyrimidin-2-yl}- (1- (R) -phenylethyl) amine
369. cyclopropyl- { 4- [4- (4-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
370. cyclopropyl- { 4- [4- (3-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
371. cyclopropyl- { 4- [4- (2-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine 372. {4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopropylamine
373. cyclopropyl- { 4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
374. cyclopropyl- {4- [2-piperazin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
375. cyclopropyl- { 4- [4- (4-methoxyphenyl) -2-piperazin- 1-yl-thiazol-5-yl] pyrimidin-2-yl} amine
376. cyclopentyl-{ 4- [4- (4-fluorophenyl) -2-piperazin-1- yl-thiazol-5-yl] pyrimidin-2-yl } amine 377. cyclopentyl-{ 4- [4- (3-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
378. cyclopentyl-{ 4- [4- (2-fluorophenyl) -2-piperazin-1- yl-thiazol-5-yl] pyrimidin-2-yl} amine
379. { 4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopentylamine 380. cyclopentyl-{4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
381. cyclopentyl-{ 4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 382. cyclopentyl-{ 4- [4- (4-methoxyphenyl) -2-piperazin- 1-yl-thiazol-5-yl] pyrimidin-2-yl} amine
383. cyclohexyl-{ 4- [4- (4-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
384. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
385. cyclohexyl-{ 4- [4- (2-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
386. { 4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclohexylamine 387. cyclohexyl-{ 4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
388. cyclohexyl-{4-[2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
389. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
390. {4- [4- (4-fluorophenyl) -2-piperazin-1-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
391. { 4- [4- (3-fluorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine 392. {4- [4- (2-fluorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
393. { 4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
394. (1- (S) -phenylethyl) - { 4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
395. (1- (S) -phenylethyl) -{4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
396. { 4- [4- (4-methoxyphenyl) -2-piperazin-l-yl-thiazol- 5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine 397. cyclopropyl-{4-[2-(2,5-diazabicyclo[2.2.1]hept-2- yl) -4- (4-fluorophenyl) thiazol-5-yl]pyrimidin-2-yl}amine
398. cyclopropyl- { 4- [4- (4-fluorophenyl) -2- (piperidin- 4-yloxy) thiazol-5-yl] pyrimidin-2-yl} amine
399. cyclopropyl- { 4- [4- (4-fluorophenyl) -2- (piperidin- 4-ylamino) thiazol-5-yl] pyrimidin-2-yl }amine
400. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
401. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol 402. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol
403. 4- [4- (3-chlorophenyl) -5- (2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
404. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol 405. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidin-4-ol
406. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol 407. 4- [5- (2-cyclopentylaminopyriraidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
408. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol
409. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol
410. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
411. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluororaethylphenyl) thiazol-2-yl] piperidin-4-ol 412. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- raethylphenyl) thiazol-2-yl] piperidin-4-ol
413. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol
414. 4- [5- (2-cyclohexylaminopyriraidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
415. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol
416. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol 417. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
418. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
419. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidin-4-ol
420. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol
421. 4-{ 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperidin-4-ol 422. 4-{4-(3-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidin-4-ol
423. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyriraidin-4-yl] thiazol-2-yl }piperidin-4-ol
424. 4-{ 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperidin-4-ol
425. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
426. 4-{ 5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl} -piperidin-4-ol 427. 4-{4-(4-methoxyphenyl) -5-[2- (l-(S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperidin-4-ol
428. 4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
429. cyclopropyl-{4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine 430. cyclopropyl-{4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
431. cyclopropyl-{4- [4- (2-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine 432. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopropylamine
433. cyclopropyl-{4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
434. cyclopropyl-{4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
435. cyclopropyl-{ 4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
436. 4- [4- (4-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine 437. cyclopentyl-{4-[4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine
438. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
439. cyclopentyl-{4- [4- (2-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
440. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
441. cyclopentyl-{ 4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine 442. cyclopentyl-{4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
443. cyclopentyl-{4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
444. cyclohexyl-{ 4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
445. cyclohexyl-{4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
446. cyclohexyl-{4-[4- (2-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine 447. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl }cyclohexylamine
448. cyclohexyl-{4-[2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}amine
449. cyclohexyl-{4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
450. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
451. {4- [4- (3-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine 452. {4- [4- (2-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
453. { 4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
454. {4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } - ( 1- (S) phenylethyl) amine
455. {4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) - phenylethyl) amine 456. { 4- [4- (4-methoxyphenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
457. cyclopropyl- { 4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
458. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
459. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
460. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopropylamine 461. cyclopropyl-{ 4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
462. cyclopropyl- { 4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
463. cyclopropyl- { 4- [4- (4-methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
464. cyclopentyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
465. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine 466. cyclopentyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyriraidin-2-yl } amine
467. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
468. cyclopentyl- { 4- [2- (4-methylpiperazin-1-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
469. cyclopentyl- {4- [2- (4-methylpiperazin-1-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
470. cyclopentyl- {4- [4- (4-methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine 471. cyclohexyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
472. cyclohexyl-{4-[4-(3-fluorophenyl) -2-(4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
473. cyclohexyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
474. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl }cyclohexylamine
475. cyclohexyl-{ 4- [2- (4-methylpiperazin-1-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine 476. cyclohexyl-{ 4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
477. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
478. {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine 479. {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
480. {4- [4-(2-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine 481. {4- [4- (3-chlorophenyl)-2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
482. {4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) - phenylethyl) amine 483. {4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) - phenylethyl) amine
484. { 4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine 485. cyclopropyl-{4- [2- (l-ethylpiperidin-4-yl) -4- (4- fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine
486. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1- isopropylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
487. l-{ 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-l-yl}ethanone
488. l-{ 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl]piperidin-l-yl}-2- dimethylaminoethanone
489. cyclopropyl- { 4- [5- (2-cycloproρylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl}methanone 490. {4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-1-yl }phenylmethanone
491. cyclopropyl- { 4- [2- (1-cyclopropylmethylpiperidin- 4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl } amine 492. cyclopropyl- {4- [2- [l-(2- dimethylaminoethyl) piperidin-4-yl] -4- (4- fluorophenyl) thiazol-5-yl] pyrimidin-2-yl } amine
493. N- {4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl}propionamide 494. 4- [4- (4-fluorophenyl) -5- (2- propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
495. 4- [5- (2-dipropionylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
496. 4- [5- [2- (cyclohexanecarbonylamino) pyrimidin-4- yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
497. 4- [5- [2- (biscyclohexanecarbonylamino) pyrimidin-4- yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
498. 4- [5- (2-benzoylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester 499. N-{4- [4- (4-fluorophenyl) -2- (4- methanesulfinylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide
500. N-{4- [4- (4-fluorophenyl) -2- (4- methanesulfonylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide
501. N- { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl] pyrimidin-2-yl}propionamide
502. N-{ 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl] pyrimidin-2-yl }benzamide
503. cyclohexanecarboxylic acid { 4- [4— ( 4- fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl] pyrimidin-2- yl} amide
504. N-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide
505. N-[4-(3-chlorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide
506. N- { 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -6, N- dimethylnicotinamide
Moreover, the present invention provides intermediate compounds expressed by Formula 2 below or pharmaceutically acceptable salts thereof: [Formula 2]
Figure imgf000066_0001
wherein Rl denotes a halogen atom, a haloalkyl of Ci-C4, an alkyl of Ci-C4 or alkoxy of Ci-C4; and Hal denotes F, Cl or I. Preferably, in Formula 2 above,
Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 or 4-OCH3; and Hal is Cl.
The substituted 1,3-thiazol derivatives expressed by Formula 1 above and the intermediate compounds expressed by Formula 2 above can be used in the form of pharmaceutically acceptable salts, i.e., metal salts, salts of organic bases, salts of inorganic acids, salts of organic acids, salts of basic or acidic amino acids, etc. Appropriate metal salts are exemplified by alkali metal salts such as sodium salt, potassium salt, etc.; alkaline-earth metal salts such as calcium salt, magnesium salt, barium salt, etc.; and aluminum salts. Suitable salts of organic bases are salts of trimethylamine, triethylamine, pyridine, picoline, 2,6- lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N- dibenzylethylenediamine, etc. Appropriate salts of inorganic acids are salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Appropriate salts of organic acids are salts of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Suitable salts of basic amino acids are salts of arginine, lysine, ornithine and the like. Appropriate salts of acidic amino acids are salts of aspartic acid, glutamic acid and the like. Especially desirable salts, if the compounds contain acidic functional groups therein, are inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline-earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.) and organic salts such as aluminum salt; and if the compounds have basic functional groups therein, such salts include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like) and salts of organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like) . Furthermore, the present invention provides a process for preparing substituted 1,3-thiazol derivatives of Formula 1 expressed by Schemes 1 to 6 below. The process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 1 below comprises the steps of:
(1) preparing a compound (IV) by treating a compound (II) with a base and reacting the base-treated compound with a compound (HI) ;
(2) preparing a compound (V) by halogenating the compound (IV) obtained in step (1);
(3) preparing a compound (VH) by reacting the compound (V) obtained in step (2) with a thioamide compound (VI); and
(4) preparing a substituted 1-3-thiazol compound ( I -a) by reacting the compound (VH) obtained in step (3) with an amine compound (VIII) .
[Scheme 1]
Figure imgf000069_0001
wherein Rl, R2 and R4 are the same as defined in Formula 1; Hal' denotes a halogen atom; and L denotes a leaving group.
Compounds II, IE, VI and Vl may be used as they are if available commercially or be prepared according to the well- known method as it is or the similar process thereto.
Compound IV is prepared by treating compound II with base and reacting with compound HI.
In compound II, Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine. The amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound II, preferably, about 1.0 to 1.2 mol.
The "base" to be applied hereto includes, for example, alkyllithium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -78 to 60°C, desirably, in the range from -78°C to the room temperature. Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Compound V is prepared by treating compound IV with halogen or metal halide. This reaction may be carried out under the presence of a base or a basic salt, if necessary.
In compound V, Hal or Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine. The amount of halogen or metal halide to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 2.0 mol.
The "halogen" includes bromine, chloride, iodine and the like. The "metal halide" includes copper halides such as copper ( II ) bromide, copper ( 13 ) chloride and the like.
The amount of base to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of compound IV, preferably, about 1.0 to 3.0 mol. The "base" includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc.; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc . It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example. Reaction temperature is generally about -20 to 150 °C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 5 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Compound VII is prepared by reacting compound V with thioamide compound VI. This reaction may be carried out under the presence of a base, if necessary.
In compound VE, Hal' denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
The amount of thioamide compound VI to be applied hereto is about 0.5 to 6.0 mol for 1.0 mol of compound V, preferably, about 0.8 to 3.0 mol. The amount of base to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound V, preferably, about 1.0 to 10.0 mol.
The "base" to be applied hereto includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, etc.; aromatic amines such as pyridine, lutidine, etc. ; and tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -5 to 200 °C, desirably, in the range from 5 to 150°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Compound I -a is prepared by reacting compound VI with amide compound Vi. This reaction may be carried out under the presence of a base, if necessary.
The amount of amide compound Vl to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
The amount of base to be applied hereto is about 0.8 to 30.0 mol for 1.0 mol of compound VH, preferably, about 1.0 to 10.0 mol.
The "base" includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -78 to 200°C, desirably, in the range from the room temperature to 170°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
In compound I -a, if R2 is
Figure imgf000075_0001
wherein X is CH, C-OH or N; and Y is N-CO-Ci-C4, compound I -a is deprotected using acid or base. The amount of acid or base to be applied hereto is about 0.1 to 50.0 mol for 1.0 mol of compound I -a, preferably, about 1.0 to 20.0 mol.
The "acid" to be applied hereto includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; Lewis acids such as boron trichloride, boron tribromide, trimethylsilyl halide, etc.; use of thiol or sulfide with Lewis acids; and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid, etc.
The "base" to be applied hereto includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc.; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, alcohol, ether, aromatic hydrocarbon, halogenated hydrocarbon, aliphatic hydrocarbon, sulfoxide or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about 0 to 200 °C, desirably, in the range from 20 to 120°C. Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours. The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Moreover, the deprotected compound of compound I -a can be methylated. This reaction may be carried out under the presence of a base, if necessary.
The amount of methylation agent to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 5.0 mol. The "methylation agent" includes, for example, methyl halide, dimethylsulfate, reductive amination using formamide, etc.
The amount of base to be applied hereto is about 1.0 to 5.0 mol for 1.0 mol of the corresponding deprotected compound of compound I -a, preferably, about 1.0 to 2.0 mol. The "base" includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc.; basic salts such as sodium carbonate, potassium carbonate, etc. ; metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; and organic salts such as triethylamine, imidazole, formamidine, etc.
The methylated compound of compound I -a is prepared by reacting the deprotected compound of compound I -a with formaldehyde using a reducing agent under the presence of an alcohol solvent via the reductive amination.
The amount of formaldehyde to be applied hereto is about 1.0 to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol. As the reducing agent, sodiumborohydride NaBH4, sodiumcyanoborohydride NaBH3CN or sodiumtriacetoxyborohydride NaB(OAc)3H is used. The amount of the reducing agent to be applied hereto is about 1.0 mol to 10.0 mol for 1.0 mol of the deprotected compound of compound I -a, preferably, about 1.0 to 3.0 mol.
Even though there are no special limitations to the solvent, alcohol, ether, aromatic hydrocarbon, halogenated hydrocarbon, aliphatic hydrocarbon, sulfoxide or a mixture of more than two of them may be used, for example. Reaction temperature is about -20 to 100°C, desirably, in the range of 0°C to the room temperature. Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
The process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 2 below comprises the steps of:
(1) treating a compound (X), obtained by protecting an amine group of a compound (IX) , with base and then reacting the compound (X) with a compound (HI) to prepare a compound (XI);
(2) preparing a compound (XII) by halogenating the compound (XI) obtained in step (1) ; (3) preparing a compound (XIII) by reacting the compound (XII) obtained in step (2) with a thioamide compound (VI) ; and
(4) preparing a substituted 1-3-thiazol compound ( I -b) by deprotecting the compound (XIII) obtained in step (3) and reacting the deprotected compound of compound (XIII) with acylation agent (XV).
[Scheme 2]
Figure imgf000080_0001
wherein Rl, R2 and R5 are the same as defined in Formula 1; Hal denotes a halogen atom; and L denotes a leaving group.
Compound X is prepared from compound IX via the process described in the references (Synthesis, 877-882, 1996, or Journal of Organic Chemistry, 61: 4810-4811, 1996) .
Compound X I is prepared by reacting compound X with compound IE in the same manner as step (1) of Scheme 1 above,
The amount of base to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound X, preferably, about 2.0 to 2.5 mol. Compound X II is prepared by halogenating compound X I obtained in the above step in the same manner as step (2) of Scheme 1 above . In compound X II , Hal denotes a halogen atom such as chlorine, bromine and iodine.
Compound XIH is prepared by reacting compound XII obtained in the above step with thioamide compound VI in the same manner as step (3) of Scheme 1.
Thioamide compound VI may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto.
Compound XIV is prepared by deprotecting compound XlH using acid or base.
Compound I -b is prepared by reacting compound XIV with acylation agent XV under the presence of a base.
The amount of acylation agent XV to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of compound XIV, preferably, about 1.0 to 3.0 mol.
The amount of base to be applied hereto is about 0.1 to 3.0 mol for 1.0 mol of compound XIV, preferably, about 0.3 to 1.2 mol.
The "base" includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- dimethylaminopyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -78 to 100°C, desirably, in the range from -78 to 70°C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 20 hours. The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
The process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 3 below comprises the steps of: (1) treating a compound (XVI) with a base and reacting the base-treated compound with a compound (HI) to prepare a compound ( XVH) ;
(2) preparing a compound (XVI) by halogenating the compound (XVI) obtained in step (1) ; (3) preparing a compound (XK) by reacting the compound (XVIII) obtained in step (2) with a thioamide compound (VI) ;
(4) preparing a compound (XX) by treating the compound (XIX) obtained in step (3) with an organic peroxy acid; and
(5) preparing a substituted 1-3-thiazol compound ( I -c) by reacting the compound (XX) obtained in step (4) with an amine compound (Vl) .
[Scheme 3]
Figure imgf000084_0001
wherein Rl, R2 and R4 are the same as defined in Formula 1; Hal denotes a halogen atom; and L denotes a leaving group.
Compound XVI may be prepared via the process described in the references such as Bioorganic & Medicinal Chemistry Letters, 13 (3) : 347-350, 2003; Organic Letters, 4(6): 979-981, 2002; or Zhurnal Organicheskoi Khimii, 12 (10) : 2063-6, 1976.
Compound XVH is prepared by reacting compound XVI with compound IH in the same manner as step (1) of Scheme 1 above. Compound XVl may be prepared by halogenating compound XVK obtained in the above step in the same manner as step (2) of Scheme 1 above.
Especially, if treating compound XVE with (a) LDA or CF3SO2Cl; or (b) TBAB, TMSCI or DMSO, to prepare a monochloride compound ( XVI) , it is possible to obtain a targeted monochloride compound (XVl) in high yield (more than 80%), expressed by Scheme 3a below:
[Scheme 3a]
Figure imgf000085_0001
wherein Rl is the same as defined in Formula 2; R2 is the same as defined in Formula 1; and Hal denotes Cl.
The base to be used in the chlorination of above (a) includes, besides LDA, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium bis (triraethylsilyl) amide and the like.
Moreover, as a chlorination reagent, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4- (trifluoromethyl) benzenesulfonyl chloride, sulfuryl chloride, etc. may be used, besides trifluoromethanesulfonyl .
The amount of chlorination agent to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XVII, preferably, about 1.0 to 2.0 mol.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -78 to 150 °C, desirably, in the range from -78°C to the room temperature. Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
In the chlorination of above (b) , the amount of TBAB applied thereto is about 0.01 to 5.0 mol for 1.0 raol of compound XVE, preferably, about 0.05 to 0.5 raol.
The amount of TMSCI to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVI, preferably, about 1.0 to 5.0 mol .
The amount of DMSO to be used is about 0.1 to 8.0 mol for 1.0 mol of compound XVH, preferably, about 1.0 to 5.0 mol .
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 150 °C, desirably, in the range from 0 to 50 °C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours. The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc. Compound XIX is prepared by reacting compound XVI obtained in the above step with thioamide compound VI in the same manner as step (3) of Scheme 1. According to International Publication No.
