WO2006071035A1 - Novel ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide derivatives - Google Patents

Novel ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide derivatives Download PDF

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WO2006071035A1
WO2006071035A1 PCT/KR2005/004524 KR2005004524W WO2006071035A1 WO 2006071035 A1 WO2006071035 A1 WO 2006071035A1 KR 2005004524 W KR2005004524 W KR 2005004524W WO 2006071035 A1 WO2006071035 A1 WO 2006071035A1
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Prior art keywords
pyridine
thiazolo
methyl
amino
urea
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PCT/KR2005/004524
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French (fr)
Inventor
Jinho Lee
Seihyun Choi
Seunghyun Yoon
Hwan Geun Choi
Yun Sik Kim
Young Kwan Kim
Kiwon Jo
Semi Kim
Sun-Young Koo
Jung In Kim
Jieun Kim
Sang-Yong Hong
Jeong-Yong Suh
Sun Hwa Lee
Hae-Seong Yoon
Heung-Soo Cho
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Lg Life Sciences, Ltd.
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Publication of WO2006071035A1 publication Critical patent/WO2006071035A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to novel compounds having ([l,3]thiazolo[5,4- 6]pyridine-2-yl)-2-carboxamide structure, and more specifically, to novel compounds for inhibition of VEGF-Receptor-2-kinase ("VEGFR2 kinase” or “KDR”, hereinafter, referred to as "KDR”) activity, as will be illustrated in Formula 1 later herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • VEGFR2 kinase VEGFR2 kinase
  • KDR a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof.
  • the compounds according to the present invention are useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the unregulated or undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • Angiogenesis referring to the physiological mechanism of generating new blood vessels for providing nutrients and oxygen required for cell survival and eliminating metabolites therefrom, allows only 0.01% of blood vessel cells to proliferate under normal conditions, thereby recovering wounded parts in blood vessels (Carmeliet et ah, 2000, Nature 407:249-257).
  • angiogenesis is further required.
  • solid tumors cannot practically grow over a certain size (e.g., about 100 - 200 ⁇ m in diameter). That is because there is a limit on the distance over which nutrients or oxygen can reach cells by diffusion (the so-called diffusion limit) (Carmeliet et ah, 2000, Nature 407:249-257).
  • cancer cells distant from blood vessels become hypoxic due to oxygen deficiency.
  • cancer cells or stromal cells secrete various pro- angiogenic factors to induce angiogenesis toward a solid tumor.
  • pro- angiogenic factors there are VEGF (Vascular Endothelial Growth Factor), bFGF (basic Fibroblast Growth factor), PDGF (Platelet-derived growth factor), and the like.
  • VEGF Vascular Endothelial Growth Factor
  • bFGF basic Fibroblast Growth factor
  • PDGF Platinum-derived growth factor
  • Rheumatoid arthritis a non-cancer angiogenesis-related disease, refers to a disease state wherein newly created capillary vessels destroy cartilaginous tissues as arthritis proceeds to chronic inflammatory disease.
  • diabetic retinopathy refers to the disease caused by invasion of capillary vessels into the vitreous body of retina. It is known that pre-angiogenic factors are secreted from ischemic retina to cause diabetic retinopathy. Since eyes are tissues with the least vascularization in body, angiogenesis results directly in the loss of eyesight. As such, the ultimate therapy can be achieved only by prevention of angiogenesis (Carmeliet P., 2000, Nature Medicine 6: 389-395, Aiello L. P., 2000, Nature Medicine 6: 379-381).
  • Angiogenesis receptor tyrosine kinases as receptors of pro-angiogenic factors, such as VEGFR2 (KDR), FGFRl, PDGFR- ⁇ and the like, have drawn attention as a target for development of anti-angiogenesis drugs.
  • Such anti- angiogenesis drugs exhibit the effect of inhibiting the activity of VEGFR2 (KDR) and simultaneously also inhibiting the activity of other angiogenesis RTK family receptors. This combined inhibition effect is known as one mechanism to significantly increase the angiogenesis inhibition effect (Adams et al., 2002, Current Opinion in Chemical Biology, 5:486-492). Therefore, much research is directed toward identifying compounds useful in the treatment and prevention of angiogenesis-related diseases such as cancers, rheumatoid arthritis, diabetic retinopathy, etc.
  • the inventors of the present invention while carrying out extensive research and many experiments, synthesized novel compounds capable of inhibiting KDR activity and, after investigating their inhibitory effect, found that they can be used in the treatment or prevention of angiogenesis-related diseases resulting from the undesired or unregulated KDR activity, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • the present invention was accomplished on the basis of such finding. According to the present invention there is provided a compound of Formula 1
  • R 1 is one selected from the group consisting of
  • Y 1 and Y 2 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl;
  • Y 3 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl, and
  • Y 4 is selected from the group consisting of hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl;
  • n is an integer from 0 to 3;
  • Zi is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl, or two substituents are combined to form a cyclic saturated alkyl or a cyclic saturated alkyl interrupted by N, O or S;
  • Z 2 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl;
  • Z 3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furane, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl; and n is an integer from 0 to 3;
  • R 2 is selected from the group consisting of cyclic alkyl, aryl, heteroaryl, optionally substituted cyclic alkyl, aryl and heteroaryl;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl;
  • X is selected from the group consisting of O, S and NR', where R' is hydrogen or lower alkyl.
  • the substituent group(s) is(are) substituted with one or more group(s) individually and independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothi
  • Typical alkyl groups may be individually or independently substituted with one or more groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "pharmaceutically acceptable salt” means a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Other terms such as “hydrate”, “solvate” and “isomer” also have the same meaning as the above.
  • Pharmaceutical salts can be prepared by treating a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid or p-toluenesulfonic acid; or organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, caproic acid, isobutanic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or salicylic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid
  • sulfonic acids such as methanesulfonic acid, ethanesul
  • Pharmaceutical salts can also be prepared by reacting a compound of the invention with a base to form salts such as ammonium salts, alkali metal salts such as sodium or a potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • salts such as ammonium salts, alkali metal salts such as sodium or a potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.
  • solvate means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts.
  • isomer means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom.
  • prodrug means an agent that is converted into the parent drug in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an active group, where the peptide is metabolized to reveal the active moiety.
  • aryl means an aryl group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine).
  • carbocyclic aryl e.g., phenyl
  • heterocyclic aryl groups e.g., pyridine
  • the term includes monocyclic or fused- ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.
  • heteroaryl means an aryl group which contains at least one heterocyclic ring.
  • heterocycle means a cyclic group in which one or more ring carbons are replaced with oxygen, nitrogen or sulfur and which includes, for example, but is not limited to furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, etc.
  • alkyl means an aliphatic hydrocarbon group.
  • the alkyl moiety may be a "saturated alkyl” group, which means that it does not contain any alkene or alkyne moieties.
  • the alkyl moiety may also be an "unsaturated alkyl” moiety, which means that it contains at least one alkene or alkyne moiety.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkyl moiety, whether saturated or unsaturated may be branched, straight chain, or cyclic.
  • the alkyl group may have 1 to 20 carbon atoms.
  • the alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds of the invention may be designated as "C 1 -C 4 alkyl" or similar designations.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfonyl* pyrrolidinone, pyrrolidine, piperidine, piperazine, thiophene, morpholine, amino including
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • R refers to a substituent selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl (bonded through a ring carbon) and optionally substituted heteroalicyclic (bonded through a ring carbon).
  • a "cyano" group refers to a -CN group.
  • An “isocyanato” group refers to a -NCO group.
  • a "thiocyanato" group refers to a -CNS group.
  • An “isothiocyanato” group refers to a -NCS group.
  • a "trihalomethanesulfonamido" group refers to a Z 3 CS( ⁇ O) 2 NR- group wherein Z and R are as defined herein, respectively.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • R 1 is preferably selected from the substituents I) - IX) as follows:
  • substituents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidin
  • alkenyl substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
  • Z 2 is optionally substituted lower alkylene
  • Z 3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl.
  • R 2 is preferably selected from the substituents I) - IV) as follows:
  • cyclic alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl ;
  • substituents selected from the group consisting of halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
  • R 2 is preferably aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl, more preferably aryl substituted with halogen, lower alkyl or hydroxy.
  • substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulf
  • R 3 is preferably selected from the substituents I) - III) as follows:
  • substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
  • R 3 is more preferably hydrogen or lower alkyl.
  • X is preferably O or S, more preferably S.
  • Representative compounds of the present invention include, for example, but are not limited to the following compounds: 1. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4- ⁇ ]pyridine-2-yl] cyclopentanecarboxamide
  • the present invention also provides processes for preparation of the compound of Formula 1.
  • the compound according to the present invention can be prepared by various processes.
  • the preparation processes described herein below are only exemplary ones and a variety of processes can also be anticipated based upon the general technologies and practices in the organic chemistry synthesis field. As such, the scope of the instant invention is not limited to the below processes.
  • the compound of Formula 1 can be prepared by the process comprising (i) a step of introducing a NR 2 R 3 substituent as defined in Formula 1 into 2-chloro-5-nitropyridine of Formula 2 below as a starting material, (ii) a step of preparing hetero pyridine, and (iii) a step of introducing carboxamide thereto.
  • the process for preparing the compound of Formula 1 comprises,
  • the process for preparing the compound of Formula 1 comprises,
  • R 4 is as defined above, R 5 is the same as R 4 , and Ra is -NZ 1 (Z 2 )H-Z 3 .
  • the compound according the present invention is effective for the treatment and prevention of diseases associated with angiogenesis, and particularly those diseases associated with unregulated or undesired KDR activity. Therefore, the present invention provides the use of the compound of Formula 1 for manufacture of a medicament for the treatment or prevention of diseases resulting from an unregulated or undesired KDR activity.
  • diseases include, for example, but are not limited to cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis, Kaposi's sarcoma, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • composition means a mixture of a compound of the invention with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but are not limited to oral, injection, aerosol, parenteral, and topical administrations.
  • Pharmaceutical compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • a therapeutically effective amount means that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease being treated.
  • a therapeutically effective amount refers to that amount which has the effect of (i) reversing the rate of progress of a disease, or, in case of cancer reducing the size of the tumor; (ii) inhibiting to some extent further progress of the disease, which in case of cancer may mean slowing to some extent, or preferably stopping tumor metastasis or tumor growth; and/or, (iii) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.
  • carrier means a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the pharmaceutical composition of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compound of the present invention to be formulated as tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension and the like, for oral ingestion by a patient.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compounds of the present invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in a conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powdered mixture of the compound and a suitable powder base such as lactose or starch.
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system may be the VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 85% w/v of the nonpolar surfactant Polysorbate 80 ® , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD:D5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution.
  • This co-solvent system dissolves hydrophobic compounds well, and itself has minimal toxicity upon systemic administration.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80 ® ; the fraction of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide may also be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 5O as determined in cell culture. Such information can be used to more accurately determine useful doses in humans.
  • Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD 50 and ED 5O . Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 5 o with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the attending physician in view of the patient's condition (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as needed.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the angiogenesis receptor tyrosine kinase inhibition effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data; e.g., the concentration necessary to achieve 50-90% inhibition of the angiogenesis receptor tyrosine kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the j udgment of the prescribing physician.
  • PREPARATION 8 Preparation of ⁇ -(2-fluorophenyl)[l,3]thiazolo[5,4-6] pyridine-2,5-diamine
  • PREPARATION 11 Preparation of iV 6 -(2-fluorophenyl)[l,3]thiazolo[5,4-fr
  • PREPARATION 12 Preparation of ⁇ -(S-fluoro ⁇ -methylphenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 13 Preparation of - ⁇ 6 -(4-chloro-2-fluorophenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 14 Preparation of ⁇ -(2,4-difluorophenyl)[l,3]thiazolo[5,4- 6]pyridine-2,5-diamine
  • PREPARATION 18 Preparation of 2-( ⁇ [5-(4-chloro-2-fluoroanilino) [1 ,3] thiazolo [5,4-6] py ridine-2-yl] amino ⁇ carbonyl)cyclopropanecarboxylic acid
  • PREPARATION 20 Preparation of iV 6 -(4-chlorophenyl)- ⁇ ' 6 -methyl [l,3]thiazoIo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 22 Preparation of - ⁇ 6 -(2,4-difluorophenyl)-iV 6 -methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 23 Preparation of iV 6 -(2,6-difluorophenyl)-iV 6 -methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
  • PREPARATION 24 Preparation of iV 6 -(4-bromo-2-fluorophenyl)- ⁇ ' 6 -methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 25 Preparation of ⁇ ' 6 -(2-methoxyphenyl)-iV 6 -methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 26 Preparation of ⁇ - ⁇ -difluorophenyO- ⁇ -methyl [ 1 ,3] thiazolo [5,4-A] py ridine-2,5-diamine
  • PREPARATION 27 Preparation of iV 6 -methyl-iV 6 -[4-(trifluoromethyl)phenyl] [l,3]thiazolo[5,4- ⁇ ]pyridine-2,5-diamine
  • PREPARATION 28 Preparation of 7V 6 -(4-methoxypheny I)-JV 6 - methy 1 [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
  • PREPARATION 29 Preparation of 7V 6 -(4-isopropyIphenyl)-i ⁇ 6 -methyl[l,3]- thiazolo[5,4- ⁇ ]pyridine-2,5-diamine
  • PREPARATION 30 Preparation of iV 6 -(2,3-dihydro-l ⁇ -indene-5-yI)-iV 6 - methy 1 [ 1 ,3] thiazolo [5,4-Z>] py ridine-2,5-diamine
  • PREPARATION 31 Preparation of ethyl 2- ⁇ 4-[2-amino[l,3]thiazolo[5,4-6] pyridine-5-yl](methyl)amino ⁇ phenyI ⁇ acetate
  • PREPARATION 32 Preparation of ⁇ - ⁇ -chlorophenylJ-iV 6 - ethyl[l,3]thiazolo[5,4-6]pyridine-2,5-diamine
  • PREPARATION 33 Preparation of ethyl 2-[4-chIoro(5-nitro-2- py ridinyl)anilino] acetate
  • PREPARATION 35 Preparation of ethyl 2-[(2-amino[l,3]thiazolo[5,4- ⁇ ]pyridine-5-yl)-4-chloroanilino]-l-ethanol
  • PREPARATION 38 Preparation of 4-[(2-amino[l,3]thiazoIo[5,4-6]pyridine-5- yl)(methyl)amino] benzoate
  • PREPARATION 40 Preparation of tert-butyl 4-((£)-3- ⁇ [5-(4-bromo-2- fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yI]amino ⁇ -3-oxo-l-(propenyl)- 1 -piperidinecarboxy late 5.96 g (11.2 mmol) of the compound obtained in PREPARATION 39 was dissolved in 100 ml of tetrahydrofuran and 3.58 g (16.8 mmol) of 4-formyl-piperidine-
  • PREPARATION 41 Preparation of (E)-N- ⁇ 5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-/>]pyridine-2-yl ⁇ -3-(4-piperidinyI)-2- propeneamide
  • PREPARATION 46 Preparation of 2-[(2-amino[l,3]thiazolo[5,4-6] ⁇ yridine-5- yI)(methyl)amino]-5-fluorophenol
  • PREPARATION 47 Preparation of 2-[ ⁇ 2-[(cyclopropylcarbonyl)amino]- [l,3]thiazolo[5,4-Z»]pyridine-5-yl ⁇ (methyl)amino]-5-fluorophenyI cyclopropanecarboxylate
  • the reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively.
  • the collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 4.68 g (11.6 mmol) of the title compound at a yield of 64%.
  • the reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively.
  • the collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 4.85 g (11.6 mmol) of the title compound at a yield of 64%.
  • EXAMPLE 16 Preparation of iV-[5-(4-fluoro-2-hydroxy ⁇ iethyIanilino [l,3]thiazolo[5,4-Z>]pyridine-2-yl]-cyclopropanecarboxyamide 56 mg (0.13 mmol) of the compound, obtained in PREPARATION 47, was dissolved in methanol/water (2 ml/2ml, v/v). To the solution, 17 mg (0.39 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature.
  • EXAMPLE 48 Preparation of iV- ⁇ 5-[4-chIoro(ethyl)aniline][l,3]thiazolo[5,4- 6]pyridine-2-yl ⁇ acrylamide
  • EXAMPLE 50 Preparation of 2-(4-chloro ⁇ 2-[(cyclopropyIcarbonyl)amino] [l,3]thiazolo[5,4-Z>]pyridine-5-yl ⁇ aniIino)acetic acid 5.77 g (13.4 mmol) of the compound as obtained in EXAMPLE 49 was dissolved in 100 ml of tetrahydrofuran/ethanol/water (3/1/1). To the solution, 1.12 g (26.8 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature. After 8 hours, the reaction solution was neutralized with IN aqueous hydrochloric acid solution.
  • reaction solution was extracted twice with 100 ml of ethyl acetate and then dried over anhydrous MgSO 4 . After removing the solvent by distillation under reduced pressure, 3.67 g (9.11 mmol) of the title compound was obtained at a yield of 68%, without any further purification step.
  • EXAMPLE 68 Preparation of (£)-7V- ⁇ 5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-£]pyridine-2-yl ⁇ -3-(l-ethyl-4-piperidinyl)-2-propeneamide 3.83 g (8.26 mmol) of the compound as obtained in PREPARATION 41 was introduced into 100 ml of dichloromethane, and 2.09 g (20.7 mmol) of triethylamine was dded thereto, followed by stirring at room temperature.
  • reaction solution was diluted with 200 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO 4 .
  • the crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol 9/1, v/v) to give 1.53 g (3.44 mmol) of the title compound at a yield of 19%.
  • EXAMPLE 72 Preparation of 4-[ ⁇ 2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yl ⁇ (methyl)amino]-7V-[2-(dimethyIaino)ethyl]benzamide
  • EXAMPLE 71 was conducted by using 1.38 g (15.6 mmol) of ⁇ iV-dimethylethylenediamine instead of acetaldehyde, thereby obtaining 2.83 g (6.45 mmol) of the title compound at a yield of 62%.
  • EXAMPLE 75 Preparation of iV- ⁇ 5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4- 6]pyridine-2-yl ⁇ -l-methyl-l//-imidazole-5-carboxamide
  • EXAMPLE 79 Preparation of (£)-iV- ⁇ 5-[4-chloro(methyl)aniIino][l,3] thiazolo[5,4-6]pyridine-2-yl ⁇ -4-(l,4-dioxa-8-azaspiro[4.5]de-8-cyl)-2-buteneamide
  • the same procedure as in EXAMPLE 70 was conducted except that 7.78 g (54.3 mmol) of 4-piperidine ethylene ketal was used instead of morpholine, thereby obtaining 903 mg (1.81 mmol) of the title compound at a yield of 10%.

Abstract

The present invention relates to novel compounds having ([1,3]thiazolo[5,4- b]pyridine-2-yl)-2-carboxamide structure, as being illustrated in Formula 1, for inhibition of angiogenesis receptor tyrosine kinases, in particular, VEGF receptor 2 kinase ('KDR') activity, methods for preparing the same, their use and a pharmaceutical composition comprising thereapeutically effective amount of the said compounds. The compounds according to the present invention are useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the unregulated or undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.

Description

NOVEL ([1,3ITHIAZOLO[S^-B]PYRIDIN-I-YL)-ICARBOXAMIDE
DERIVATIVES
FIELD OFTHE INVENTION
The present invention relates to novel compounds having ([l,3]thiazolo[5,4- 6]pyridine-2-yl)-2-carboxamide structure, and more specifically, to novel compounds for inhibition of VEGF-Receptor-2-kinase ("VEGFR2 kinase" or "KDR", hereinafter, referred to as "KDR") activity, as will be illustrated in Formula 1 later herein, or a pharmaceutically acceptable salt, hydrate, solvate, isomer, and prodrug thereof. The compounds according to the present invention are useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the unregulated or undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
BACKGROUND OF THE INVENTION
Angiogenesis, referring to the physiological mechanism of generating new blood vessels for providing nutrients and oxygen required for cell survival and eliminating metabolites therefrom, allows only 0.01% of blood vessel cells to proliferate under normal conditions, thereby recovering wounded parts in blood vessels (Carmeliet et ah, 2000, Nature 407:249-257).
However, fast-growing tissues such as solid tumors have elevated demand for nutrients and oxygen, thus angiogenesis is further required. Without any angiogenesis, solid tumors cannot practically grow over a certain size (e.g., about 100 - 200 μm in diameter). That is because there is a limit on the distance over which nutrients or oxygen can reach cells by diffusion (the so-called diffusion limit) (Carmeliet et ah, 2000, Nature 407:249-257).
Cancer cells distant from blood vessels become hypoxic due to oxygen deficiency. In such a condition, cancer cells or stromal cells secrete various pro- angiogenic factors to induce angiogenesis toward a solid tumor. Among these pro- angiogenic factors, there are VEGF (Vascular Endothelial Growth Factor), bFGF (basic Fibroblast Growth factor), PDGF (Platelet-derived growth factor), and the like. Angiogenesis processes activated by these growth factors result in the proliferation of cancer cells (Carmeliet P., 2000, Nature Medicine 6:389-395, Yancopoulos et ah, 2000, Nature 407:242-248).
Rheumatoid arthritis, a non-cancer angiogenesis-related disease, refers to a disease state wherein newly created capillary vessels destroy cartilaginous tissues as arthritis proceeds to chronic inflammatory disease.
Meanwhile, diabetic retinopathy refers to the disease caused by invasion of capillary vessels into the vitreous body of retina. It is known that pre-angiogenic factors are secreted from ischemic retina to cause diabetic retinopathy. Since eyes are tissues with the least vascularization in body, angiogenesis results directly in the loss of eyesight. As such, the ultimate therapy can be achieved only by prevention of angiogenesis (Carmeliet P., 2000, Nature Medicine 6: 389-395, Aiello L. P., 2000, Nature Medicine 6: 379-381).
Angiogenesis receptor tyrosine kinases (RTKs) as receptors of pro-angiogenic factors, such as VEGFR2 (KDR), FGFRl, PDGFR-β and the like, have drawn attention as a target for development of anti-angiogenesis drugs. Such anti- angiogenesis drugs exhibit the effect of inhibiting the activity of VEGFR2 (KDR) and simultaneously also inhibiting the activity of other angiogenesis RTK family receptors. This combined inhibition effect is known as one mechanism to significantly increase the angiogenesis inhibition effect (Adams et al., 2002, Current Opinion in Chemical Biology, 5:486-492). Therefore, much research is directed toward identifying compounds useful in the treatment and prevention of angiogenesis-related diseases such as cancers, rheumatoid arthritis, diabetic retinopathy, etc.
As representative examples of compounds of inhibiting KDR kinase activity, known are 2-indolinone derivatives (WO 9850356), quinazoline derivatives (EP 0566266 Al), triazole derivatives (WO 02057240), diaminothiazole derivatives (WO 0075120), and benzothiazole derivatives (WO 0157008), but these compounds do not have any similarity to the compounds according to the present invention in view of chemical structure.
SUMMARY OF THE INVENTION
The inventors of the present invention, while carrying out extensive research and many experiments, synthesized novel compounds capable of inhibiting KDR activity and, after investigating their inhibitory effect, found that they can be used in the treatment or prevention of angiogenesis-related diseases resulting from the undesired or unregulated KDR activity, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc. The present invention was accomplished on the basis of such finding. According to the present invention there is provided a compound of Formula 1
or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof,
where
A) R1 is one selected from the group consisting of
I) hydrogen;
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl;
IH) optionally substituted alkenyl;
IV) optionally substituted aryl;
V) optionally substituted heterocycle;
VI) perhaloalkyl;
VII) a substituent of formula -CY1Y2(Y3)H-Y4, where Y1 and Y2 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl; Y3 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl, and Y4 is selected from the group consisting of hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl; n is an integer from 0 to 3;
VIII) a substituent of formula -NZ1(Z2)H1-Z3, where
Zi is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl, or two substituents are combined to form a cyclic saturated alkyl or a cyclic saturated alkyl interrupted by N, O or S;
Z2 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl;
Z3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furane, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl; and n is an integer from 0 to 3;
B) R2 is selected from the group consisting of cyclic alkyl, aryl, heteroaryl, optionally substituted cyclic alkyl, aryl and heteroaryl;
C) R3 is selected from the group consisting of hydrogen, optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl; and
D) X is selected from the group consisting of O, S and NR', where R' is hydrogen or lower alkyl.
DISCLOSURE OF THE INVENTION
Some terms used in the present disclosure are briefly explained below.
When the term "optionally substituted" is used without any separate or additional descriptions in the present disclosure, it is understood to comprise both unsubstituted and substituted cases. In case of substituted case, the substituent group(s) is(are) substituted with one or more group(s) individually and independently selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfonyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone(oxo-pyrrolidine), piperidine, piperidinone (oxo-piperidine), piperazine, thiophene, morpholine, dioxolane, amino including mono- and di- substituted amino groups, and the protected derivatives thereof. If necessary, they may also be optionally substituted. Further, these substituents may be mutually combined to form cyclic structures.