WO/2001/030778, there has been disclosed that compound XIX is prepared in the yield of 24% by reacting compound XVl, of which Rl is 4-F and Hal is bromine, with thioamide compound VI, of which R2 is N-ethoxycarbonyl-piperydin-4-yl . However, as a result that the inventors of the present invention have carried out the reaction under the same conditions as disclosed in the above patent, the yield of compound XIX is very low as about 7%.
On the other hand, the inventors of the present invention have prepared compound XIX by reacting compound XM, of which Rl is 4-F and Hal is Cl, with thioamide compound VI, in accordance with Scheme 3a, in very high yield of 60 to 70%.
Compound X X is prepared by treating compound XIX with organic peroxy acid.
The amount of organic peroxy acid to be applied hereto is about 0.8 to 10.0 mol for 1.0 mol of compound XIX, preferably, about 1.0 to 3.0 mol. The "organic peroxy acid" includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example. Reaction temperature is generally about -20 to 130 °C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
Alternatively, compound X X is prepared by treating compound XlX with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
The amount of hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of .compound
XIX, preferably, about 1.0 to 3.0 mol. The "alkyl hydroperoxide" includes, for example, tert- butyl hydroperoxide, cumene hydroperoxide, etc.
The amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XK, preferably, about 0.8 to 5.0 mol. The "base" includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
The "acid" includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc.; and organic acids such as formic acid, acetic acid, etc.
The "metal oxide" includes, for example, vanadium oxide (V2O5) , osmium tetroxide (OSO4) , tungsten oxide (WO3) , selenium dioxide (SeO2), chrome oxide (CrO3), etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 130 °C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Compound I -c is prepared by reacting compound X X obtained in the above step with an amine compound (Vl) in the same manner as step (4) of Scheme 1. In compound I -c, if R2 is
Figure imgf000091_0001
wherein X is CH, C-OH or N; and Y is N-CO-Ci~C4, compound I -c is deprotected using acid or base in the same manner as the deprotection of Scheme 1.
Moreover, the deprotected compound of compound I -c can be methylated in the same manner as the methylation of Scheme 1.
The process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 4 below comprises the steps of: (1) preparing a compound (XXII) by reacting a compound ( XVHI) with a thiourea compound (XXI);
(2) preparing a compound (X XIH) by halogenating the compound (XXII) obtained in step (1) ;
(3) preparing a compound (XXV) by reacting the compound (XXIII) obtained in step (2) with a compound (XXIV);
(4) preparing a compound (XXVI) by treating the compound (XXV) obtained in step (3) with an organic peroxy acid; and
(5) preparing a substituted 1-3-thiazol compound
(X XVE) by reacting the compound (XXVI) obtained in step (4) with an amine compound (VI) .
Meanwhile, it is possible to protect nitrogen prior to the oxidation of the compound (XXV) in step (4).
[Scheme 4]
Figure imgf000093_0001
wherein Rl, R4 and Y are the same as defined in Formula 1; Hal denotes a halogen atom; and PG is a protective group. Compound X X II may be prepared in the same manner of step (3) of Scheme 3.
Compound XXHI is prepared by halogenating compound X X π with tert-butyl nitrite and metal halide (Sandmeyer reaction) . The halogenation reaction may be a general one.
In compound XXHI, Hal denotes a halogen atom such as fluorine, chlorine, bromine and iodine.
The amount of tert-butyl nitrite to be applied hereto is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
The amount of metal halide to be used is about 1.0 to 8.0 mol for 1.0 mol of compound XXII, preferably, about 1.0 to 2.0 mol.
The "metal halide" includes copper halides such as copper ( II ) bromide, copper ( II ) chloride and the like.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, ether, ester, aromatic hydrocarbon, aliphatic hydrocarbon, amide, halogenated hydrocarbon, nitrile, sulfoxide, organic acid, aromatic amine or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 150°C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Compound XXV is prepared by reacting compound XXIH with compound XXIV. This reaction may be carried out under the presence of a base, if necessary.
Compound XXIV may be used as it is if available commercially or be prepared according to the well-known method as it is or the similar process thereto. The amount of compound XXIV to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXHI, preferably, about 1.0 to 10.0 mol.
The amount of base to be used is about 0.8 to 30.0 mol for 1.0 mol of compound XXIII, preferably, about 1.0 to 10.0 mol.
The "base" includes, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N, N-dimethylaniline, N- methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydrides such as sodium hydride, potassium hydride, etc.; metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, etc.; and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example . Reaction temperature is generally about -78 to 200 °C, desirably, in the range from the room temperature to 170 "C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc. In compound XXV, if Y is CH2 or CHCH3, compounds XXVI and XXVE may be prepared according to steps (4) and (5) of Scheme 3, respectively.
In compound XXV, if Y is NH, compound X XVI may be prepared by protecting NH of compound XXV, and compounds X X IX and XXX may be prepared according to steps (4) and (5) of Scheme 3, respectively.
In compound XXX, the protective group (PG) is deprotected in the same manner as the deprotection of Scheme 1.
Moreover, the deprotected compound may be methylated in the same manner as the methylation of Scheme 1.
The process for preparing a substituted 1,3-thiazol derivative expressed by Scheme 5 below comprises the steps of:
(1) preparing a compound (XXXII) by reacting a compound (XVIII) with a thioformamide compound (XXXI); (2) preparing a compound (XXXIII) by treating the compound (XXXII) obtained in step (1) with an organic peroxy acid;
(3) preparing a compound (XXXlV) by reacting the compound (X X XIH) obtained in step (2) with an amine compound (M) ; (4) preparing a compound (XXXVI) by treating the compound (XXXIV) obtained in step (3) with a base and reacting the base-treated compound with a compound (XXXV); and
(5) preparing a substituted 1-3-thiazol compound (XXXVE) by deprotecting the compound (XXXVI) obtained in step (4) .
[Scheme 5]
Figure imgf000098_0001
wherein Rl, R4 and Y are the same as defined in Formula 1; and Hal denotes a halogen atom.
Compounds XXXII, XXXHI and XXXIV may be prepared according to steps (3), (4) and (5) of Scheme 3, respectively.
Compound XXXVI is prepared by treating compound XXXIV with a base and reacting the base-treated compound with compound XXXV, if Y is an alkyl of N-C1--C4 in compound XXXV.
If Y is N-CO2t-Bu in compound XXXV, compound X X XVII is prepared by deprotecting compound X X XVI, obtained in step (4) above, in the same manner as the deprotection of Scheme 1. The amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXIV, preferably, about 1.0 to 1.2 mol.
The "base" includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -78 to 60°C, desirably, in the range from -78 °C to the room temperature. Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 3 hours.
Alternatively, other process for preparing the compound (XIX) of Scheme 3 is expressed by Scheme 6 below and comprises the steps of:
(1) preparing a compound (X X XK) by halogenating a compound ( X X XVl) ;
(2) preparing a compound (XXXX) by reacting the compound (XXXlX) obtained in step (1) with a thioamide compound (VI) ; and
(3) treating the compound (XXXX) obtained in step (2) with base, ZnCl2 and reacting the base-treated compound with Pd (PPh3) 4 and a compound (XXXXI).
A basic framework of Formula 1 may be prepared via Negishi type coupling reaction.
[Scheme 6]
Figure imgf000101_0001
wherein Rl and R2 are the same as defined in Formula 1; and Hal and Hal' denote a halogen atom.
Compound XXXX may be prepared according to steps {2] and (3) of Scheme 3.
Compound XXXXI may be prepared via the process described in the reference (Tetrahedron, 45(3): 993, 1989).
Compound XIX is prepared treating compound XXXX with base, ZnCl2, and reacting the base-treated compound with Pd (PPh3) 4 and compound XXXXI.
The amount of base to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
The amount of ZnCl2 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol .
The amount of Pd(PPh3) 4 to be used is about 0.8 to 5.0 mol for 1.0 mol of compound XXXX, preferably, about 1.0 to 1.5 mol. The "base" includes, for example, alkyllitium such as n-butyllitium and the like, metal amides such as sodium amide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide and the like.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example . Reaction temperature is generally about -78 to 200 °C, desirably, in the range from -78 to 100°C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 0.5 to 12 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc. Thioamide compound VI is prepared according to Scheme 7 below.
[Scheme 7]
R2CN (XXXKlI)
Figure imgf000103_0001
R2CSNH, (Vl)
Figure imgf000103_0002
R2CONH,(XXXXIIS) Lawesson regent
wherein R2 is the same as defined in Formula 1.
Thioamide compound VI may be prepared by treating compound XXXXII with hydrogen sulfide.
The amount of hydrogen sulfide to be applied hereto is about 1.0 to 30.0 mol for 1.0 mol of compound XXXXII.
The amount of base to be used is about 1.0 to 30.0 mol for 1.0 mol of compound X X X X II , preferably, about 1.0 to 10.0 mol.
The "base" includes, for example, aromatic amines such as pyridine, lutidine, etc.; tertiary amines such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N- dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N- methylmorpholine, etc.; and ammonia. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, aromatic amine or a mixture of more than two of them may be used, for example.
This reaction is carried out under atmospheric pressure or pressurized condition. Reaction temperature is generally about -20 to 80°C, desirably, in the range from - 10 to 30°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 30 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Alternatively, compound VI may be prepared by treating compound X X X X II with diethyl dithiophosphate under the presence of an acid.
The amount of diethyl dithiophosphate to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXII, preferably, about 1.0 to 3.0 mol. The amount of acid to be used is about 1.0 to 30.0 mol for 1 . 0 mol of compound X X X X II , preferably, about 1 . 0 to
8 . 0 mol .
The "acid" includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, alcohol, ester or a mixture of more than two of them may be used, for example. Reaction temperature is generally about -20 to 100 °C, desirably, in the range from 0 to 50°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 24 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc. Furthermore, compound VI may be prepared by treating compound XXXXIII with phosphorus pentasulfide or Lawesson' s reagent under the presence of a base.
The amount of phosphorus pentasulfide or Lawesson' s reagent to be used is about 1.0 to 10.0 mol for 1.0 mol of compound XXXXIII, preferably, about 0.5 to 3.0 mol.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture of more than two of them may be used, for example.
Reaction time is generally about 10 minutes to 50 hours, desirably, about 0.5 to 12 hours. Reaction temperature is generally about 0 to 150 °C, desirably, in the range from the room temperature to 120°C.
The product (VI) may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
In addition, if compound I (including compounds I -a, I -b and I -c) is an acylamino compound, compound I is prepared by applying the corresponding amine compound directly to the well-known acylation reaction.
For example, the compound, in which R2 is an acylamino having any substitution groups in compounds I , is prepared by reacting the corresponding 2-thiazolamine compound with an acylation agent under the presence of any bases or acids.
The amount of acylation agent to be used is about 1.0 to 5.0 rtiol for 1.0 mol of the corresponding 2-thiazolamine, preferably, about 1.0 to 2.0 mol. The "acylation agent" includes, for example, carboxylic acid corresponding to the target acyl group or its reactive derivative (e.g., acid halide, acid anhydride, ester, etc. ) .
The amount of base or acid to be applied hereto is about 0.8 to 5.0 mol for 1.0 mol of the corresponding 2- thiazolamine, preferably, about 1.0 to 2.0 mol.
The "base" includes, for example, triethylamine, pyridine, 4-dimethylaminopyridine, etc.
The "acid" includes, for example, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, ether, amide, nitrile, sulfoxide, aromatic amine or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 150°C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 24 hours, desirably, about 10 minutes to 5 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
Moreover, if compound I (including compounds I -a, I - b and I -c) is a sulfonyl or sulfinyl compound, compound I is prepared by applying the corresponding sulfide compound directly to the well-known oxidation reaction.
For example, the compound, in which R2 is a methanesulfonylphenyl or methanesulfinylphenyl having any substitution groups in compounds I , is prepared by treating the corresponding 2-methylsulfanyl thiazol compound with an organic peroxy acid.
The amount of organic peroxy acid to be used is about 0.8 to 10.0 mol for 1.0 mol of the corresponding 2- methylsulfanyl thiazol compound, preferably, about 1.0 to 3.0 mol .
The "organic peroxy acid" includes, for example, peracetic acid, trifluoroperacetic acid, m-chloroperbenzoic acid, etc. It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 130 "C, desirably, in the range from 0 to 100 °C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
Alternatively, compound I is prepared by treating 2- methylsulfanyl thiazol compound with hydrogen peroxide or alkyl hydroperoxide under the presence of base, acid or metal oxide.
The amount hydrogen peroxide or alkyl hydroperoxide to be used is about 0.8 to 10.0 mol for 1.0 mol of the 2- methylsulfanyl thiazol compound, preferably, 1.0 to 3.0 mol.
The "alkyl hydroperoxide" includes, for example, The "alkyl hydroperoxide" includes, for example, tert-butyl hydroperoxide, cumene hydroperoxide, etc.
The amount of base, acid or metal oxide to be used is about 0.1 mol to 30.0 mol for 1.0 mol of compound XIX, preferably, about 0.8 to 5.0 mol. The "base" includes, for example, metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; and basic salts such as sodium carbonate, potassium carbonate, sodium acetate, etc.
The "acid" includes, for example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, etc.; Lewis acids such as boron trifluoride, aluminum chloride, titan tetrachloride, etc. ; and organic acids such as formic acid, acetic acid, etc.
The "metal oxide" includes, for example, vanadium oxide (V2O5) , osmium tetroxide (OSO4) , tungsten oxide (WO3) , selenium dioxide (SeO2) , chrome oxide (CrO3) , etc.
It is desired that this reaction be performed without solvent, or under the presence of an inert solvent. During the reaction, even though there are no special limitations to the solvent, halogenated hydrocarbon, aliphatic hydrocarbon, aromatic hydrocarbon, organic acid, ether, amide, sulfoxide, alcohol, nitrile, ketone or a mixture of more than two of them may be used, for example.
Reaction temperature is generally about -20 to 130 °C, desirably, in the range from 0 to 100°C. Reaction time is generally about 5 minutes to 72 hours, desirably, about 0.5 to 12 hours.
The product may be used as a reactant solution itself or used in the next reaction as an auxiliary product; however, the product can be isolated from the resulting mixture according to an ordinary method and be purified readily by means of separation such as recrystallization, distillation, chromatography, etc.
In the respective reactions, if the starting material has amino, carboxy or hydroxy as substitution group, it is possible to introduce the protective group commonly used in peptide chemistry, etc. into such groups and to prepare a target compound by removing the protective group used, if necessary.
The protective group for amino to be used includes, for example, formyl or Ci~C6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.) phenylcarbonyl, Ci-Cδ alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C7~Cio aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), trityl, phthaloyl, etc., which may have a substitution group, respectively. Such substitution group includes, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3.
The protective group for carboxy to be used includes, for example, Ci-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc., which may have a substitution group, respectively. Such substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl, etc.), nitro, Ci-C6 alkyl (e.g., methyl, ethyl, propyl, tert-butyl, etc.), C6-CiO aryl (e.g., phenyl, naphthyl, etc.) and the like, and the number of the substitution groups is 1 to 3.
The protective group for hydroxy to be used may include, for example, Ci-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C7-Cn aralkyl (e.g., benzyl, etc.), formyl, Ci-C6 alkyl-carbonyl (e.g., acetyl, propionyl, etc.), phenyloxycarbonyl, C7-Cn aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, silyl, etc., which may have a substitution group, respectively. Such substitution group may include, for example, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), Ci-C6 alkyl (e.g., methyl, ethyl, tert-butyl, etc.), C7-Cn aralkyl (e.g., benzyl, etc.), C6-CiO aryl (e.g., phenyl, naphthyl, etc.), nitro, etc., and the number of the substitution groups is 1 to 3. In addition, the protective groups may be removed according to the well-known method as it is or the similar process thereto, for example, the methods of treating or reducing with acid, base, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc., may be used.
In any case, compound I may be synthesized by carrying out the well-known deprotection, acylation, alkylation, hydrogenation, oxidation, reduction, carbon chain extension and substitution group exchange reactions solely or in association with at least two of them. As these reactions, those disclosed in the reference (Shinjikkenkagakukoza 14, Vo. 15, 1997, Maruzen Press) are used.
If a target product is prepared in the form of glass via the above reactions, the product can be converted into salts according to an ordinary method, whereas, if a target product is prepared as a salt, it can be converted into the form of glass or other salts according to an ordinary method. Compound ( I ) prepared like that may be isolated and purified readily from the resulting solution via the well- known methods such as concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.
If compound I exists with configurational isomers, diastereoisomers, conformers, etc., each can be isolated selectively by means of the isolation and purification.
Moreover, if compound I is in the form of racemates thereof, they can be resolved into S- or R- enantiomers via any optical resolutions.
If compound I exists with stereoisomers, two isomers themselves and a mixture of the respective isomers come within the category of the present invention.
Furthermore, compound I may be hydrated or dehydrated.
Compound I may be labeled with isotopes (e.g., 3H, 14C, 35S, etc.) .
Prodrug of compound I is referred to such compounds that are converted into compound I by enzymes, gastric acids, etc. under physiological conditions, that is, the prodrug includes compounds converted into compound I via enzymatic oxidation, reduction, hydrolysis, etc. and compounds converted into compound I via hydrolysis by gastric acids, etc. The prodrug of compound I includes: compounds that the amino group of compound I is changed into acyl, alkyl, or phosphoryl group (e.g., compounds that the amino group of compound I is changed into eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-l, 3-dioxolen-4- yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl or tert-butyl group) ; compounds that the hydroxy group of compound I is changed into acyl, alkyl, phosphoryl or boryl group (e.g., compounds that the hydroxy group of compound I is changed into acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl group) ; compounds that the carboxyl group of compound I is changed into ester or amide group (e.g., compounds that the carboxyl group of compound I is changed into ethylester, phenylester, carboxymethylester, dimethylaminomethylester, pivaloyloxymethylester, ethoxycarbonyloxyethylester, phthalidylester, (5-methyl-2-oxo-l, 3-dioxol-4-yl)methylester, cyclohexyloxycarbonylethylester or methylamide group) and the like. Such compounds may be prepared from compound I according to the well-known method as it is.
Alternatively, the prodrugs of compound I may be the compounds that are converted into compound I under the physiological conditions disclosed in the reference (Iyakuhin no kaihatsu, Hirokawashoten, pressed in 1990, Vol. 7, Melecular Design: 163-198) . Moreover, the present invention provides a pharmaceutical composition comprising substituted 1,3- thiazol derivatives or pharmaceutically acceptable salts for preventing and treating TNF-α related diseases.
The compound of the present invention shows a very low toxicity in a concentration of 3 μM, whereas, shows a noticeable toxicity in a concentration of 10 μM for the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, and exhibits little toxicity for the murine macrophage-derived cell line, RAW264.7.
Moreover, the compound of the present invention strongly inhibits the production of TNF-α by the human macrophage-derived cancer cell line, THP-I cell, the murine macrophage-derived cancer cell line, RAW264.7, the murine marrow cell-derived macrophage and macrophages in vivo.
Furthermore, the compound of the present invention inhibits the inflammatory reactions in vivo.
Accordingly, the compound of the present invention having excellent TNF-α inhibitory activity and inflammation inhibitory activity can be effectively used as a safe drug based on such activities.
For example, the pharmaceutical composition comprising compound I of the present invention can be applied to mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as an agent for the prevention or treatment of a variety of TNF-α related diseases such as arthritides (e.g., rheumatic arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, synovitis, etc.), toxemias (e.g., sepsis, septic shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome, etc.), inflammatory intestinal diseases (e.g., Crohn's disease, ulcerative colonitis, etc.), inflammatory pulmonary diseases (e.g., chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis, etc.), cachexias (e.g., cachexia due to infection, cancer cachexia, cachexia due to acquired immune deficiency syndrome (AIDS), etc.), cancers (e.g., hematologic malignancy, breast cancer, lung cancer, renal cancer, gastric cancer, hepatoma, etc.), multiple myeloma, cardiovascular diseases (e.g., arteriosclerosis, hyperlipidemia, hypertension, etc.), coronary heart diseases (e.g., angina pectoris, myocardial infarction, etc.), chronic obstructive pulmonary diseases (adult respiratory distress syndrome (ARDS) ) , Creutzfeldt-Jakob disease, viral infections (e.g., cytomegalovirus (CMV), influenza virus, herpes virus, etc.), autoimmune diseases (e.g., Behcet's disease, systemic lupus erythematosus (SLE) , rheumatic arthritis, etc.)/ atopic dermatitis, psoriasis, paralysis, dementia, cerebral paralysis, AIDS encephalopathy, meningitis, congestive heart failure (CHF) , hepatitis, dialysis hypotension, disseminated intravascular coagulation (DIC), etc.
The composition comprising compound I of the present invention having a low toxicity can be administrated as it is, or by mixing compound I with pharmaceutically acceptable carriers according to the well-known methods generally used in preparing pharmaceutical formulations, safely by oral and parenteral (e.g., local, rectal or intravenous, etc.) administrations. For example, such pharmaceutical formulations include tablets (e.g., sugar coating tablet, film coating tablet, etc.), powders, granules, capsules (including soft capsules) , solutions, injections, suppositories, sustained-release forms, etc. The content of compound I in accordance with the present invention may be within 0.01 to 100 weight% based on the total weight of the preparation.
The pharmaceutically acceptable carrier that may be used in preparing the formulations in accordance with the present invention includes various organics or carrier-free as pharmaceutical materials, for example, excipients, lubricants, bonding agents and disintergrants in solid preparations, and solvents, solubilizers, suspending agents, isotonic agents, buffering agents and soothing agents in liquid preparations. Moreover, optimum quantity of additives such as general preservatives, oxidation inhibitors, colorants, sweeteners, absorbents, humectants, etc., may be appropriately used, if necessary.
The excipient includes, for example, lactose, sucrose,
D-mannitol, starch, corn starch, crystalline cellulose, rigid silica, etc. The lubricant includes, for example, magnesium stearate, calcium stearate, talc, colloidal silica, etc.
The bonding agent includes, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, gelatin, methyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc. The solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame seed oil, corn oil, olive oil, etc. The solubilizer includes, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.
The suspending agent includes surfactants, such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, etc., and hydrophilic polymers, such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, etc.
The isotonic agent includes, for example, glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol, etc.
The buffering agent includes buffer solutions such as phosphate, acetate, carbonate, citrate, etc.
The soothing agent includes, for example, benzyl alcohol, etc.
The preservative includes, for example, p- hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc.
The oxidation inhibitor includes, for example, sulfate, ascorbic acid, α-tocopherol, etc.
[Mode for Invention] Hereinafter, the present invention will now be described more fully with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
In the following Preparation Examples and Examples, "room temperature" indicates the temperatures generally in the range from 10°C to 35°C; "%" denotes the percentage by weight, unless otherwise indicated; and "yield" represents mol/mol% .
Abbreviations used elsewhere indicate the following meanings : s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, ddd: double double doublet, dt : double triplet, br: broad,
J: coupling constant, Hz: Hertz,
CDC13: deuterated chloroform,
DMSO-d6: deuterated dimethylsulfoxide,
1H-NMR: proton nuclear magnetic resonance,
Me: methyl, Et: ethyl, and t-Bu: t-butyl.
Preparation Example 1: N-ethoxycarbonylpiperidine-4- thioamide
Figure imgf000122_0001
A solution of N-ethoxycarbonylpiperidine-4- carboxyamide (12.5 g, 62.5 mmol) in toluene (600 itiL) was admixed with Lawesson's reagent (12.6 g, 31.2 ramol) and then the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel column chromatography (acetone: cyclohexane = 1:4) to give the title compound (12.1 g, 55.9 mmol, yield 89%)
1H-NMR (CDCl3) δ: 1.27 (t, 3H), 1.72-1.83 (dq, 2H), 1.93 (d, 2H), 2.68-2.88 (m, 3H), 4.14 (q, 2H), 4.28 (br s, 2H), 6.97 (br s, IH), 7.56 (br s, IH)
Preparation Example 2 : N-tert- butoxycarbonylpiperidine-4-thioamide
Figure imgf000122_0002
In the same process as Preparation Example 1, the title compound was synthesized using N-tert- butoxycarbonylpiperidine-4-carboxyamide instead of N- ethoxycarbonylpiperidine-4-carboxyamide.
1H-NMR (CDCl3) δ: 1.47 (s, 9H), 1.66-1.80 (m, 2H), 1.91 (br d, 2H), 2.66-2.80 (m, 3H), 4.23 (br d, 2H), 6.98 (br s, IH) , 7.55 (br s, IH)
Preparation Example 3: 4- (methylthio) thiobenzamide
Figure imgf000123_0001
4- (Methylthio) benzonitrile (12 g, 80.0 mmol) was dissolved in 4N hydrogen chloride in ethyl acetate (130 mL) , O,O-diethyl dithiophosphate (18.2 g, 88.0 mmol) was added, and the mixture was stirred at room temperature for 22 hours, Water (100 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The precipitated materials were filtered off and the filtrate was washed with saturated sodium chloride, dried, and concentrated. The residue was recrystallized from ethyl acetate to give the title compound (10 g, 54.5 mmol, yield 68%).
IH-NMR (DMSO-d3) δ: 2.43 (s, 3H), 7.13 (s, 2H), 7.81 (m, 2H) , 8.32 (br s, 2H)
Preparation Example 4 : thiopropioamide
Figure imgf000123_0002
In the same process as Preparation Example 3, the title compound was synthesized using propionitrile instead of 4- (methylthio) benzonitrile, the title compound was synthesized. 1H-NMR (CDCl3) δ: 1.31 (t, 3H), 2.70 (q, 2H), 7.00 (br s, IH) , 7.85 (br s, IH)
Preparation Example 5: 4-iodo-2-methylthiopyrimidine
Figure imgf000124_0001
4-Chloro-2-methylthiopyrimidine (9 g, 56.0 mmol) was added to 47% HI (55 mL) solution and the mixture was stirred at room temperature for 48 hours. The precipitated solids were filtered, dissolved in water (100 mL) and added 20% NaOH to adjust pH 8. The mixture was extracted with chloroform and the extract was washed with water and dried over MgSO4 and, subsequently, the solvent was evaporated. The residue was recrystallized from petroleum ether to give the title compound (9.5 g, 36.7 mmol, yield 67%).
1H-NMR (CDCl3) δ: 2.54 (s, 3H), 7.41 (d, IH), 8.01 (d, IH)
Preparation Example 6: 1- (3-chlorophenyl) -2- (2-fluoro- 4-pyridyl) ethanone
Figure imgf000125_0001
A solution of 2-fluoro-4-methylpyridine (3.O g, 27.0 itimol) in anhydrous tetrahydrofurane (14 itiL) was cooled to - 78 °C and a 1.8M lithium diisopropylamide-hexane solution (17 mL, 34 mmol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min, then, a solution of 3-chloro-N-methoxy-N- methylbenzylamide (5.4 g, 27.3 mmol) in anhydrous tetrahydrofurane (3 mL) was added dropwise. After completion of dropwise addition, the temperature was raised to room temperature, water (50 m£) was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from tert-butyl methyl ketone/hexane to give the title compound (5.2 g, 20.8 mmol, yield 77%) .
1H-NMR (CDCl3) δ: 4.32 (s, 2H), 6.86 (s, IH), 7.09 (d, IH), 7.47 (t, IH), 7.60 (m, IH), 7.88 (m, IH), 7.98 (t, IH), 8.21 (d, IH) Preparation Example 7: 1- (4-fluorophenyl) -2- (2-fluoro-
4-pyridyl) ethanone
Figure imgf000126_0001
In the same process as Preparation Example 6, the title compound was synthesized using 4-fluoro-N-methoxy-N- methylbenzylamide instead of 3-chloro-N-methoxy-N- methylbenzylamide .
1H-NMR (CDCl3) δ: 4.33 (s, 2H), 6.87 (s, IH), 7.10 (d, IH), 7.19 (t, 3H), 8.04 (m, IH), 8.20 (d, IH)
Preparation Example 8: 2- (2-tert-butoxycarbonylamino-
4-pyridyl) -1- (4-fluoro phenyl) ethanone
Figure imgf000126_0002
A solution of 2-tert-butoxycarbonylamino-4- methylpyridine (1.0 g, 4.8 mmol) in anhydrous tetrahydrofurane (15 mL) was cooled to -78 °C and a 1.6M n- butyllithium-hexane solution (7.1 mL, 11.3 mmol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min at 0°C, then, the mixture was cooled to -78 °C . Subsequently, a solution of 4-fluoro-N-methoxy-N-methylbenzylamide (1.2 g, 6.4 mmol) in anhydrous tetrahydrofurane (3 πiL) was added thereto dropwise. After completion of dropwise addition, the mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from ethyl acetate/hexane to give the title compound (1.1 g, 3.3 mmol, yield 70%).
1H-NMR (CDCl3) δ: 1.54 (s, 9H), 4.27 (s, 2H), 6.88 (d, IH), 7.17 (t, 2H), 7.80 (s, IH), 7.94 (s, IH), 8.01-8.06 (m, 2H), 8.20 (d, IH)
Preparation Example 9 : 1- (3-chlorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone
Figure imgf000127_0001
A solution of 2-methylthio-4-methylpyrimidine (5.6 g, 40.0 mmol) in anhydrous tetrahydrofurane (40 mL) was cooled to -78 °C and a 1.8M lithium diisopropylamide-hexane solution (25 itiL, 45.1 ramol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min, then, a solution of 3-chloro- N-methoxy-N-methylbenzylamide (8.0 g, 40.0 mmol) in anhydrous tetrahydrofurane (8 mL) was added thereto dropwise, After completion of dropwise addition, the temperature was raised to room temperature, water (50 mL) was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from tert-butyl methyl ketone/hexane to give the title compound (9.2 g, 33 mmol, yield 83%).
1H-NMR (CDCl3) δ: 2.63 (s, 3H), 5.98 (s, IH), 6.68 (d, IH), 7.40 (m, 2H), 7.71 (m, IH), 7.83 (m, IH), 8.35 (d, IH). Since keto-enol tautomers exist based on pH values, there are two sets of signals.
Preparation Example 10: 1- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone
Figure imgf000128_0001
In the same process as Preparation Example 9, the title compound was synthesized using 4-fluoro-N-methoxy-N- methylbenzylamide instead of 3-chloro-N-methoxy-N- methylbenzylamide .
1H-NMR (CDCl3) δ: 2.63 (s, 3H), 5.94 (s, IH), 6.66 (d, IH), 7.13 (t, 2H), 7.84 (dd, 2H), 8.29 (d, IH). Since keto- enol tautomers exist based on pH values, there are two sets of signals.
Preparation Example 11: 2-bromo-l- (3-chlorophenyl) -2-
(2-fluoro-4-pyridyl) ethanone
Figure imgf000129_0001
Bromine (3.3 g, 20.8 mmol) was added to l-(3- chlorophenyl) -2- (2-fluoro- 4-pyridyl) ethanone (5.2 g, 20.8 mmol) in acetic acid (50 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated to give the title compound (6.8 g, 20.8 ramol, yield 100%) which was used in the next reaction without purification.
1H-NMR (CDCl3) δ: 6.14 (s, IH), 7.14 (t, IH), 7.34 (d, IH), 7.48 (t, IH), 7.63 (m, IH), 7.90 (dd, IH), 8.01 (t, IH), 8.28 (d, IH)
Preparation Example 12: 2-bromo-l- (4-fluorophenyl) -2- (2-fluoro-4-pyridyl) ethanone
Figure imgf000130_0001
In the same process as Preparation Example 11, the title compound was synthesized using 1- (4-fluorophenyl) -2- (2-fluoro-4-pyridyl) ethanone instead of 1- (3-chlorophenyl) - 2- (2-fluoro-4-pyridil) ethanone.
1H-NMR (CDCl3) δ: 6.17 (s, IH), 7.10-7.23 (m, IH), 7.34 (d, IH), 8.07 (m, 2H), 8.26 (d, IH)
Preparation Example 13: 2-bromo-2- (2-tert- butoxycarbonylamino-4-pyridyl) -1- (4-fluorophenyl) ethanone
Figure imgf000131_0001
In the same process as Preparation Example 11, the title compound was synthesized using 2-(2-tert- butoxycarbonylamino-4-pyridyl) -1- ( 4-fluorophenyl) ethanone instead of 1- (3-chlorophenyl) -2- (2-fluoro-4- pyridyl) ethanone .
1H-NMR (CDCl3) δ: 1.56 (s, 9H), 6.18 (s, 2H), 7.16-7.23 (m, 3H), 8.04-8.08 (m, 2H), 8.15 (s, IH), 8.30 (d, 2H), 8.35 (s, IH)
Preparation Example 14: 2-bromo-l- (3-chlorophenyl) -2- (2-methylthio-4- pyrimidyl) ethanone
Figure imgf000131_0002
In the same process as Preparation Example 11, the title compound was synthesized using 1- (3-chlorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone instead of l-(3- chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone .
1H-NMR (CDC13) δ: 2.54 (s, IH), 6.17 (s, IH), 7.42 (t, IH), 7.47 (d, IH), 7.61 (m, IH), 7.92 (d, IH), 8.05 (m, IH), 8.61 (d, IH)
Preparation Example 15: 2-bromo-l- (4-fluorophenyl) -2- (2-methylthio-4- pyriinidyl) ethanone
Figure imgf000132_0001
In the same process as Preparation Example 11, the title compound was synthesized using 1- (4-fluorophenyl) -2- (2-methylthio-4-pyrimidyl) ethanone instead of l-(3- chlorophenyl) -2- (2-fluoro-4-pyridyl) ethanone .
1H-NMR (CDCl3) δ: 2.53 (s, 3H), 6.18 (s, IH), 7.18 (t, 2H), 7.41 (d, IH), 8.10 (dd, 2H), 8.61 (d, IH)
Preparation Example 16: 4- [4- (4-fluorophenyl) thiazol- 5-yl] -2-fluoropyridine
Figure imgf000133_0001
2-Bromo-l- (4-fluorophenyl) -2- (2-fluoro-4- pyridyl) ethanone (112 mg, 3.59 iranol) was dissolved in N, N- dimethylformamide (5 mL) , thiobenzamide (439 mg, 7.17 mmol) was added thereto, and the mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate (50 mL) was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSC>4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:4) to give the title compound (480 mg, 1.74 mmol, yield 49%).
1H-NMR (CDCl3) δ: 6.92 (d, IH), 7.12 (m, 3H), 7.51 (m, 2H), 8.20 (d, IH), 8.94 (s, IH)
Preparation Example 17: [4- (3-chlorophenyl) -5- (2- fluoropyridin-4-yl) thiazol-2- yl] amine
Figure imgf000134_0001
2-Bromo-l- (3-chlorophenyl) -2- (2-fluoro-4- pyridyl) ethanone (1.0 g, 3.04 mmol) was dissolved in ethanol(30 mL) , thiourea (231 mg, 3.04 mmol) was added thereto, and the mixture was refluxed 1 hour. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from methylene chloride/n-hexane to give the title compound (820 mg, 2.68 mmol, yield 88%).
1H-NMR (CDCl3) δ: 5.25 (br s, 2H), 6.75 (s, IH), 6.98 (d, IH), 7.27-7.37 (m 3H) , 7.53 (s, IH), 8.07 (d, IH)
Preparation Example 18: 4- [2-ethyl-4- (3- chlorophenyl) thiazol-5-yl] -2-fluoropyridine
Figure imgf000135_0001
In the same process as Preparation Example 11, the title compound was synthesized using thiopropioamide instead of thiourea.
1H-NMR (CDCl3) δ: 1.48 (t, 3H), 3.11 (q, 2H), 6.87 (s, IH), 7.08 (m, IH), 7.27-7.38 (m, 3H), 7.58 (s, IH), 8.16 (d, IH)
Preparation Example 19: 4- [4- (4-fluorophenyl) thiazol- 2-yl]piperidine-l-carboxyliα acid tert-butyl ester
Figure imgf000135_0002
α-Bromo-4-fluoroacetophenone (2.0 g, 9.0 mmol) was dissolved in ethanol (20 mL) , N-tert- butoxycarbonylpiperidine-4-thioamide (2.0 g, 8.2 mmol) was added thereto, and the mixture was refluxed 1 hour. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was dissolved in N,N-diraethylformamide (15 mL) , di-tert- butyldicarbonate (1.4 g, 6.1 mmol) and triethylamine (0.7 g, β.l mmol) were added thereto, and the mixture was stirred at 50 °C for 2 hours. The reaction mixture was cooled to room temperature, water (150 mL) was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:3) to give the title compound (1.7 g, 4.7 mmol, yield 53%).