Typical alkyl groups may be individually or independently substituted with one or more groups selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
As used herein, the term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Other terms such as "hydrate", "solvate" and "isomer" also have the same meaning as the above. Pharmaceutical salts can be prepared by treating a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid or p-toluenesulfonic acid; or organic carbonic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, caproic acid, isobutanic acid, oxalic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid or salicylic acid, and the like. Pharmaceutical salts can also be prepared by reacting a compound of the invention with a base to form salts such as ammonium salts, alkali metal salts such as sodium or a potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine or tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like.
As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound thereto by non-covalent intermolecular forces.
As used herein, the term "solvate" means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound thereto by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. As used herein, the term "isomer" means a compound of the present invention or a salt thereof, that has the same chemical formula or molecular formula but is optically or stereochemically different therefrom.
As used herein, the term "prodrug" means an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example of a prodrug, without limitation, would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transport across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an active group, where the peptide is metabolized to reveal the active moiety.
The expression "compound(s) of the present invention" or "compound(s) of Formula 1", even when a separate explanation is not added thereto, is intended to include the compound itself, and/or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof.
As used herein, the term "aryl" means an aryl group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused- ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term "heteroaryl" means an aryl group which contains at least one heterocyclic ring.
The term "heterocycle" means a cyclic group in which one or more ring carbons are replaced with oxygen, nitrogen or sulfur and which includes, for example, but is not limited to furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, etc.
The term "alkyl" means an aliphatic hydrocarbon group. The alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any alkene or alkyne moieties. The alkyl moiety may also be an "unsaturated alkyl" moiety, which means that it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
The alkyl group may have 1 to 20 carbon atoms. The alkyl group may also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds of the invention may be designated as "C1-C4 alkyl" or similar designations. By way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acetyl, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfonyl* pyrrolidinone, pyrrolidine, piperidine, piperazine, thiophene, morpholine, amino including mono- and di-substituted amino groups, and the protected derivatives thereof. If necessary, they may also be optionally substituted.
Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The substituent "R", as a designation used in the present disclosure, appearing by itself and without a number designation refers to a substituent selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl (bonded through a ring carbon) and optionally substituted heteroalicyclic (bonded through a ring carbon).
An "O-carboxy" group refers to a RC(=O)O- group wherein R is as defined herein.
A "C-carboxy" group refers to a -C(=O)OR group wherein R is as defined herein.
An "acetyl" group refers to a -C(=O)CH3 group. A "trihalomethanesulfonyl" group refers to a Z3CSC=O)2 group wherein Z is a halogen.
A "cyano" group refers to a -CN group.
An "isocyanato" group refers to a -NCO group.
A "thiocyanato" group refers to a -CNS group.
An "isothiocyanato" group refers to a -NCS group.
A "sulfinyl" group refers to a -S(=O)-R group wherein R is as defined herein.
A "S-sulfonamido" group refers to a -S(=O)2NR group wherein R is as defined herein.
A "N-sulfonamido" group refers to a RSC=O)2NH- group wherein R is as defined herein.
A "trihalomethanesulfonamido" group refers to a Z3CS(^O)2NR- group wherein Z and R are as defined herein, respectively.
An "O-carbamyl" group refers to a -0C(=0)-NR group wherein R is as defined herein.
An "N-carbamyl" group refers to a R0C(=0)NH- group wherein R is as defined herein.
An "O-thiocarbamyl" group refers to a -OC(=S)-NR group wherein R is as defined herein. An "N-thiocarbamyl" group refers to an ROC(=S)NH- group wherein R is as defined herein.
A "C-amido" group refers to a -C(=O)-NR2 group wherein R is as defined herein.
An "N-amido" group refers to a RC(=O)NH- group wherein R is as defined herein.
The term "perhaloalkyl" refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
Other terms used herein can be interpreted as having their usual meanings in the art to which the present invention pertains.
In the compound of Formula 1 above, R1 is preferably selected from the substituents I) - IX) as follows:
I) lower alkyl;
II) lower alkyl substituted with one or more substituents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, thiophene, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
HI) cyclic alkyl or heterocycle;
IV) cyclic alkyl or heterocycle substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
V) alkenyl;
VI) alkenyl substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
VII) aryl or heteroaryl;
VIII) aryl or heteroaryl substituted with one or more substitutents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkyl, lower alkoxy, amine, lower alkylamine, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl;
IX) a substituent of formula -NZ1(Z2)-Z3, where Z1 is selected from the group consisting of hydrogen and optionally substituted lower alkyl;
Z2 is optionally substituted lower alkylene;
Z3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl.
In the compound of Formula 1 above, R2 is preferably selected from the substituents I) - IV) as follows:
I) cyclic alkyl;
II) cyclic alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl ;
III) heteroaryl;
IV) heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
R2 is preferably aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl, more preferably aryl substituted with halogen, lower alkyl or hydroxy.
In the compound of Formula 1 above, R3 is preferably selected from the substituents I) - III) as follows:
I) hydrogen;
II) lower alkyl;
III) lower alkyl substituted with one or more substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
R3 is more preferably hydrogen or lower alkyl.
X is preferably O or S, more preferably S.
Representative compounds of the present invention include, for example, but are not limited to the following compounds: 1. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-δ]pyridine-2-yl] cyclopentanecarboxamide
2. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
3. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-ό]pyridine-2-yl]-2-(thiophene-2-yl) acetamide
4. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-3- cyclopentylpropaneamide
5. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-2-(4- morpholinyl)acetamide
6. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-2-(l- pyrrolidinyl)acetamide
7. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-&]pyridine-2-yl]-2- (diethylamino)acetamide
8. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-Z>]pyridine-2-yl]acetamide
9. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-2- methylpropaneamide
10. iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine-2- yl] cyclobutanecarboxamide
11. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]-3-(4- moφholinyl)propaneamide 12. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-2-(4-methyl-l- piperazinyl) acetamide
13. ethyl l-({[5-(4-chloroanilino)[l,3]thiazolo[5,4-b]pyridine-2-yl]amino} carbonyl) cyclopropanecarboxylate
14. l-({[5-(4-chloroanilino)[l,3]thiazolo[5,4-έ]pyridine-2-yl]amino}carbonyl) cyclopropanecarboxylic acid
15. iV-[5-(4-chloro-2-fluoromethylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-iV'- [2-(4-morpholinyl)ethyl]urea
16. N-[5-(4-fluoro-2-hydroxymethylanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl cyclopropanecarboxyamide
17. iV-[5-(cyclohexylamino)[l,3]thiazolo[5,4-Z>]pyridine-2- yl] cyclopropanecarboxamide
18. N-[5-(cyclopentylamino)[l,3]thiazolo[5,4-ό]pyridine-2- yl] cyclopropanecarboxamide
19. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-3- (diethylamino)propaneamide
20. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-δ]pyridine-2-yl]-3-(l -piperidinyl) propaneamide
21. N-[5-(3-chloroanilino)[l ,3]thiazolo[5,4-&]pyridine-2- yl] cyclopropanecarboxamide
22. iV-[5-(2-chloroanilino)[l ,3]thiazolo[5,4-&]pyridine-2- yl] cycloproanecarboxamide
23. N-[5-(2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
24. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
25. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-Z>]ρyridine-2-yl]-2-(4- morpholinyl)acetamide
26. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-3-(4- morpholinyl)propaneamide
27. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
28. 2-({[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] amino } carbonyl)cyclopropanecarboxylic acid
29. N-[5-(4-bromo-2-fluoroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl] cyclopropanecarboxamide
30. N-[5-(3-fluoro-4-methylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
31. N-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
32. iV-[5-(2,4-difluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide 33. iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-2-[(4- methyl- 1 -piperazinyl)carbonyl]cyclopropanecarboxamide
34. N1-[2-(diethylamino)ethyl]-N2-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4- 6]pyridine-2-yl] - 1 ^-cyclopropanedicarboxamide
35. (E)-N-[5-(2-fluoro-4-methylanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl]-3- phenyl-2-propeneamide
36. iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]acrylamide
37. N1-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]-N2-[2-(4- morpholinyl)ethyl] - 1 ^-cyclopropanedicarboxamide
38. N1-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-N2-[2-(2- pyridinyl)ethyl]- 1 ,2-cyclopropanedicarboxamide
39. iV-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]acrylamide
40. N-[5-(4-chloro2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-3-methyl-3- buteneamide
41. N-[5-(4-chloro2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]-3-methyl-2- buteneamide
42. N-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-3- buteneamide
43. (E)-N-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-2- buteneamide
44. iV-[5-(2,6-difluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
45. iV-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl} cyclopropanecarboxamide
46. iV-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}acrylamide
47. jV-{5-[4-chloro(ethyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
48. N-{5-[4-chloro(ethyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}acrylamide
49. ethyl 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-ό] pyridine-5 -yl } anilino)acetamide
50. 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl}anilino)acetic acid
51. 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-ό]pyridine-5- yl } anilino)ethyl cyclopropanecarboxylate
52. iV-{5-[4-chloro(2-hydroxyethyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
53. J/V-[5-(4-chloro-2-fluromethylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
54. iVr-{5-[2,4-difluoro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
55. N-{5-[2,6-difluoro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide 56. Λ/-[5-(4-bromo-2-fluoromethylanilino)[l,3]thiazolo[5,4-έ]pyridine-2-yl] cyclopropanecarboxamide
57. 7V-{5-[2-methoxy(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
58. iV-{5-[3,4-difluoro(methyl)anilino][l ,3]thiazolo[5,4-6]ρyridine-2-yl} cyclopropanecarboxamide
59. iV-{5-[methyl-4-(trifluoromethyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
60. iV-{5-[4-methoxy(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
61. N-{5-[4-cyano(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
62. N-{5-[4-isopropyl(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
63. N-{5-[2,3-dihydro-lH-indene-5-yl(methyl)anilino][l,3]thiazolo[5,4- 6]pyridine-2-yl } cyclopropanecarboxamide
64. N- {5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-ό]pyridine-2-yl} - 1 -methyl- 1 - H-pyrrole-2-carboxamide
65. ethyl 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-ό]pyridine-5-yl} (methyl)amino]benzoate
66. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-Z>]pyridine-5-yl} (methyl)amino] benzoic acid
67. (E)-iV-[5-(4-bromo-2-fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]- 3-(4-piperidinyl)-2-propeneamide
68. (E)-iV-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-Z>]pyridine-2-yl}-3-(l- ethyl-4-piperidinyl)-2-propeneamide
69. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl}-3-(l- methyl-4-piperidinyl)-2-propeneamide
70. (E)-7V-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl}-4-(4- morpholinyl)-2-buteneamide
71. 4[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl } (methyl)amino] -JV, JV-dimethylbenzamide
72. 4[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- y 1 } (methyl)amino] -JV- [2-(dimethylamino)ethyl] benzamide
73. JV- { 5 - [4-chloro(methyl)anilino] [ 1 ,3]thiazolo [5,4-ό]pyridine-2-yl } - 1 -methyl- l//-imidazole-4-carboxamide
74. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl}(methyl)amino]-JV-methylbenzamide
75. JV-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl}-l-methyl-l- H-imidazole-5 -carboxamide
76. (E)-N- { 5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-6]pyridine-2-yl } -3-( 1 - (methylsulfonoyl)-4-piperidinyl)-2-propeneamide 77. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl} (methyl)amino]benzamide
78. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl}-4-(l- piperidinyl)-2-buteneamide
79. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}-4-(l,4- dioxa-8-azaspiro [4.5 ] de- 8 -cyl] -2-buteneamide
80. (E)-J/V-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl}-4- (dimethylamino)-2-buteneamide
81. ethyl 2-{4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl } (methyl)amino]phenyl } acetamide
82. 2-{4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl}(methyl)amino]phenyl}acetic acid
83. N-{5-[4-[2-(dimethylamino)-2-oxoethyl](methyl)anilino][l,3]thiazolo[5,4- δ]pyridine-5-yl}cyclopropanecarboxamide
84. ethyl 4-[(E)-3-({5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2- yl } amino)-3 -oxo- 1 -propenyl] - 1 -piperidinecarboxylate
85. methyl 4-[(£)-3-({5-[4-chloro(methyl)anilino][l ,3]thiazolo[5,4-6]pyridine-2- yl}amino)-3-oxo- 1 -propenyl] -1 -piperidinecarboxylate
86. (E)-3-(l-acetyl-4-piperidinyl)-iV-{5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-δ]pyridine-2-yl}-2-propeneamide
87. iV-[5-(4-chloro-2-fluoromethylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-iV)- [2-(4-morpholinyl)ethyl]-urea
88. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-ethyl-urea
89. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-diethylamino-ethyl)-urea
90. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(3 -hydroxy-propyl)-urea
91. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5 ,4-ό]pyridine-2- yl}-3-(3-morpholine-4-yl-propyl)-urea
92. l-{5- [(4-chloro-2-fluoro-phenyl)-methylamino] -thiazolo [5 ,4-δ] pyridine-2- yl} -3-(2-methoxy-ethyl)-urea
93. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(2-pyrrolidine- 1 -yl-ethyl)-urea
94. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl}-3-[3-(4-methyl-piperazine-l -yl)-propyl]-urea
95. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-(3-dimethylamino-propyl)-urea
96. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl } -3 -(3 -diethylamino-propyl)-urea
97. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [2-( 1 -methyl-pyrrolidine-2-yl)-ethyl] -urea 98. l-{5-[(4-chloro-2-fluoro-phenyl)-niethylamino]-thiazolo[5,4-&]pyridine-2- yl}-3-(2-pyridine-2-yl-ethyl)-urea
99. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl } -3 -(2-hydroxy-ethyl)-urea
100. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-hydroxy- 1 -methyl-ethyl)-urea
101. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-hydroxy-propyl)-urea
102. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-dimethylamino-ethyl)-urea
103. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -cyclopentyl-urea
104. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -cyclohexyl-urea
105. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2-yl}- 3 -(2-piperidine- 1 -yl-ethyl)-urea
106. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(5-methyl-pirazine-2-ylmethyl)-urea
107. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl}-3-(2-pyridine-4-yl-ethyl)-urea
108. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -pyridine-4-yl-urea
109. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl } -3 -( 1 ,5 -dimethyl- 1 H-pyrrole-3 -ylmethyl)-urea
110. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2-yl}- 3-thiophene-3-ylmethyl-urea
111. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -furan-3 ylmethyl-urea
112. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl } - 1 -(2-hydroxy-ethyl)- 1 -methyl-urea
113. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -((R)- 1 -(hydroxymethyl-propyl)-urea
114. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -pyridine-4-ylmethy 1-urea
115. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -pyridine-3 -ylmethyl-urea
116. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -pyridine-2-ylmethyl-urea
117. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl} -3 -pyridine-3 -yl -urea
118. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-pyridine-2-yl-urea 119. 4-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-ureido)-piperidine-l-carboxylic acid tert-butyl ester
120. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2-yl } - 3 -cyclopropylmethyl-urea
121. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -cyclohexylmethyl-urea
122. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -phenyl-urea
123. l-benzyl-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-urea
124. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl}-3-phenethyl-urea
125. 4-(3-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-ureidomethyl)-piperidine-l-carboxylic acid tert-butyl ester
126. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(4-hydroxy-butyl)-urea
127. 3-(3- { 5 - [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-ό]pyridine-2- yl}-ureidomethyl)-piperidine-l-carboxylic acid tert-butyl ester
128. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [2-(3 -hydroxy-propoxy)-ethyl] -urea
129. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(( R)-2-hydroxy- 1 -methyl-ethyl)-urea
130. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl}-3-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethyl}-urea
131. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-{2-[(4-hydroxy-piperidine-l-yl)-ethyl]-urea
132. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl}-3-{3- [(2-hydroxy-ethyl)-methyl-amino] -propyl } -urea
133. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl } -3 - [3-(4-hydroxy-piperidine- 1 -yl)-propyl] -urea
134. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl}-3-{3- [4-(2-hydroxy-ethyl)-piperidine- 1 -yl)-propyl] -urea
135. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-δ]pyridine-2- yl } -3 -hydroxy-urea
136. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -methoxy-urea
137. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(carboxymethyloxy)-urea
138. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}- ureido)-ethyl] -acetamide
139. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(methyl-amino)-urea 140. 1 - { 5 - [(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5 ,4-ό]pyridine-2-yl } - 3-(2-hydroxyethylamino)-urea
141. l-(4-aminomethyl-benzyl)-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-&]pyridine-2-yl}-urea
142. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(3 -pyridine- 1 -yl-propyl)-urea
143. 1 - { 5 -[(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-ό]pyridine-2- yl } -3 - [3-(4-hydroxymethyl-piperidine- 1 -yl)-propyl] -urea
144. {(S)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- δ]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-3-yl}-carbamic acid tert-butyl ester
145. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 ,4-dihydroxy-benzyl)-urea
146. 1 -(4-amino-benzyl)-3- { 5 - [(4-chloro-2-fluoro-phenyl)-methyl-amino] - thiazolo[5,4-ό]pyridine-2-yl}-urea
147. 1 -(3 -aminobenzyl)-3 - { 5 - [(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-&]pyridine-2-yl}-urea
148. 1 -(2-amino-benzyl)-3 - { 5 - [(4-chloro-2-fluoro-phenyl)-methyl-amino] - thiazolo[5,4-ό]pyridine-2-yl}-urea
149. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(tetrahydrofuran-2-ylmethyl)-urea
150. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 -imidazole- 1 -yl-propyl)-urea
151. 1 -(4-amino-cyclohexyl)-3 - { 5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] - thiazolo[5,4-6]pyridine-2-yl}-urea
152. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(4-hydroxy-cyclohexyl)-urea
153. (S)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- δ]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester
154. (R)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- δ]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester
155. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl } -3 - [3 -(4-oxo-piperidine- 1 -yl)-propyl] -urea
156. 3-{5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-6] pyridine-2- yl} - 1 -(2-hydroxy-ethyl)- 1 -methyl-urea
157. 1 -{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl}-3-(2-piperidine-4-yl-ethyl)-urea
158. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}- 3 -piperidine-4-yl-urea
159. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-piperidine-4-ylmethyl-urea
160. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-piperidine-3-ylmethyl-urea 161. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(3 -piperazine- 1 -yl-propyl)-urea
162. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl}-3-(S)-pyrrolidine-3-yl-urea
163. 1 -[3 -((S)-3 -amino-pyrrolidine- 1 -yl)-propyl] -3 - { 5- [(4-chloro-2-fluoro-phenyl)- methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-urea
164. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-methyl-amino-ethyl)-urea
165. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [3 -(4-hydroxyimino-piperidine- 1 -yl)-propyl] -urea
166. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl } -3 - [3 -(R)-2-hydroxymethyl-pyrrolidine- 1 -yl] -propyl] -urea
167. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}- 3 -[3 -((S)-2-hydroxymethyl-pyrrolidine- 1 -yl)-propyl] -urea
168. 4-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-ureido)-propyl]-piperazine-l-carboxylic acid ethyl ester
169. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-Z)]pyridine-2- yl} -3 -[3 -(4-methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
170. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}- 3 - [3 -(4-ethanesulfonyl-piperazine- 1 -yl)-propyl] -urea
171. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-chloro-2-fluoro-phenyl)- methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
172. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 - [3 -(4-cyclopropyl-piperazine- 1 -yl)-propyl] -urea
173. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-{3- [4-(2-fluoro-ethyl)-piperazine- 1 -yl)-propyl] -urea
174. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 - [3 -(4-propionyl-piperazine- 1 -yl)-propyl] -urea
175. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-[3-(4-cyclopropionyl-piperazine-l-yl)-propyl]-urea
176. 1 -[2-(4-acetyl-piperazine- 1 -yl)-ethyl] -3 - { 5 - [(4-chloro-2-fluoro-phenyl)- methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
177. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-[2-(l-methyl-piperidine-4-yl)-ethyl]-urea
178. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo [5 ,4-6]pyridine-2-yl } - 3-[2-(l -ethyl-piperidine-4-yl)-ethyl]-urea
179. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-(l-methyl-piperidine-4-yl)-urea
180. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3-( 1 -ethyl-piperidine-4-yl)-urea
181. 1 -{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-b]pyridine-2- yl } -3 -( 1 -methyl -piperidine-4-ylmethyl)-urea 182. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -( 1 -ethyl-piperidine-4-ylmethyl)-urea
183. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl} -3 -( 1 -methyl-piperidine-3 -ylmethyl)-urea
184. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -( 1 -ethyl-piperidine-3 -ylmethyl)-urea
185. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl} -3 -((S)- 1 -methyl-pyrrolidine-3 -yl)-urea
186. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -((S)- 1 -ethyl-pyrrolidine-3 -yl)-urea
187. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 - [3-((S)-3 -dimethyl-amino-pyrrolidine- 1 -yl)-propyl] -urea
188. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(4-dimethyl-amino-cyclohexyl)-urea
189. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3- [3 -(4-ethyl-piperazine- 1 -yl)-propyl] -urea
190. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [3-(4-isopropyl-piperazine- 1 -yl)-propyl] -urea
191. 1 - { 5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-ό]pyridine-2- yl}-3-[3 -(4-isobutyl-piperazine- 1 -yl)-propyl] -urea
192. l-[3-(4-sec-butyl-piperazine-l-yl)-propyl]-3-{5-[(4-chloro-2-fluoro-phenyl)- methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl } -urea
193. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl} -3 -[3 -(4-methyl-piperazine- 1 -yl)-3 -oxo-propyl] -urea
194. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-έ]pyridine-2- yl}-3-[4-(4-methyl-piperazine-l-yl)-butyl]-urea
195. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-[2-(4-methyl-piperazine-l-yl)-ethyl]-urea
196. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine-2-yl}-3-(2-morpholine-4- yl-ethyl)-urea
197. l-ethyl-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-urea
198. 1 -[5-(methyl-p-tolyl-amino)-thiazolo [5 ,4-6]pyridine-2-yl]-3 -(3 -morpholine-4- yl-propyl)-urea
199. l-(2-diethylamino-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine- 2-yl]-urea
200. l-[3-(4-methyl-piperazine-l-yl)-propyl-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-&]pyridine-2-yl]-urea
201. l-(3-hydroxy-propyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine-2- yl]-urea
202. l-(3-diethylamino-propyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό] pyridine-2-yl]-urea
203. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-Z>]pyridine-2-yl]-3-pyridine-2-yl methyl-urea
204. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-pyridine-3-yl methyl-urea
205. 1 -[5 -(methyl -p-tolyl-amino)-thiazolo [5 ,4-6]pyridine-2-yl]-3 -pyridine-4- ylmethyl-urea
206. l-(5-methyl-pyrazine-2-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
207. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(2-pyridine-2-yl- ethyl)-urea
208. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(2-pyridine-4-yl- ethyl)-urea
209. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine-2-yl]-3-(2-pyrrolidine-l- yl-ethyl)-urea
210. l-(l,5-dimethyl-lH-pyrrole-3-ylmethyl)-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-δ]pyridine-2-yl]-urea
211. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(2-pyridine-3-yl- ethyl)-urea
212. l-(4-hydroxy-butyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2- yl]-urea