1H-NMR (CDCl3) δ: 1.49 (s, 9H), 1.80 (d q, 2H), 2.17 (d, 2H), 2.94(t, 2H), 3.21(m, IH), 4.24(m, 2H), 7.12 (t, 2H), 7.32(s, IH), 7.87 (m, 2H)
Preparation Example 20: 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl]piperidine-l- carboxylic acid ethyl ester
Sodiumsulfate (2.2 g, 15.4 mmol) was added to N, N- dimethylformamide (30 mL) , the mixture was stirred at 120 °C for lOmin, N-ethoxycarbonylpiperidine-4-thioamide (3.3 g, 15.5 mmol) was added thereto, and the mixture was stirred for 5min. A solution of 2-bromo-l- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (2.6g, 7.7mmol) in N, N- dimethylformamide (8 mL) was added thereto for 3 seconds and stirred for 5min. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate (200 mL) was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSCU and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:4) to give the title compound (260 mg, 0.57 mmol, yield 7%).
Preparation Example 21: 4- [4- (4-fluorophenyl) -5- (2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl]piperidine-l- carboxylic acid ethyl ester
Figure imgf000137_0001
A solution of 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester (360 mg, 0.78 mmol) in methylene chloride (3 mL) was cooled to 0 °C , 65% m- chloroperoxybenzoic acid (250 mg, 0.94 mmol) was added thereto while stirring. After completion of addition, the mixture was stirred for 30min. The reaction mixture was added to 2N sodium carbonate (30 itiL) and extracted with methylenechloride . The extract was washed with water, dried over MgS04and the solvent was evaporated. The residue was purified by silica gel column chromatography (acetone :n- hexane = 5:8) to give the title compound (250 mg, 0.52 mmol, yield 67%) .
1H-NMR (CDCl3) δ: 1.29 (t, 3H), 1.83 (m, 2H), 2.18 (m, 2H), 2.96 (m, 5H), 3.21 (m, IH), 4.17 (q, J=I .1, 2H), 4.30 (br, 2H), 7.16 (m, 3H), 7.55 (m, 2H), 8.73 (d, IH)
Example 1 : [4- (3-chlorophenγl) -5- (2-fluoropyridin-4- yl) thiazol-2-yl]methylamine (1)
2-Bromo-l- (3-chlorophenyl) -2- (2-fluoro-4- pyridyl) ethanone (1.0 g, 3.04 mmol) was dissolved in ethanol(30 mL) , N-methylthiourea (274 mg, 3.04 mmol) was added thereto, and the mixture was refluxed 2 hour. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was recrystallized from methylene chloride/n-hexane to give the title compound (770 mg, 2.41 mmol, yield 79%). The structure and 1H-NMR data of compound 1 were shown in the following Table 1. Examples 2 to 4 :
In the same process as Example 1, compounds 2 to 4 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 1. [Table 1]
Figure imgf000139_0001
Example 5 : 4 - [ 4 - ( 4 -fluorophenyl ) -2 - ( 4 - methyl su If any lphenyl) thiazol-5-yl]pyridin-2-ylamine (5) Trifluoroacetic acid (20 mL) was added to {4- [4- (4- Fluorophenyl) -2- (4-methylsulfanylphenyl) thiazol-5- yl]pyridin-2-yl}carbaraic acid tert-butyl ester (1.12 g, 2.23 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated sodium bicarbonate (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:1) to give the title compound (0.74 g, 1.88 mmol, yield 83%). The structure and 1H-NMR data of compound 5 were shown in the following Table 2.
Example 6 : 4- (3-chlorophenyl) -5- (2- iαethylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (6)
2-Bromo-l- (3-chlorophenyl) -2- (2-methylthio-4- pyrimidyl) ethanone (2.36 g, 6.60 mmol) was dissolved in ethanol(60 mL) , thiourea (0.50 g, 6.60 mmol) was added, and the mixture was refluxed 1 hour. The reaction mixture was cooled to room temperature and concentrated. Saturated sodium bicarbonate (50 mL) was added to the residue and stirred. The precipitated solids were collected by filtration and washed with acetone (20 mL) to give the title compound (1.66 g, 4.96 mmol, yield 75%) . The structure and 1H-NMR data of compound 6 were shown in the following Table 2.
Examples 7 to 31:
In the same process as Example 6, compounds 7~31 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 2.
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Example 32: 4- [2-chloro-4- (4-fluorophenyl) thiazol-5- yl] -2-methylsulfanylpyrimidine (32)
CuC12 (632 mg, 4.70 mmol) and tert-butylnitrite (567 mg, 5.50 mmol) were added to acetonitrile (60 mL) , 4-(4- fluorophenyl) -5- (2-methysulfanylpyrimidine-4-yl) thiazol-2- ylamine (1.25 g, 3.92 mmol) was added thereto slow, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:4) to give the title compound (540 mg, 1.60 mmol, yield 41%). The structure and 1H-NMR data of compound 32 were shown in the following Table 3.
Examples 33 to 38 : In the same process as Example 32 , compounds 33 to 38 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 3.
Figure imgf000146_0001
Example 39: 4- [4- (4-fluorophenyl) -2-piperidin-l- ylthiazol-5-γl] -2-methylsulfanylpyrimidine (39)
4- [2-Chloro-4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine (150 mg, 0.44 ramol) was dissolved in tetrahydrofurane (3 mL) , a solution of piperidine (76 mg, 0.89 rnmol) in tetrahydrofurane (1 mL) was added at 0 °C, and the mixture was stirred at room temperature for 1 day. The reaction mixture was added to saturated sodium bicarbonate, extracted with ethyl acetate, dried over MgSCU and the solvent was evaporated to give the title compound (163 mg, 0.42 mmol, yield 95%) which was used in the next reaction without purification. The structure and 1H-NMR data of compound 39 were shown in the following Table 4.
Examples 40 to 62 :
In the same process as Example 39, compounds 40 to 62 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 4.
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Example 63 : 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl]piperazine-l- carboxylic acid tert-butyl ester (63) 4- [4- (4-Fluorophenyl) -2-piperazin-l-yl-thiazol-5-yl] - 2-methylsulfanylpyrimidine (1.95 g, 5.03 mmol) , di-tert- butyl dicarbonate (1.1 g, 5.03 mmol), and triethylamine (0.51 g, 5.03 mmol) were dissolved in tetrahydrofurane (70 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water (150 mL) and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSCU and the solvent was evaporated. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (2.04 g, 4.18 mmol, yield 83%) . The structure and IH-NMR data of compound 63 were shown in the following Table 5.
Examples 64 to 70 :
In the same process as Example 63, compounds 64 to 70 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 5.
Figure imgf000152_0001
Figure imgf000153_0001
Example 71 : 4- (3-chlorophenyl) -5- (2- methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine (71)
A solution of 4- (3-Chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (l.Og, 2.99 mmol) in methylene chloride (200 mL) was cooled to 0 °C and 65% m-chloroperoxybenzoic acid (950 mg, 3.58 mmol) was added thereto while stirring. After completion of addition, the mixture was stirred for 30 min. The reaction mixture was added to 2N sodium carbonate (30 mL) and extracted with methylene chloride. The extract was washed with water, dried over MgSC>4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (acetone : n-hexane = 5:8) to give the title compound (550 mg, 1.58 mmol, yield 53%). The structure and 1H-NMR data of compound 71 were shown in the following Table 6.
Examples 72 to 114:
In the same process as Example 71, compounds 72 to 114 were synthesized. The structure and H-NMR data of them were shown in the following Table β.
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Example 115: {4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl]pyridin-2-yl}cyclohexylamine (115)
A reaction mixture of [4- (3-Chlorophenyl) -5- (2- fluoropyridin-4-yl) thiazol-2-yl]methylamine (768 mg, 2.51 mmol) and cyclohexylamine (1.99 g, 20.08 itimol) was stirred at 150 °C for 4 hours. The reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration, and washed with ethyl acetate (5 mL) to give the title compound (370 mg, 0.96 mmol, yield 38%). The structure and 1H-NMR data of compound 115 were shown in the following Table 7. Examples 116 to 121:
In the same process as Example 115, compounds 116 to 121 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 7.
[Table 7]
Figure imgf000161_0001
Figure imgf000162_0001
Example 122: {4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl]pyrimidin-2-yl}cyclohβxylamine (122)
A reaction mixture of 4- (3-chlorophenyl) -5- (2- methanesulfinylpyrimidin-4-yl) thiazol-2-ylamine (90 mg, 0.257 iranol) and cyclohexylamine (216 mg, 2.18 mmol) was stirred at 100 °C for 1 hour. The reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration, and washed with ethyl acetate (5 mL) to give the title compound (31 mg, 0.08 mmol, yield 31%) The structure and 1H-NMR data of compound 122 were shown in the following Table 8.
Examples 123 to 277: In the same process as Example 122, compounds 123 to 277 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 8. [Table 8]
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Example 278: 4- [5- (2-cyclopropylaminopyrimidin-4-yl) - 4- (4-fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol (278)
A solution of cyclopropyl-{ 4- [4- (4- fluorophenyl) thiazol-5-yl] pyrimidin- 2-yl}amine (60 mg, 0.19 iranol) in anhydrous tetrahydrofurane (2 inL) was cooled to - 40 °C and a 1.6M n-butyllithium-hexane solution (0.25 mL, 0.40 mmol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min, then, a solution of N-methyl-4-piperidone (57 mg, 0.51 mmol) in anhydrous tetrahydrofurane (1 mL) was added thereto dropwise. After completion of dropwise addition, the mixture was stirred for 30 min, saturated sodium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol rmethylene chloride = 1:1) to give the title compound (48 mg, 0.11 mmol, yield 59%). The structure and 1H-NMR data of compound 278 were shown in the following Table 9.
Examples 279 to 305:
In the same process as Example 278, compounds 279 to 305 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 9. [Table 9]
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Example 306: 4- [5- (2-cyclopropylaminopyrimidin-4-yl) - 4- (4-fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester (306) A solution of cyclopropyl-{4- [4- (4- fluorophenyl) thiazol-5-yl] pyrimidin- 2-yl}amine 150 rag, 0.48 mmol) in anhydrous tetrahydrofurane 4 mL) was cooled to - 40 °C and a 1.6M n-butyllithium-hexane solution 0.6 mL, 0.96 ramol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 30min, then a solution of 4-oxopiperidine-l-carboxylic acid tert-butyl ester (258 mg, 1.23 mmol) in anhydrous tetrahydrofurane (1 mL) was added thereto dropwise. After completion of dropwise addition, the mixture was stirred for 30 min, saturated sodium chloride was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:2) to give the title compound (106 mg, 0.21 mmol, yield 43%). The structure and 1H-NMR data of compound 306 were shown in the following Table 10.
Examples 307 to 333:
In the same process as Example 306, compounds 307 to 333 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 10.
[Table 10]
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Example 334 : cydopropyl- { 4- [4- (4 -fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl]pγrimidin-2-yl}amine (334)
A solution of 4- [5- (2-Cyclopropylaminopyrimidin-4-yl) - 4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester (180 mg, 0.38 mmol) in chloroform (5 mL) was admixed with iodotrimethylsilane (230 mg, 1.16 mmol) and the mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to 0 °C , 6N hydrogen chloride- propanol (1.6 mL) was added thereto, and homogenized while stirring. 2N Sodium hydroxide was added to the reaction mixture and the mixture was extracted with methylenechloride, The extract was washed with water, dried over MgSCu and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1:1) to give the title compound (100 mg, 0.25 mmol, yield 66%) . The structure and 1H-NMR data of compound 334 were shown in the following Table 11.
Examples 335 to 368:
In the same process as Example 334, compounds 335 to 368 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 11. [Table 11]
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Example 369: cyclopropyl-{4- [4- (4-fluorophenyl) -2- piperazin-l-yl-thiazol-5-yl]pyrimidin-2-yl}amine (369)
Trifluoroacetic acid (5 mL) was added to a solution of 4- [5- (2-Cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester (352 mg, 0.67 ramol) in methylene chloride (5 mL) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, saturated sodium bicarbonate was added to the residue and the mixture was extracted with methylene chloride. The extract was washed with water, dried over MgSCU and the solvent was evaporated to give the title compound (254 mg, 0.60 mmol, yield 89%). The structure and 1H-NMR data of compound 369 were shown in the following Table 12.
Examples 370 to 427:
In the same process as Example 369, compounds 370 to 427 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 12.
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Example 428: 4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] -2- methylsulfanylpyrimidine (428)
4- [2-Chloro-4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine (430 mg, 1.27 mmol) was dissolved in tetrahydrofurane (9 mL) , a solution of 4-methylpiperazine (255 mg, 2.55 mmol) in tetrahydrofurane (3 mL) was added thereto at 0 "C, and the mixture was stirred at room temperature for 1 day. The reaction mixture was added to saturated sodium bicarbonate, extracted with ethyl acetate, dried over MgSU4 and the solvent was evaporated to give the title compound (473 mg, 1.18 mmol, yield 93%). The structure and 1H-NMR data of compound 428 were shown in the following Table 13.
Example 429 : cyclopropyl-{4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl]pyrimidin-2-yl}amine (429)
A solution of cyclopropyl-{ 4- [4- (4-fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl} amine (50 mg, 0.13 mmol) in methanol (1.5 mL) was added to 37% formaldehyde (20 mg, 0.26 mmol) and sodiumborohydride (10 mg, 0.26 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to water (15 mL) and extracted with ethyl acetate. The extract was washed with water, dried over MgSC>4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol:methylene chloride = 1:1) to give the title compound (33 mg, 0.08 mmol, yield 31%). The structure and 1H-NMR data of compound 429 were shown in the following Table 13.
Examples 430 to 484:
In the same process as Example 429, compounds 430 to 484 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 13.
[Table 13]
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Example 485: cyclopropyl-{4- [2- (l-ethylpiperin-4-yl) - 4- (4-fluorophenyl) thiazol-5-yl]pyrimidin-2-yl}amine (485)
A solution of cyclopropyl- { 4- [4- (4-fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl]pyrimidin-2-yl} amine (100 mg, 0.25 iranol) in ethanol (8 mL) was admixed with iodoethane
(241 mg, 1.54 mmol) and potassium carbonate (253 mg, 1.83 mmol) and the mixture was stirred at room temperature for 1 day. The reaction mixture was admixed with water (50 mL) and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography
(methanol:methylene chloride = 1:1) to give the title compound (65 mg, 0.15 mmol, yield 61%). The structure and 1H-NMR data of compound 485 were shown in the following Table 14. Example 486: cyclopropyl-{4- [4- (4-fluorophenyl) -2- (1- isopropylpiperidin-4-yl) thiazol-5-yl]pyrimidin-2-yl}amine 486)
In the same process as Example 485, compound 486 was synthesized using 2-iodopropane instead of iodoethane. The structure and 1H-NMR data of compound 486 were shown in the following Table 14.
Example 487: l-{4- [5- (2-cyclopropylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl]piperidin-l-yl}ethanone (487)
A solution of cyclopropyl-{ 4- [4- (4-fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl]pyrimidin-2-yl}amine (238 mg, 0.60 mmol) and triethylamine (61 mg, 0.60 mmol) in tetrahydrofurane ( 6 inL) was admixed with acetyl chloride (47 mg, 0.60 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was admixed with water (50 mL) and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (140 mg, 0.32 mmol, yield 53%). The structure and 1H-NMR data of compound 487 were shown in the following Table 14. Examples 488 to 490:
In the same process as Example 487, compounds 488 to 490 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 14.
[Table 14]
Figure imgf000234_0001
Figure imgf000235_0001
Example 491: cyclopropyl-{4- [2- (1- cyclopropylmethylpiperidin-4-yl) -4- (4-fluorophenyl) thiazol- 5-yl]pyrimidin-2-yl}amine (491)
A solution of cyclopropyl-{ 4- [5- (2- cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2- yl]piperidin-l-yl}methanone (200 mg, 0.43 mmol) and lithiumaluminiumhydride (32 mg, 0.84 mmol) in tetrahydrofurane (8 mL) was stirred at room temperature for 1 hour. The reaction mixture was admixed with water (50 mL) and extracted with ethyl acetate. The extract was washed with water, dried over MgSC^ and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol : methylene chloride = 1:20)) to give the title compound (74 mg, 0.16 mmol, yield 38%). The structure and 1H-NMR data of compound 491 were shown in the following Table 15.
Example 492: cyclopropyl-{4- [2- [1- (2- dimethylaminoethyl)piperidin-4-yl] -4- (4- fluorophenyl) thiazol-5-yl]pyrimidin-2-yl}amine (492)
In the same process as Example 491, compound 492 was synthesized using l-{4- [5- (2-cyclopropylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-l-yl}-2- dimethylaminoethanone instead of cyclopropyl-{ 4- [5- (2- cyclopropylaminopyrimidin-4-yl) -4- (4-fluorophenyl) thiazol-2- yl] piperidin-1-yl }methanone . The structure and 1H-NMR data of compound 492 were shown in the following Table 15.
Example 493: N- {4- [4- (4-Fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl]pyridin-2-yl}propionamide (493)
A solution of 4- [4- (4-fluorophenyl) -2- (4- methylsulfanyl) thiazol-5-yl]pyridin-2-ylamine (710 mg, 1.80 mraol) in tetrahydrofurane (10 mL) was cooled to 0 °C and propionyl chloride (190 mg, 2.00 mmol) and triethylamine (190 mg, 1.87 mmol) were added thereto while stirring. After completion of addition, the mixture was stirred at room temperature for 1 hour and the reaction mixture was added to saturated sodium bicarbonate (50 mL) . The precipitated crystals were collected by filtration and washed with water. The crystals were added to ethyl acetate (10 mL) and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to give the title compound (660 mg, 1.46 mmol, yield 81%). The structure and 1H-NMR data of compound 493 were shown in the following Table 15.
Examples 494 to 498:
In the same process as Example 493, compounds 494 to 498 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 15.
[Table 15]
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Example 499: N-{4- [4- (4-Fluorophenyl) -2- (4- methanesulfinylphenyl) thiazol-5-yl]pyridin-2-yl}propionamide 499) A solution of N-{ 4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide (300 mg, 0.66 mmol) in methylenechloride (100 mL) was cooled to 0 °C , 65% ra-chloroperoxybenzoic acid (212 mg, 0.80 mmol) was added thereto while stirring. After completion of addition, the mixture was stirred for 30min. The reaction mixture was added to 2N sodium carbonate (100 mL) and extracted with methylene chloride. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol rmethylenechloride = 1:1) to give the title compound (139 mg, 0.300 mmol, yield 45%). The structure and 1H-NMR data of compound 499 were shown in the following Table 16.