213. l-(2-hydroxy-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2- yl]-urea 214. l-((R)-2-hydroxy-l-methyl-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
215. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-[3-(2-oxo- pyrrolidine- 1 -yl)-propyl] -urea
216. l-[2-(2-hydroxy-ethyoxy)-ethyl]-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- δ]pyridine-2-yl] -urea
217. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(3-pyrrolidine-l - yl-propyl)-urea
218. l-[2-(4-hydroxy-piperidine-l-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
219. l-{3- [(2-hydroxy-ethyl)-methyl-amino] -propyl } -3 - [5 -(methyl-p-tolyl-amino)- thiazolo[5,4-&]pyridine-2-yl]-urea
220. l-{3-[(4-hydroxy-piperidine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-yl]-urea
221. 1 - [3 -((R)-3 -hydroxy-pyrrolidine- 1 -yl)-propyl] -3 - [5 -(methyl-p-tolyl-amino)- thiazolo[5,4-δ]pyridine-2-yl]-urea
222. l-[3-(4-hydroxymethyl-piperidine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
223. (R)-2-{3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]- ureidomethyl } -pyrrolidine- 1 -carboxylic acid tert-butyl ester
224. l-[2-(4-acetyl-piperazine-l-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
225. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-piperidine-4-yl- urea
226. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-piperidine-4- ylmethyl-urea
227. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-piperidine-3- ylmethyl-urea
228. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(2-piperidine-4- yl-ethyl)-urea
229. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-(3-piperazine-l-yl- propyl)-urea
230. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(S)-pyrrolidine- 3-yl-urea
231. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(R)-l- pyrrolidine-2-ylmethyl-urea
232. l-[2-(l-methyl-piperidine-4-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
233. l-[2-(l-methyl-piperidine-4-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-ό]pyridine-2-yl]-urea
234. 1 -(I -methyl-piperidine-3-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl]-urea 235. 1 -( 1 -ethyl-piperidine-3 -ylmethyl)-3 - [5-(methyl-p-tolyl-amino)-thiazolo [5 ,4- &]pyridine-2-yl] -urea
236. 1 -(I -niethyl-piperidine-4-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- δ]pyridine-2-yl] -urea
237. l-(l-ethyl-piperidine-4-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
238. l-(l-methyl-piperidine-4-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- ό]pyridine-2-yl]-urea
239. l-[3-(4-ethyl-piperazine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
240. l-[3-(4-isopropyl-piperazine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-έ]pyridine-2-yl]-urea
241. l-((S)-methyl-pyrrolidine-3-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- ό]pyridine-2-yl]-urea
242. 1 -((S)-ethyl-pyrrolidine-3-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- δ]pyridine-2-yl]-urea
243. 1 -((R)- 1 -furan-2-ylmethyl-pyrrolidine-2-ylmethyl)-3 - [5 -(methyl-p-tolyl- amino)-thiazolo[5,4-δ]pyridine-2-yl]-urea
244. l-[(R)-l-(l-methyl-lH-pyrrole-2-ylmethyl)-ρyrrolidine-2-ylmethyl]-3-[5- (methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-urea
245. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-[3-(4-propionyl- piperazine- 1 -yl)-propyl] -urea
246. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-[3-(4-propionyl- piperazine- 1 -yl)-propyl]-urea
247. 1 -[3-(4-methanesulfonyl-piperazine- 1 -yl)-propyl]-3-[5-(methyl-p-tolyl- amino)-thiazolo [5 ,4-δ]pyridine-2-yl] -urea
248. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl]-3-[3- (4-methyl-piperazine- 1 -yl)-propyl] -urea
249. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
250. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
251. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3- [2-(4-methyl-piperazine- 1 -yl)-ethyl] -urea
252. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3- (1 -methyl-piperidine-4-y lmethyl)-urea
253. 1 - { 5-[(2,4-difluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl } -3 - [3 - (4-isopropyl-piperazine- 1 -yl)-propyl]-urea
254. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [3 -(4-ethyl-piperazine- 1 -y l)-propyl] -urea
255. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3- [3 -(4-methanesulfonyl -piperazine- 1 -yl)-propyl] -urea 256. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [2-(4-ethyl-piperazine- 1 -yl)-ethyl]-urea
257. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(2,4-difluoro-phenyl)-methyl- amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
258. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- (3 -pyrazole- 1 -yl-propyl)-urea
259. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-[3- (4-propionyl-piperazine- 1 -yl)-propyl] -urea
260. l-[3-(4-cyclopropanecarbonyl-piperazine-l-yl)-propyl]-3-{5-[(2,4-difluoro- phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-urea
261. 1 -[3-(4-ethyl-piperazine-l -yl)-propyl]-3-[5-(methyl-phenyl-amino)- thiazolo[5,4-&]pyridine-2-yl}-urea
262. 1 -[3-(4-isopropyl-piperazine- 1 -yl)-propyl]-3-[5-(methyl-phenyl-amino)- thiazolo[5,4-ό]pyridine-2-yl}-urea
263. l-[5-(methyl-phenyl-amino)-thiazolo[5,4-δ]pyridine-2-yl]-3-[3-(4-methyl- piperazine- 1 -yl)-propyl] -urea
264. l-[5-(methyl-phenyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-(3-morpholine-4- yl-propyl)-urea
265. 1 - [5-(methyl-phenyl-amino)-thiazolo [5 ,4-6]pyridine-2-yl]-3 -(2-morpholine-4- yl-ethyl)-urea
266. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-[5-(methyl-phenyl-amino)- thaizolo[5,4-6]pyridine-2-yl]-urea
267. l-[5-(methyl-phenyl-amino)-thiazolo[5,4-ή]pyridine-2-yl]-3-[3-(4-propionyl- piperazine- 1 -yl)-propyl] -urea
268. 1 -[3-(4-cyclopropanecarbonyl-piperazine- 1 -yl)-propyl]-3-[5-(methyl-phenyl- amino)-thiazolo [5 ,4-b] pyridine-2-yl } -urea
269. l-[3-(4-methyl-piperazine-l-yl)-propyl]-3-{5-[methyl-(4-trifluoromethyl- phenyl-amino)-thiazolo[5,4-6]pyridine-2-yl}-urea
270. l-{5-[methyl-(4-trifluoromethyl-phenyl)-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-niorpholine-4-yl-ethyl)-urea
271. l-{5-[methyl-(4-trifluoromethyl-phenyl)-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(3-morpholine-4-yl-propyl)-urea
272. 1 -[3 -(4-ethyl-piperazine- 1 -yl-propyl] -3 - { 5 - [methyl-(4-trifluoromethyl-phenyl- amino)-thiazolo[5,4-ό]pyridine-2-yl}-urea
273. 1 -[3 -(4-isopropyl-piperazine- 1 -yl-propyl] -3 - { 5- [methyl-(4-trifluoromethyl- phenyl)-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
274. l-[2-(4-methyl-piperazine-l-yl)-ethyl]-3-{5-[methyl-(4-trifluoromethyl- phenyl)-amino] -thiazolo [5,4-ό]pyridine-2-yl } -urea
275. 1 -( 1 -methyl-piperidine-4-ylmethyl)-3 - { 5 - [methyl-(4-trifluoromethyl-phenyl)- amino] -thiazolo[5 ,4-6]pyridine-2-yl } -urea
276. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea 277. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
278. l-{5- [(4-cyano-phenyl)-methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl } -3 - [3 -(4- methyl-piperazine- 1 -yl)-propyl] -urea
279. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-[2-(4- methyl-piperazine- 1 -yl)-ethyl] -urea
280. 1 - { 5 - [(4-cyano-phenyl)-methyl-amino] -thiazolo [5 ,4-&]pyridine-2-yl } -3 -( 1 - methyl-piperidine-4-ylmethyl)-urea
281. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3-(4- ethyl-piperazine- 1 -y l)-propyl] -urea
282. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methanesulfonyl-piperazine- 1 -yl)-propyl]-urea
283. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -yl)-propyl]-urea
284. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-[2-(4- ethyl-piperazine- 1 -yl)-ethyl] -urea
285. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-cyano-phenyl)-methyl- amino] -thiazolo [5,4-6] pyridine-2-yl } -urea
286. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(3- pyrazole-l-yl-propyl)-urea
287. 1 - { 5- [(4-fluoro-ρhenyl)-methyl-amino] -thiazolo[5,4-6]ρyridine-2-yl } -3 - [3 -(4- methyl-piperazine- 1 -yl)-propyl] -urea
288. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(2- moφholine-4-yl-ethyl)-urea
289. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]ρyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
290. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-[2-(4- methyl-piperazine- 1 -yl)-ethyl] -urea
291. 1 - { 5-[(4-fluoro-phenyl)-methyl-amino] -thiazolo [5,4-6]pyridine-2-yl } -3 -( 1 - methyl-piperidine-4-ylmethyl)-urea
292. l-{5-[(4-fluoro-ρhenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -y l)-propyl] -urea
293. 1 -[3-(4-ethyl-piperazine- 1 -yl)-propyl]-3- { 5-[(4-fluoro-phenyl)-methyl- amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
294. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
295. 1 -[2-(4-ethyl-piρerazine- 1 -yl)-propyl]-3- { 5-[(4-fluoro-phenyl)-methyl- amino] -thiazolo [5,4-6] pyridine-2-yl } -urea
296. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-ό]pyridine-2-yl}-urea
297. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl] -urea 298. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
299. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-(l- methyl-piperidine-4-yl-methyl)-urea
300. 1 - { 5- [(4-fluoro-ρhenyl)-methyl-amino] -thiazolo [5,4-δ]ρyridine-2-yl } -3 -(2- morpholine-4-yl-ethyl)-urea
301. 1 - { 5 -[(4-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-&]pyridine-2-yl } -3 - [2-(4- methyl-piperazine- 1 -yl)-ethyl] -urea
302. l-[3-(4-ethyl-piperazine-l-yl)-propyl]-3-{5-[(2-fluoro-4-methoxy-phenyl)- ethyl-amino] -thiazolo [5 ,4-&]pyridine-2-yl } -urea
303. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -y l)-propyl] -urea
304. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methylsulfonyl-piperazine- 1 -yl)-propyl] -urea
305. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
306. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3-(3 -hydroxy-propyl)-urea
307. 1 - { 5- [(4-chloro-2-hydroxy-phenyl)-methyl-amino] -thiazolo [5 ,4-Z>]pyridine-2- yl } -3 -(3 -morpholine-4-yl-propyl)-urea
308. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(3-diethylamino-propyl)-urea
309. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-morpholine-4-yl-ethyl)-urea
310. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl}-3-(3 -pyrrolidine- 1 -yl-propyl)-urea
311. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine- 2-yl } -3 -[2-(4-methyl-piperazine- 1 -yl)-ethyl] -urea
312. 1 - [3 -(4-acetyl-piperazine- 1 -yl)-propyl] -3 - { 5- [(4-chloro-2-hydroxy-phenyl)- methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
313. 1 - { 5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl} -3 -[3- (4-ethyl-piperazine- 1 -yl)-propyl] -urea
314. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-b]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -yl)-propyl]-urea
315. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl]-urea
316. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
317. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
318. 1 -[3 -(4-acetyl-piperazine- 1 -yl)-propyl] -3 - { 5- [(4-bromo-phenyl)-methyl- amino]-thiazolo[5,4-6]pyridine-2-yl}-urea 319. l-{5-[(3,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3- [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
320. l-{5-[(2,6-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
321. 1 -{5-[(4-chloro-3-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}- 3 -[3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
322. l-{5-[(2,3-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3- [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
323. l-{5-[(2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl] -urea
324. l-{5-[(2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3- (4-methyl-piperazine- 1 -yl)-propyl] -urea
325. l-[3-(4-methyl-piperazine-l-yl)-propyl]-3-{5-[methyl-(2,3,4-trifluoro- phenyl)-amino] -thiazolo [5,4-6]pyridine-2-yl } -urea
The present invention also provides processes for preparation of the compound of Formula 1. As can be seen in PREPARATIONS and EXAMPLES to be explained later, the compound according to the present invention can be prepared by various processes. The preparation processes described herein below are only exemplary ones and a variety of processes can also be anticipated based upon the general technologies and practices in the organic chemistry synthesis field. As such, the scope of the instant invention is not limited to the below processes.
In an embodiment, the compound of Formula 1 can be prepared by the process comprising (i) a step of introducing a NR2R3 substituent as defined in Formula 1 into 2-chloro-5-nitropyridine of Formula 2 below as a starting material, (ii) a step of preparing hetero pyridine, and (iii) a step of introducing carboxamide thereto.
oλ fTJYN°2 (2)
In an embodiment of preparing the compound of Formula 1 where X is S, the process for preparing the compound of Formula 1 comprises,
(a) a step of reacting the compound of Formula 2 with amine to produce the compound of Formula 3 below;
R
Figure imgf000049_0001
(3)
where R2 and R3 are the same as in Formula 1 ,
(b) a step of converting the nitro group of Formula 3 into amine to produce the compound of Formula 4 below;
Figure imgf000049_0002
(c) a step of reacting the compound of Formula 4 with tihocyanate to produce the compound of Formula 5 below; and
Figure imgf000050_0001
(d) a step of introducing carboxamide into the compound of Formula 5.
The more detailed reaction steps based upon the above preparation process are illustrated in below; however they are provided only to aid the skilled persons' understanding, and are not intended to limit the scope of the present invention.
The following reaction scheme illustrates the preparation of the compound of Formula 1.
Figure imgf000050_0002
In another embodiment, the process for preparing the compound of Formula 1 comprises,
a) a step of introducing bromoacetyl group into the compound of Formula 5 to produce the compound of Formula 6 below;
Figure imgf000051_0001
b) a step of reacting the compound of Formula 6 with triethyl phosphate to produce the compound of Formula 7 below;
Figure imgf000051_0002
(c) a step of reacting the compound of Formula 7 with aldehyde to produce the compound of Formula 1 where R1 is optionally substituted unsaturated alkyl substituent.
The reaction scheme below illustrates the preparation of a compound of Formula 1 where R1 is (4-piperidinyl)-2-propeneamide.
Figure imgf000052_0001
reflux
Figure imgf000052_0002
DCM
The reaction scheme below illustrates the preparation of a compound of Formula 1 where R1 is -NZ1(Z2)H-Z3.
Figure imgf000052_0003
where R4 is as defined above, R5 is the same as R4, and Ra is -NZ1(Z2)H-Z3.
A person skilled in the art to which the present invention pertains can easily understand the detailed reaction conditions for preparation of the compound of the present invention, based upon many PREPARATIONS and EXAMPLES to be illustrated later, thus explanations thereof are omitted herein in the interest of brevity.
The compound according the present invention is effective for the treatment and prevention of diseases associated with angiogenesis, and particularly those diseases associated with unregulated or undesired KDR activity. Therefore, the present invention provides the use of the compound of Formula 1 for manufacture of a medicament for the treatment or prevention of diseases resulting from an unregulated or undesired KDR activity. These diseases include, for example, but are not limited to cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis, Kaposi's sarcoma, etc.
Also, the present invention provides a pharmaceutical composition comprising
(a) a therapeutically effective amount of a compound of the present invention, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
The term "pharmaceutical composition" as used herein means a mixture of a compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but are not limited to oral, injection, aerosol, parenteral, and topical administrations. Pharmaceutical compositions can also be obtained by reacting compounds with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
The term "therapeutically effective amount" means that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease being treated. Thus, a therapeutically effective amount refers to that amount which has the effect of (i) reversing the rate of progress of a disease, or, in case of cancer reducing the size of the tumor; (ii) inhibiting to some extent further progress of the disease, which in case of cancer may mean slowing to some extent, or preferably stopping tumor metastasis or tumor growth; and/or, (iii) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with the disease.
The term "carrier" means a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.
The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the ionic strength conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
The compounds described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
a) Routes of Administration
Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a solid tumor, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tumor-specific antibody. The liposomes will thus be targeted to and taken up selectively by the tumor.
b) Composition/Formulation
The pharmaceutical composition of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
For injection, the agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compound of the present invention to be formulated as tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension and the like, for oral ingestion by a patient. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more compounds of the present invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.
For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powdered mixture of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 85% w/v of the nonpolar surfactant Polysorbate 80®, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:D5W) consists of VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself has minimal toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80®; the fraction of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide may also be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
Many of the compounds of the present invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
c) Effective Dosage.
Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
For any compound used in the methods of the present invention, the therapeutically effective dose can be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC5O as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED5O. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED5o with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the attending physician in view of the patient's condition (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as needed.
Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the angiogenesis receptor tyrosine kinase inhibition effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; e.g., the concentration necessary to achieve 50-90% inhibition of the angiogenesis receptor tyrosine kinases using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
Dosage intervals can also be determined using MEC value. Compounds should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the j udgment of the prescribing physician.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention will now be illustrated in more detail by the following preparations and examples. However, it will be understood that the present invention is not limited to these specific preparations and examples, but is subject to various modifications that will be recognized by one skilled in the art to which the present invention pertains.
PREPARATION 1: Preparation of N-(4-chlorophenyl)-5-nitro-2-pyridineamine
5.00 g (31.5 mmol) of 2-chloro-5-nitropyridine was dissolved in 100 ml of dimethyl sulfoxide, and 4.02 g (31.5 mmol) of 4-chloroanilino was added thereto, followed by heating under reflux with stirring. After 5 hours, the temperature was cooled to room temperature. The resulting reaction mixture was diluted with 500 ml of ethyl acetate and then washed with 300 ml of water and 300 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained by removing solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane) to give 5.43 g (21.7 mmol) of the title compound at a yield of 69%.
1H NMR(DMSO, ppm); δ 6.93(1H, d), 7.33(2H, d), 7.73(2H, d), 7.91(1H, d), 9.14(1H,
s)
ESI MS(m/e)=250[M+l]
PREPARATION 2: Preparation of iV2-(4-chIorophenyl)-2,5-pyrimidineamine
5.43 g (21.7 mmol) of the compound as obtained in PREPARATION 1 was dissolved in 150 ml of ethyl acetate, and 9.79 g (43.4 mmol) of tin(II) chloride dihydrate was added thereto, followed by stirring at room temperature. After 5 hours, the resulting reaction mixture was diluted with 500 ml of ethyl acetate and then washed with 300 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained by removing solvent by distillation under reduced pressure, was purified by column chromatography (hexane/ethyl acetate = 2/1, v/v) to give 2.53 g (11.5 mmol) of the title compound at a yield of 53%.
1H NMR(DMSO, ppm); δ 6.93(1H, d), 7.10(2H, d), 7.57(3H, m), 7.81 (IH, d)
ESI MS(m/e)=220[M+l] PREPARATION 3: Preparation of Λ^-(4-chlorophenyl)[l,3]thiazolo[5,4- Z>]pyridine-2,5-diamine
2.53 g (11.5 mniol) of the compound obtained in PREPARATION 2 was dissolved in 100 ml of acetic acid and 3.35 g (34.5 mmol) of potassium thiocyanate was added thereto, which was then cooled to -20°C. The resulting mixture was stirred by a mechanical stirrer and 1.84 g (11.5 mmol) of bromine was slowly added thereto. The temperature was elevated to room temperature over 2 hours. The mixture was further stirred for 8 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was dissolved in 300 ml of ethyl acetate, then washed with 150 ml of water and 150 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained by removing the solvent by distillation under reduced pressure, was purified by column chromatography (hexane/ethyl acetate = 1/1, v/v) to give 2.40 g (8.67 mmol) of the title compound at 75% yield.
1H NMR(DMSO, ppm); δ 6.93(1H, d), 7.33(2H, d), 7.74(2H, d), 7.9O(1H, d), 9.45(1H,
s)
ESI MS(m/e)=277[M+l]
PREPARATION 4: Preparation of iV6-cyclohexyl[l,3]thiazolo[5,4-A]pyridine-2,5- diamine
2.50 g (10.1 mmol, yield of 32%) of the title compound was obtained from 3.12 g (31.5 mmol) of hexaylamine instead of 4-chloroanilino in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 1.01-1.84(1 IH, m), 6.93(1H, d), 7.91(1H, d)
ESI MS(m/e)=249[M+l]
PREPARATION 5: Preparation of i^-cyclopentylfl.Slthiazoloβ.^pyridine- 2,5-diamine
3.30 g (14.1 mmol, yield of 45%) of the title compound was obtained from 2.68 g (31.5 mmol) of pentylamine instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 1.12-1.82(9H, m), 6.93(1H, d), 7.91(1H, d)
ESI MS(m/e)=235[M+l]
PREPARATION 6: Preparation of Λ^-p-chlorophenylHl^lthiazoloβ^-ft] pyridine-2,5-diamine
3.44 g (12.4 mmol, yield of 39%) of the title compound was obtained from 4.02 g (31.5 mmol) of 3-chloroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 6.3O(1H, dd), 6.95(1H5 d), 7.31(1H, t), 7.58(1H, dd), 7.89(1H, t), 7.94(1H, d) ESI MS(m/e)=277[M+l]
PREPARATION 7: Preparation of ^-(l-chlorophenylHl^thiazoloβ^-A] pyridine-2,5-diamine
3.11 g (11.2 mmol, yield of 36%) of the title compound was obtained from
4.02 g (31.5 mmol) of 2-chloroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 7.04(1H, t), 7.08(1H, d), 7.32(1H, t), 7.48(1H, d), 7.92(1H, d), 8.00(1H, d), 8.61(1H, s)
ESI MS(m/e)=277[M+l]
PREPARATION 8: Preparation of Λ^-(2-fluorophenyl)[l,3]thiazolo[5,4-6] pyridine-2,5-diamine
2.53 g (9.72 mmol, yield of 31%) of the title compound was obtained from 3.50 g (31.5 mmol) of 2-fluoroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 7.04(1H, t), 7.08(1H, d), 7.32(1H, t), 7.48(1H, d), 7.92(1H, d), 8.00(1H, d), 8.61(1H, s)
ESI MS(m/e)=261[M+l] PREPARATION 9: Preparation of ^-(l-fluoro^-methylphenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
2.85 g (10.4 mmol, yield of 33%) of the title compound was obtained from 3.94 g (31.5 mmol) of 2-fluoro-4-methhylaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 2.29(3H, s), 6.61(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(lH, t)
ESI MS(m/e)=275[M+l]
PREPARATION 10: Preparation of ^-(l-fluoro^-methoxyphenyl) [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
2.56 g (8.82 mmol, yield of 28%) of the title compound was obtained from 4.45 g (31.5 mmol) of 2-fluoro-4-methoxyaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 3.77(3H, s), 6.79(1H, dd), 6.87(1H, d), 6.91(1H, t), 7.75(1H, t), 7.85(lH, d), 8.65(1H, s)
ESI MS(m/e)=291 [M+l]
PREPARATION 11: Preparation of iV6-(2-fluorophenyl)[l,3]thiazolo[5,4-fr| pyridine-2,5-diamine
2.88 g (8.51 mmol, yield of 27%) of the title compound was obtained from 5.99 g (31.5 mmol) of 2-fluoro-4-bromoaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO5 ppm); δ 7.14(1H, d), 7.37(1H, d), 7.55(1H, d), 7.94(1H, d), 8.25(1H,
t)
ESI MS(m/e)=340[M+l]
PREPARATION 12: Preparation of ^-(S-fluoro^-methylphenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
2.85 g (10.4 mmol, yield of 33%) of the title compound was obtained from 3.94 g (31.5 mmol) of 3-fluoro-4-methylaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3.
1H NMR(DMSO, ppm); δ 2.17(3H, s), 6.92(1H, d), 7.23(2H, q), 7.68(1H, d), 7.91(1H, d)
ESI MS(m/e)=275[M+l]
PREPARATION 13: Preparation of -\6-(4-chloro-2-fluorophenyl) [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
2.79 g (9.45 mmol, yield of 30%) of the title compound was obtained from 4.59 g (31.5 mmol) of 2-fluoro-4-chloroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3
1H NMR(DMSO, ppm); δ 7.14(1H, d), 7.26(1H, d), 7.45(1H, dd), 7.94(1H, d), 8.29(1H, t)
ESI MS(m/e)=295[M+l]
PREPARATION 14: Preparation of Λ^-(2,4-difluorophenyl)[l,3]thiazolo[5,4- 6]pyridine-2,5-diamine
2.63 g (9.45 mmol, yield of 30%) of the title compound was obtained from 4.07 g (31.5 mmol) of 2,4-difluoroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3
1H NMR(DMSO, ppm); δ 7.02(1H, d), 7.08(1H, t), 7.3O(1H, t), 7.91(1H, d), 8.09(1H, m)
ESI MS(m/e)=279[M+l]
PREPARATION 15: Preparation of N6-(2,6-difluorophenyl)[l,3]thiazolo[5,4- Z>]pyridine-2,5-diamine
2.19 g (7.88 mmol, yield of 25%) of the title compound was obtained from
4.07 g (31.5 mmol) of 2,6-difluoroaniline instead of 4-chloroaniline in PREPARATION 1 in the same manner as in PREPARATIONS 2 and 3
1H NMR(DMSO, ppm); δ 6.53(1H, d), 7.28(2H, t), 7.47(1H, m), 7.85(1H, d)
ESI MS(m/e)=279[M+l] PREPARATION 16: Preparation of ethyl l-(chlorocarbonyl) cyclopropanecarboxylate
5.00 g (26.9 mmol) of diethyl ljl-cyclopropandicarboxylate was dissolved in 100 ml of ethanol, and 1.51 g (26.9 mmol) of potassium hydroxide was added thereto, followed by heating under reflux with stirring. After 4 hours, ethanol was removed by distillation under reduced pressure. To the residue, 50 ml of IN aqueous hydrochloric acid solution was added. The resulting solution was then extracted three times with 100 ml of diethyl ether, respectively. The organic layer was dried over anhydrous MgSO4 and subjected to distillation under reduced pressure to obtain 3.49 g (22.1 mmol) of carboxylic acid. The obtained compound, without any further purification step, was dissolved in 50 ml of chloroform and 5.26 g (44.2 mmol) of thionyl chloride was added thereto, followed by stirring at room temperature. After 3 hours, the solvent and an excess of thionyl chloride were removed by distillation under reduced pressure to give 3.01 g (17.0 mmol) of the title compound at a 63% yield, without any further purification step.
1H NMR(CDCl3, ppm); δ 1.29(3 H, t), 1.79(2H, m), 1.90(2H, m), 4.24(2H, q)
ESI MS(m/e)=177[M+l]
PREPARATION 17: Preparation of ethyl 2-(chlorocarbonyl) cyclopropanecarboxylate
3.18 g (18.0 mmol, yield of 67%) of the title compound was obtained from 5.00 g (26.9 mmol) of diethyl 1,2-cyclopropanedicarboxylate instead of diethyl 1,1- cyclopropanedicarboxylate in PREPARATION 16 in the same manner as in PREPARTIONS 2 and 3.
1H NMR(DMSO, ppm); δ 1.29(3H, t), 1.40(2H, m), 2.02(1H, m), 2.5O(1H, m), 4.24(2H, q)
ESI MS(m/e)=177[M+l]
PREPARATION 18: Preparation of 2-({[5-(4-chloro-2-fluoroanilino) [1 ,3] thiazolo [5,4-6] py ridine-2-yl] amino}carbonyl)cyclopropanecarboxylic acid
The same procedure as in PREPARATION 30 was conducted except that 5.00 g (17.0 mmol) of the compound obtained in PREPARATION 13 was used instead of the compound obtained in PREPARATION 9, thereby obtaining 4.01 g (9.86 mmol) of the title compound at a yield of 58%.
1H NMR(DMSO, ppm); δ 1.40(2H, m), 2.02(1H, m), 2.5O(1H, m), δ 7.14(1H, d), 7.26(1H, d), 7.45(1H, dd), 7.94(1H, d), 8.29(1H, t)
ESI MS(m/e)=407[M+l]
PREPARATION 19: Preparation of iV-(4-chlorophenyl)-iV-methyl-5-nitro-2-
pyridineamine
5.00 g (20.0 mmol) of the compound obtained in PREPARATION 1 was dissolved in 50 ml of dimethylformamide, and 1.20 g (30.0 mmol) of sodium hydride
(60% dispersion in mineral oil) was added thereto, followed by stirring for 5 minutes. 3.41 g (24.0 mmol) of iodomethane was added, and the resulting mixture was stirred at room temperature. After 2 hours, the reaction was quenched and excess sodium hydride was destroyed by careful addition of water. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 200 ml of ethyl acetate. The organic layer was washed with 100 ml of water and 100 ml of aqueous saturated NaCl solution, dried over anhydrous MgSO4, and then filtered. The crude compound, obtained after removing the solvent by concentration under reduced pressure, was purified by column chromatography (hexane/ethyl acetate = 2/1, v/v) to give 4.59 g (17.4 mmol) of the title compound at a 87% yield.
1H NMR(DMSO, ppm); δ 3.51(3H, s), 6.93(1H, d), 7.33(2H, d), 7.73(2H, d), 7.91(1H, d), 9.14(lH, s)
ESI MS(m/e)=264[M+l]
PREPARATION 20: Preparation of iV6-(4-chlorophenyl)-Λ'6-methyl [l,3]thiazoIo[5,4-Z>]pyridine-2,5-diamine
The same procedure as in PREPARATION 2 was conducted by using 4.59 g (17.4 mmol) of the compound obtained in PREPARATION 19, and then the same procedure as in PREPARATION 3 was conducted, thereby obtaining 2.58 g (8.87 mmol) of the title compound at a yield of 51%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d)
ESI MS(m/e)=291[M+l] PREPARATION 21: Preparation of iV6-(4-chloro-2-fluorophenyl)-iV6-methyl [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.0O g (34.4 mmol) of the compound instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.23 g (7.22 mmol) of the title compound at a yield of 21%.
1H NMR(MeOD, ppm); δ 3.29(3H, s), 6.52(1H, d), 7.29(1H, d), 7.34(1H, dd), 7.38(1H, t), 7.73(1H, d)
ESI MS(m/e)=309[M+l]
PREPARATION 22: Preparation of -\6-(2,4-difluorophenyl)-iV6-methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (38.7 mmol) of 2,4-difluoroaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.41 g (8.25 mmol) of the title compound at a yield of 24%.
1H NMR(DMSO, ppm); δ 3.37(3H, s), 6.46(1H, d), 7.20-7.58(3H, m), 7.8O(1H, d)
ESI MS(m/e)=293[M+l]
PREPARATION 23: Preparation of iV6-(2,6-difluorophenyl)-iV6-methyl [l,3]thiazolo[5,4-Z>]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (38.7 mmol) of 2,6-difluoroaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.41 g (8.25 mmol) of the title compound at a yield of 24%.
1H NMR(DMSO, ppm); δ 3.37(3H, s), 6.54(1H, d), 7.25-7.49(3H, m), 7.85(1H, d)
ESI MS(m/e)=293[M+l]
PREPARATION 24: Preparation of iV6-(4-bromo-2-fluorophenyl)-Λ'6-methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (26.3 mmol) of 2-fluoro-4-bromoaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.04 g (5.79 mmol) of the title compound at a yield of 22%.
1H NMR(CDCl3, ppm); δ 3.46(3H, s), 6.43(1H, dd), 7.22(1H, t), 7.33-7.39(2H, m), 7.64(1H, d)
ESI MS(m/e)=354[M+l]
PREPARATION 25: Preparation of Λ'6-(2-methoxyphenyl)-iV6-methyl [l,3]thiazolo[5,4-6]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (40.6 mmol) of 2-methoxyaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 3.60 g (12.6 mmol) of the title compound at a yield of 31%.
1H NMR(CDCl3, ppm); δ 3.46(3H, s), 3.77(3H, s), 6.27(1H, d), 7.02(1H, d), 7.25(1H, d), 7.31(lH, td), 7.54(1H, d)
ESI MS(m/e)=287[M+l]
PREPARATION 26: Preparation of Λ^-β^-difluorophenyO-Λ^-methyl [ 1 ,3] thiazolo [5,4-A] py ridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g
(38.7 mmol) of 3,4-difluoroaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.41 g (8.25 mmol) of the title compound at a yield of 24%.
1H NMR(DMSO, ppm); δ 3.37(3H, s), 6.7O(1H, d), 7.19(1H, m), 7.48(2H, m), 7.80(lH, d)
ESI MS(m/e)=293[M+l]
PREPARATION 27: Preparation of iV6-methyl-iV6-[4-(trifluoromethyl)phenyl] [l,3]thiazolo[5,4-ό]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g
(31.0 mmol) of 4-trifluoroaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 1.91 g (5.90 mmol) of the title compound at a yield of 19%.
1H NMR(DMSO, ppm); δ 3.37(3H, s), 7.01(1H, d), 7.45(1H, d), 7.7O(1H, d), 7.9O(1H,
d)
ESI MS(m/e)=325[M+l]
PREPARATION 28: Preparation of 7V6-(4-methoxypheny I)-JV6- methy 1 [ 1 ,3] thiazolo [5,4-6] py ridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.0O g (40.6 mmol) of 4-methoxyaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 3.60 g (12.6 mmol) of the title compound at a yield of 31%.
1H NMR(CDCl3, ppm); δ 3.46(3H, s), 3.82(3H, s), 6.43(1 H, d), 6.95(2H, d), 7.18(2H, d), 7.54(1H, d)
ESI MS(m/e)=287[M+l]
PREPARATION 29: Preparation of 7V6-(4-isopropyIphenyl)-i\6-methyl[l,3]- thiazolo[5,4-ό]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (37.0 mmol) of 4-isopropylaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.98 g (9.99 mmol) of the title compound at a yield of 27%.
1H NMR(CDCl3, ppm); δ 1.28(6H, d), 2.94(1H, m), 3.51(3H, s), 6.56(1H, d), 7.19(2H, d), 7.27(2H, d), 7.55(1H, d)
ESI MS(m/e)=299[M+l]
PREPARATION 30: Preparation of iV6-(2,3-dihydro-l^-indene-5-yI)-iV6- methy 1 [ 1 ,3] thiazolo [5,4-Z>] py ridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (37.5 mmol) of 4-isopropylaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 1.78 g (6.01 mmol) of the title compound at a yield of 16%.
1H NMR(CDCl3, ppm); δ O.95(1H, m), LlO(IH, m), 2.93(4H, t), 3.50(3H, s), 6.53(1H, d), 7.12(1H, s), 7.26(2H, m), 7.54(1H, d)
ESI MS(m/e)=297[M+l]
PREPARATION 31: Preparation of ethyl 2-{4-[2-amino[l,3]thiazolo[5,4-6] pyridine-5-yl](methyl)amino}phenyI}acetate
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (27.9 mmol) of ethyl 4-aminophenylacetate instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 1.72 g (5.02 mmol) of the title compound at a yield of 18%. 1H NMR(CDCl3, ppm); δ 1.40(3H, t), 2.92(2H, s), 3.60(3H, s), 4.38(2H, q), 6.93(1H, d), 7.42(2H, d), 7.90(2H, d), 8.11(1H, d)
ESI MS(m/e)=343[M+l]
PREPARATION 32: Preparation of Λ^-^-chlorophenylJ-iV6- ethyl[l,3]thiazolo[5,4-6]pyridine-2,5-diamine
The same procedure as in PREPARATION 1 was conducted by using 5.00 g (32.1 mmol) of iV-ethyl-4-chloroaniline instead of 4-chloroaniline, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 2.64 g (8.67 mmol) of the title compound at a yield of 27%.
1H NMR(DMSO, ppm); δ 1.03(3H, t), 3.63(2H, q), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1 H, d)
ESI MS(m/e)=305[M+l]
PREPARATION 33: Preparation of ethyl 2-[4-chIoro(5-nitro-2- py ridinyl)anilino] acetate
The same procedure as in PREPARATION 19 was conducted by using 4.01 g (24.0 mmol) of ethyl α-bromoacetate instead of iodomethane, thereby obtaining 6.04 g (18.0 mmol) of the title compound at a yield of 90%.
1H NMR(DMSO, ppm); δ 1.03(3H, t), 4.11(2H, q), 4.62(2H, s), 6.70(1 H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 9.11(1H, s) ESI MS(m/e)=336[M+l]
PIUEPARATION 34: Preparation of ethyl 2-[(2-amino[l,3]thiazolo[5,4- 6]pyridine-5-yl)-4-chloroanilino]acetate
The same procedure as in PREPARATION 2 was conducted by using 6.04 g
(18.0 mmol) of the compound obtained in PREPARATION 33 instead of the compound obtained in PREPARATION 1, and then the same procedure as in PREPARATION 3 was conducted, thereby obtaining 3.98 g (11.0 mmol) of the title compound at a yield of 61%.
1H NMR(DMSO, ppm); δ 1.03(3H, t), 4.11(2H, q), 4.62(2H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1 H, d)
ESI MS(m/e)=363[M+l]
PREPARATION 35: Preparation of ethyl 2-[(2-amino[l,3]thiazolo[5,4- ό]pyridine-5-yl)-4-chloroanilino]-l-ethanol
3.98 g (11.0 mmol) of the compound obtained in PREPARATION 34 was dissolved in 100 ml of tetrahydrofuran and 417 mg (11.0 mmol) of lithium aluminum hydride was added thereto at 00C, followed by stirring at room temperature. After 1 hour, the reaction solution was cooled to 00C. To the solution, 0.42 ml of water, 0.42 ml of 15% sodium hydroxide and 1.26 ml of water were added to complete the reaction. Solid impurites were removed by filtration. The obtained organic layer was removed by distillation under reduced pressure to give 3.18 g (9.90 mmol) of the title compound at a yield of 90%, without further purification step.
1H NMR(DMSO, ppm); δ 4.21(2H, t), 4.29(2H, t), 6.70(1 H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d)
ESI MS(m/e)=321 [M+l]
PREPARATION 36: Preparation of 4-[(5-nitro-2-pyridinyl)amino]benzonitrile
5.00 g (31.5 mmol) of 2-chloro-5-nitropyridine was dissolved in 100 ml of tetrahydrofuran, and 2.52 g (60%, 63.0 mmol) of sodium hydroxide was added slowly at 0°C, followed by stirring for 5 minutes. To the resulting mixture, 5.59 g (47.3 mmol) of 4-cyanoaniline was added, followed by heating under reflux with stirring. After 4 hours, the reaction solution was cooled to room temperature, and then water was added to stop the activity of sodium hydroxide. The resulting solution was diluted with 200 ml of ethyl acetate, and then washed with 100 ml of water and 100 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (hexane/ethyl acetate = 2/2, v/v) to give 4.77 g (19.8 mmol) of the title compound at a yield of 63%.
1H NMR(DMSO, ppm); δ 7.12(1H, d), 7.29(2H, d), 7.70(2H, d), 7.94(1H, d), 9.14(1H, s)
ESI MS(m/e)=255[M+l] PREPARATION 37: Preparation of 4-[(2-amino[l,3]thiazolo[5,4-6]pyridine-5- yl)(methyl)amino]benzonitrile
The same procedure as in PREPARATION 19 was conducted by using 4.77 g
(19.8 mmol) of the compound obtained in PREPARATION 36 instead of the compound obtained in PREPARATION 1, and then the same procedure as in
PREPARATIONS 2 and 3 was conducted, thereby obtaining 1.45 g (5.15 mmol) of the title compound at a yield of 26%.
1H NMR(DMSO, ppm); δ 3.47(3H, s), 7.12(1H, d), 7.29(2H, d), 7.70(2H, d), 7.94(1H, d)
ESI MS(m/e)=282[M+l]
PREPARATION 38: Preparation of 4-[(2-amino[l,3]thiazoIo[5,4-6]pyridine-5- yl)(methyl)amino] benzoate
The same procedure as in PREPARATION 36 was conducted by using 7.81 g (47.3 mmol) of ethyl 4-aminobenzoate instead of 4-cyananiline in PREPARATION 36, and then the same procedure as in PREPARATIONS 19, 2 and 3 was conducted, thereby obtaining 1.14 g (3.47 mmol) of the title compound at a yield of 11%.
1H NMR(CDCl3, ppm); δ 1.40(3H, t), 3.60(3H, s), 4.38(2H, q), 6.93(1H, d), 7.28(2H, d), 7.70(2H, d), 8.03(1H, d)
ESI MS(m/e)=329[M+l] PREPARATION 39: Preparation of diethyl 2-{[5-(4-bromo-2- fluoromethylanilino)[l,3]thiazoIo[5,4-6]pyridine-2-yl]amino}-2-oxoethyI phosphonate
5.00 g (14.2 mmol) of the compound obtained in PREPARATION 24 was dissolved in 100 ml of dichloromethane, and 4.30 g (21.3 mmol) of 2-bromoacetyl bromide was added thereto, followed by stirring at room temperature. After 2 hours, the solvent was removed by distillation under reduced pressure and the residue was dissolved in 150 ml of ethyl acetate. The resulting solution was washed with 50 ml of aqueous saturated ammonium chloride solution and 50 ml of aqueous saturated NaCl solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was dissolved in 100 ml of toluene. 4.72 g (28.4 mmol) of triethyl phosphate was added to the resulting solution and then heated under reflux with stirring. After 8 hours, the solvent was removed by distillation under reduced pressure, and then purified by column chromatography (dichloromethane/methanol = 95/5, v/v) to give 5.96 g (11.2 mmol) of the title compound at a yield of 79%.
1H NMR(CDCl3, ppm); δ 1.36(6H, t), 3.20(2H, d), 3.41(3H, s), 4.24(4H, q), 6.39(1H, d), 7.13-7.35(3H, m), 7.57(1H, d), 11.13(1H, br s)
ESI MS(m/e)=532[M+l]
PREPARATION 40: Preparation of tert-butyl 4-((£)-3-{[5-(4-bromo-2- fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yI]amino}-3-oxo-l-(propenyl)- 1 -piperidinecarboxy late 5.96 g (11.2 mmol) of the compound obtained in PREPARATION 39 was dissolved in 100 ml of tetrahydrofuran and 3.58 g (16.8 mmol) of 4-formyl-piperidine-
1-carboxylic acid tert-butyl ester and 2.56 g (16.8 mmol) of DBU were added thereto, followed by stirring at room temperature. After 5 hours, the resulting solution was diluted with 100 ml of ethyl acetate, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (hexane/ethyl acetate = 1/1, v/v) to give 5.75 g (9.74 mmol) of the title compound at a yield of 87%.
1H NMR(CDCl3, ppm); δ 1.30(2H, qd), 1.46(9H, s), 1.68(2H, d), 2.27(1 H, m), 2.73(2H, t), 3.49(3H, s), 4.12(2H, q), 5.94(1H, d), 6.45(1H, d), 7.09(1H, q), 7.39(1H, t), 7.38(2H, t), 7.65(1H, d)
ESI MS(m/e)=591[M+l]
PREPARATION 41: Preparation of (E)-N-{5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-/>]pyridine-2-yl}-3-(4-piperidinyI)-2- propeneamide
The same procedure as in PREPARATION 39 was conducted by using 5.00 g (17.2 mmol) of the compound obtained in PREPARATION 20 instead of the compound obtained in PREPARATION 24, and then the same procedure as in
PREPARATIONS 39, 40 and EXAMPLE 69 was conducted, thereby obtaining 3.53 g
(8.26 mmol) of the title compound at a yield of 48%. 1H NMR(CDCl3, ppm); δ 1.47(2H, qd), 1.68(2H, d), 1.90(2H, t), 1.94(2H, d), 2.11(1H, m), 3.46(3H, s), 6.43(1H, dd), 5.93(1H, d), 6.61(1H, d), 7.11(1H, dd), 7.21(2H, d), 7.36(2H, d), 7.61(1H, d)
ESI MS(m/e)=428[M+l]
PREPARATION 42: Preparation of tert-butyl 4-fluoro-2- hydroxyphenylcarbamate
3.8 g (30.0 mmol) of 2-amino-5-chorophenol was dissolved in 150 ml of dichloromethane and 6.5 g (30.0 mmol) of di -tert-butyl dicarbonate was added thereto, followed by stirring at room temperature. After 12 hours, 200 ml of dichloromethane was added. The resulting solution was washed with 200 ml of aqueous saturated sodium hydrogen carbonate solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/hexane = 1/6, v/v) to give 4.26 g (18.75 mmol) of the title compound at a yield of 63%.
1H NMR(DMSO, ppm); δ 1.44 (9H, s), 6.57-6.62(3H, m), 7.48(1H, br s), 7.23(3H, m), 7.86(1H, s), 10.17(lH, br s)
PREPARATION 43: Preparation of 5-fluoro-2-(methylamino)phenol
3.3 g (15.0 mmol) of the compound obtained in PREPARATION 42 was dissolved in 60 ml of tetrahydrofuran and 1.1 g (29.4 mmol) of lithium aluminum hydride was added thereto, followed by heating under reflux with stirring. After 12 hours, the resulting solution was cooled to room temperature. To the solution, water and 10% aqueous sodium hydroxide solution were added. The resulting solid was removed by filtration and the filtrate was eluted by using ethyl acetate, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/hexane = 1/3, v/v) to give 0.87 g (0.62 mmol) of the title compound at a yield of 42%.
1H NMR(DMSO, ppm); δ 2.63 (3H, s), 6.33(1H, m), 6.45(2H, m), 7.86(1H, s)
PREPARATION 44: Preparation of 5-fluoro-2[methyl(5-nitro-2- pyridinyl)amino] phenol
0.85 g (5.4 mmol) of 2-chloro-5-nitropyridine was dissolved in 30 ml of dimethyl sulfoxide and 0.80 g (5.7 mmol) of the compound obtained in PREPARTION 43 was added thereto, followed by heating under reflux with stirring. After 5 hours, the resulting solution was cooled to room temperature. To the solution, 500 ml of ethyl acetate was added. The resulting solution was washed with 300 ml of water and 300 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/hexane = 1/4, v/v) to give 0.38 g (1.44 mmol) of the title compound at a yield of 26%.
1H NMR(DMSO, ppm); δ 3.39(3H, s), 6.17(1H, m), 6.76-6.82(2H, m), 7.31 (IH, m), 8.12(1Hm), 9.03(1H, m), 1O.44(1H, br s) ESI MS(m/e)=264[M+l]
PREPARATION 45: Preparation of 2-[(5-amino-2-pyridinyl)(methyl)amino]-5- fluorophenol
0.34 g (1.3 mmol) of the compound obtained in PREPARATION 44 was dissolved in 25 ml of ethyl acetate and 2.33 g (10.3 mmol) of tin(II) chloride dihydrate was added thereto, followed by stirring at room temperature. After 5 hours, 100 ml of ethyl acetate was added thereto and the resulting solution was washed with 80 ml of IN aqueous sodium hydroxide solution and 1000 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/dichloromethane = 2/1, v/v) to give 0.18 g (0.77 mmol) of the title compound at a yield of 59%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 6.32(1H, m), 6.82-6.79 (2H, m), 7.35 (lH,m), 7.54(2H, br s), 8.12(1H, m), 9.03(1H, m), 9.97( IH, br s)
ESI MS(m/e)=234[M+l]
PREPARATION 46: Preparation of 2-[(2-amino[l,3]thiazolo[5,4-6]ρyridine-5- yI)(methyl)amino]-5-fluorophenol
0.27 g (1.20 mmol) of the compound as obtained in PREPARATION 45 was dissolved in 25 ml of acetic acid, and 0.90 g (9.30 mmol) of potassium thiocyanate was added thereto, and then cooled to -20 °C. While stirring with a mechanical stirrer, 0.19 g (1.20 mmol) of bromine was added slowly. The reaction was allowed to warm gradually to room temperature over 2 hours and further stirred for 8 hours. After the completion of the reaction, the solvent was removed by distillation under reduced pressure and 100 ml of ethyl acetate was added thereto. The resulting solution was washed with 50 ml of water and 50 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude compound was purified by column chromatography (ethyl acetate/hexane = 2/3, v/v) to give 0.15 g (0.52 mmol) of the title compound at 45% yield.
1H NMR(DMSO, ppm); δ 3.25(3H, s), 5.76(1H, s), 6.15(1H, d), 6.67(2H, m), 7.36(2H, s), 7.37(1H, d), 9.03(1H, m), 9.97(1H, s)
ESI MS(m/e)=291[M+l]
PREPARATION 47: Preparation of 2-[{2-[(cyclopropylcarbonyl)amino]- [l,3]thiazolo[5,4-Z»]pyridine-5-yl}(methyl)amino]-5-fluorophenyI cyclopropanecarboxylate
40 mg (0.14 mmol) of the compound as obtained in PREPARATION 46 was dissolved in 3 ml of tetrahydrofuran, and 63 mg (0.62 mmol) of triethyl amine and 43 mg (0.41 mmol) of cyclopropanecarbonyl chloride were added thereto, followed by stirring at room temperature. After 30 minutes, 5 ml of methanol was added to the resulting solution, followed by stirring for 1 hour. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. 100 ml of ethyl acetate was added thereto and the resulting solution was washed with 10 ml of water and 10 ml of aqueous saturated NaCl solution. The organic layer was dried over anhydrous MgSO4. The crude compound, obtained by removing solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/hexane = 1/2, v/v) to give 56 mg (0.13 mmol) of the title compound at 95% yield.
1H NMR(DMSO, ppm); δ 0.91(4H, m), 1.10(4H, m), 1.93-1.99(2H, m), 3.28(3H, s), 6.06(1H, d), 6.68(1H, d), 6.74(1H, s), 7.01(lH,d), 7.62(1H, d), 9.55(1H, br s)
ESI MS(m/e)=427[M+l]
EXAMPLE 1: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-£]pyridine- 2-yl] cyclopentanecarboxamide
5.00 g (18.1 mmol) of the compound obtained in PREPARATION 3 was dissolved in 150 ml of dichloromethane. To the resulting solution, 2.75 g (27.2 mmol) of triethylamine and 2.88 g (21.7 mmol) of cyclopentanecarbonyl chloride were added, followed by stirring at room temperature. After 2 hours, the resulting solution was diluted with 100 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous NaCl solution and dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 98/2, v/v) to give 5.74 g (15.4 mmol) of the title compound at a yield of 85%.
1H NMR(DMSO, ppm); δ 1.24-1.92(8H, m), 2.95(1H, m), 6.93(1H, d), 7.33(2H, d), 7.74(2H, d), 7.90(1 H, d), 9.45(1 H, s) ESI MS(m/e)=373[M+l]
EXAMPLE 2: Preparation of N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine- 2-yl]cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted by using 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 5.68 g (16.5 mmol) of the title compound at a yield of 91%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.99(1H, m), 6.93(1H, d), 7.33(2H, d), 7.73(2H, d), 7.91(1H, d), 9.42(1H, s)
ESI MS(m/e)=345[M+l]
EXAMPLE 3: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine- 2-yl]-2-(thiophene-2-yl)acetamide
The same procedure as in EXAMPLE 1 was conducted by using 3.49 g (21.7 mmol) of 2-thiophenacetyl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 6.62 g (16.5 mmol) of the title compound at a yield of 91%.
1H NMR(DMSO, ppm); δ 4.06(2H, s), 6.94(1H, d), 7.01(2H, m), 7.33(2H, d), 7.43(1H, d), 7.74(2H, d), 7.94(1H, d), 9.46(1H, s), 12.47(1H, s)
ESI MS(m/e)=401[M+l] EXAMPLE 4: Preparation of JV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-£]pyridine- 2-yl]-3-cyclopentylpropaneamide
The same procedure as in EXAMPLE 1 was conducted by using 3.49 g (21.7 mmol) of 3-cyclopentylpropionyl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 6.32 g (15.8 mmol) of the title compound at a yield of 87%.