Example 500: N- {4- [4- (4-Fluorophenyl) -2- (4- methanesulfonylphenyl) thiazol-5-yl]pyridin-2-yl}propionamide (500)
A solution of N- { 4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide (300 mg, 0.66 itimol) in methylenechloride (100 mL) was admixed with 65% m-chloroperoxybenzoic acid (400 mg, 1.50 mmol) while stirring. After completion of addition, the mixture was stirred for 1 hour, 2N sodium carbonate (100 mL) was added, and extracted with methylenechloride. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1:1) to give the title compound (70 mg, 0.14 mmol, yield 22%). The structure and 1H-NMR data of compound 500 were shown in the following Table 16.
Example 501: N-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl]pyrimidin-2-yl}propionamide (501) A solution of 4- [4- (4-fluorophenyl) -5- (2- propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester (56 mg, 0.12 mmol) in chloroform(3 mL) was admixed with iodotrimethylsilane (140 mg, 0.52 mmol) and the mixture was stirred at 60 °C for 5 hours. The reaction mixture was cooled to 0 °C , 6N hydrogen chloride-propanol (1.6 mL) was added thereto, and homogenized while stirring. 2N Sodium hydroxide was added to the reaction mixture and the mixture was extracted with methylenechloride. The extract was washed with water, dried over MgSCU and the solvent was evaporated. The residue was purified by silica gel column chromatography (methanol :methylene chloride = 1:1) to give the title compound (8 mg, 0.02 mmol, yield 17%). The structure and 1H-NMR data of compound 501 were shown in the following Table 16.
Examples 502 to 503:
In the same process as Example 501, compounds 502 to 503 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 16.
Example 504: N- [4- (3-chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide (504) A solution of 6-methylnicotinic acid (310 mg, 4.44 mmol) in benzene (5 mL) was cooled to 0 "C and a solution of oxalyl chloride (378 mL, 4.44 mmol) in benzene (2 mL) was added thereto while stirring. After completion of addition, N,N-dimethylformamide (25 mL) was added thereto. The reaction mixture was admixed with 4- (3-Chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamine (1.03 g, 3.07 mmol) and 4- (dimethylamino) pyridine (126 mg, 1.03 mmol) and the mixture was stirred at 80 °C for overnight. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate (200 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:2) to give the title compound (570 mg,1.22 mmol, yield 41%). The structure and 1H-NMR data of compound 504 were shown in the following Table 16.
Example 505: N- [4- (3-Chlorophenyl) -5- (2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethyln±cot±namide (505)
A solution of N- [4- (3-Chlorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6, N- dimethylnicotinamide (531 mg, 1.13 mmol) in methylene chloride (20 mL) was cooled to 0 °C and 65% m- chloroperoxybenzoic acid (279 mg, 1.13 mmol) was added thereto while stirring. After completion of addition, the mixture was stirred for 10 min, 2N sodium carbonate (30 mL) was added thereto, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over MgSθ4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :methanol = 30:1) to give the title compound (457 mg, 0.94 mmol, yield 84%). The structure and 1H-NMR data of compound 505 were shown in the following Table 16. Example 506: N-{4- (3-Chlorophenyl) -5- [2- (1- (s) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -6 ,N- d±methyln±cotinam±de (506)
A solution of β-methylnicotinic acid (146 mg, 1.06 mmol) in benzene (2 mL) was cooled to 0 "C and a solution of oxalyl chloride (90 mL, 1.06 mmol) in benzene (1 mL) was added thereto while stirring. After completion of addition, N, N- dimethylformamide (10 mL) was added thereto. The reaction mixture was admixed with {4- [4- (3-chlorophenyl) -2- methylaminothiazol-5-yl]pyrimidine-2-yl}- (1- (S) - phenylethyl) amine (300 mg, 0.71 mmol) and 4- (dimethylamino) pyridine (28 mg, 0.23 mmol) and the mixture was stirred at 80 °C for overnight. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate (100 mL) was added, and extracted with ethyl acetate. The extract was washed with water, dried over MgSU4 and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate :n-hexane = 1:2) to give the title compound (142 mg, 0.26 mmol, yield 37%). The structure and 1H-NMR data of compound 506 were shown in the following Table 16. [Table 16]
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Example 507: 2-chloro-l- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (507) (Compound of Formula 2) A solution of 1- (4-fluorophenyl) -2- (2-methylthio-4- pyrimidyl) ethanone (131 mg, 0.5 itimol) in anhydrous tetrahydrofurane (3 mL) was cooled to -78 °C and a 1.8M lithium diisopropylamide-hexane solution (306 mL, 0.55 mmol) was added thereto dropwise while stirring. After completion of dropwise addition, the mixture was stirred for 20min, then anhydrous trifluoromethylsulfonyl chloride (53 mL, 0.50 mmol) was added dropwise. After completion of dropwise addition, the temperature was raised to room temperature, water (20 mL) was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated to give the title compound (130 mg, 0.44 mmol, yield 88%) which was used in the next reaction without purification. The structure and 1H-NMR data of compound 507 were shown in the following Table 17. Example 507-1: Another process for preparing 2-chloro- 1- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidγl) ethanone (507)
Trimethylchlorosilane (11.7 g, 107.5 ramol) was added to a solution of tetrabutylammoniumbromide (2 g, 10.7 mmol) in tetrahydrofurane (650 mL) and the mixture was stirred for 30min. The mixture cooled to 0 °C , 1- (4-fluorophenyl) -2- (2- methylthio-4-pyrimidyl) ethanone (9.4 g, 35.8 mmol) and dimethylsulfoxide (2.9 g, 37.6 mmol) were added thereto, and stirred at room temperature for 2 hours. The reaction mixture was concentrated, extracted with ethyl acetate, and washed with saturated sodium bicarbonate. The extract was washed with water, dried over MgSO4 and the solvent was evaporated to give the title compound (10.3 g, 34.7 mmol, yield 97%) which was used in the next reaction without purification.
Examples 508 to 513:
In the same process as Example 507 or 507-1, compounds 508 to 513 were synthesized. The structure and 1H-NMR data of them were shown in the following Table 17. [Table 17]
Figure imgf000246_0001
Figure imgf000247_0001
Rl, R2, R3 and Z in the examples 1 to 506 compounds of the present invention are shown in the following table 18. [Table 18]
Figure imgf000247_0002
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Experimental Example 1 : Toxicity assessment of the compounds of the present invention on non-immune cells
To assess the toxicities of the compounds in accordance with the present invention on non-immune cells, the following experiment was carried out using sulforhodamine B (SRB) assay.
Cell lines used in the present experiment were the human breast cancer cell line, MDA-MB-231, the human lung cancer cell line, A549, the human renal cancer cell line, ACHN, the human gastric cancer cell line, SUN216, and the human hepatoma cell line, SUN709, which were purchased from American Type Culture Collection.
Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . Cells were added in a 96-well plate in an appropriate concentration (IXlO6 cells/ml) and cultured under the conditions of 5%, CO2 and 37°C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 μM thereto. After adding such samples, the culturing further proceeded for 48 hours. Then, 5% trichloroacetic acid was added thereto to fix the cells on the bottom of the culture vessel. Proteins of the fixed cells were dyed with a sulforhodamine B (SRB) solution to measure absorbance at 595 nm. With the increase of living cells the level of absorbance also increased and the results were shown as rates of living cells to the control group (100%) in Tables 19 to 23 below.
[Table 19]
Toxicity of compounds of the invention on the human
Figure imgf000274_0001
[Table 20]
Toxicity of compounds of the invention on the human lun cancer cell line, A549
Figure imgf000274_0002
[Table 21]
Toxicity of compounds of the invention on the human renal cancer cell line, ACHN
Figure imgf000274_0003
Figure imgf000275_0001
[Table 22]
Toxicity of compounds of the invention on the human astric cancer cell line, SUN216
Figure imgf000275_0002
[Table 23]
Toxicity of compounds of the invention on the human hepatoma cell line, SUN709
Figure imgf000275_0003
As shown in Tables 19 to 23 above, the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention showed very low toxicities in a concentration of 3 μM, whereas, showed noticeable toxicities in a concentration of 10 μM.
Experimental Example 2 : Toxicity assessment of the compounds of the present invention on macrophage lines
To assess the toxicities of the compounds in accordance with the present invention on macrophage lines, the following experiment was carried out using MTT assay.
MTT [3- (4, 5-dimethylthiazolyl-2) -2, 5- diphenyltetrazolium bromide] has been widely used in measuring the number of living cells, since it is a colorless reagent, whereas, changed into colored formazan when it is decomposed by living cells.
The cell line applied to the present experiment was the murine macrophage-derived cancer cell line, RAW264.7, purchased from American Type Culture Collection. Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added in a 96-well plate in an appropriate concentration (IXlO6 cells/ml) and cultured under the conditions of 5%, CO2 and 37°C. After 24 hours, the compounds prepared in Examples 115, 126, 334 and 429 were added in concentrations of 1-10 μM thereto. After adding such samples, the culturing further proceeded for 24 hours. Then, the MTT was added thereto and, after the lapse of 4 hours, the amount of formazan produced by living cells was measured at 595 nm. The results were shown as rates to the control group (100%l in Table 24 below.
[Table 24]
Toxicity of compounds of the invention on the murine macrophage-derived cancer cell line, RAW264.7
I I Number of living cells (%)
Figure imgf000277_0001
As shown in Table 24 above, the compounds in accordance with Examples 115 and 126 of the present invention showed little toxicities up to the concentration of 10 μM, whereas, the compounds of Examples 334 and 429 exhibited low toxicities in the concentration of 10 μM.
In the following experiments, the concentrations of the compounds in accordance with the present invention were less than 1 μM in order to identify the effects of immunosuppression in such concentrations that there is no cell toxicity.
Experimental Example 3: TNF-cc production inhibitory effects of the compounds of the present invention on the human macrophage-derived cancer cell line, THP-I cells
To examine the TNF-α production inhibitory effects of the compounds in accordance with the present invention on the human macrophage-derived cancer cell line, THP-I cells, the following experiment was carried out. The cell line applied to the present experiment was the human macrophage-derived cancer cell line, THP-I cells, purchased from American Type Culture Collection.
Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . THP-I cells were added in a 96- well plate in an appropriate concentration (IXlO6 cells/ml) and cultured under the conditions of 5%, CO2 and 37 °C. The production of TNF-α was induced by using lipopolysaccharide (final concentration: 1 mg/ml) (Sigma, USA) and the compounds prepared in Examples 115, 126, 334 and 429 were added thereto in concentrations of 0.0003-1 μM. After 24 hours, the culture solutions were collected and the amount of TNF-α existing in the cell culture solutions were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 25 below.
[Table 25]
Toxicity of compounds of the invention on the murine macro ha e-derived cancer cell line, THP-I
Figure imgf000278_0001
As shown in Table 24 above, it was seen that the compounds in accordance with Examples 115, 126, 334 and 429 of the present invention inhibited the production of TNF-α of THP-I cells concentration-dependently. Particularly, the compound of Example 429 showed the most excellent inhibitory effect with 0.28 nM of 50% inhibitory concentration (IC50) and the compounds of Examples 334, 126 and 115 exhibited 1 nM, 1.5 nm, and 0.48 nm of 50% inhibitory concentration (IC50), respectively.
Some compounds selected from those prepared in Examples 1 to 506 above were added in a concentration of 1 μM under the same conditions as Examples 115, 126, 334 and 429 above. After 24 hours, the culture solutions were collected. The amounts of TNF-α induced by LPS in the experimental groups, where some compounds selected from those prepared in accordance with the present invention were added, were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) , based on the amount of 100% TNF-α induced by treating only LPS existing in the cell culture solution. The results were depicted in Tables 26 to 30 below.
[Table 26]
Figure imgf000279_0001
Figure imgf000280_0001
It could be understood from the results of Table 26 that most compounds of Examples in accordance with the present invention added to the media in the concentration of 1 μM showed excellent TNF-α inhibitory effects. Moreover, it could be learned that the compounds of Examples 116, 117, 121, 127, etc. were especially excellent.
[Table 27]
Figure imgf000280_0002
Figure imgf000281_0002
It was verified from the results of Table 27 that most compounds of Examples in accordance with the present invention added to the media in the concentration of 1 μM showed excellent TNF-α inhibitory effects, except for some compounds. Especially, the compounds of Examples 123, 124, etc. exhibited excellent TNF-α inhibitory effects.
[Table 28]
Figure imgf000281_0001
It could be learned from the results of Table 28 that most compounds of Examples in accordance with the present invention added to the media in the concentration of 1 μM showed excellent TNF-α inhibitory effects, except for some compounds. Especially, the compounds of Examples 177, 154, etc. exhibited excellent TNF-α inhibitory effects.
[Table 29]
Figure imgf000282_0001
It was identified from the results of Table 29 that most compounds of Examples in accordance with the present invention added to the media in the concentration of 1 μM showed excellent TNF-α inhibitory effects, except for some compounds. Especially, the compounds of Examples 369, 376, 464, etc. exhibited excellent TNF-α inhibitory effects.
[Table 30]
Figure imgf000283_0001
It could be aware from the results of Table 30 that most compounds of Examples in accordance with the present invention added to the media in the concentration of 1 μM showed excellent TNF-α inhibitory effects by inhibiting the amount of TNF-α produced not exceeding 60%.
Next, the following experiments were carried out for the rest compounds of the present invention excluded in the 1 μM experiments, of which results were depicted in Tables 26 to 30, by reducing the concentration of 1/1,000 (1 nM) , based on the compound of Example 334 that showed excellent TNF-α inhibitory effects. And the results were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) and depicted in Tables 31 to 46 below.
[Table 31]
Figure imgf000284_0001
It could be understood from the results of Table 30 that the compounds of Examples 100 and 221 in accordance with the present invention showed excellent TNF-α inhibitory effects and the compound of Example 334 or the compounds exhibiting TNF-α inhibitory effects lower than the LPS treated group still had excellent TNF-α inhibitory effects, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000. [Table 32]
Figure imgf000285_0001
It could be learned from the results of Table 32 that the compounds of Examples 349, 356, 362, 378, 385, 392, 430, 438, 445 and 451 showed excellent TNF-α inhibitory effects and, particularly, it was confirmed that the compound of Examples 349 and 451 exhibited remarkable TNF-α inhibitory effects nearly two times than the compound of Example 334. Meanwhile, it could be aware that the rest compounds still had excellent TNF-α inhibitory effects, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 33]
Figure imgf000286_0001
It was identified from the results of Table 33 that the compounds of Examples 266, 273, 289, 301, 423, 466 and 473 showed excellent TNF-α inhibitory effects and, particularly, it was confirmed that the compound of Example's 294, 409 and41β exhibited noticeable TNF-α inhibitory effects about three times than the compound of Example 334.
Figure imgf000286_0002
Figure imgf000287_0001
It was verified from the results of Table 34 that the compounds of Examples 84, 164 and 431 showed very remarkable TNF-α inhibitory effects exceeding four times than the compound of Example 334. Meanwhile, it could be aware that the rest compounds still had excellent TNF-α inhibitory effects, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 35]
Figure imgf000287_0002
Figure imgf000288_0001
It could be understood from the results of Table 35 that the compounds of Examples 337, 384, 391, 458 and 472 showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Meanwhile, it could be aware that the rest compounds still had excellent TNF-α inhibitory effects, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 36]
Figure imgf000288_0002
Figure imgf000289_0001
It could be learned from the results of Table 36 that the compounds of Examples 286 and 401 showed TNF-α inhibitory effects about two to three times than the compound of Example 334 and it could be aware that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 37]
Figure imgf000289_0002
Figure imgf000290_0001
It was confirmed from the results of Table 37 that the compounds of Examples 335 and 336 showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be aware that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 38]
Figure imgf000290_0002
Figure imgf000291_0001
It was verified from the results of Table 38 that the compounds of Examples 352, 441, 448 and 454 showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be seen that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 39]
Figure imgf000291_0002
Figure imgf000292_0001
It was confirmed from the results of Table 39 that the compounds of Examples 387, 461, etc. showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be seen that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000. [Table 40]
Figure imgf000293_0001
It was identified from the results of Table 40 that the compounds of Examples 2879, 296, 411, etc. showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be seen that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 41]
Figure imgf000293_0002
Figure imgf000294_0001
It was verified from the results of Table 41 that the compounds of Examples 382, 389, 396, 477, 484, etc. showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be understood that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
Figure imgf000294_0002
Figure imgf000295_0001
It was confirmed from the results of Table 42 that the compounds of Examples 284, 291, 298, 413, 435, etc. showed excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could be learned that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000. [Table 43]
Figure imgf000296_0001
It was identified from the results of Table 43 that the compounds of Examples 351, 364, 440, 447, 453, etc. showed TNF-α inhibitory effects about one and a half times to two times than the compound of Example 334. Moreover, it could be seen that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 44]
Figure imgf000297_0001
It was verified from the results of Table 44 that the compounds of Examples 288, 295, 302, etc. showed outstanding TNF-α inhibitory effects about four and a half to nine times than the compound of Example 334. Moreover, it could be aware that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 45]
Figure imgf000298_0001
Figure imgf000299_0001
It was confirmed from the results of Table 45 that the compounds of Examples 344, 353, 360, 366, 442, etc. showed TNF-α inhibitory effects about two times than the compound of Example 334 and the compounds 410, 417, 434, 499, etc. exhibited excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Moreover, it could bee seen that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 46]
Figure imgf000299_0002
Figure imgf000300_0001
It was identified from the results of Table 46 that the compounds of Examples 283, 290, 381, 388, 395, 469, 476, etc. showed TNF-α inhibitory effects about one and a half to two times than the compound of Example 334 and the other compounds exhibited excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Furthermore, it could be understood that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
[Table 47]
Figure imgf000300_0002
Figure imgf000301_0001
It was verified from the results of Table 47 that the compounds of Examples 412, 419, 297, etc. showed TNF-α inhibitory effects about one and a half to two times than the compound of Example 334 and the compounds of Examples 304, 318, 405, 426, etc. exhibited excellent TNF-α inhibitory effects or equal effects to the compound of Example 334. Furthermore, it could be understood that the compounds exhibiting TNF-α inhibitory effects lower than the compound of Example 334 still showed significant results, if considering the fact that the concentration was 1 nM that the administration amount was reduced to 1/1,000.
Consequently, it could be learned from the results of Tables 25 to 47 that the compounds in accordance with the present invention inhibited the production of TNF-α induced by LPS in THP-I cells even in nano-concentrations as well as in micro concentrations.