1H NMR(DMSO, ppm); δ 1.12(2H, m), 1.48-1.97(1 IH, m), 6.93(1H, d), 7.33(2H, d), 7.74(2H, d), 7.91 (IH, d), 9.42(1 H, s), 12.15(1 H, s)
ESI MS(m/e)=401[M+l]
EXAMPLE 5: Preparation of N-[5-(4-chloroaniIino)[l,3]thiazolo[5,4-6]pyridine- 2-yI]-2-(4-morpholinyl)acetamide
5.00 g (18.1 mmol) of the compound, obtained in PREPARATION 3, was dissolved in 150 ml of dichloromethane, and 2.75 g (27.2 mmol) of triethylamine and 5.48 g (27.2 mmol) of 2-bromoacetyl bromide were added, followed by stirring at room temperature. After 1 hour, the resulting solution was diluted with 100 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was dissolved in 15 ml of morpholine and stirred at room temperature for 2 hours. The reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively. The collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 9/1, v/v) to give 4.68 g (11.6 mmol) of the title compound at a yield of 64%.
1H NMR(CDCl3, ppm); δ 2.65(4H, t), 3.29(2H, s), 3.80(4H, t), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 1O.24(1H, s)
ESI MS(m/e)=404[M+l]
EXAMPLE 6: Preparation of 7V-[5-(4-chloroanilino)[l,3]thiazolo[5,4-*]pyridine- 2-yl]-2-(l-pyrrolidinyl)acetamide
The same procedure as in EXAMPLE 5 was conducted by using 15 ml of pyrrolidine instead of morpholine, thereby obtaining 3.37 g (8.69 mmol) of the title compound at a yield of 48%.
1H NMR(CDCl3, ppm); δ 1.88(4H, br m), 2.73(4H, br m), 3.42(2H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1 H, d)
ESI MS(m/e)=388[M+l]
EXAMPLE 7: Preparation of JV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-A]pyridine- 2-yl]-2-(diethylamino)acetamide
The same procedure as in EXAMPLE 5 was conducted by using 15 ml of diethylamine instead of morpholine, thereby obtaining 3.39 g (8.69 mmol) of the title compound at a yield of 48%.
1H NMR(CDCl3, ppm); δ 1.11(6H, t), 2.68(4H, q), 3.29(2H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d)
ESI MS(m/e)=390[M+l]
EXAMPLE 8: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine- 2-yl]-acetamide
The same procedure as in EXAMPLE 1 was conducted by using 1.70 g (21.7 mmol) of acetyl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 5.54 g (17.4 mmol) of the title compound at a yield of 96%.
1H NMR(DMSO, ppm); δ 2.19(3H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 9.44(1H, s), 12.19(1H, s)
ESI MS(m/e)=319[M+l]
EXAMPLE 9: Preparation of 7V-[5-(4-chloroanilino)[l,3]thiazolo[5,4-£]pyridine- 2-yl] -2-methylpropaneamide
The same procedure as in EXAMPLE 1 was conducted by using 2.31 g (21.7 mmol) of isobutyryl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 5.52 g (15.9 mmol) of the title compound at a yield of 88%.
1H NMR(CDCl3, ppm); δ 1.27(6H, m), 2.71(1H, m), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d) ESI MS(m/e)=347[M+l]
EXAMPLE 10: Preparation of iV-[5-(4-chIoroanilino)[l,3]thiazolo[5,4-*]pyridine- 2-yl] -l-cyclobutanecarboxamide
The same procedure as in EXAMPLE 1 was conducted by using 2.57 g (21.7 mmol) of cyclobutanecarbonyl chloride instead of cyclopentanecarbonyl chloride, thereby obtaining 5.26 g (14.7 mmol) of the title compound at a yield of 81%.
1H NMR(CDCl3, ppm); δ 2.05(2H, m), 2.26(2H, m), 2.44(2H, m), 3.26(1H, m), 6.66(1H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 9.21(1H, s)
ESI MS(m/e)=359[M+l]
EXAMPLE 11: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-£]pyridine- 2-yl]-3-(4-morpholinyl)propaneamide
5.00 g (18.1 mmol) of the compound, obtained in PREPARATION 3, was dissolved in 150 ml of dichloromethane, and 2.75 g (27.2 mmol) of triethylamine and 4.66 g (27.2 mmol) of 2-bromopropionyl chloride were added thereto, followed by stirring at room temperature. After 1 hour, the resulting solution was diluted with 100 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The compound, obtained after removing the solvent by distillation under reduced pressure, was dissolved in 15 ml of morpholine and stirred at room temperature for 2 hours. The reaction solution was dissolved in 50 ml of water and then extracted three times with 100 ml of ethyl acetate, respectively. The collected organic layer was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 9/1, v/v) to give 4.85 g (11.6 mmol) of the title compound at a yield of 64%.
1H NMR(DMSO, ppm); δ 2.41 (4H, brs), 2.65(4H, brs), 3.57(4H, t), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 9.44(1H, s), 12.28(1H, s)
ESI MS(m/e)=418[M+l]
EXAMPLE 12: Preparation of N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-£]pyridine- 2-yl] -2-(4-methy 1-1 -piperazinyl)acetamide
The same procedure as in EXAMPLE 5 was conducted by using 15 ml of N- methylpiperazine instead of morpholine, thereby obtaining 3.32 g (7.96 mmol) of the title compound at a yield of 44%.
1H NMR(CDCl3, ppm); δ 2.30(3H, br s), 2.65(4H, br m), 2.88(4H, br m), 3.29(2H, s), 3.80(4H, t), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 1O.24(1H, s)
ESI MS(m/e)=417[M+l]
EXAMPLE 13: Preparation of ethyl l-({[5-(4-chIoroanilino)[l,3]thiazolo[5,4- 6]pyridine-2-yl]amino}carbonyl)cyclopentanecarboxyIate
The same procedure as in EXAMPLE 1 was conducted by using 3.83 g (21.7 mmol) of the compound obtained in PREPARATION 16 instead of cyclopentanecarbonyl chloride, thereby obtaining 5.66 g (13.6 mmol) of the title compound at a yield of 75%.
1H NMR(CDCl3, ppm); δ 1.29(3H, t), 1.79(2H, m), 1.90(2H, m), 4.24(2H, q), 6.55(1H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 12.15(1H, s)
ESI MS(m/e)=417[M+l]
EXAMPLE 14: Preparation of l-({[5-(4-chloroanilino)[l,3]thiazolo[5,4- Z>]pyridine-2-yI] amino} carbonyl)cyclopentanecarboxylic acid
5.66 g (13.6 mmol) of the compound, obtained in EXAMPLE 1, was dissolved in 100 ml of tetrahydrofuran: methanol: water = 3: 1: 1 solution. To the solution, 856 mg (20.4 mmol) of lithium hydroxide monohydrate was added and then stirred at room temperature. After 4 hours, the solution was neutralized with IN aqueous hydrochloric acid solution and then extracted three times with 100 ml of ethyl acetate, respectively. The resulting solution was washed with 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The solvent was removed by distillation under reduced pressure to give 3.60 g (9.25 mmol) of the title compound at a yield of 68%, without any further purification.
1H NMR(DMSO, ppm); δ 1.55(4H, br s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d), 9.4O(1H, s), 12.48(1H, s)
ESI MS(m/e)=389[M+l] EXAMPLE 15: Preparation of iV-[5-(4-chloro-2-fluoromethylanilino) [l,3]thiazolo[5,4-Λ]pyridine-2-yl]-7V'-[2-(4-morphoIinyl)ethyl]urea
10.0 g (32.4 mmol) of the compound, obtained in PREPARATION 21, was dissolved in 200 ml of tetrahydrofuran, and 6.6 g (32.4 mmol) of 4-nitrophenyl- chloroformate and 5.2 g (64.8 mmol) of pyridine were added thereto, followed by stirring at room temperature. After 2 hours, the solvent was removed by distillation under reduced pressure. The obtained solid compound was washed with ether to give 15.0 g of {5-[(4-chloro-2-fluorophenyl)-methylamino]-thiazolo[5,4,b]pyridine-2- yl}carbamic acid 4-nitrophenyl ester. 2.0 g (4.2 mmol) of the resultant compound was dissolved in 50 ml of tetahydrofuran. To the solution, 1.1 g (8.4 mmol) of 4-(2- aminoethyl)morpholine and 1.3 g (64.8 mmol) of triethylamine were added, followed by heating under reflux with stirring. After 1 hour, the resulting solution was diluted with 200 ml of ethyl acetate, washed with 100 ml of aqueous saturated sodium hydrogen carbonate solution and then dried over anhydrous MgSO4. The compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane /methanol = 9/1, v/v) to give 1.5 g of the title compound at a yield of 79%.
1H NMR(CDCl3, ppm); δ 2.54 (4H, br), 2.60(2H, m), 3.44(3H, s), 3.47(2H, m), 3.75(4H, br), 6.4O(1H, d), 7.23(3H, m), 7.79(1H, d)
ESI MS(m/e)= 465[M+l]
EXAMPLE 16: Preparation of iV-[5-(4-fluoro-2-hydroxyπiethyIanilino [l,3]thiazolo[5,4-Z>]pyridine-2-yl]-cyclopropanecarboxyamide 56 mg (0.13 mmol) of the compound, obtained in PREPARATION 47, was dissolved in methanol/water (2 ml/2ml, v/v). To the solution, 17 mg (0.39 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature.
After 1 hour, the reaction solution was neutralized with IN aqueous hydrochloric acid solution. The solvent was removed by distillation under reduced pressure. The obtained residue was washed with 10 ml of water and 10 ml of aqueos saturated NaCl solution. The collected organic layer was dried over anhydrous MgSO4. The compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (ethyl acetate/hexane = 1/1, v/v) to give 39 mg (0.09 mmol) of the title compound at a yield of 83%.
1H NMR(DMSO, ppm); δ 0.91(2H, m), 1.10(2H, m), 1.93 (IH, m), 3.28(3H, s), 6.02(1H, d), 6.65(1H, d), 6.64(1H, s), 7.05(lH,d), 7.66(1H, d), 9.52(1H, br s), 12.32(1 H, br s)
ESI MS(m/e)=359[M+l]
EXAMPLE 17: Preparation of N-[5-(cyclohexylamino)[l,3]thiazolo[5,4- Λ]pyridine-2-yl]-cyclopropanecarboxyamide
The same procedure as in EXAMPLE 1 was conducted except that 4.5O g
(18.1 mmol) of the compound obtained in PREPARATION 4 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbony chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 4.47 g (14.1 mmol) of the title compound at a yield of 78%. 1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.01-1.84(11H, m), 1.99(1H, m), 6.93(1H, d), 7.91(1H, d)
ESI MS(m/e)=317[M+l]
EXAMPLE 18: Preparation of 7V-[5-(cyclohexylamino)[l,3]thiazolo[5,4- όjpyridine-l-ylj-cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 4.24 g
(18.1 mmol) of the compound obtained in PREPARATION 5 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbony chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 4.71 g (15.6 mmol) of the title compound at a yield of 86%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.12-1.82(9H, m), 1.99(1H, m), 6.93(1H, d), 7.91(1H, d)
ESI MS(m/e)=303[M+l]
EXAMPLE 19: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazoIo[5,4-6]pyridine- 2-yl]-3-(diethylamino)propaneamide
The same procedure as in EXAMPLE 11 was conducted by using 15 ml of diethylamine instead of morpholine, thereby obtaining 2.71 g (6.70 mmol) of the title compound at a yield of 37%.
1H NMR(CDCl3, ppm); δ 1.18(6H, t), 2.60(2H, t), 2.74(4H, q), 2.83(2H, t), 6.63(1 H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d)
ESI MS(m/e)=404[M+l]
EXAMPLE 20: Preparation of iV-[5-(4-chloroanilino)[l,3]thiazolo[5,4-Z>]pyridine- 2-yl]-3-(l-piperidinyl)propaneamide
The same procedure as in EXAMPLE 11 was conducted by using 15 ml of piperidine instead of morpholine, thereby obtaining 3.16 g (7.60 mmol) of the title compound at a yield of 42%.
1H NMR(CDCl3, ppm); δ 1.57(2H, br s), 1.78(4H, m), 2.63(5H, m), 2.96(2H, t), 6.58(1H, s), 6.85(1H, d), 7.30(2H, d), 7.43(2H, d), 7.84(1H, d)
ESI MS(m/e)=416[M+l]
EXAMPLE 21: Preparation of iV-[5-(3-chloroanilino)[l,3]thiazolo[5,4-*]pyridine- 2-yl]-cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.01 g
(18.1 mmol) of the compound obtained in PREPARATION 6 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.38 g (15.6 mmol) of the title compound at a yield of 86%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 2.00(1H, m), 6.3O(1H, dd), 6.95(1H, d), 7.31(1H, t), 7.58(1H, dd), 7.89(1H, t), 7.94(1H, d), 9.51(1H, s), 12.51(1H, s) ESI MS(m/e)=345[M+l]
EXAMPLE 22: Preparation of Λ45-(2-chloroanilino)[l,3]thiazolo[5,4-*]pyridine- 2-yl]-cycIopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.01 g
(18.1 mmol) of the compound obtained in PREPARATION 7 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.00 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 2.00(1H, m), 7.04(1H, t), 7.08(1H, d), 7.32(1H, t), 7.48(1H, d), 7.92(1H, d), 8.00(1H, d), 8.61(1H, s), 12.54(1H, s)
ESI MS(m/e)=345[M+l]
EXAMPLE 23: Preparation of iV-[5-(2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine- 2-yl]-cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 4.71 g
(18.1 mmol) of the compound obtained in PREPARATION 8 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.17 g (15.7 mmol) of the title compound at a yield of 87%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 2.00(1H, m), 7.04(1H, t), 7.08(1H, d), 7.32(1H, t), 7.48(1H, d), 7.92(1H, d), 8.00(1H, d), 8.61(1H, s), 12.54(1H, s)
ESI MS(m/e)=329[M+l]
EXAMPLE 24: Preparation of iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazoIo[5,4- 6]pyridine-2-yl]cycIopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 4.71 g
(18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.08 g (14.8 mmol) of the title compound at a yield of 82%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 2.00(1H, m), 2.29(3H, s), 6.61(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t)
ESI MS(m/e)=343[M+l]
EXAMPLE 25: Preparation of Λ-[5-(2-fluoro-4-niethylanilino)[l,3]thiazolo[5,4- b] py ridine-2-yl] -2-(4-morpholinyl)acetamide
The same procedure as in EXAMPLE 5 was conducted except that 4.71 g (18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3, thereby obtaining 3.71 g (9.23 mmol) of the title compound at a yield of 51%.
1H NMR(CDCl3, ppm); δ 2.34(3H, s), 2.66(4H, t), 3.28(2H, s), 3.80(4H, t), 6.61(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t)
ESI MS(m/e)=402[M+l]
EXAMPLE 26: Preparation of iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4- £]pyridine-2-yl]-3-(4-morphoIinyl)propaneamide
The same procedure as in EXAMPLE 11 was conducted except that 4.71 g (18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3, thereby obtaining 3.16 g (7.60 mmol) of the title compound at a yield of 42%.
1H NMR(CDCl3, ppm); δ 2.34(3H, s), 2.66(6H, m), 2.82(2H, t), 3.92(4H, t), 6.61(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t)
ESI MS(m/e)=416[M+l]
EXAMPLE 27: Preparation of 7V-[5-(2-fluoro-4-methoxyanilino)[l,3]thiazolo[5,4- b] py ridine-2-yl] cy clopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 4.71 g
(18.1 mmol) of the compound obtained in PREPARATION 8 was used instead of the compound obtained in PREPARATION 3 and 2.27 (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.17 g (15.7 mmol) of the title compound at a yield of 87%.
1H NMR(DMSO, ppm); δ 0.93(4H, m), 1.97(1H, m), 3.77(3H, s), 6.79(1H, dd), 6.87(1H, d), 6.91(1H, t), 7.75(1H, t), 7.85(1H, d), 8.65(1H, s), 12.42(1H, s)
ESI MS(m/e)=359[M+l]
EXAMPLE 28: Preparation of 2-({[5-(2-fluoro-4-methoxyanilino) [l,3]thiazolo[5,4-A]pyridine-2-yl]amino}carbonyl)cyclopropanecarboxylic acid
The same procedure as in EXAMPLE 14 was conducted except that 4.71 g
(18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3 and 3.83 g (21.7 mmol) of the compound obtained in PREPARATION 17 was used instead of cyclopentanecarbonyl chloride, thereby obtaining 3.01 g (7.78 mmol) of the title compound at a yield of 43%.
1H NMR(DMSO, ppm); δ 1.40(2H, m), 2.02(1H, m), 2.29(3H, s), 2.5O(1H, m), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t), 8.82(1H, s), 12.5O(1H, s)
ESI MS(m/e)=387[M+l]
EXAMPLE 29: Preparation of JV-[5-(4-bromo-2-fluoroanilino) [l,3]thiazolo[5,4- b] py ridine-2-yl] cy clopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 6.14 g
(18.1 mmol) of the compound obtained in PREPARATION 11 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 6.39 g (15.7 mmol) of the title compound at a yield of 87%. 1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.98(1H, m), 7.14(1H, d), 7.37(1H, d), 7.55(1H, d), 7.94(1H, d), 8.25(1H, t), 9.08(1H, s), 12.53(1H, s)
ESI MS(m/e)=408[M+l]
EXAMPLE 30: Preparation of 7V-[5-(3-fluoro-4-methylanilino) [l,3]thiazolo[5,4- A]pyridine-2-yl]cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 4.97 g
(18.1 mmol) of the compound obtained in PREPARATION 12 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 4.96 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.99(1H, m), 2.17(3H5 s), 6.92(1H, d), 7.23(2H, q), 7.68(1H, d), 7.91(1H, d), 9.41(1H, s), 12.49(1H, s)
ESI MS(m/e)=343[M+l]
EXAMPLE 31: Preparation of N-[5-(4-chloro-2-fIuoroanilino)[l,3]thiazolo[5,4- Z>]pyridine-2-yl]cycIopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.33 g
(18.1 mmol) of the compound obtained in PREPARATION 13 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.32 g (14.7 mmol) of the title compound at a yield of 81%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.99(1H, m), 7.14(1H, d), 7.26(1H, d), 7.45(1H, dd), 7.94(1H, d), 8.29(1H, t), 9.08(1H, s), 12.53(1H, s)
ESI MS(m/e)=363[M+l]
EXAMPLE 32: Preparation of iV-[5-(2,4-difluoroanilino)[l,3]thiazolo[5,4- A]pyridine-2-yl]cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.04 g
(18.1 mmol) of the compound obtained in PREPARATION 14 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.45 g (15.7 mmol) of the title compound at a yield of 87%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.99(1H, m), 7.02(1H, d), 7.08(1H, t), 7.3O(1H, t), 7.91(1H, d), 8.09(1H, m), 8.91(1H, s), 12.48(1H, s)
ESI MS(m/e)=347[M+l]
EXAMPLE 33: Preparation of iV-[5-(2-fluoro-4-methyIaniIino)[l,3]thiazolo[5,4- 6]pyridine-2-yl]-2-[(4-methyl-l-piperazinyl)carbonyI]cycIopropanecarboxamide
3.01 g (7.78 mmol) of the compound as obtained in EXAMPLE 28 was dissolved in 50 ml of dichloroethane. To the solution, 2.78 g (23.3 mmol) of thionyl chloride was added, follwed by stirring at room temperature. After 1 hour, the solvent and an excess of thionyl chloride were removed by distillation under reduced pressure. The residue was dissolved in 100 ml of dichloromethane. To the solution, 1.56 g (15.6 mmol) of JV-methyl piperidine and 1.58 g (15.6 mmol) of triethylamine were added, followed by stirring at room temperature. After 2 hours, the resulting solution was diluted with 100 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 95/5, v/v) to give 2.66 g (5.68 mmol) of the title compound at a yield of 73%.
1H NMR(CDCl3, ppm); δ 1.40(2H, m), 2.10-2.48(6H, m), 2.29(3H, s), 3.75(4H, m), 6.58(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t), 10.85(1H, s)
ESI MS(m/e)=469[M+l]
EXAMPLE 34: Preparation of N1-[2-(diethylamino)ethyI]-N1-[5-(2-fluoro-4- methylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yI]-l,2-cyclopropanedicarboxamide
The same procedure as in EXAMPLE 33 was conducted except that 1.81 g (15.6 mmol) of 7V,JV-diethylethylene diamine was used instead of iV-methylpiperidine, thereby obtaining 2.49 g (5.14 mmol) of the title compound at a yield of 66%.
1H NMR(CDCl3, ppm); δ 1.40(2H, m), 2.10-2.48(9H, m), 2.29(3H, s), 3.75(4H, m), 6.78(1H, s), 6.82(1H, d), 6.96(2H, m), 7.83(1H, d), 7.99(1H, t)
ESI MS(m/e)=485[M+l] EXAMPLE 35: Preparation of (£)-7V-[5-(2-fluoro-4-methyIanilino) [l,3]thiazoIo[5,4-6]pyridine-2-yl]-3-phenyI-2-propeneamide
The same procedure as in EXAMPLE 1 was conducted except that 4.71 g (18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3 and 3.62 g (21.7 mmol) of cinnamoyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.27 g
(13.0 mmol) of the title compound at a yield of 72%.
1H NMR(DMSO, ppm); δ 2.30(3H, s), 7.01(4H, m), 7.44(1H, s), 7.45(2H, d), 7.66(2H, d), 7.77(1H, d), 7.91(1H, d), 7.97(1H, t), 8.85(1H, s)
ESI MS(m/e)=405[M+l]
EXAMPLE 36: Preparation of iV-[5-(2-fluoro-4-methyIanilino) [l,3]thiazolo[5,4- ό]pyridine-2-yl]acrylamide
The same procedure as in EXAMPLE 1 was conducted except that 4.71 g
(18.1 mmol) of the compound obtained in PREPARATION 9 was used instead of the compound obtained in PREPARATION 3 and 1.96 g (21.7 mmol) of acryloyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 4.75 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(DMSO, ppm); δ 2.30(3 H, s), 5.94(1H, d), 6.54(2H, m), 6.98-7.10(3H, m), 7.89-7.97(2H, m), 8.84(1H, s), 12.42(1H, s) ESI MS(m/e)=329[M+l]
EXAMPLE 37: Preparation of N^S-^-chloro^-fluoroanilino) [l,3]thiazolo[5,4- 6]pyridine-2-yl]-N2-[2-(4-morpholmyl)ethyl]-l,2-cycIopropanedicarboxamide
The same procedure as in EXAMPLE 35 was conducted except that 3.17 g
(7.78 mmol) of the compound obtained in PREPARATION 18 was used instead of the compound obtained in EXAMPLE 28 and 2.03 g (15.6 mmol) of 4-(2- aminoehtyl)morpholine was used instead of iV-methylpiperazine, thereby obtaining 2.46 g (4.74 mmol) of the title compound at a yield of 61%.
1H NMR(DMSO, ppm); δ 1.30(2H, m), 2.28(1H, m), 2.33(7H, m), 3.20(2H, m), 3.59(4H, m), 7.14(1H, d), 7.26(1H, d), 7.45(1H, dd), 7.94(1H5 d), 8.29(1H, t), 9.08(1H, s), 12.53(1H, s)
ESI MS(m/e)=519[M+l]
EXAMPLE 38: Preparation of N^S-^-chloro^-fluoroanilino) [l,3]thiazolo[5,4- ό]pyridine-2-yl]-N2-[2-(2-pyridinyl)ethyl]-l,2-cyclopropanedicarboxamide
The same procedure as in EXAMPLE 35 was conducted except that 3.17 g
(7.78 mmol) of the compound obtained in PREPARATION 18 was used instead of the compound obtained in EXAMPLE 28 and 1.91 g (15.6 mmol) of 2-(2- aminoehtyl)pyridine was used instead of iV-methylpiperazine, thereby obtaining 1.47 g
(2.88 mmol) of the title compound at a yield of 37%. 1H NMR(DMSO, ppm); δ 1.30(2H, m), 2.28(1H, m), 2.33(1H, m), 2.88(2H, t), 3.46(2H, t), 7.14(1H, d), 7.26(3H, m), 7.45(1H, dd), 7.7O(1H, t), 7.94(1H, d), 8.29(1H, t), 8.42(1H, d), 8.49(1H, d), 9.08(1H, s), 12.53(1H, s)
ESI MS(m/e)=511[M+l]
EXAMPLE 39: Preparation of iV-[5-(4-chloro-2-fluoroaniIino) [l,3]thiazolo[5,4- 6]pyridine-2-yl]acrylamide
The same procedure as in EXAMPLE 1 was conducted except that 5.33 g
(18.1 mmol) of the compound obtained in PREPARATION 13 was used instead of the compound obtained in PREPARATION 3 and 1.96 g (21.7 mmol) of acryloyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.06 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(DMSO, ppm); δ 5.95(1H, d), 6.43(1H, d), 6.58(1H, m), 7.16(1H, d), 7.27(1H, d), 7.46(1H, d), 7.96(1H, d), 8.31(1H, t), 9.1O(1H, s), 12.48(1H, s)
ESI MS(m/e)=349[M+l]
EXAMPLE 40: Preparation of iV-[5-(4-chloro-2-fluoroanilino) [l,3]thiazolo[5,4- 6]pyridine-2-yI]-3-methyl-3-buteneamide
The same procedure as in EXAMPLE 1 was conducted except that 5.33 g (18.1 mmol) of the compound obtained in PREPARATION 13 was used instead of the compound obtained in PREPARATION 3 and 2.57 g (21.7 mmol) of 3,3-dimethyl acryloyl chloride was used instead of cyclopentanecarbonyl chloride, thereby collecting a compound eluted at HPLC (acetonitrile/water = 70/30, v/v) retention time 8.72 minute to give 1.16 g (3.08 mmol) of the title compound at a yield of 17%.