Experimental Example 4 : TNF-α production inhibitory effects of the compounds of the present invention on the murine macrophage-derived cancer cell line, RAW264.7
To identify the TNF-α production inhibitory effects of the compounds in accordance with the present invention on the murine macrophage-derived cancer cell line, RAW264.7, the following experiment was carried out.
The cell line applied to the present experiment was the murine macrophage-derived cancer cell line, RAW264.7, purchased from American Type Culture Collection.
Cells were cultured in RPMI medium containing 10% fetal bovine serum (FBS). RAW264.7 cells were added in a 96-well plate in an appropriate concentration (IXlO6 cells/ml) and cultured under the conditions of 5%, CO2 and 37 °C . The production of TNF-α was induced by using lipopolysaccharide (final concentration: 1 mg/ml) (Sigma, USA) and the compounds prepared in Examples 334 and 429 were added thereto in concentrations of 0.01-1 UM. After 24 hours, the culture solutions were collected and the amount of TNF-α existing in the cell culture solutions were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 48 below.
[Table 48]
TNF-α production inhibitory effects of the compounds of the present invention on the murine macrophage-derived cancer cell line, RAW264.7
Figure imgf000302_0001
Figure imgf000303_0001
As shown in Table 48, the compounds of Examples 334 and 429 inhibited the production of TNF-α of RAW264.7 cells concentration-dependently . Particularly, the compounds of Examples 334 and 429 that exhibited the strong TNF-α production inhibitory effects on the human macrophage- derived cancer cell line, THP-I cells, also indicated the strong inhibitory effects on the murine macrophage-derived cancer cell line, RAW264.7 cells.
Experimental Example 5: TNF-α production inhibitory effects of the compounds of the present invention on the murine marrow cell-derived macrophages
To examine the TNF-α production inhibitory effects of the compounds in accordance with the present invention on the murine marrow cell-derived macrophages, the following experiment was carried out.
Cells separated from the marrow cells of a normal mouse were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . 10 mg/ml of M-CSF was added thereto and cultured for 10 days to form normal macrophages. The production of TNF-α was induced by using lipopolysaccharide (final concentration: 1 mg/ml) (Sigma, USA) and the compounds prepared in Examples 334 were added thereto in concentrations of 0.01-1 μM. After 24 hours, the culture solutions were collected and the amount of TNF-α existing in the cell culture solutions were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 48 below.
[Table 49]
TNF-α production inhibitory effects of the compounds of the present invention on the murine marrow cell-derived macrophages
Figure imgf000304_0001
As shown in Table 49, the compound of Example 334 inhibited the production of TNF-α of the murine marry cell- derived macrophages concentration-dependently.
Experimental Example 6 : Effects of the compounds of the present invention on T-cell and B-cell proliferations
To identify the effects of the compounds in accordance with the present invention on T-cell and B-cell proliferations, the following experiment was carried out. Although the inflammatory diseases are induced mainly by macrophages, whereas, it has been known that T-cells are associated with the inflammatory diseases such as arthritis, etc. Immune cells separated from the spleen of a normal mouse were cultured in RPMI medium containing 10% fetal bovine serum (FBS) . The immune cells were added in a 96- well plate in an appropriate concentration (IXlO6 cells/ml) and cultured under the conditions of 5%, CO2 and 37 "C.
Concanavaline A was added thereto in a concentration of 1 μg/ml to induce the proliferation of T-cells and lipopolysaccharide was added thereto in a concentration of 1 μg/ml to induce the proliferation of B-cells. Subsequently, the compounds prepared in Examples 334 and 429 were added thereto in concentrations of 0.1-1 μM. After culturing for 56 hours, [3H] -thymidine was added there to in a concentration of 1 μCi/well and the culturing further proceeded for 16 hours. While the immune cells proliferated, the amounts of irradiations introduced into DNA were measured by a beta-counter.
The effects of the compounds of the present invention on T-cell proliferation were depicted in Table 50 and those on B-cell proliferation were depicted in Table 51.
[Table 50]
Effects of the compounds of the present invention on the T-cell roliferation
Figure imgf000305_0001
Figure imgf000306_0001
[Table 51]
Effects of the compounds of the present invention on the T-cell proliferation
Figure imgf000306_0002
As shown in Tables 50 and 51, the compound of Example 429 inhibited the proliferation of T-cells in the maximum concentration 0.1-1 μM. However, it could be learned that the inhibition effects were low compared with Experimental Examples 3 to 5. The compound of Example 334 did not influence the T-cell and B-cell proliferations. Accordingly, it could be understood that the compounds of the present invention were derived mainly from the TNF-α production inhibition of macrophages. Experimental Example 7 : Acute toxicity of the compounds of the present invention on mice
To examine the acute toxicity of the compounds in accordance with the present invention on mice, the following experiment was carried out.
To each ten mice per experimental group the compound prepared in Example 334 was orally administrated in concentration of 0.3-100 mg/kg and the number of survived mice was counted for 14 days. The results were shown in Table 52.
[Table 52]
Figure imgf000307_0001
As depicted in Table 52, all animals to which the compounds of Example 334 were administrated were survived for 14 days and showed normal increases of weight.
In the following animal experiments, the concentrations were set below 10 mg/kg.
Experimental Example 8 : TNF-ot production inhibitory effects of the compounds of the present invention in vivo
To identify the TNF-α production inhibitory effects of the compounds in accordance with the present invention in vivo, the following experiment was carried out. Lipopolysaccharide was administrated to mice via intraperitoneal injections in a concentration of 2 mg/kg to induce the production of TNF-α and the compound prepared in Example 334 was orally administrated in concentrations of 0.1-10 mg/kg. After 90 minutes from the administration of lipopolysaccharide, sera were separated and the amounts of TNF-α in the sera were quantified using a Quantikine colorimetric sandwich ELISA kit (R&D. Systems, USA) . The results were depicted in Table 53 below.
[Table 53]
Figure imgf000308_0001
As shown in Table 53, the compound of Example 334 inhibited the production of TNF-α of macrophages in vivo concentration-dependently . Accordingly, it could be learned that the compound of the present invention exhibited pharmacological activity. Experimental Example 9 : Effects of the compounds of the present invention on zymosan-induced inflammation
To examine the effects of the compound in accordance with the present invention on zymosan-induced inflammation, the following experiment was carried out.
If administrating inflammation-inducing substances such as zymosan, etc. to a hind leg of mouse via hypodermic injection, inflammatory disease is induced in the joint and the lymph node enlargement that inflammatory cells excessively infiltrate into the lymph node is shown characteristically.
In the present experiment, each 150 μg of zymosan was injected into subcutaneous tissue of hind legs of mice to induce inflammations. After a week, popliteal lymph nodes were separated and their weights were measured. The compound prepared in Example 334 was orally administrated in concentrations of 0.1, 1 and 10 mg/kg daily.
Moreover, the toxicity of samples was measured by recording the weights of mice during the experiment. The results were depicted in Table 54.
[Table 54]
Figure imgf000309_0001
Figure imgf000310_0001
As depicted in Table 54, the compound of Example 334 inhibited the inflammatory reaction in vivo concentration- dependently. Moreover, the weights of mice were not varied during the administration period and no significant toxic symptoms were observed with naked eyes.
Accordingly, it could be understood that the compound of the present invention had therapeutic effect on the inflammations in vivo.
Experimental Example 10: Measurement of efficacies on inflammatory bowel disease (IBD)
To measure the efficacies of the compounds of the present invention on inflammatory bowel disease induced by TNBS (2, 4, β-trinitrobenzensulfonic acid solution, Fluka) , the following animal experiment was carried out.
Subject animals were nonpathogenic male SD rats aged 7 years and weighed about 200 to 300 g, supplied by Orient Co., Ltd. Total thirty rats were randomly divided into three groups and each of five rats divided was tested covering a couple of days. The subject animals were fasted for 24 hours before the test and. Then, 30 minutes before administrating TNBS, each 0.74 ml of ketamine (Ketalar; Yuhan Co., Korea) and acepromazine (Sedaject; Samu Chemical Co., Korea) mixed in the ratio of 4:1 was injected into the muscle of rat's hind leg to be anesthetized. After confirming the anesthesia, TNBS was first injected in a concentration of 50 mg/0.25 ml to each rat using a syringe that PE tube (8 cm) was put to a needle thereof when the tube was completely inserted through rectum into colon. After the injection, the tube was pulled out and anus was shut by the operator' s hand for three minutes while lifting nates over a 50 ml conical tube in order to prevent the TNBS injected from being lost with feces. After the lapse of 2 hours from the first injection of TNBS, TNBS was second injected in a concentration of each 20 mg/0.14 ml to each rat in the same manner as the first injection. Here, the suture time was set to 5 minutes. As drug administration, the compound of Example 334 in accordance with the present invention was used. The drug administrations were made first 3 hours before IBD induced and then once a day after IBD induced for 6 days, thus administrating 7 times for 7 days in total.
Efficacy measurements were made by (1) measuring the weight of colons of 10 cm extracted after sacrificing the IBD-induced rats or (2) assessing the grades, if finding no injuries, at 0; if finding a bleeding, at 1; if intestinal war was thickened and if finding a bleeding, at 2; if there was linear ulceration without bleedings or thickened intestinal wars, at 3; if finding more than two ulcers and/or inflammatory areas, at 4; if the more than two ulcers and inflammatory areas were extended over 1 cm in the longitudinal direction of the colon, at 5; and, if the size of the ulcer was over 2 cm, at 6, and +1 if the size was increased by 1 cm (i.e., if 3 cm, it was assessed at 7). Moreover, the measurements were made by assessing the grades, if the colon adhesion grade was normal, at 0; if the adhesion could be separated by hand, at 1; if it could be separated by scissors, at 2; and, if a perforation occurs during the separation, at 3. Furthermore, the measurements were added by assessing the grades, if finding no diarrhea/melena, at 0; if finding diarrhea, at 1; and, if finding diarrhea/melena all, at 2. In addition, the weight of subject animals was measured for 7 days and the assessments of weight increase and decrease were carried out together. All data were expressed by average± standard error and all groups were verified with a t-test by comparing with the control groups, prednisolone (PD) and vehicle. The measurement results were depicted in Table 55 below.
[Table 55]
Figure imgf000313_0001
As depicted in Table 55, the weights of colons were decreased in the order from the group of Example 334 to PD control compared with the vehicle group; however, they did not significant differences. In the gross examination, two groups of the PD and the group of Example 334 were decreased by similar values compared with the vehicle group; however, they did not significant differences likewise. In the item of adhesion, the two groups of the PD and the compound of Example 334 all indicated significant differences. In the item of diarrhea/melena, the two groups of the PD and the compound of Example 334 were all decreased compared with the vehicle group; however, they did not significant differences likewise. Last, in the item of weight changes, the vehicle group and the PD group were all decreased; however, the group of Example 334 indicated the increase and showed the significant differences.
Meanwhile, Figs. 1 to 3 show photographs of colons applied to the present experiments. It can be clearly learned from the colons of the vehicle group that their diseases including the adhesion grades and ulceration are serious compared with the PD group or the group of the Example 334 even with naked eyes. In addition, it can be seen that the adhesion grades of the PD group are serious much more that those of the group of Example 334.
Accordingly, it can be understood that the compound of Example 334, one of the compounds of the present invention can be effectively used in treating the inflammatory bowel disease (IBD) .
Hereinafter, the formulation examples for the composition of the present invention will now be exemplified.
Formulation Examples : Preparation of pharmaceutical formulations 1. Preparation of Powders
Substituted 1,3-thiazol derivative of Formula 1 2 g Lactose 1 g
The above ingredients were mixed with each other and packed in an air-tight bag, thus preparing the powders.
2. Preparation of Tablets
Substituted 1,3-thiazol derivative of Formula 1 500 mg
Corn starch 100 mg
Lactose 100 mg Magnesium stearate 2 mg The above ingredients were mixed with one another and tableted according to an ordinary method of preparing tablets, thus preparing a table.
3. Preparation of Capsules
Substituted 1,3-thiazol derivative of Formula 1 500 mg Corn starch 100 mg
Lactose 100 mg
Magnesium stearate 2 mg The above ingredients were mixed with one another and packed in a gelatin capsule according to an ordinary method of preparing capsules, thus preparing a capsule.
3. Preparation of Injections Substituted 1,3-thiazol derivative of Formula 1 500 mg Citrate buffer solution kept pH at 3.5
Dextrose isotonic
The substituted 1,3-thiazol derivative, sodium citrate, citric acid and dextrose were charged into a 20 ml sterilized injection vial and sealed using an aluminum cap. For use, the above mixture was dissolved using distilled water for injection and, then, diluted with distilled water for injection of appropriate volume, thus preparing an injection.

Claims

[CLAIMS] [Claim l] A substituted 1,3-thiazol derivative expressed by formula 1 below or a pharmaceutically acceptable salt thereof having immunosuppression and inflammation inhibitory activities : wherein Z denotes CH or N; Rl denotes a halogen atom, a haloalkyl of Ci~C4, an alkyl of Ci-C4 or alkoxy of Ci-C4; R2 denotes H, a halogen atom, an alkyl of Ci-C4, -NH-R4, an alkyl-S (O)n-phenyl of Ci-C4, in which X denotes CH, C-OH or N; and Y denotes CH2, an alkyl of CH-Ci-C4, NH, an alkyl of N-Ci-C4, an alkyl of amino-Ci~C4 of N-Ci-C4, an alkyl of N-CO-Ci-C4, a cycloalkyl of N-C0-C3~Cs, an aryl of N-CO-Cs-Ca, an alkyl of amino-Ci~C4 of N-CO-Ci-C4 or an alkoxy of N-Co-N-Ci-C4; R3 denotes a halogen atom, -NH-R4, -NH-C0-R5, -N-(CO- R5)2 or an alkyl of -S(O)n-Ci-C4 ; R4 denotes H, an alkyl of Ci-C4, a cycloalkyl of C3-Ca, a cycloalkylalkyl of C3-C8, an aryl of Cs-Cs, CH(Ci-C4 alkyl) - phenyl or amine; R5 denotes an alkyl of Ci-C4, a cycloalkyl of C3-Ca, an aryl of Cs-Cβ or an alkoxy of Ci-C4; m is 1 or 2; and n is 0, 1 or 2. [Claim 2] The substituted 1,3-thiazol derivative expressed by formula 1 or the pharmaceutically acceptable salt thereof as recited in claim 1, wherein, in formula 1, Z is CH or N; Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 or 4-OCH3; R2 is H, Cl, ethyl, amino, NHNH2, methylamino, 6, N- dimethylnicotinilamino, 4- methylsulfanylphenyl, 4- methanesulfinylphenyl, 4-methanesulfonylphenyl, piperidin-1- yl, 4-methyl-piperidin-l-yl, piperidin-4-yl, N-methyl piperidin-4-yl, N-ethyl- piperidin-4-yl, N-isopropyl- piperidin-4-yl, N-cyclopropylmethyl-piperidin-4-yl, N- dimethylaminoethyl- piperidin-4-yl, N-methylcarbonyl- piperidin-4-yl, N-cyclopropylcarbonyl-piperidin-4-yl, N- dimethylaminomethylcarbonyl-piperidin-4-yl, N- phenylcarbonyl-piperidin-4-yl, ethoxycarbonyl-piperidin-4-yl, N-butoxycarbonyl-piperidin-4-yl, piperazin-1-yl, N-methyl- piperazin-1-yl, N-bytoxycarbonyl-piperazin-1-yl, 4-methyl-4- oxypiperazin-1-yl, 4-hydroxy--piperidin-4-yl, N-methyl-4- hydroxy-piperidin-4-yl, N-butoxycarbonyl-4-hydroxy- piperidin-4-yl, 2, 5-diazabicyclo [2.2.1] -hept-2-yl, N-t- butoxycarbonyl-2, 5-diazabicyclo [2.2.1] -hept-2-yl, piperidin- 4-ylamino, N-t-butoxycarbonyl-piperidin-4-ylamino, piperidin-4-yloxy or N-t-butoxycarbonyl-piperidin-4-yloxy; and R3 is F, amino, cyclopropylamino, cyclopropylmethylamino, cyclobutylamino, cyclopentylaraino, cyclohexylamino, cycloheptylamino, phenylamino, benzylamino, (S) -1-phenylethylamino, (R) -1-phenylethylamino, ethylcarbonylamino, N, N-diethylcarbonylamino, cyclohexylcarbonylaraino, N, N-dicyclohexylcarbonylamino, phenylcarbonylamino, t-butoxycarbonylamino, methylsulfanyl, methanesulfinyl or methanesulfonyl . [Claim 3] The substituted 1,3-thiazol derivative expressed by formula 1 or the pharmaceutically acceptable salt thereof as recited in claim 1, wherein the derivative of formula 1 is,
1. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4- yl) thiazol-2-yl]methylamine
2. [4- (3-chlorophenyl) -5- (2-fluoropyridin-4- yl) thiazol-2-yl] hydrazine
3. 4-[2-ethyl-4- (4-fluorophenyl) thiazol-5-yl] -2- fluoropyridine
4. {4-[4-(4-fluorophenyl)-2-(4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl}carbamic acid tert-butyl ester
5. 4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-ylamine
6. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
7. [4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-yl] methylamine
8. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2- methylsulfanylpyrimidine
9. 4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
10. 4- (3-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
11. 4- (2-fluorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
12. 4- (3-chlorophenyl) -5- (2-methylsulfanylpyrimidin-4- yl) thiazol-2-ylamine
13. 5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-ylamine
14. 5- (2-methylsulfanylpyriraidin-4-yl) -4- (3- methylphenyl) thiazol-2-ylamine
15. 4- (4-methoxyphenyl) -5- (2-methylsulfanylpyrimidin- 4-yl) thiazol-2-ylamine
16. [4- (4-fluorophenyl) -5- (2-methylsulfanylpyrimidin- 4-yl) thiazol-2-yl]methylamine
17. 4- [4- (4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid tert-butyl ester
18. 4- [5- (2-aminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
19. 4- [4- (3-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
20. 4-[4-(2-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
21. 4-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
22. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
23. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
24. 4-[4-(4-methoxyphenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
25. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
26. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
27. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
28. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
29. 2-methylsulfanyl-4-[4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
30. 2-methylsulfanyl-4-[4- (3-methylphenyl) thiazol-5- yl] pyrimidine
31. 4- [4- (4-methoxyphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
32. 4- [2-chloro-4- (4-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
33. 4- [2-chloro-4- (3-fluorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
34. 4- [2-chloro-4- (2-fluorophenyl) thiazol-5-yl] -2- raethylsulfanylpyrimidine
35. 4- [2-chloro-4- (3-chlorophenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
36. 4- [2-chloro-4- (3-trifluoromethylphenyl) thiazol-5- yl] -2-methylsulfanylpyrimidine
37. 4- [2-chloro-4- (3-methylphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
38. 4- [2-chloro-4- (4-methoxyphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
39. 4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
40. 4- [4- (3-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
41. 4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
42. 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
43. 2-methylsulfanyl-4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
44. 2-methylsulfanyl-4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidine
45. 4- [4- ( 4-methoxyphenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
46. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
47. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
48. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
49. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
50. 4- [2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] -2- methylsulfanylpyrimidine
51. 4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] -2-methylsulfanylpyrimidine
52. 4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
53. 4- [4- (4-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
54. 4- [4- (3-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
55. 4- [4- (2-fluorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
56. 4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
57. 2-methylsulfanyl-4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
58. 2-methylsulfanyl-4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidine
59. 4- [4- (4-methoxyphenyl) -2-piperazin-l-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
60. 2-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2, 5- diazabicyclo [2.2.1] heptane
61. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1- carboxylic acid tert-butyl ester
62. 4-[4-(4-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-ylamino] piperidine-1- carboxylic acid tert-butyl ester
63. 4-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
64. 4-[4-(3-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
65. 4- [4- (2-fluorophenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
66. 4-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
67. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
68. 4- [5- (2-methylsulfanylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
69. 4- [4- (4-methoxyphenyl) -5- (2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
70. 5-[4-(4-fluorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -2, 5- diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
71. 4- (3-chlorophenyl) -5- (2-methanesulfinylpyrimidin- 4-yl) thiazol-2-ylamine
72. 4- [4- (3-chlorophenyl) -2-ethylthiazol-5-yl] -2- methanesulfinylpyrimidine
73. 4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin- 4-yl) thiazol-2-ylamine 74. [4- (4-fluorophenyl) -5- (2-methanesulfinylpyrimidin-
4-yl) thiazol-2-yl]methylamine
75. 4-[4-(4-fluorophenyl)-5-(2- methanesulfonylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
76. 4-[4-(4-fluorophenyl) -5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid tert-butyl ester
77. 4-[4-(3-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
78. 4-[4-(2-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
79. 4-[4-(3-chlorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
80. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
81. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
82. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
83. 4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
84. 4- [4- (3-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
85. 4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
86. 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
87. 2-methanesulfinyl-4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
88. 2-methanesulfinyl-4- [2-piperidin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidine
89. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- piperidin-1-yl-thiazol-5-yl] pyrimidine
90. 4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
91. 4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
92. 4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
93. 4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] -2-methanesulfinylpyrimidine
94. 2-methanesulfinyl-4- [2- (4-methylpiperidin-l-yl) -4- (3-trifluoromethylphenyl) thiazol-5-yl] pyrimidine
95. 2-methanesulfinyl-4- [2- (4-methylpiperidin-l-yl) -4- (3-methylphenyl) thiazol-5-yl] pyrimidine
96. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidine
97. 4- [4- (4-fluorophenyl) -2- (4-methyl-4-oxypiperazin- 1-yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
98. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
99. 4-[4-(3-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
100. 4-[4-(2-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
101. 4-[4-(3-chlorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
102. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
103. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
104. 4- [5- (2-methanesulfinylpyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
105. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yloxy] piperidine-1- carboxylic acid tert-butyl ester
106. 4-[4-(4-fluorophenyl)-5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-ylamino] piperidine- 1-carboxylic acid tert-butyl ester
107. 5-[4-(4-fluorophenyl)-5-(2- raethanesulfinylpyrimidin-4-yl) thiazol-2-yl] -2,5- diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester
108. 4- [4- (4-fluorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
109. 4- [4- (3-fluorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
110. 4- [4- (2-fluorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
111. 4- [4- (3-chlorophenyl) thiazol-5-yl] -2- methanesulfinylpyrimidine
112. 2-methanesulfinyl-4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidine
113. 2-methanesulfinyl-4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidine
114. 2-methanesulfinyl-4- [4- (4-methoxyphenyl) thiazol- 5-yl] pyrimidine
115. {4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl]pyridin-2-yl}cyclohexylamine
116. { 4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyridin-2-yl }cyclohexylamine
117. {4- [4- (3-chlorophenyl) -2-hydrazinothiazol-5- yl] pyridin-2-yl } cyclohexylamine
118. { 4- [4- (3-chlorophenyl) -2-ethylthiazol-5- yl] pyridin-2-yl}- (1- (S) -phenylethyl) amine
119. cyclohexyl-{4- [4- (4-fluorophenyl) thiazol-5- yl] pyridin-2-yl } amine
120. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyridin-2-yl }- (1- (S) -phenylethyl) amine
121. cyclohexyl-{ 4- [2-ethyl-4- (4-fluorophenyl) thiazol- 5-yl] pyridin-2-yl } amine
122. {4- [2-amino-4- (3-chlorophenyl) thiazol-5- yl] pyrimidin-2-yl } cyclohexylamine
123. {4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyrimidin-2-yl }cyclopentylamine
124. {4- [4- (3-chlorophenyl) -2-ethylthiazol-5- yl] pyrimidin-2-yl}- (1- (s) -phenylethyl) -amine
125. { 4- [4- (3-chlorophenyl) -2-methylaminothiazol-5- yl] pyrimidin-2-yl } - (1- (s) -phenylethyl) amine
126. {4- [2-amino-4- (4-fluorophenyl) thiazol-5-yl] - pyrimidin-2-yl }- (1- (s) -phenylethyl) amine
127. { 4- [4- (4-fluorophenyl) -2-methylaminothiazol-5- yl] -pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
128. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
129. 4- [5- (2-cyclobutylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
130. 4- [5- (2-cycloheptylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
131. 4- [5- [2- (cyclopropylmethylamino) pyrimidin-4-yl] - 4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
132. 4- [5- (2-benzylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
133. 4- [4- (4-fluorophenyl) -5- (2-phenylaminopyrimidin- 4-yl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
134. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
135. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
136. 4- [4- (3-chlorophenyl) -5- (2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
137. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
138. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl]piperidine-l-carboxylic acid ethyl ester
139. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
140. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert- butyl ester
141. 4- [5- (2-cyclopentylarainopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert- butyl ester
142. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
143. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
144. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
145. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
146. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
147. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
148. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert- butyl ester
149. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
150. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
151. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
152. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
153. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
154. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
155. 4- { 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid tert-butyl ester
156. 4-{4- (4-fluorophenyl) -5- [2- (1- (R) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
157. 4-{ 4- (3-fluorophenyl) -5- [2- (1- (s) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
158. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperidine-1- carboxylic acid ethyl ester
159. 4-{4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
160. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
161. 4-{5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl}piperidine-l-carboxylic acid ethyl ester
162. 4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid ethyl ester
163. cyclopropyl- { 4- [4- (4-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
164. cyclopropyl- {4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
165. cyclopropyl- { 4- [4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
166. { 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl]pyrimidin-2-yl}cyclopropylamine
167. cyclopropyl- { 4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
168. cyclopropyl- {4- [2-piperidin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
169. cyclopropyl- {4- [4- (4-methoxyphenyl) -2-piperidin- 1-yl-thiazol-5-yl] pyrimidin-2-yl} amine
170. cyclopentyl-{4- [4- (4-fluorophenyl) -2-piperidin-l- ylthiazol-5-yl] pyrimidin-2-yl } amine
171. cyclopentyl-{ 4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
172. cyclopentyl-{4- [4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
173. { 4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopentylamine
174. cyclopentyl-{4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
175. cyclopentyl-{4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
176. cyclopentyl-{4- [4- (4-methoxyphenyl) -2-piperidin- l-yl-thiazol-5-yl] pyrimidin-2-yl} amine
177. cyclohexyl-{ 4- [4- (4-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
178. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
179. cyclohexyl-{4-[4- (2-fluorophenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
180. {4-[4-(3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }cyclohexylamine
181. cyclohexyl-{4- [2-piperidin-l-yl-4- (3- trifluoromethylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
182. cyclohexyl-{4- [2-piperidin-l-yl-4- (3- methylphenyl) thiazol-5-yl]pyrimidin-2-yl}amine
183. cyclohexyl-{ 4- [4- (4-Methoxyphenyl) -2-piperidin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
184. {4- [4- (4-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
185. {4- [4- (3-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
186. {4- [4- (2-fluorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (s) -phenylethyl) amine
187. {4- [4- (3-chlorophenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
188. (1- (S)-phenylethyl)-{4-[2-piperidin-l-yl~4- (3- trifluoromethylphenyl) thiazol-5-yl]pyrimidin-2-yl} amine
189. (1- (S) -phenylethyl) -{4- [2-piperidin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
190. {4- [4- (4-methoxyphenyl) -2-piperidin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
191. cyclopropyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] -pyrimidin-2-yl} amine
192. cyclopropyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
193. cyclopropyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
194. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl }cyclopropylamine
195. cyclopropyl-{ 4- [2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
196. cyclopropyl-{ 4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
197. cyclopropyl-{4- [4- (4-Methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl]pyrimidin-2-yl}amine
198. cyclopentyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
199. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
200. cyclopentyl-{4-[4-(2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
201. {4- [4- (3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
202. cyclopentyl-{4-[2- (4-methylpiperidin-1-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
203. cyclopentyl-{4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
204. cyclopentyl-{4- [4- (4-Methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
205. cyclohexyl-{4-[4-(4-fluorophenyl) -2-(4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
206. cyclohexyl-{4-[4-(3-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
207. cyclohexyl-{4-[4-(2-fluorophenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
208. {4- [4- (3-Chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclohexylamine
209. cyclohexyl-{4-[2- (4-methylpiperidin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
210. cyclohexyl-{ 4- [2- (4-methylpiperidin-l-yl) -4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
211. cyclohexyl-{4- [4- (4-methoxyphenyl) -2- (4- methylpiperidin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
212. {4- [4- (4-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
213. {4- [4- (3-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl]pyrimidin-2-yl} - (1- (s) -phenylethyl) amine
214. {4- [4- (2-fluorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (s) -phenylethyl) amine 215. {4-[4-(3-chlorophenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
'
216. {4-[2-(4-methylpiperidin-l-yl)-4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) - phenylethyl) amine
217. {4-[2-(4-methylpiperidin-l-yl)-4-(3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) - phenylethyl) amine
218. { 4- [4- (4-methoxyphenyl) -2- (4-methylpiperidin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
219. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl]piperazine-l-carboxylic acid tert- butyl ester
220. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
221. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
222. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
223. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
224. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
225. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- Methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
226. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
227. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
228. 4- [5- (2-cyclopentylaminopyriraidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
229. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
230. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
231. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
232. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
233. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
234. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
235. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
236. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
237. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
238. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert- butyl ester
239. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperazine-1-carboxylic acid tert-butyl ester
240. 4-{ 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperazine-l- carboxylic acid tert-butyl ester
241. 4- { 4- (3-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperazine-l- carboxylic acid tert-butyl ester
242. 4-{ 4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperazine-l- carboxylic acid tert-butyl ester
243. 4-{4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperazine-1- carboxylic acid tert-butyl ester
244. 4-[5-[2-(1-(S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperazine-1- carboxylic acid tert-butyl ester
245. 4-{5-[2-(l-(S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl} -piperazine-1-carboxylic acid tert-butyl ester
246. 4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperazine-1- carboxylic acid tert-butyl ester
247. 5- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -2, 5-diazabicyclo [2.2.1] heptane-2- carboxylic acid tert-butyl ester
248. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yloxy] piperidine-1-carboxylic acid tert-butyl ester
249. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-ylamino] piperidine-1-carboxylic acid tert-butyl ester
250. cyclopropyl-{ 4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl }amine
251. cyclopropyl- {4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
252. cyclopropyl- {4- [4- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
253. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl}cyclopropylamine
254. cyclopropyl- {4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
255. cyclopropyl- { 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl } amine
256. cyclopropyl- { 4- [4- (4-Methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl }amine
257. cyclopentyl- { 4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
258. cyclopentyl- { 4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
259. cyclopentyl-{ A-[A- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
260. [A-[A- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } cyclopentylamine
261. cyclopentyl-{4-[4-(3- trifluoromethylphenyl ) thiazol-5-yl] pyrimidin-2-yl } amine
262. cyclopentyl-{ 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl } amine
263. cyclopentyl- { 4- [4- (4-methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl} amine
264. cyclohexyl-{ 4- [4- (4-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl }amine
265. cyclohexyl-{ 4- [4- (3-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
266. cyclohexyl-{4- [4- (2-fluorophenyl) thiazol-5- yl] pyrimidin-2-yl } amine
267. { 4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } cyclohexylamine
268. cyclohexyl-{4-[4-(3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
269. cyclohexyl-{ 4- [4- (3-methylphenyl) thiazol-5- yl] pyrimidin-2-yl } amine
270. cyclohexyl-{ 4- [4- (4-methoxyphenyl) thiazol-5- yl] pyrimidin-2-yl }amine
271. {4- [4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2- yl } - ( 1- ( S ) -phenylethyl) amine
272. {4- [4- (3-fluorophenyl) thiazol-5-yl] pyrimidin-2- yl } - (1- (S) -phenylethyl) amine
273. { 4- [4- (2-fluorophenyl) thiazol-5-yl] pyrimidin-2- yl}- (1- (S) -phenylethyl) amine
274. {4- [4- (3-chlorophenyl) thiazol-5-yl] pyrimidin-2- yl } - ( 1- ( S) -phenylethyl) amine
275. (1- (S) -phenylethyl) -{4- [4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
276. (1- (S) -phenylethyl) -{4- [4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
277. { 4- [4- (4-methoxyphenyl) thiazol-5-yl] pyrimidin-2- yl } - ( 1- (S) -phenylethyl) amine
278. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
279. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
280. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
281. 4- [4- (3-chlorophenyl) -5- (2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
282. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
283. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
284. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl ) thiazol-2-yl] -l-methylpiperidin-4-ol
285. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
286. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
287. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
288. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
289. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
290. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
291. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
292. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
293. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
294. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
295. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -1- methylpiperidin-4-ol
296. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
297. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
298. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -l-methylpiperidin-4-ol
299. 4-{ 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) -pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
300. 4-{ 4- (3-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
301. 4-{4-(2-fluorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}-l- methylpiperidin-4-ol
302. 4-{ 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
303. l-methyl-4-[5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
304 . l-methyl-4- { 5- [ 2- ( l- ( S ) - phenylethylamino) pyrimidin-4-yl ] -4 - ( 3-methylphenyl ) thiazol- 2-yl }-piperidin-4-ol
305. 4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -1- methylpiperidin-4-ol
306. 4- [5- (2-cyclopropylaminopyriraidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
307. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic ' acid tert-butyl ester
308. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
309. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] -A- hydroxypiperidine-1-carboxylic acid tert-butyl ester
310. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester
311. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
312. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
313. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
314. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
315. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
316. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
317. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester
318. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
319. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
320. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
321. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxyllc acid tert-butyl ester
322. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
323. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
324. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l- carboxylic acid tert-butyl ester
325. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
326. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] -4-hydroxypiperidine-l-carboxylic acid tert-butyl ester
327. 4- { 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino)pyrimidin-4-yl] thiazol-2-yl} -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
328. 4- { 4- (3-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }-4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
329. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
330. 4-{ 4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -4- hydroxypiperidine-1-carboxylic acid tert-butyl ester
331. 4-hydroxy-4-[5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidine-1-carboxylic acid tert-butyl ester
332. 4-hydroxy-4-{5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] -4- (3-methylphenyl) thiazol- 2-yl }piperidine-l-carboxylic acid tert-butyl ester
333. 4-hydroxy-4-{4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidine-l- carboxylic acid tert-butyl ester
334. cyclopropyl-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl} amine
335. cyclobutyl-{4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
336. cycloheptyl-{ 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl} amine
337. cyclopropylmethyl-{ 4- [4- (4-fluorophenyl) -2- piperidin-4-yl-thiazol-5-yl] pyrimidin-2-yl } amine
338. benzyl- { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl] pyrimidin-2-yl} amine
339. {4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl }phenylamine
340. cyclopropyl- { 4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl} amine
341. cyclopropyl- { 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
342. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl }cyclopropylamine
343. cyclopropyl- {4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
344. cyclopropyl- {4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
345. cyclopropyl- { 4- [4- (4-methoxyphenyl) -2-piperidin- 4-yl-thiazol-5-yl] pyrimidin-2-yl} amine
346. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5- yl] -2-methylsulfanylpyrimidine