1H NMR(DMSO, ppm); δ 1.78(3H, s), 3.22(2H, s), 4.90(2H, d), 7.14(1H, d), 7.26(1H, d), 7.45(1H, dd), 7.94(1H, d), 8.29(1H, t), 9.08(1H, s), 12.53(1H, s)
ESI MS(m/e)=377[M+l]
EXAMPLE 41: Preparation of iV-[5-(4-chloro-2-fluoroanilino) [l,3]thiazolo[5,4- 6]pyridine-2-yl]-3-methyl-2-buteneamide
2.73 g ((7.24 mmol) of the title compound was obtained with a yield of 40% by collecting a compound which was eluted at HPLC (acetonitrile/water = 70/30, v/v) Retnetion Time 10.14 minute.
1H NMR(DMSO, ppm); δ 1.92(3H, s), 2.22(3H, s), 6.03(1H, s), 7.13(1H5 d), 7.25(1H, d), 7.43(1H, d), 7.92(1H, d), 8.30(1H, t), 9.06(1H, s), 12.11(1H, s)
ESI MS(m/e)=377[M+l]
EXAMPLE 42: Preparation of iV-[5-(4-chIoro-2-fluoroanilino) [l,3]thiazolo[5,4- Z>]pyridine-2-yl]-3-buteneamide
The same procedure as in EXAMPLE 1 was conducted except that 5.33 g (18.1 mmol) of the compound obtained in PREPARATION 13 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of crotonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby collecting a compound eluted at HPLC (acetonitrile/water = 70/30, v/v) retention time 7.30 minute to give 788 mg (2.17 mmol) of the title compound at a yield of 12%.
1H NMR(DMSO, ppm); δ 3.30(2H, d), 5.20(2H, t), 5.98(1H, m), 7.15(1H, d), 7.25(1H, d), 7.44(1H, d), 7.94(1H, d), 8.31(1H, t), 9.07(1H, s), 12.28(1H, s)
ESI MS(m/e)=363[M+l]
EXAMPLE 43: Preparation of (£)-7V-[5-(4-chloro-2-fluoroaniIino) [ 1 ,3] thiazolo [5,4-A] py ridine-2-y 1] -2-bu teneamide
2.04 g (5.61 mmol) of the title compound was obtained at a yield of 31% by collecting a compound which was eluted at HPLC (acetonitrile/water = 70/30, v/v) Retnetion Time 7.62 minute.
1H NMR(DMSO, ppm); δ 1.91(2H, d), 6.26(1H, d), 6.99(1H, q), 7.13(1H, d), 7.26(1H, d), 7.43(1H, d), 7.94(1H, d), 8.31(1H, t), 9.07(1H, s), 12.27(1H, s)
ESI MS(m/e)=363[M+l]
EXAMPLE 44: Preparation of JV-[5-(2,6-difluoroanilino)[l,3]thiazolo[5,4- 6]pyridine-2-yl]cycIopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.04 g (18.1 mmol) of the compound obtained in PREPARATION 15 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 4.70 g (15.7 mmol) of the title compound at a yield of 75%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1 H, m), 6.53(1 H, d), 7.28(2H, t), 7.47(1H, m), 7.85(1H, d), 9.03(1H, s), 12.48(1H, s)
ESI MS(m/e)=347[M+l]
EXAMPLE 45: Preparation of 7V-{5-[4-chIoro(methyl)aniline][l,3]thiazolo[5,4- £]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.26 g (18.1 mmol) of the compound obtained in PREPARATION 20 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.13 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.42(3H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=359[M+l]
EXAMPLE 46: Preparation of iV-{5-[4-chloro(methyl)aniline][l,3]thiazolo[5,4- A]pyridine-2-yl}acrylamide
The same procedure as in EXAMPLE 1 was conducted except that 5.26 g
(18.1 mmol) of the compound obtained in PREPARATION 20 was used instead of the compound obtained in PREPARATION 3 and 1.96 g (21.7 mmol) of acryloyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.24 g (15.2 mmol) of the title compound at a yield of 84%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 5.94(1H, d), 6.50(2H, qd), 6.71(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=345[M+l]
EXAMPLE 47: Preparation of iV-{5-[4-chloro(ethyI)aniline][l,3]thiazolo[5,4- Z>]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.52 g
(18.1 mmol) of the compound obtained in PREPARATION 32 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.33 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.03(3H, t), 1.97(1H, m), 3.63(2H, q), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=373[M+l]
EXAMPLE 48: Preparation of iV-{5-[4-chIoro(ethyl)aniline][l,3]thiazolo[5,4- 6]pyridine-2-yl}acrylamide
The same procedure as in EXAMPLE 1 was conducted except that 5.52 g (18.1 mmol) of the compound obtained in PREPARATION 32 was used instead of the compound obtained in PREPARATION 3 and 1.96 g (21.7 mmol) of acryloyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 3.90 g (10.9 mmol) of the title compound at a yield of 60%.
1H NMR(DMSO, ppm); δ 1.03(3H, t), 3.63(2H, q), 5.94(1H, d), 6.50(2H, qd), 6.71(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=359[M+l]
EXAMPLE 49: Preparation of ethyl 2-(4-chloro{2-[(cyclopropylcarbonyl) amino] [l,3]thiazolo[5,4-6]pyridine-5-yl}aniIino)acetate
The same procedure as in EXAMPLE 1 was conducted except that 6.57 g
(18.1 mmol) of the compound obtained in PREPARATION 34 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.77 g (13.4 mmol) of the title compound at a yield of 74%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.03(3H, t), 1.97(1H, m), 4.11(2H, q), 4.62(2H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=431[M+l]
EXAMPLE 50: Preparation of 2-(4-chloro{2-[(cyclopropyIcarbonyl)amino] [l,3]thiazolo[5,4-Z>]pyridine-5-yl}aniIino)acetic acid 5.77 g (13.4 mmol) of the compound as obtained in EXAMPLE 49 was dissolved in 100 ml of tetrahydrofuran/ethanol/water (3/1/1). To the solution, 1.12 g (26.8 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature. After 8 hours, the reaction solution was neutralized with IN aqueous hydrochloric acid solution. The reaction solution was extracted twice with 100 ml of ethyl acetate and then dried over anhydrous MgSO4. After removing the solvent by distillation under reduced pressure, 3.67 g (9.11 mmol) of the title compound was obtained at a yield of 68%, without any further purification step.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 4.62(2H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1 H, d), 12.48(1 H, s)
ESI MS(m/e)=403[M+l]
EXAMPLE 51: Preparation of 2-(4-chloro{2-[(cyclopropylcarbonyl)amino] [l,3]thiazoIo[5,4-6]pyridine-5-yI}anilino)ethyl cyclopropanecarboxylate
5.81 g (18.1 mmol) of the compound as obtained in PREPARATION 35 was dissolved in 150 ml of dichloromethane. To the solution, 5.49 g(54.3 mmol) of triethylamine and 6.01 g (45.3 mmol) of cyclopentane carbonyl chloride were added, followed by stirring at room temperature. After 2 hours, the reaction solution was diluted with 200 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 98/2, v/v) to give 7.04 g (15.4 mmol) of the title compound at a yield of 85%.
1H NMR(DMSO, ppm); δ 0.68(2H, m), 0.77(2H, m), 0.94(4H, m), 1.48(1H, m), 1.97(1H, m), 4.21(2H, t), 4.29(2H, t), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=457[M+l]
EXAMPLE 52: Preparation of JV-{5-[4-chloro(2-hydroxyethyl)anilino] [l^JthiazoloIS^-frlpyridine^-ylJcyclopropanecarboxamide
7.04 g (15.4 tnmol) of the compound as obtained in EXAMPLE 51 was dissolved in 150 ml of tetrahydrofuran/ethanol/water (3/1/1). To the solution, 1.29 g
(30.8 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature. After 8 hours, the reaction solution was neutralized with IN aqueous hydrochloric acid solution. The reaction solution was extracted twcie with
100 ml of ethyl acetate, and then dried over anhydrous MgSO4. After removing the solvent by distillation under reduced pressure, 3.71 g (9.55 mmol) of the title compound was obtained at a yield of 62%, without any further purification step.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.61(2H, t), 3.97(2H, t), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 12.48(1H, s)
ESI MS(m/e)=389[M+l]
EXAMPLE 53: Preparation of iY-[5-(4-chloro-2-fluoromethylanilino)[l,3] thiazoloβ^-άjpyridine-l-yllcyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.59 g
(18.1 mmol) of the compound obtained in PREPARATION 21 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.39 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(MeOD, ppm); δ 0.97(2H, m), 1.03(2H, m), 1.9O(1H, m), 3.29(3H, s), 6.52(1H, d), 7.29(1H, d), 7.34(1H, dd), 7.38(1H, t), 7.73(1H, d)
ESI MS(m/e)=377[M+l]
EXAMPLE 54: Preparation of N-{5-[2,4-difluoro(methyl)aniIine][l,3] thiazolo[5,4-6]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.29 g
(18.1 mmol) of the compound obtained in PREPARATION 22 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.15 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.37(3H, s), 6.46(1H, d), 7.20- 7.58(3H, m), 7.8O(1H, d), 12.48(1H, s)
ESI MS(m/e)=361[M+l] EXAMPLE 55: Preparation of iV-{5-[2,6-difluoro(methyl)anilino][l,3] thiazoIoβ^-Λjpyridine-l-ylJcyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.29 g
(18.1 mmol) of the compound obtained in PREPARATION 23 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.15 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.37(3H, s), 6.54(1H, d), 7.25- 7.49(3H, m), 7.85(1H, d), 12.48(1H, s)
ESI MS(m/e)=361[M+l]
EXAMPLE 56: Preparation of N-[5-(4-bromo-2-fluoromethylanilino)[l,3] thiazolo[5,4-£]pyridine-2-yI]cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 6.39 g (18.1 mmol) of the compound obtained in PREPARATION 24 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.26 g (12.5 mmol) of the title compound at a yield of 69%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.63(1H, m), 3.46(3H, s), 6.43(1H, dd), 7.22(1H, t), 7.33-7.39(2H, m), 7.64(1H, d)
ESI MS(m/e)=422[M+l] EXAMPLE 57: Preparation of 7V-{5-[2-methoxy(methyl)anilino][l,3] thiazolo [5,4-6] pyridine-2-ylJcyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.18 g (18.1 mmol) of the compound obtained in PREPARATION 25 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.84 g (16.5 mmol) of the title compound at a yield of 91%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.63(1H, m), 3.46(3H, s), 3.77(3H, s), 6.27(1H, d), 7.02(1H, d), 7.25(1H, d), 7.31(1H, td), 7.54(1H, d)
ESI MS(m/e)=355[M+l]
EXAMPLE 58: Preparation of JV-{5-[3,4-difluoro(methyl)aniIino][l,3] thiazolo [5,4-6] pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.29 g
(18.1 mmol) of the compound obtained in PREPARATION 26 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.15 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.37(3H, s), 6.7O(1H, d), 7.19(1H, m), 7.48(2H, m), 7.8O(1H, d), 12.48(1H, s) ESI MS(m/e)=361 [M+l]
EXAMPLE 59: Preparation of iV-{5-[methyl-4-(trifluoromethyl)anilino][l,3] thiazolo[5,4-6]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.87 g
(18.1 mmol) of the compound obtained in PREPARATION 27 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.33 g (13.6 mmol) of the title compound at a yield of 75%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.37(3H, s), 7.01(1H, d), 7.45(1H, d), 7.7O(1H, d), 7.9O(1H, d), 12.57(1H, s)
ESI MS(m/e)=393[M+l]
EXAMPLE 60: Preparation of 7V-{5-[4-methoxy(methyl)anilino][l,3] thiazoloβ^-^pyridine-l-ytycyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.18 g
(18.1 mmol) of the compound obtained in PREPARATION 28 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.84 g (16.5 mmol) of the title compound at a yield of 91%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.63(1H, m), 3.46(3H, s), 3.82(3H, s), 6.43(1H, d), 6.95(2H, d), 7.18(2H, d), 7.54(1H, d)
ESI MS(m/e)=355[M+l]
EXAMPLE 61: Preparation of JV-{5-[4-cyano(methyl)anilino][l,3] thiazolo[5,4- 6]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.09 g
(18.1 mmol) of the compound obtained in PREPARATION 37 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.44 g (15.6 mmol) of the title compound at a yield of 86%.
1H NMR(DMSO, ppm); δ 0.94(4H, m), 1.97(1H, m), 3.47(3H, s), 7.12(1H, d), 7.29(2H, d), 7.70(2H, d), 7.94(1H, d), 12.62(1H, s)
ESI MS(m/e)=350[M+l]
EXAMPLE 62: Preparation of 7V-{5-[4-isopropyl(methyl)anilino][l,3] thiazolo[5,4-6]pyridine-2-yl}cycIopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.40 g
(18.1 mmol) of the compound obtained in PREPARATION 29 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.31 g (14.5 mmol) of the title compound at a yield of 80%. 1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.28(6H, d), 1.63(1H, m), 2.94(1H, m), 3.51(3H, s), 6.56(1H, d), 7.19(2H, d), 7.27(2H, d), 7.55(1H, d)
ESI MS(m/e)=367[M+l]
EXAMPLE 63: Preparation of N-{5-[2,3-dihydro-l#-indene-5-yI(methyl)anilino] [1,3] thiazolo[5,4-Z»]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.36 g
(18.1 mmol) of the compound obtained in PREPARATION 30 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.28 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(CDCl3, ppm); δ 0.95(3H, m), LlO(IH, m), 1.22(2H, m), 1.65(1 H, m), 2.93(4H, t), 3.50(3H, s), 6.53(1H, d), 7.12(1H, s), 7.26(2H, m), 7.54(1H, d)
ESI MS(m/e)=365[M+l]
EXAMPLE 64: Preparation of JV-{5-[4-chIoro(methyl)aniIino][l,3] thiazolo[5,4- 6]pyridine-2-yl}l-methyl-l/-r-pyrrole-2-carboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.26 g
(18.1 mmol) of the compound obtained in PREPARATION 20 was used instead of the compound obtained in PREPARATION 3 and 3.12 g (21.7 mmol) of 1 -methylpyrrole-
2-carbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.69 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 3.93(3H, s), 6.15(1H, s), 6.7O(1H, d), 7.16(1H, s), 7.34(2H, d), 7.4O(1H, s), 7.46(2H, d), 7.79(1H, d), 12.18(1H, s)
ESI MS(m/e)=398[M+l]
EXAMPLE 65: Preparation of ethyl 4-[{2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yI}(methyl)amino]benzoate
The same procedure as in EXAMPLE 1 was conducted except that 5.94 g
(18.1 mmol) of the compound obtained in PREPARATION 38 was used instead of the compound obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.75 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.40(3H, t), 1.65(1H, m), 3.60(3H, s), 4.38(2H, q), 6.93(1H, d), 7.28(2H, d), 7.70(2H, d), 8.03(1H, d)
ESI MS(m/e)=397[M+l]
EXAMPLE 66: Preparation of iV-[{2-[(cycIopropyIcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yl}(methyl)amino]benzoic acid
5.75 g (14.5 mmol) of the compound as obtained in EXAMPLE 65 was dissolved in 150 ml of ethanol/water (4/1). To the solution, 1.21 g (29.0 mmol) of lithium hydroxide monohydrate was added, followed by stirring at room temperature. After 8 hours, the reaction solution was neutralized with IN aqueous hydrochloric acid solution. The resulting white solid was filtered and washed with diethyl ether. Wihout any further purification step, 3.84 g (10.4 mmol) of the title compound was obtained at a yield of 72%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.91(1H, m), 3.60(3H, s), 6.93(1H, d), 7.28(2H, d), 7.70(2H, d), 8.03(1H, d)
ESI MS(m/e)=369[M+l]
EXAMPLE 67: Preparation of (£)-iV-[5-(4-bromo-2-fluoromethylanilino)[l,3] thiazoIo[5,4-6]pyridine-2-yl]-3-(4-piperidinyl)2-propeneamide
5.75 g (9.74 mmol) of the compound as obtained in PREPARATION 40 was introduced into 100 ml of tetrahydrofuran, and 5 ml of 6N aqueous hydrochloric acid solution was added thereto, followed by heating under reflux with stirring. After 5 hours, the solvent was removed by distillation under reduced pressure to give 4.77 g (9.06 mmol) of hydrochloride at a yield of 93%, without any further purification step. 1H NMR(DMSO, ppm); δ 1.47(2H, qd), 1.68(2H, d), 1.90(2H, t), 1.94(2H, d), 2.11(1H, m), 3.46(3H, s), 6.43(1H, dd), 5.93(1H, d), 7.11(1H, dd), 7.22(1H, t), 7.33- 7.39(2H, m), 7.64(1H, d)
ESI MS(m/e)=491 [M+l]
EXAMPLE 68: Preparation of (£)-7V-{5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-£]pyridine-2-yl}-3-(l-ethyl-4-piperidinyl)-2-propeneamide 3.83 g (8.26 mmol) of the compound as obtained in PREPARATION 41 was introduced into 100 ml of dichloromethane, and 2.09 g (20.7 mmol) of triethylamine was dded thereto, followed by stirring at room temperature. After 10 minutes, 1.09 g (24.8 mmol) of acetaldehyde and 6.97 g (33.0 mmol) of sodium triacetoxyborohydride were added to the solution, followed by stirring at room termperature. After 4 hours, 100 ml of aqueous saturated sodium hydrogen carbonate solution was added, and extracted two times with 100 ml of dichlormethane, respectively. The collected organic layer was washed with 100 ml of aqueous saturated NaCl solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 9/1, v/v) to give 2.18 g (4.79 mmol) of the title compound at a yield of 58%.
1H NMR(CDCl3, ppm); δ 1.08(3H, t), 1.47(2H, qd), 1.68(2H, d), 1.90(2H, t), 1.94(2H, d), 2.11(1H, m), 2.30(2H, q), 3.46(3H, s), 6.43(1H, dd), 5.93(1H, d), 6.61(1H, d), 7.11(1H, dd), 7.21(2H, d), 7.36(2H, d), 7.61(1H, d)
ESI MS(m/e)=456[M+l]
EXAMPLE 69: Preparation of (£)-iV-{5-[4-chIoro(methyl)anilino][l,3] thiazolo[5,4-A]pyridine-2-yl}-3-(l-methyl-4-piperidinyl)-2-propeneamide
The same procedure as in EXAMPLE 68 was conducted by using 2.12 g (35%,
24.8 mmol) of formamide instead of acetaldehyde, thereby obtaining 1.86 g (4.21 mmol) of the title compound at a yield of 51%. 1H NMR(CDCl3, ppm); δ 1.47(2H, qd), 1.68(2H, d), 1.90(2H, t), 1.94(2H, d), 2.11(1H, m), 2.30(3H, s), 3.46(3H, s), 6.43(1H, dd), 5.93(1H, d), 6.61(1H, d), 7.11(1H, dd), 7.21(2H, d), 7.36(2H, d), 7.61(1H, d)
ESI MS(m/e)=442[M+l]
EXAMPLE 70: Preparation of (£)-JV-{5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-6]pyridine-2-yl}-4-(4-morpholinyl)-2-buteneamide
4.48 g (27.2 mmol) of 4-bromocrotonic acid was dissolved in 50 ml of dichloromethane, 4.31 g (36.2 mmol) of thionyl chloride was added thereto, followed by stirring at room temperature. After 2 hours, the compound, obtained after removing the solvent by distillation under reduced pressure, was added to 100 ml of dichloromethane solution containing 5.26 g (18.1 mmol) of the compound as obtained in PREPARATION 20 and 3.66 g (36.2 mmol) of triethylamine, followed by stirring at room temperature. After 30 minutes, 4.73 g (54.3 mmol) of morpholine was added to the reaction solution, followed by stirring at room temperature. After 2 hours, the reaction solution was diluted with 200 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 9/1, v/v) to give 1.53 g (3.44 mmol) of the title compound at a yield of 19%.
1U NMR(CDCl3, ppm); δ 2.47(4H, br s), 3.18(2H, d), 3.51(3H, s), 3.70(4H, t), 6.18(1H, d), 6.63(1H, d), 7.13(1H, m), 7.23(2H, d), 7.36(2H, d), 7.61(1H, d), 10.40(1H, s)
ESI MS(m/e)=444[M+l]
EXAMPLE 71: Preparation of 4-[{2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-Z>]pyridine-5-yl}-(methyl)amino]-Λr,Af-dimethyIbenzamide
3.84 g (10.4 mmol) of the compound as obtained in EXAMPLE 66 was dissolved in 50 ml of dimethylformamide, and 7.80 ml (2N, 15.6 mmol) of dimethylamine, 2.99 g (15.6 mmol) of EDC [N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide] and 2.11 g (15.6 mmol) of HOBT (1-hydroxybenzotriazole) were added thereto, followed by stirring at room temperature. After 3 hours, the resulting solution was diluted with 150 ml of ethyl acetate, washed twice with 100 ml of aqueous saturated NaCl and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 95/5, v/v) to give 3.25 g (8.22 mmol) of the title compound at a yield of 79%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.23(2H, m), 1.65(1H, m), 3.10(6H, br s), 3.56(3H, s), 6.76(1H, d), 7.29(2H, d), 7.48(2H, d), 7.64(1H, d), 1 LlO(IH, s)
ESI MS(m/e)=396[M+l]
EXAMPLE 72: Preparation of 4-[{2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yl}(methyl)amino]-7V-[2-(dimethyIaino)ethyl]benzamide The same procedure as in EXAMPLE 71 was conducted by using 1.38 g (15.6 mmol) of ΛζiV-dimethylethylenediamine instead of acetaldehyde, thereby obtaining 2.83 g (6.45 mmol) of the title compound at a yield of 62%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.23(2H, m), 1.65(1H, m), 2.34(6H, s), 2.62(2H, t), 3.56(3H, s), 3.59(2H, t), 6.83(1H, d), 7.27(2H, d), 7.66(1H, d), 7.82(2H,
d)
ESI MS(m/e)=439[M+l]
EXAMPLE 73: Preparation of 4-{5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4- A]pyridine-2-yl}-l-methyl-l//-imidazole-4-carboxamide
2.74 g (21.7 mmol) of l-methyl-imidazole-4-carboxylic acid, obtained by the method disclosed in Henry Rapoport, Synthesis, 1988, 10, 767-771, was dissolved in 50 ml of dichloromethane, and 3.87 g (32.6 mmol) of thionyl chloride was added thereto, followed by stirring at room temperature. After 1 hour, the same procedure as in EXAMPLE 1 was conducted except that 5.26 g (18.1 mmol) of the compound, obtained after removing the solvent by distillation under reduced pressure, was used instead of cyclopentanecarbonyl chloride and 5.26 g (18.1 mmol) of the compound as obtained in PREPARATION 20 was used instead of the compound as obtained in PREPARATION 3, thereby obtaining 3.47 g (8.69 mmol) of the title compound at a yield of 48%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 3.76(3H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 7.82(1H, s), 8.06(1H, s), 11.53(1H, s) ESI MS(m/e)=399[M+l]
EXAMPLE 74: Preparation of 4-[{2-[(cyclopropyIcarbonyl)amino][l,3] thiazolo[5,4-Z>]pyridine-5-yl}(methyl)amino]-jV-methyIbenzamide
The same procedure as in EXAMPLE 71 was conducted by using 7.80 ml (2N,
15.6 mmol) of monomethylamine instead of dimethylamine, thereby obtaining 2.46 g (6.45 mmol) of the title compound at a yield of 62%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.99(1H, m), 2.79(3H, d), 3.48(3H, s), 6.87(1H, d), 7.35(2H, d), 7.48(2H, d), 7.85(1H, d), 8.37(1H, br s)
ESI MS(m/e)=382[M+l]
EXAMPLE 75: Preparation of iV-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4- 6]pyridine-2-yl}-l-methyl-l//-imidazole-5-carboxamide
The same procedure as in EXAMPLE 1 was conducted except that 5.26 g (18.1 mmol) of the compound as obtained in PREPARATION 20 instead of the compound as obtained in PREPARATION 3 and 3.12 g (21.7 mmol) of 1- methylimidazole-5-carbonyl chloride was used instead of cyclopetanecarbonyl chloride, thereby obtaining 5.69 g (14.3 mmol) of the title compound at a yield of 79%.
1H NMR(DMSO, ppm); δ 3.42(3H, s), 3.91(3H, s), 6.7O(1H, d), 7.34(2H, d), 7.46(2H, d), 7.79(1H, d), 8.13(1H, s), 8.49(1H, s), 12.56(1H, s)
ESI MS(m/e)=399[M+l] EXAMPLE 76: Preparation of (£>iV-{5-[4-chloro(methyl)aniIino][l,3] thiazoIo[5,4-Z»]pyridine-2-yl}-3-(l-methylsulfonyl)-4-piperidinyl)-2-propeneamide
3.83 g (8.26 mmol) of the compound as obtained in PREPARATION 41 was introduced into 100 ml of dichloromethane, and 2.51 g (24.8 mmol) of triethylamine and 1.42 g (12.4 mmol) of methane sulfonyl chloride were added, followed by stirring at room temperature. After 1 hour, the reaction solution was diluted with 100 ml of dichloromethane, washed with 100 ml of aqueous saturated ammonium chloride solution and 100 ml of aqueous saturated NaCl solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography
(dichloromethane/methanol = 98/2, v/v) to give 3.34 g (6.61 mmol) of the title compound at a yield of 80%.
1H NMR(CDCl3, ppm); δ 1.51(2H, qd), 1.85(2H, br d), 2.29(1H, m), 2.72(2H, td), 2.79(3H, s), 3.51(3H, s), 3.79(2H, br d), 5.97(1H, d), 6.61(1H, d), 7.11(1H , dd), 7.22(2H, d), 7.38(2H, d), 7.61(1H, d)
ESI MS(m/e)=506[M+l]
EXAMPLE 77: Preparation of 4-[{2-[(cyclopropylcarbonyl)amino][l,3] thiazolo [5,4-6] py ridine-5-y 1} (methy l)amino] benzamide
3.84 g (10.4 mmol) of the compound as obtained in EXAMPLE 66 was dissolved in 50 ml of tetrahydrofuran. To the solution, 1.58 g (15.6 mmol) of triethylamine and 1.56 g (11.4 mmol) of isobutylchloroformate were added, followed by stirring at room temperature. After 30 minutes, 6 ml of liquid ammonia was added, followed by stirring for 3 hours. The resulting solid was fitered and washed with diethyl ether. Without any further purification step, 1.49 g (4.06 mmol) of the title compound was obtained at a yield of 39%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.99(1H, m), 3.48(3H, s), 6.88(1H, d), 7.34(2H, d), 7.84(1H, d), 7.89(2H, d)
ESI MS(m/e)=368[M+l]
EXAMPLE 78: Preparation of (jF)-iV-{5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-Z>]pyridine-2-yl}-4-(l-piperidinyl)-2-buteneamide
The same procedure as in EXAMPLE 70 was conducted except that 4.62 g (54.3 mmol) of piperidine was used instead of morpholine, thereby obtaining 1.04 g (2.35 mmol) of the title compound at a yield of 13%.
1H NMR(CDCl3, ppm); δ 0.84(2H, m), 1.24(4H, m), 2.55(4H, m), 3.20(2H, d), 3.50(3H, s), 6.18(1H, d), 6.63(1H, d), 7.13(1H, m), 7.23(2H, d), 7.36(2H, d), 7.61(1H, d), 10.40(1 H, s)
ESI MS(m/e)=442[M+l]
EXAMPLE 79: Preparation of (£)-iV-{5-[4-chloro(methyl)aniIino][l,3] thiazolo[5,4-6]pyridine-2-yl}-4-(l,4-dioxa-8-azaspiro[4.5]de-8-cyl)-2-buteneamide The same procedure as in EXAMPLE 70 was conducted except that 7.78 g (54.3 mmol) of 4-piperidine ethylene ketal was used instead of morpholine, thereby obtaining 903 mg (1.81 mmol) of the title compound at a yield of 10%.
1H NMR(CDCl3, ppm); δ 1.71(4H, t), 2.54(4H, br s), 3.18(2H, d), 3.52(3H, s), 3.94(4H, s), 6.18(1H, d), 6.63(1H, d), 7.13(1H, m), 7.23(2H, d), 7.36(2H, d), 7.61(1H, d), 10.40(1H, s)
ESI MS(m/e)=500[M+l]
EXAMPLE 80: Preparation of (£)-N-{5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-Z>]pyridine-2-yl}-4-(dimethylaniino)-2-buteneamide
The same procedure as in EXAMPLE 70 was conducted except that 27.2 ml (2N, 54.3 mmol) of dimethylamine was used instead of morpholine, thereby obtaining 727 mg (1.81 mmol) of the title compound at a yield of 10%.
1H NMR(CDCl3, ppm); δ 2.55(6H, br s), 3.18(2H, d), 3.52(3H, s), 6.18(1H, d), 6.63(1H, d), 7.13(1H, m), 7.23(2H, d), 7.36(2H, d), 7.61(1H, d), 10.40(1H, s)
ESI MS(m/e)=402[M+l]
EXAMPLE 81: Preparation of ethyl 2-{4-[{2-[(cydopropylcarbonyl)amino][l,3] thiazoIo[5,4-Z>]pyridine-5-yl}(methyl)amino] phenyl} acetate
The same procedure as in EXAMPLE 1 was conducted except that 6.20 g
(18.1 mmol) of the compound as obtained in PREPARATION 31 was used instead of the compound as obtained in PREPARATION 3 and 2.27 g (21.7 mmol) of cyclopropanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride, thereby obtaining 5.95 g (14.5 mmol) of the title compound at a yield of 80%.
1H NMR(CDCl3, ppm); δ 0.95(2H, m), 1.22(2H, m), 1.40(3H, t), 1.65(1H, m), 2.92(2H, s), 3.60(3H, s), 4.38(2H, q), 6.93(1H, d), 7.42(2H, d), 7.90(2H, d), 8.11(1H,
d)
ESI MS(m/e)=411 [M+l]
EXAMPLE 82: Preparation of 2-{4-[{2-[(cyclopropylcarbonyl)amino][l,3] thiazolo[5,4-6]pyridine-5-yl}(methyl)amino]phenyl}acetic acid
The same procedure as in EXAMPLE 66 was conducted except that 5.95 g (14.5 mmol) of the compound as obtained in EXAMPLE 91 was used instead of the compound as obtained in EXAMPLE 65, thereby obtaining 3.77 g (9.86 mmol) of the title compound at a yield of 68%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.65(1H, m), 2.80(2H, s), 3.60(3H, s), 6.93(1H, d), 7.42(2H, d), 7.90(2H, d), 8.11(1H, d)
ESI MS(m/e)=383[M+l]
EXAMPLE 83: Preparation of iV-{5-[4-[2-(dimethylamino)-2-oxoethyl](methyl) anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}cyclopropanecarboxamide
The same procedure as in EXAMPLE 71 was conducted except that 3.98 g (10.4 mmol) of the compound as obtained in EXAMPLE 82 was used instead of the compound as obtained in EXAMPLE 66, thereby obtaining 2.64 g (6.45 mmol) of the title compound at a yield of 62%.
1H NMR(DMSO, ppm); δ 0.95(4H, m), 1.65(1H, m), 2.80(2H, s), 3.10(6H, br s), 3.60(3H, s), 6.93(1H, d), 7.42(2H, d), 7.90(2H, d), 8.11(1H, d)
ESI MS(m/e)=410[M+l]
EXAMPLE 84: Preparation of ethyl 4-[(^-3-({5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-6]pyridine-2-yl}amino)-3-oxo-l-propenyl]-l-piperidinecarboxyIate
The same procedure as in EXAMPLE 76 was conducted except that 1.35 g
(12.4 mmol) of ethylchloroformate was used instead of methanesulfonyl chloride, thereby obtaining 3.76 g (7.52 mmol) of the title compound at a yield of 91%.
1H NMR(CDCl3, ppm); δ 1.25(3H, t), 1.33(2H, qd), 1.72(2H, br d), 2.31(1H, m), 2.79(2H, br t), 3.51(3H, s), 4.14(2H, br s), 4.14(2H, q), 5.97(1H, d), 6.61(1H, d), 7.11(1H , dd), 7.22(2H, d), 7.38(2H, d), 7.61(1H, d)
ESI MS(m/e)=500[M+l]
EXAMPLE 85: Preparation of methyl 4-[(£>3-({5-[4-chloro(methyl)anilino][l,3] thiazolo[5,4-6]pyridine-2-yl}amino)-3-oxo-l-propenyl]-l-piperidinecarboxylate
The same procedure as in EXAMPLE 76 was conducted except that 1.17 g
(12.4 mmol) of methylchloroformate was used instead of methanesulfonyl chloride, thereby obtaining 3.65 g (7.52 mmol) of the title compound at a yield of 91%.
1H NMR(CDCl3, ppm); δ 1.33(2H, qd), 1.72(2H, br d), 2.31(1H, m), 2.79(2H, br t), 3.51(3H, s), 3.71(3H, s), 4.12(2H, br s), 5.97(1H, d), 6.61(1H, d), 7.11(1H , dd), 7.22(2H, d), 7.38(2H, d), 7.61(1H, d)
ESI MS(m/e)=486[M+l]
EXAMPLE 86: Preparation of (£)-3-(l-acetyl-4-piperidinyl)-iV-{5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}-2-propeneamide
The same procedure as in EXAMPLE 76 was conducted except that 1.27 g (12.4 mmol) of acetic anhydride was used instead of methanesulfonyl chloride, thereby obtaining 2.91 g (6.20 mmol) of the title compound at a yield of 75%.
1H NMR(CDCl3, ppm); δ 1.38(2H, qd), 1.82(2H, br t), 2.12(3H, s), 2.31(1H, m), 2.63(1H, br t), 3.11(1H, td), 3.51(3H, s), 3.84(1H, d), 4.64(2H, d), 5.97(1H, d), 6.61(1H, d), 7.11(1H , dd), 7.22(2H, d), 7.38(2H, d), 7.61(1H, d)
ESI MS(m/e)=470[M+l]
PREPARATION 48: 4-nitrophenyl 5-(4-chloro-2-fluoromethylanilino)[l,3] thiazolo[5,4-Z>]pyridine-2-ylcarbamate
10.0 g (32.4 mmol) of the compound as obtained in PREPARATION 21 was dissolved in 200 ml of tetrahydrofuran, and 6.6 g (32.4 mmol) of 4-nitrophenyl- chloroformate and 5.2g (64.8 mmol) of pyridine were added thereto, followed by stirring at room temperature. After 2 hours, the solid compound, obtained after removing the solvent by distillation under reduced pressure, was washed with ether to give 15.O g of the title compound quantitatively. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
EXAMPLE 87: N- [5-(4-chloio-2-fluoromethv lanilino) [1 ,3] thiazolo [5,4-
6]pyridine-2-yl]-iV'-[2-(4-morpholinyl)ethyl]urea
2.0 g (4.2 mmol) of the compound as obtained in PREPARATION 42 was dissolved in 50 ml of tetrahydrofuran. To the solution, 1.1 g (8.4 mmol) of 4-(2- aminoethyl)morpholine and 1.3 g (64.8 mmol) of triethylamine were added, followed by heating under reflux with stirring. After 1 hour, the reaction solution was diluted with 200 ml of ethyl acetate, washed with 100 ml of aqueous saturated sodium hydrogen carbonate solution, and then dried over anhydrous MgSO4. The crude compound, obtained after removing the solvent by distillation under reduced pressure, was purified by column chromatography (dichloromethane/methanol = 9/1, v/v) to give 1.5 g of the title compound at a yield of 79%.
1H NMR(CDCl3, ppm); δ 7.79(1H, d), 7.23(3H, m), 6.4O(1H, d), 3.75(4H, br), 3.47(2H, m), 3.44(3H, s), 2.60(2H, m), 2.54 (4H, br)
ESI MS(m/e)= 465[M+l]
In TABLE 1 below, the titled compounds were synthesized in the same manner as in EXAMPLE 87 by using the compound as obtained in PREPARATION 8.
[TABLE 1]
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
PREPARATION 49: 4-[2-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-6]pyridine-2-yl-ureido}-ethyl)-piperidine-l-carboxylic acid tert-butyl ester
The title compound was obtained from the compound obtained in
PREPARATION 48 and 4-(2-amino-ethyl)-piperidine-l-carboxylic acid tert-butyl ester in the same manner as in EXAMPLE 87.
1H NMR(CDCl3, ppm); δ 7.51(1H, d), 7.21(3H, m), 6.38(1H, d), 3.41(3H, s), 3.40(4H5 m), 2.75(2H, t), 2.03(1H, m), 1.88(2H, m), 1.45(m, 2H), 1.33(9H, s)
ESI MS(m/e)= 563 [M+ 1] EXAMPLE 157: l-{5-[(4-chloro-2-fluoro-phenyl)-methyI-amino]-thiazolo[5,4- ό]pyridine-2-yl}-3-(2-piperidine-4-yl-ethyl)-urea
500 mg (0.890 mmol) of the compound as obtained in PREPARATION 49 was dissolved in 10 ml of dichloromethane, and 5 ml of 4N hydrochloric acid in 1,4- dixoane solution was added thereto, followed by stirring for 2 hours. After the completion of the reaction, the reaction solution was concentrated. The residue was redissolved in 30 ml of water, and the solution was neutralized with aqueous saturated sodium hydrogen carbonate solution, filtered and dried to give 390 mg (0.844 mmol, yield of 95%) of the title compound.
1H NMR(CDCl3, ppm); δ 7.5O(1H, d), 7.22(3H, m), 6.39(1H, d), 3.43(3H, s), 3.40(4H, m), 2.75(2H, t), 2.03(1H, m), 1.88(2H, m), 1.45(m, 2H)
ESI MS(m/e)= 463 [M+ 1]
EXAMPLE 158: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-piperidine-4-yl-urea
The title compound was obtained from the compound obtained in EXAMPLE 119 in the same manner as in EXAMPLE 157.
1H NMR(DMSOd6, ppm); δ 8.76(1H, s), 8.68(1H, s), 7.77(1H, d), 7.6O(1H, d), 7.52- 7.44(2H, m), 7.36(1H, d), 6.51(1H, d), 3.83(1H, m), 3.36(3H, s), 3.33(2H, m), 3.02(2H, m), 1.99(2H5 m), 1.66(2H, m) ESI MS(m/e)= 435 [M+l]
EXAMPLE 159: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-piperidine-4-yImethyI-urea
The title compound was obtained from the compound obtained in EXAMPLE
125 in the same manner as in EXAMPLE 157.
1H NMR(DMSO-d6, ppm); δ 8.69(1H, s), 8.36(1H, s), 7.73(1H, d), 7.6O(1H, d), 7.5O(1H, t), 7.39(1H, d), 7.11(1H, t), 6.51(1H, d), 3.37(3H, s), 3.28(2H, m), 3.08(2H, m), 2.86(2H, m), 1.81(3H, m), 1.33(2H, m)
ESI MS(m/e)= 449 [M+l]
EXAMPLE 160: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-piperidine-3-ylmethyl-urea
The title compound was obtained from the compound obtained in EXAMPLE 160 in the same manner as in EXAMPLE 157.
1H NMR(DMSO-d6, ppm); δ 8.86(1H, s), 8.6O(1H, s), 7.73(1H, d), 7.6O(1H, d), 7.5O(1H, t), 7.39(1H, d), 7.29(1H5 1), 6.51(1H, d), 3.39(3H, s), 3.20(2H, m), 3.12(2H, m), 2.67(1H, m), 2.55(1H, m), 1.99(1H, m), 1.77(2H, m), 1.6O(1H, m), 1.18(1H, m)
ESI MS(m/e)= 449 [M+l] PREPARATION 50: 4- [3-(3- {5- |(4-chloro-2-fluoro-phenγl)-incthyl-ani ino ] - thiazolo[5,4-o]pyridine-2-yl-ureido}-propyI)-piperazine-l-carboxyIic acid tert- butyl ester
The title compound was obtained from the compound obtained in PREPARATION 48 and 4-(3-amino-propyl)-piperazine-l-carboxylic acid tert-butyl ester in the same manner as in EXAMPLE 87.
1H NMR(CDCl3, ppm); δ 7.35(1H, d), 7.02(3H, m), 6.49(1H, d), 3.42(3H, s), 3.30(2H, m), 3.25(4H, m), 2.65(4H, m), 2.52(2H, m), 1.75(2H, m), 1.34(9H, s)
ESI MS(m/e)= 578 [M+ 1]
EXAMPLE 161: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- b] py ridine-2-y 1} -3-(3-piperazine- 1 -y 1-propy l)-urea
The title compound was obtained from the compound obtained in PREPARATION 50 in the same manner as in EXAMPLE 157.
1H NMR(CD3OD, ppm); δ 7.36(1H, d), 7.32(3H, m), 6.48(1H, d), 3.41(3H, s), 3.31(2H, m), 3.25(4H, m), 2.65(4H, m), 2.52(2H, m), 1.75(2H, m)
ESI MS(m/e)= 478 [M+ 1]
PREPARATION 51 : (S)-3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-A]pyridine-2-yl}-ureido)-pyrroIidine-l-carboxylic acid tert-butyl ester The title compound was obtained from the compound obtained in PREPARATION 48 and (S)-3 -amino-pyrrolidine- 1-carboxylic acid tert-butyl ester in the same manner as in EXAMPLE 87.
1H NMR(DMSOd6, ppm); δ 9.21(1H, s), 9.01(1H, s), 7.71(1H, d), 7.52(1H, d), 7.42(2H, m), 7.31(1H, d), 6.48(1H, d), 3.32(3H, s), 3.3O(1H, m), 3.22(1H, m), 3.05(1H, m), 2.12(1H, m), 1.85(2H, m), 1.39(9H, s), 1.12(1H, m)
ESI MS(m/e)= 521 [M+ 1]
EXAMPLE 162: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- £]pyridine-2-yl}-3-(S)-pyrrolidine-3-yl-urea
The title compound was obtained from the compound obtained in PREPARATION 51 in the same manner as in EXAMPLE 157.
1H NMR(DMSO-d6, ppm); δ 9.2O(1H, s), 9.01(1H, s), 7.72(1H, d), 7.53(1H, d), 7.45(2H, m), 7.31(1H, d), 6.47(1H, d), 3.39(3H, s), 3.3O(1H, m), 3.22(1H, m), 3.05(1H, m), 2.12(1H, m), 1.85(2H, m), 1.12(1H, m)
ESI MS(m/e)= 421 [M+l]
EXAMPLE 163: l-[3-((S)-3-amino-pyrrolidine-l-yl)-propyl]-3-{5-[(4-chIoro-2- fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
The title compound was obtained from the compound obtained in EXAMPLE
144 in the same manner as in EXAMPLE 157. IH NMR(DMSO-d6, ppm); δ 8.52(1H, s), 8.45(1H, s), 7.68(1H, d), 7.55(1H, d), 7.5O(1H, t), 7.32(1H, d), 7.01(1H, t), 6.49(1H, d), 4.00(1H, m), 3.87(2H, s), 3.75(1H, m), 3.60(2H, m), 3.31(3H, s), 3.18(4H, m), 3.06(1H, m), 2.11(1H, m), 1.98(1H, m), 1.80(2H, m)
ESI MS(m/e)= 478 [M+ 1]
PREPARATION 52: [2-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-6]pyridine-2-yl}-ureido)-ethyl]-methyI-carboxylic acid tert-butyl ester
The title compound was obtained from the compound obtained in
PREPARATION 48 and (2-amino-ethyl)-methyl carbamic acid tert-butyl ester in the same manner as in EXAMPLE 87.
IH NMR(CD3OD, ppm); δ 7.83(1H, d), 7.43(3H, m), 6.65(1H, d), 3.61(2H, m), 3.41(3H, s), 3.22(2H, m), 2.77(3H, s), 1.42(9H, s)
ESI MS(m/e)= 509 [M+ 1]
EXAMPLE 164: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-(2-methylamino-ethyl)-urea
The title compound was obtained from the compound obtained in PREPARATION 52 in the same manner as in EXAMPLE 157.
IH NMR(CD3OD, ppm); δ 7.85(1H, d), 7.43(3H, m), 6.67(1H, d), 3.61(2H, m), 3.47(3H, s), 3.22(2H, m), 2.77(3H, s)
ESI MS(m/e)= 409 [M+l]
EXAMPLE 165 : 1 - {5- [(4-chloro-2-fluoro-phenyl)-methyI-amino] -thiazolo [5,4- 6]pyridine-2-yl}-3-[3-(4-hydroxyimino-piperidine-l-yl)-propyl]-urea
50 mg (0.102 mmol) of the compound as obtained in EXAMPLE 155 was dissolved in 10 ml of ethanol, and 35 mg (0.51 mmol) of hydroxylamine hydrochloride and 50 mg (0.51 mmol) of potassium acetate were added thereto, followed by stirring under reflux for 2 hours. After the completion of the reaction, the reaction solution was filtered to remove solid, and then the filtrate was concentrated. The residue was purified by column chromatography to give 48 mg (0.095 mmol, yield of 93%) of the title compound.
1R NMR(DMSO-d6, ppm); δ 1O.57(1H, s), 7.78(1H, d), 7.67(1H, d), 7.59(1H, t), 7.31(1H, d), 6.82(1H, s, br), 6.55(1H, d), 3.6O(1H, s), 3.32(3H, s), 3.19(2H, t), 3.03(2H, m), 2.52-2.15(8H, m), 1.17(2H, quin)
ESI MS(m/e)= 506 [M+l]
EXAMPLE 166: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- ό]pyridine-2-yl}-3-[3-(R)-2-hydroxymethyl-pyrrolidine-l-yl]-propyI]-urea
180 mg (0.32 mmol) of the compound as obtained in EXAMPLE 154 was dissolved in 15 ml of tetrahydrofuran and cooled to 0°C. To the solution, 49 mg (1.28 mmol) of lithium aluminum hydride was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, 0.1 ml of water was added to the solution. The resulting solid was filtered through celite. After concentration of the filtrate, the resulting residue was triturated by addition of 10 ml of diethyl ether and stirring for 10 minute. The resulting solid was filtered to give 133 mg (0.272 mmol, yield of 85%) of the title compound.
1H NMR(DMSO-d6, ppm); δ 1O.56(1H, s), 7.67(1H, d), 7.54(1H, d), 7.47(1H, t), 7.31(1H, d), 6.73(1H, s), 6.48(1H, d), 4.38(1H, s), 3.30(3H, s), 3.12(4H, m), 3.02(H, m), 2.87(1H, m), 2.32(1H, m), 2.2O(1H, m), 2.01(1H, m), 1.72(1H, m), 1.54(5H, m)
ESI MS(m/e)= 493 [M+ 1 ]
EXAMPLE 167: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- Λ]pyridine-2-yl}-3-[3-((S)-2-hydroxymethyl-pyrrolidine-l-yl)-propyl]-urea
The title compound was obtained from the compound obtained in EXAMPLE 153 in the same manner as in EXAMPLE 166.
1H NMR(DMSO-d6, ppm); δ 10.53(1H, s), 7.48(1H, d), 7.35(1H, d), 7.27(1H, t), 7.2O(1H, d), 6.26(2H, m), 3.31(3H, s), 3.17(2H, m), 3.04(3H, m), 2.71(1H, m), 2.3O(1H, m), 2.18(1H, m), 2.02(1H, m), 1.82(1H, m), 1.50(5H, m)
ESI MS(m/e)= 493 [M+ 1]
EXAMPLE 168: 4-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-6]pyridine-2-yl}-ureido)-propyl]-piperazine-l-carboxylic acid ethyl ester
50 mg (0.0907 mmol) of the compound as obtained in EXAMPLE 161 was dissolved in 10 ml of dichloromethane, and 29 ul (0.363 mmol) of pyridine and 9.2 ul (0.18 mmol) of ethyl chloroformate were added thereto, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was washed twice wih 10 ml of water, concentrated and subjected to column chromatography to give 43 mg (0.0783 mmol, yield of 86%) of the title compound.
1H NMR(DMSOd6, ppm); δ 1O.55(1H, s), 7.73(1H, d), 7.6O(1H, d), 7.51(1H, t), 7.37(1H, d), 6.99(1H, s), 6.52(1H, d), 4.07(2H, q), 3.60-3.41(6H, m), 3.31(3H, s), 3.23(2H, m), 1.78(4H, m), 1.41(2H, m), 1.12(3H, t)
ESI MS(m/e)= 550 [M+ 1]
EXAMPLE 169: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazoIo[5,4- ό]pyridine-2-yl}-3-[3-(4-methanesulfonyl-piperazine-l-yl)-propyl]-urea
The same procedure as in EXAMPLE 168 was conducted by using methanesulfonyl chloride instead of ethyl chloroformate in EXAMPLE 168, thereby obtaining the title compound.