347. 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol-5- yl] -2-methanesulfinylpyrimidine
348. cyclopentyl- { 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
349. cyclopentyl- {4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
350. cyclopentyl- { 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
351. {4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopentylamine
352. cyclopentyl- { 4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl]pyrimidin-2-yl} amine
353. cyclopentyl- {4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
354. cyclopentyl- {4- [4- (4-methoxyphenyl) -2-piperidin- 4-yl-thiazol-5-yl] pyrimidin-2-yl} amine
355. cyclohexyl-{ 4- [4- (4-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] -pyrimidin-2-yl }amine
356. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
357. cyclohexyl-{ 4- [4- (2-fluorophenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
358. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclohexylamine
359. cyclohexyl-{4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
360. cyclohexyl-{ 4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
361. cyclohexyl-{4- [4- (4-methoxyphenyl) -2-piperidin-4- yl-thiazol-5-yl] pyrimidin-2-yl } amine
362. { 4- [4- (3-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
363. {4- [4- (2-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
364. { 4- [4- (3-chlorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl }- (1- (S) -phenylethyl) amine
365. (1- (S) -phenylethyl) -{4- [2-piperidin-4-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
366. (1- (S) -phenylethyl) -{4- [2-piperidin-4-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
367. {4- [4- (4-methoxyphenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
368. { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (R) -phenylethyl) amine
369. cyclopropyl-{ 4- [4- (4-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
370. cyclopropyl-{4- [4- (3-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
371. cyclopropyl-{ 4- [4- (2-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
372. { 4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol- 5-yl] pyrimidin-2-yl } cyclopropylamine
373. cyclopropyl-{ 4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
374. cyclopropyl-{ 4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
375. cyclopropyl-{ 4- [4- (4-methoxyphenyl) -2-piperazin- l-yl-thiazol-5-yl] pyrimidin-2-yl } amine
376. cyclopentyl- { 4- [4- (4-fluorophenyl) -2-piperazin-1- yl-thiazol-5-yl] pyrimidin-2-yl } amine
377. cyclopentyl-{ 4- [4- (3-fluorophenyl) -2-piperazin-1- yl-thiazol-5-yl] pyrimidin-2-yl } amine
378. cyclopentyl-{ 4- [4- (2-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl }amine
379. {4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }cyclopentylamine
380. cyclopentyl-{4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
381. cyclopentyl-{4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
382. cyclopentyl- { 4- [4- (4-methoxyphenyl) -2-piperazin- l-yl-thiazol-5-yl] pyrimidin-2-yl} amine
383. cyclohexyl-{4- [4- (4-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
384. cyclohexyl-{4- [4- (3-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl} amine
385. cyclohexyl-{4- [4- (2-fluorophenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
386. {4- [4- (3-chlorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }cyclohexylamine
387. cyclohexyl-{ 4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
388. cyclohexyl-{4-[2-piperazin-l-yl-4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
389. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2-piperazin-l- yl-thiazol-5-yl] pyrimidin-2-yl } amine
390. { 4- [4- (4-fluorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
391. { 4- [4- (3-fluorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl }- (1- (S) -phenylethyl) amine
392. { 4- [4- (2-fluorophenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
393. { 4- [4- (3-chlorophenyl) -2-piperazin-1-yl-thiazol- 5-yl] pyrimidin-2-yl }- (1- (S) -phenylethyl) amine
394. (1- (S) -phenylethyl) -{4- [2-piperazin-l-yl-4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}amine
395. (1- (S) -phenylethyl) -{4- [2-piperazin-l-yl-4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
396. { 4- [4- (4-methoxyphenyl) -2-piperazin-l-yl-thiazol- 5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
397. cyclopropyl- { 4- [2- (2 , 5-diazabicyclo [2.2.1] hept-2- yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl} amine
398. cyclopropyl- { 4- [4- (4-fluorophenyl) -2- (piperidin- 4-yloxy) thiazol-5-yl] pyrimidin-2-yl} amine
399. cyclopropyl-{ 4- [4- (4-fluorophenyl) -2- (piperidin- 4-ylamino) thiazol-5-yl] pyrimidin-2-yl } amine
400. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
401. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol
402. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol
403. 4-[4-(3-chlorophenyl)-5-(2- cyclopropylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
404. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
405. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidin-4-ol
406. 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol
407. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
408. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol
409. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol
410. 4-[4-(3-chlorophenyl)-5-(2- cyclopentylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
411. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
412. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidin-4-ol
413. 4- [5- (2-cyclopentylaminopyrimidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol
414. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-4-ol
415. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- fluorophenyl) thiazol-2-yl] piperidin-4-ol
416. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (2- fluorophenyl) thiazol-2-yl] piperidin-4-ol
417. 4-[4-(3-chlorophenyl)-5-(2- cyclohexylaminopyrimidin-4-yl) thiazol-2-yl] piperidin-4-ol
418. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
419. 4- [5- (2-cyclohexylaminopyrimidin-4-yl) -4- (3- methylphenyl) thiazol-2-yl] piperidin-4-ol
420. 4- [5- (2-cyclohexylaminopyriraidin-4-yl) -4- (4- methoxyphenyl) thiazol-2-yl] piperidin-4-ol
421. 4- { 4- (4-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl }piperidin-4-ol
422. 4- { 4- (3-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperidin-4-ol
423. 4- {4- (2-fluorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl}piperidin-4-ol
424. 4-{4-(3-chlorophenyl)-5-[2-(l-(S)- phenylethylamino) pyrimidin-4-yl] thiazol-2-yl } -piperidin-4-ol
425. 4- [5- [2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-trifluoromethylphenyl) thiazol-2-yl] piperidin-4-ol
426. 4-{5-[2- (1- (S) -phenylethylamino) pyrimidin-4-yl] - 4- (3-methylphenyl) thiazol-2-yl } -piperidin-4-ol
427. 4- {4- (4-methoxyphenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl ] thiazol-2-yl } -piperidin-4-ol
428. 4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
429. cyclopropyl- {4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl]pyrimidin-2-yl} amine
430. cyclopropyl- {4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
431. cyclopropyl- {4- [4- (2-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
432. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl }cyclopropylamine
433. cyclopropyl- {4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
434. cyclopropyl-{ 4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
435. cyclopropyl- {4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
436. 4- [4- (4-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] -2-methylsulfanylpyrimidine
437. cyclopentyl-{4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
438. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
439. cyclopentyl-{4-[4- (2-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
440. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
441. cyclopentyl-{4- [2- (1-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl }amine
442. cyclopentyl-{ 4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
443. cyclopentyl-{ 4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
444. cyclohexyl-{4- [4- (4-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
445. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl} amine
446. cyclohexyl-{4-[4- (2-fluorophenyl) -2-(l- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
447. { 4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } cyclohexylamine
448. cyclohexyl-{4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
449. cyclohexyl-{ 4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl } amine
450. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2- (1- methylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl } amine
451. {4- [4- (3-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
452. {4- [4- (2-fluorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
453. {4- [4- (3-chlorophenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine
454. {4- [2- (l-methylpiperidin-4-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) - phenylethyl) amine
455. {4- [2- (l-methylpiperidin-4-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) - phenylethyl) amine
456. { 4- [4- (4-methoxyphenyl) -2- (l-methylpiperidin-4- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine
457. cyclopropyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
458. cyclopropyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl}amine
459. cyclopropyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
460. {4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopropylamine
461. cyclopropyl-{ 4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
462. cyclopropyl-{ 4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl ) thiazol-5-yl ] pyrimidin-2-yl } amine
463. cyclopropyl-{ 4- [4- (4-methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
464. cyclopentyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
465. cyclopentyl-{4- [4- (3-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
466. cyclopentyl-{4- [4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
467. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclopentylamine
468. cyclopentyl-{4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
469. cyclopentyl-{4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
470. cyclopentyl-{4- [4- (4-Methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
471. cyclohexyl-{4- [4- (4-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
472. cyclohexyl-{ 4- [4- (3-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl }amine
473. cyclohexyl-{4-[4- (2-fluorophenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl} amine
474. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } cyclohexylamine
475. cyclohexyl-{4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
476. cyclohexyl-{4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} amine
477. cyclohexyl-{ 4- [4- (4-methoxyphenyl) -2- (4- methylpiperazin-1-yl) thiazol-5-yl] pyrimidin-2-yl } amine
478. {4- [4- (4-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
479. {4- [4- (3-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) -phenylethyl) amine
480. {4- [4- (2-fluorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl } - (1- (S) -phenylethyl) amine
481. { 4- [4- (3-chlorophenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl] pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
482. {4- [2- (4-methylpiperazin-l-yl) -4- (3- trifluoromethylphenyl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) - phenylethyl) amine
483. {4- [2- (4-methylpiperazin-l-yl) -4- (3- methylphenyl) thiazol-5-yl] pyrimidin-2-yl} - (1- (S) - phenylethyl) amine
484. { 4- [4- (4-methoxyphenyl) -2- (4-methylpiperazin-l- yl) thiazol-5-yl]pyrimidin-2-yl}- (1- (S) -phenylethyl) amine
485. cyclopropyl-{4- [2- (l-ethylpiperidin-4-yl) -4- (4- fluorophenyl) thiazol-5-yl] pyrimidin-2-yl } amine
486. cyclopropyl-{4- [4- (4-fluorophenyl) -2- (1- isopropylpiperidin-4-yl) thiazol-5-yl] pyrimidin-2-yl }amine
487. l-{ 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-1-yl }ethanone
488. l-{ 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-1-yl} -2- dimethylaminoethanone
489. cyclopropyl-{4- [5- (2-cyclopropylaminopyrimidin-4- yl) -4- (4-fluorophenyl) thiazol-2-yl] piperidin-1-yl }methanone
490. { 4- [5- (2-cyclopropylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidin-1-yl }phenylmethanone
491. cyclopropyl-{ 4- [2- (1-cyclopropylmethylpiperidin- 4-yl) -4- (4-fluorophenyl) thiazol-5-yl] pyrimidin-2-yl }amine
492. cyclopropyl-{4-[2-[l-(2- dimethylaminoethyl) piperidin-4-yl] -4- (4- fluorophenyl) thiazol-5-yl] pyrimidin-2-yl } amine
493. N-{4- [4- (4-fluorophenyl) -2- (4- methylsulfanylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide
494. 4- [4- (4-fluorophenyl) -5- (2- propionylaminopyrimidin-4-yl) thiazol-2-yl] piperidine-1- carboxylic acid ethyl ester
495. 4- [5- (2-dipropionylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
496. 4- [5- [2- (cyclohexanecarbonylamino) pyrimidin-4- yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
497. 4- [5- [2- (ciscyclohexanecarbonylamino) pyrimidin-4- yl] -4- (4-fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
498. 4- [5- (2-benzoylaminopyrimidin-4-yl) -4- (4- fluorophenyl) thiazol-2-yl] piperidine-1-carboxylic acid ethyl ester
499. N- {4- [4- (4-fluorophenyl) -2- (4- methanesulfinylphenyl) thiazol-5-yl] pyridin-2-yl}propionamide
500. N- { 4- [4- (4-fluorophenyl) -2- (4- methanesulfonylphenyl) thiazol-5-yl] pyridin-2-yl }propionamide
501. N- { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl]pyrimidin-2-yl}propionamide
502. N- { 4- [4- (4-fluorophenyl) -2-piperidin-4-yl- thiazol-5-yl] pyrimidin-2-yl }benzamide
503. cyclohexanecarboxylic acid {4- [4- (4- fluorophenyl) -2-piperidin-4-yl-thiazol-5-yl]pyrimidin-2- yl}amide
504. N-[4-(3-chlorophenyl)-5-(2- methylsulfanylpyrimidin-4-yl) thiazol-2-yl] -6, N- dimethylnicotinamide
505. N-[4-(3-chlorophenyl)~5-(2- methanesulfinylpyrimidin-4-yl) thiazol-2-yl] -6,N- dimethylnicotinamide
506. N- {4- (3-chlorophenyl) -5- [2- (1- (S) - phenylethylamino) pyrimidin-4-yl] thiazol-2-yl} -6, N- dimethylnicotinamide . [Claim 4]
An intermediate compound expressed by formula 2 below or a pharmaceutically acceptable salt thereof:
Figure imgf000366_0001
wherein Rl denotes a halogen atom, a haloalkyl of Ci~C4, an alkyl of C1-C4 or alkoxy of Ci-C4; and
Hal denotes F, Cl or I.
[Claim 5]
The intermediate compound expressed by scheme 2 or the pharmaceutically acceptable salt thereof as recited in claim 4, wherein, in formula 2,
Rl is 2-F, 3-F, 4-F, 3-Cl, 3-CF3, 3-CH3 or 4-OCH3; and Hal is Cl.
[Claim 6] A process for preparing a substituted 1,3-thiazol derivative expressed by scheme 1 below or a pharmaceutically acceptable salt thereof in claim 1, the process comprising:
(1) preparing a compound (IV) by treating a compound (II) with a base and reacting the base-treated compound with a compound (HI) ;
(2) preparing a compound (V) by halogenating the compound (IV) obtained in step (1) ;
(3) preparing a compound (VII) by reacting the compound (V) obtained in step (2) with a thioamide compound (VI); and
(4) preparing a substituted 1-3-thiazol compound ( I -a) by reacting the compound (VH) obtained in step (3) with an amine compound (VI) ,
[Scheme 1]
Figure imgf000367_0001
wherein Rl, R2 and R4 are the same as defined in formula 1 in claim 1;
Hal or Hal' denotes a halogen atom; and L denotes a leaving group.
[Claim 7]
A process for preparing a substituted 1,3-thiazol derivative expressed by scheme 2 below or a pharmaceutically acceptable salt thereof in claim 1, the process comprising: (1) treating a compound (X), obtained by protecting an amine group of a compound (K) , with base and then reacting the compound (X) with a compound (HI) to prepare a compound
(XI);
(2) preparing a compound (XII) by halogenating the compound (XI) obtained in step (1);
(3) preparing a compound (XIH) by reacting the compound (XII) obtained in step (2) with a thioamide compound (VI) ; and
(4) preparing a substituted 1-3-thiazol compound ( I -b) by deprotecting the compound (XHI) obtained in step (3) and reacting the deprotected compound of compound (XIH) with acylation agent (XV), [Scheme 2]
Figure imgf000369_0001
wherein Rl, R2 and R5 are the same as defined in formula 1;
Hal denotes a halogen atom; and L denotes a leaving group.
[Claim 8]
A process for preparing a substituted 1,3-thiazol derivative expressed by scheme 3 below or a pharmaceutically acceptable salt thereof in claim 1, the process comprising:
(1) treating a compound (XVI) with a base and reacting the base-treated compound with a compound (HI) to prepare a compound ( XYII) ;
(2) preparing a compound (XVl) by halogenating the compound (XVH) obtained in step (1) ;
(3) preparing a compound (XIX) by reacting the compound (XVl) obtained in step (2) with a thioamide compound (VI) ;
(4) preparing a compound (XX) by treating the compound (XIX) obtained in step (3) with an organic peroxy acid; and
(5) preparing a substituted 1-3-thiazol compound ( I -c) by reacting the compound (XX) obtained in step (4) with an amine compound (Vl) ,
[Scheme 3]
Figure imgf000370_0001
wherein Rl, R2 and R4 are the same as defined in formula 1;
Hal denotes a halogen atom; and L denotes a leaving group.
[Claim 9]
The process for preparing the substituted 1,3-thiazol derivative or the pharmaceutically acceptable salt thereof in claim 1, as recited in claim 8, wherein, in step (2), a compound ( XVl) is prepared by treating the compound (XVII) with LDA, CF3SO2Cl; or TBAB, TMSCI or DMSO to be chlorinatd; and a compound (XIX) is prepared by reacting the compound (XVl) with a thioamide compound (VI), as expressed by scheme 3a below: [Scheme 3a]
Figure imgf000371_0001
wherein Rl is the same as defined in formula 2; R2 is the same as defined in formula 1; and Hal denotes Cl. [Claim lθ]
A process for preparing a substituted 1,3-thiazol derivative expressed by scheme 4 below or a pharmaceutically acceptable salt thereof in claim 1, the process comprising:
(1) preparing a compound (XXII) by reacting a compound ( XVI) with a thiourea compound (XXI);
(2) preparing a compound (X XUI) by halogenating the compound (XXII) obtained in step (1); (3) preparing a compound (XXV) by reacting the compound (XXIII) obtained in step (2) with a compound (XXIV);
(4) preparing a compound (XXVI) by treating the compound (XXV) obtained in step (3) with an organic peroxy acid; and
(5) preparing a substituted 1-3-thiazol compound (XXVII) by reacting the compound (XXVI) obtained in step (4) with an amine compound (Vl),
[Scheme 4]
Figure imgf000373_0001
wherein Rl, R4 and Y are the same as defined in Formula 1;
Hal denotes a halogen atom; and PG is a protective group. [Claim 111
The process for preparing the substituted 1,3-thiazol derivative or the pharmaceutically acceptable salt thereof in claim 1, as recited in claim 10, wherein, if Y is NH in the compound (XXV) in step (4), the nitrogen is protected prior to an oxidation reaction and, then, the oxidation reaction is caused to prepare a compound (XXIX); and the compound (XXIX) is reacted with the amine compound (Vl) to prepare a compound (XXX).
[Claim 12] The process for preparing the substituted 1,3-thiazol derivative or the pharmaceutically acceptable salt thereof in claim 1, as recited in claim 11, wherein, the compound (XXX) is deprotected and the deprotected compound of the compound (XXX) is methylated.
[Claim 13]
A process for preparing a substituted 1,3-thiazol derivative expressed by scheme 5 below or a pharmaceutically acceptable salt thereof in claim 1, the process comprising: (1) preparing a compound (XXXlI) by reacting a compound (XH) with a thioformamide compound (XXXI); (2) preparing a compound (XXXDI) by treating the compound (XXXII) obtained in step (1) with an organic peroxy acid; (3) preparing a compound (XXXIV) by reacting the compound (X X XIII) obtained in step (2) with an amine compound (Vl) ;
(4) preparing a compound (XXXVI) by treating the compound (XXXIV) obtained in step (3) with a base and reacting the base-treated compound with a compound (XXXV); and
(5) preparing a substituted 1-3-thiazol compound (XXXVtt) by deprotecting the compound (XXXVI) obtained in step (4), [Scheme 5]
Figure imgf000376_0001
wherein Rl, R4 and Y are the same as defined in Formula 1; and Hal denotes a halogen atom.
[Claim 14]
The process for preparing the substituted 1,3-thiazol derivative or a pharmaceutically acceptable salt thereof as recited in claim 8, wherein the compound (XK) in step (3) is prepared in the steps of:
(1) preparing a compound (XXXIX) by halogenating a compound (XXXVI);
(2) preparing a compound (XXXX) by reacting the compound (XXXIX) obtained in step (1) with a thioamide compound (VI) ; and
(3) treating the compound (XXXX) obtained in step (2) with a base, ZnCl2, and reacting the base-treated compound with Pd (PPh3) 4 and a compound (XXXXI), as expressed by scheme 6 below,
[Scheme 6]
Figure imgf000377_0001
wherein Rl and R2 are the same as defined in Formula 1; and Hal and Hal' denote a halogen atom.
[Claim 15] The process for preparing the substituted 1,3-thiazol derivative or a pharmaceutically acceptable salt thereof as recited in claims 6 or 8, wherein, in the compound ( I -a) or ( I -b) , if R2 is
Figure imgf000378_0001
the compound ( I -c) or ( I -b) is deprotected and the deprotected compound is methylated.
[Claim 16]
A pharmaceutical composition for preventing and treating TNF-α related diseases comprising the substituted 1,3-thiazol derivative or pharmaceutically acceptable salt thereof in claim 1.
[Claim 17]
The pharmaceutical composition for preventing and treating TNF-α related diseases as recited in claim 16, wherein the TNF-α related diseases includes arthritides, toxemias, inflammatory intestinal diseases, inflammatory pulmonary diseases, cachexias, cancers, multiple myeloma, cardiovascular diseases, coronary heart diseases, chronic obstructive pulmonary diseases,
Creutzfeldt-Jakob disease, viral infections, autoimmune diseases, atopic dermatitis, psoriasis, paralysis, dementia, cerebral paralysis, AIDS encephalopathy, meningitis, congestive heart failure, hepatitis, dialysis hypotension or disseminated intravascular coagulation.
PCT/KR2006/002325 2005-06-20 2006-06-16 New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory acitivity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same WO2006137658A1 (en)

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