1H NMR(DMSOd6, ppm); δ 1O.52(1H, s), 7.73(1H, d), 7.6O(1H, d), 7.51(1H, t), 7.38(1H, d), 6.99(1H, s), 6.52(1H, d), 3.55(4H, m), 3.32(3H, s), 3.22-3.10(8H, m), 2.92(3H, s), 1.73(2H, m)
ESI MS(m/e)= 556 [M+l] EXAMPLE 170: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- A]pyridine-2-yl}-3-[3-(4-ethanesulfonyl-piperazine-l-yI)-propyl]-urea
The same procedure as in EXAMPLE 168 was conducted by using ethanesulfonyl chloride instead of ethyl chloroformate in EXAMPLE 168, thereby obtaining the title compound.
1H NMR(DMSOd6, ppm); δ 1O.54(1H, s), 7.73(1H, d), 7.6O(1H, d), 7.51(1H, t), 7.38(1H, d), 6.72(1H, s), 6.5O(1H, d), 3.31(3H, s), 3.20(6H, m), 3.06(2H, q), 2.44- 2.38(6H, m), 1.64(2H, m), 1.21(3H, t)
ESI MS(m/e)= 570 [M+l]
EXAMPLE 171: l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-chloro-2-fluoro- phenyl)-methyI-amino]-thiazolo[5,4-Z>]pyridine-2-yl}-urea
The same procedure as in EXAMPLE 168 was conducted by using acetyl chloride instead of ethyl chloroformate in EXAMPLE 168, thereby obtaining the title compound.
1H NMR(DMSO-d6, ppm); δ 1O.52(1H, s), 7.69(1H, d), 7.51(1H, d), 7.47(1H, t), 7.36(1H, d), 6.7O(1H, s), 6.48(1H, d), 3.38(6H, m), 3.30(3H, s), 3.16(4H, m), 2.40(3H, s), 2.32(2H, m), 1.61(2H, m)
ESI MS(m/e)= 520[M+l] EXAMPLE 172: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-[3-(4-cylcopropyl-piperazine-l-yl)-propyl]-urea
210 mg (0.440 mmol) of the compound as obtained in EXAMPLE 161 was dissolved in 20 ml of tetrahydrofuran, and 0.186 ml (0.92 mmol) of (1- ethoxycyclopropoxy)trimethylsilan, 58 mg (0.092 mmol) of sodium cyanoborohydride, 0.2 ml of acetic acid and 0.2 ml of methanol were added thereto, followed by stirring under reflux for 3 hours. After the completion of the reaction, 30 ml of water was added to the resulting solution. The resulting solution was extracted twice with 20 ml of ethyl acetate, concentrated and subjected to column chromatography to give 123 mg (0.238 mmol, yield of 54%) of the title compound.
1H NMR(DMSOd6, ppm); δ 1O.57(1H, s), 7.74(1H, d), 7.61(1H, d), 7.52(1H, t), 7.38(1H, d), 6.72(1H, s), 6.5O(1H, d), 3.31(3H, s), 3.30(1H, m), 3.15(6H, m), 2.44- 2.38(6H, m), 1.64(2H, m), 0.49(2H, m), 0.31(2H, m)
ESI MS(m/e)= 518[M+l]
EXAMPLE 173: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-{3-[4-(2-fluoro-ethyl)-piperazine-l-yl]-propyl}-urea
70 mg (0.147 mmol) of the compound as obtained in EXAMPLE 161 was dissolved in 15 ml of 1,4-dioxane, and 40 mg (0.294 mmol) of potassium carbonate and 37.3 mg (0.294 mmol) of l-bromo-2-fluoroethane were added thereto, followed by stirring under reflux for 5 hours. After the completion of the reaction, 20 ml of water was added to the resulting solution. The resulting solution was extracted twice with 20 ml of ethyl acetate, concentrated and subjected to column chromatography to give 49 mg (0.0941 mmol, yield of 64%) of the title compound.
1H NMR(DMSOd6, ppm); δ 1O.54(1H, s), 7.74(1H, d), 7.6O(1H, d), 7.51(1H, t), 7.38(1H, d), 6.96(1H, s), 6.52(1H, d), 4.69(1H, m), 4.62, 4.57, 4.33, 4.25, 3.41 (4H, m), 3.32(3H, s), 3.21 (2H, m), 3.10(4H, m), 1.81(2H, m)
ESI MS(m/e)= 524 [M+ 1]
EXAMPLE 174: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-[3-(4-propionyl-piperazine-l-yl)-propyl]-urea
The same procedure as in EXAMPLE 168 was conducted by using propanoyl chloride instead of ethyl chloroformate in EXAMPLE 168, thereby obtaining the title compound.
1H NMR(DMSO-d6, ppm); δ 1O.52(1H, s), 7.69(1H, d), 7.56(1H, d), 7.47(1H, t), 7.33(1H, d), 6.7O(1H, s), 6.47(1H, d), 3.41(6H, m), 3.31(3H, s), 3.17(2H, q), 2.32- 2.23(6H, m), 1.60(2H, m), 0.92(3H, t)
ESI MS(m/e)= 534 [M+l]
EXAMPLE 175 : l-{5- [(4-clilo ro-2-fluoro-phenyl)-nieth\ 1-ani ino] -thiazolo [5,4- 6]pyridine-2-yl}-3-[3-(4-cyclopropionyl-piperazine-l-yl)-propyl]-urea
The same procedure as in EXAMPLE 168 was conducted by using cyclopropylcarbonyl instead of ethyl chloride in EXAMPLE 168, thereby obtaining the title compound.
1H NMR(DMSO-(I6, ppm); δ 1O.56(1H, s), 7.69(1H, d), 7.52(1H, d), 7.4O(1H, t), 7.16(1H, d), 6.61(1H, s), 6.37(1H, d), 3.41(6H, m), 3.35(1H, m), 3.31(3H, s), 3.25(2H, m), 2.41-2.33(6H, m), 0.44(2H, m), 0.32(2H, m)
ESI MS(m/e)= 546 [M+l]
EXAMPLE 176: l-[2-(4-acetyl-piperazine-l-yl)-ethyl]-3-{5-[(4-chloro-2-fluoro- phenyl)-methyl-amino]-thiazolo[5,4-Z>]pyridine-2-yl}-urea
The title compound was obtained from the compound obtained in EXAMPLE 157 in the same manner as in EXAMPLE 171.
1H NMR(DMSO-d6, ppm); δ 1O.54(1H, s), 7.67(1H, d), 7.5O(1H, d), 7.41(1H, t), 7.16(1H, d), 6.72(1H, s), 6.38(1H, d), 3.40(6H, m), 3.31(3H, s), 3.25(2H, m), 2.42- 2.33(6H, m), 1.96(3H, s)
ESI MS(m/e)= 506 [M+l]
EXAMPLE 177: 1- {5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5,4- 6]pyridine-2-yl}-3-[2-(l-methyl-piperidine-4-yl)-ethyl]-urea
73 mg (0.158 mmol) of the compound as obtained in EXAMPLE 157 was dissolved in 15 ml of dichloromethane, and 47 ul(0.632 mmol) of formalin was added thereto, followed by stirring for 5 minutes. To the solution, 134 mg (0.632 mmol) of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was washed twice with 10 ml of water and then concentrated. The residue was subjected to column chromatography to give 56 mg (0.118 mmol, yield of 74%) of the title compound.
1H NMR(CDCl3, ppm); δ 7.52(1H, d), 7.26(3H, m), 6.41(1H, d), 3.43(3H, s), 3.40(2H, m), 2.97(2H, m), 2.35(3H, s), 2.02(2H, m), 1.76(2H, m), 1.59(2H, m), 1.43(2H, m), 1.26(lH, m)
ESI MS(m/e)= 477 [M+l]
In TABLE 2 below, the titled compounds were synthesized by reductive animation reaction as in EXAMPLE 177.
[TABLE 2]
Figure imgf000154_0001
Figure imgf000155_0001
PREPARATION 53: 3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-Z>]pyridine-2-yl-ureido}-propionic acid
The title compound was obtained from the compound obtained in PREPARATION 48 in the same manner as in EXAMPLE 87.
1H NMR(DMSO-d6, ppm); δ 1O.53(1H, s), 7.68(1H, d), 7.53(1H, d), 7.46(1H, t), 7.32(1H, d), 6.81(1H, t), 6.47(1H, d), 3.40(2H, m), 3.31(3H, s), 2.30(2H, t)
ESI MS(m/e)= 424 [M+l]
EXAMPLE 193: l-{5-[(4-chloro-2-Huoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-[3-(4-methyl-piperidine-l-yl)-3-oxo-propyl]-urea
43 mg (0.100 mmol) of the compound as obtained in PREPARATION 53 was dissolved in 10 ml of N,N-dimethylformamide, and 17 ul(0.150 mmol) of N- methylpiperazine, 46 mg (0.340 mmol) of 1-hydroxybenzotriazole and 33 mg (0.170 mmol) of EDC [N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide] were added thereto, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was concentrated and redissolved in 20 ml of ethyl acetate. The resulting solution was washed with 20 ml of aqeous saturated sodium hydrogen carbonate solution, and the concentrated. The residue was subjected to column chromatography to give 44 mg (0.0871 mmol, yield of 87%) of the title compound.
1H NMR(DMSO-d6, ppm); δ 10.55(1H, s), 7.69(1H, d), 7.55(1H, d), 7.47(1H, t), 7.33(1H, d), 6.81(1H, t), 6.47(1H, d), 3.45(4H, m), 3.40(2H, m), 3.30(3H, s), 3.27(3H, s), 2.64(4H, m), 2.30(2H, t)
ESI MS(m/e)= 506 [M+ 1] EXAMPLE 194: 1- {5- [(4-chloro-2-fluoro-phenyl)-methyI-amino] -thiazolo [5,4- 6]pyridine-2-yl}-3-[4-(4-methyl-piperazine-l-yl)-butyl]-urea
The title compound was obtained from the compound obtained in PREPARATION 48 and 4-(4-aminobutyl)-l-methylpiperazine in the same manner as in EXAMPLE 87.
1H NMR(DMSO-d6, ppm); δ 1O.54(1H, s), 7.68(1H, d), 7.53(1H, d), 7.46(1H, t), 7.32(1H, d), 6.81(1H, t), 6.47(1H, d), 3.40(4H, m), 3.43(2H, t), 3.33(3H, s), 3.29(3H, s), 3.14(2H, q), 2.46(4H, m), 1.47(4H, m)
ESI MS(m/e)= 506 [M+l]
EXAMPLE 195: l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-3-[2-(4-methyl-piperazine-l-yl)-ethyI]-urea
The title compound was obtained from the compound obtained in PREPARATION 48 and l-methyl-4-(2-aminoethyl)piperazine in the same manner as in EXAMPLE 87.
1H NMR(DMSO-d6, ppm); δ 10.55(1H, s), 7.67(1H, d), 7.51(1H, d), 7.42(1H, t), 7.3O(1H, d), 6.8O(1H, t), 6.47(1H, d), 3.40(4H, m), 3.43(2H, q), 3.31(3H, s), 3.26(3H, s), 3.14(2H, t), 2.44(4H, m),
ESI MS(m/e)= 478 [M+l]
PREPARATION 54: [5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]- carbamic acid 4-nitro-pheyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-p-tolyl-thiazol[5,4-6]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
EXAMPLE 196: l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-A]pyridine-2-yl]-3-(2- morpholine-4-yl-ethyl)-urea
The title compound was obtained from the compound obtained in
PREPARATION 54 in the same manner as in EXAMPLE 87.
1H NMR(CDCl3, ppm); δ 7.56(1H, d), 7.22(2H, d), 7.16(2H, d), 6.54(1H, d), 3.77(4H, br), 3.50(2H, t), 3.48(3H, s), 2.61(2H, t), 2.55(4H, br), 2.38(3H, s)
ESI MS(m/e)= 427 [M+ 1]
In TABLE 3 below, the titled compounds were synthesized by using the compound as obtained in PREPARATION 54 in the same manner as in EXAMPLE 196.
[TABLE 3]
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
PREPARATION 55: 4-{3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2- yl]-ureido}-piperidine-l-carboxylic acid tert-butyl ester
The title compound was obtained from the compound obtained in PREPARATION 54 in the same manner as in EXAMPLE 196.
1H NMR(DMSOd6, ppm); δ 1O.53(1H, s), 7.63(1H, d),7.23(2H, d), 7.17(2H, d), 6.93(1H, d), 6.48(1H, d), 3.81(2H, m), 3.7O(1H, m), 3.38(3H, s), 2.91(2H, m), 2.31(3H, s), 1.80(2H, m), 1.41(9H, s), 1.31(2H, m)
ESI MS(m/e)= 497 [M+l] EXAMPLE 225: l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3- piperidine-4-yl-urea
The title compound was obtained from the compound obtained in PREPARATION 55 in the same manner as in EXAMPLE 157.
1H NMR(DMSO-d6, ppm); δ 1O.54(1H, s), 7.64(1H, d),7.25(2H, d), 7.17(2H, d), 6.93(1H, d), 6.49(1H, d), 3.82(2H, m), 3.7O(1H, m), 3.38(3H, s), 2.92(2H, m), 2.32(3H, s), 1.80(2H, m), 1.31(2H, m)
ESI MS(m/e)= 397 [M+l]
In TABLE 4 below, the compound as obtained in PREPARATION 54 was reacted with amines, which are protected by Boc group, in the same manner as in EXAMPLE 196 and then subjected to deprotection reaction in the same manner as in EXAMPLE 157 to give title compounds.
[TABLE 4]
Figure imgf000161_0001
l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(R)-
231 397 1 -pyrrolidine-2-ylmethyl-urea
In TABLE 5 below, the titled compounds were synthesized by subjecting the compounds as in above table to reactive amination reaction in the same manner as in EXAMPLE 177.
[TABLE 5]
Figure imgf000162_0001
Figure imgf000163_0001
EXAMPLE 245: l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-[3- (4-propionyl-piperazine-l-yl)-propyl]-urea
The title compound was obtained from the compound obtained in EXAMPLE 229 and propanoyl chloride in the same manner as in EXAMPLE 168.
1H NMR(DMSOd6, ppm); δ 1O.55(1H, s), 7.59(1H, d), 7.23(2H, d), 7.14(2H, d), 6.7O(1H, s), 6.43(1H, d), 3.42(6H, m), 3.34(3H, s), 3.11(2H, q), 2.29-2.24(9H, m), 1.62(2H, m), 0.95(3H, t)
ESI MS(m/e)= 496 [M+ 1]
EXAMPLE 246: l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-[3- (4-propionyl-piperazine-l-yl)-propyI]-urea
The title compound was obtained by using cyclopropylcarbonyl chloride instead of propanoyl chloride in the same manner as in EXAMPLE 245.
1H NMR(DMSO-d6, ppm); δ 1O.54(1H, s), 7.59(1H5 d), 7.23(2H, d), 7.14(2H, d), 6.7O(1H, s), 6.43(1H, d), 3.42(6H, m), 3.34(3H, s), 2.29-2.24(9H, m), 2.19(1H, m), 1.62(2H, m), 0.44(2H, m), 0.32(2H, m) ESI MS(m/e)= 508 [M+ 1]
EXAMPLE 247: l-[3-(4-methanesulfonyl-piperazine-l-yl)-propyI]-3-[5-(methyl- p-tolyl-amino)-thiazolo[5,4-A]pyridine-2-yl]-urea
The title compound was obtained by using methanesulfonyl chloride instead of propanoyl chloride in the same manner as in EXAMPLE 245.
1H NMR(DMSOd6, ppm); δ 1O.56(1H, s), 7.63(1H, d), 7.26(2H, d), 7.19(2H, d), 6.79(1H, s), 6.5O(1H, d), 3.39(3H, s), 3.21(2H, m), 3.13(4H, m), 2.88(3H, s), 2.56- 2.47(6H, m), 2.34(3H, s), 1.78(2H, m)
ESI MS(m/e)= 518 [M+ 1]
PREPARATION 56: {5- [(2,4-diflιioro-phenyl)-methy 1-amino] -thiazolo [5,4- 6]pyridine-2-yl}-carbamic acid 4-nitro-pheyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(2,4-difluorophenyl)-thiazol[5,4-6]pyridine-2,5-diamine as synthesized in
Korean patent application No.04117617 instead of the compound as obtained in
PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
In TABLE 6 below, the titled compounds were synthesized by using the compound as obtained in PREPARATION 56 in the same manner as in EXAMPLE 87.
[TABLE 6]
Figure imgf000165_0001
PREPARATION 57: [5-(methyl-phenyl-amino)-thiazolo [5,4-6]pyridine-2-yl]- carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-phenyl-thiazol[5,4-ό]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21 , thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
PREPARATION 58: {5-[methyl-(4-trifluoromethyl-phenyl)-amino]-thiazolo[5,4- ό]pyridine-2-yI}-carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(4-trifluoromethyl)phenyl-thiazol[5,4-ό]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
PREPARATION 59: {5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-£] pyridine-2-yl}-carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(4-cyanophenyl)-thiazol[5,4-ό]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
PREPARATION 60 : {5- [(4-fluoro-phenyl)-methyl-amino]-thiazolo [5,4-6] pyridine-2-yl}-carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(4-fluorophenyl)-thiazol[5,4-6]pyridine-2,5-diamine as synthesized in
Korean patent application No.04117617 instead of the compound as obtained in
PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
PREPARATION 61 : {5-[(2-fluoro-4methoxy-phenyl)-methyl-amino]-thiazolo [5,4-ό]pyridine-2-yl}-carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(2-methoxy-4-methoxyphenyl)-thiazol[5,4-&]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable.
PREPARATION 62: {5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo [5,4-Λ]pyridine-2-yI}-carbamic acid 4-nitro-phenyl ester The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(4-hydroxy-4-chlorophenyl)-thiazol[5,4-ό]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable
PREPARATION 63 : {5- [(4-bromo-phenyl)-methyl-amino] -thiazolo [5,4-b] pyridine-2-yl}-carbamic acid 4-nitro-phenyl ester
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(2,4-difluorophenyl)-thiazol[5,4-ό]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the title compound. The obtained compound was used immediately for the next reaction without confirmation, since it was unstable
In TABLE 7 below, the titled compounds were synthesized by using the compounds as obtained in PREPARATIONS 57~63 in the same manner as in EXAMPLE 48.
[TABLE 7]
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
EXAMPLE 319: l-{5-[(3,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4- Λ]pyridine-2-yI}-3-[3-(4-methyl-piperazine-l-yl)-propyl]-urea
The same procedure as in PREPARATION 48 was conducted by using N5- methyl-N5-(3,4-difluorophenyl)-thiazol[5,4-6]pyridine-2,5-diamine as synthesized in Korean patent application No.04117617 instead of the compound as obtained in PREPARATION 21, thereby obtaining the intermediate. The title compound was obtained from the intermediate and iV-methylpiperazine in the same manner as in EXAMPLE 87.
1H NMR(DMSO-d6, ppm); δ 1O.54(1H, s), 7.72(1H, d), 7.50-7.42(2H, m), 7.17(1H, m), 6.74(1H, s), 6.69(1H, d), 3.41(3H, s), 3.31(4H, m), 3.20(2H, q), 2.32-2.29(6H, m), 2.17(3H, s), 1.62(2H, quin)
ESI MS(m/e)= 476 [M+ 1]
In TABLE 8 below, the titled compounds were synthesized by using various aminothiazol synthesized as in Korean patent application No. 04117617 in the same manner as in EXAMPLE 319.
[TABLE 8]
Figure imgf000174_0001
EXPERIMENT 1: Test of the inhibitory effect of the compounds according to the present invention on the activity of various RTKs (Receptor Tyrosine Kinases)
To ascertain the inhibitory effect of the compounds according to the present invention on the activity of tyrosine kinases, in vitro experiments were carried out using five kinds of RTKs, as follows. First, only kinase domains of KDR, FLT-3,
EGFR, FGFRl and PDGFR-β in the form of GST fusion or His-tag proteins were expressed in insect cells (SF21) and purified.
For the KDR assay, a reaction using 20 mM Tris-HCl (pH 7.5), 10 raM MgCl2, 1 mM MnCl2, 2 mM DTT, 0.1 mM sodium orthovanadate, 10 μM ATP, 0.2 μCi [γ-
P32]_ATP, 69 μg/ml poly Glu:Tyr peptide (4:1) (Sigma), and 3 μg/ml of purified
GST:KDR protein was performed under the following conditions. The reaction was carried out in a total reaction volume of 20 μl, with the respective compounds contained in 5% DMSO at varied concentrations of the compound, at 30°C for 10 minutes, then stopped by the addition of 10% phosphoric acid. The resultant reaction solution was transferred onto Immobilon-PVDF membrane (Milipore) of 96-well format, washed four times with 0.5% phosphoric acid, and the amount of radiation adhered onto the membrane was quantified with Phosphorimager (Molecular
Dynamics). IC50, the concentration of a compound inhibiting 50% of the total activity, was determined by the mean value calculated from more than three repetitions of the assay, using Linear regression analysis.
For the FLT3 assay, using 20 mM Tris-HCl (pH 7.5), 3 mM MgCl2, 7 mM MnCl2> 2 mM DTT, 0.1 mM sodium orthovanadate (Sigma), 8 μM ATP, 0.2 μCi [γ- P32J-ATP, 69 μg/ml poly Glu:Tyr peptide (4:1) (Sigma), and 8 μg/ml of purified His- Tag:FLT3 protein, a reaction was performed for 15 minutes under the same conditions as in the KDR assay.
For the EGFR assay, using 20 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 1 mM MnCl2, 2 mM DTT, 0.1 mM sodium orthovanadate, 10 μM ATP, 0.2 μCi [γ-P32]-ATP,
690 μg/ml poly Glu:Tyr peptide (4:1) (Sigma), and 5 μg/ml of purified His-Tag:EGFR, a reaction was performed for 20 minutes under the same conditions as in the KDR assay.
For the FGFRl assay, using 20 mM Tris-HCl (pH 7.5), 3 mM MgCl2, 3 mM MnCl2, 2 mM DTT, 10 μM sodium orthovanadate, 0.25 mg/ml PEG3350, 8 μM ATP,
0.2 μCi [γ-P32]-ATP , 69 μM poly Glu:Tyr peptide (4:1) (Sigma), and 6.25 μg/ml of purified GST: FGFRl protein, a reaction was performed for 10 minutes under the same conditions as in the KDR assay.
For the PDGFRβ assay, using 25 mM HEPES (pH 7.4), 150 mM NaCl, 10 mM MnCl2, 2 mM DTT, 0.2 mM Sodium Orthovanadate, 2 μM ATP, 0.2 μCi [γ-P32]-
ATP, 690 μg/ml Poly Glu:Tyr peptide (4:1) (Sigma), and 8 μg/ml of purified
GST:PDGFRβ, a reaction was performed for 10 minutes under the same condition as in the KDR assay.
EXPERIMENT 2: Test of the inhibitory effect of the compounds according to the present invention on VEGF- or bFGF-dependent HUVEC (Human Umbilical Vein Endothelial Cell) growth HUVEC cells separated from placenta were seeded into 0.3% Gelatin-coated 96-well plates at a density of 5x103 cells per well, and cultured in M 199 media (Gibco BRL; supplemented with 10% FBS, 30 μg/ml ECGS, 50 μg/ml Heparin, IX Penicillin/Streptomycin and 0.5 mM Glutamine) at 37°C in a 5% CO2 incubator for one day. Thereafter, serum starvation was performed in Ml 99 starvation medium supplemented with 0.5% FBS for 24 hours, after which time the starvation medium was replaced with a working medium containing compounds diluted at graded concentrations. After 2 hours, the cells were treated with 10 ng/ml of VEGF (R&D systems) or 5 ng/ml of bFGF (Upstate). After incubation for 2 days, BrdU Cell Proliferation ELISA (Roche) was carried out following the instructions of the manufacturer. IC50, the concentration of compounds inhibiting 50% of the cell growth induced by VEGF or bFGF, was determined using mean values from three experiments using Linear regression analysis.
EXPERIMENT 3: Test of the inhibitory effect of the compounds according to the present invention on PDGF-BB dependent PASMC (Pulmonary Artery Smooth Muscle Cell) growth
PASMC cells (5x103 cells/well: Clonetics) were seeded into 96-well plates and cultured in DMEM medium (Gibco BRL; supplemented with 10% FBS, IX Penicillin/Streptomycin and 0.5 mM Glutamine) at 37°C in a 5% CO2 incubator for one day. Thereafter, serum starvation was performed in DMEM starvation medium supplemented with 0.1% FBS for 24 hours, after which time the starvation medium was replaced with a working medium containing compounds diluted at graded concentrations. After 2 hours, the cells were treated with 20 ng/ml of PDGF-BB (Upstate). After incubation for 2 days, BrdU Cell Proliferation ELISA (Roche) was carried out following the instructions of the manufacturer. IC5O, the concentration of compounds inhibiting 50% of cell growth induced by PDGF-BB, was determined using mean values from three experiments using Linear regression analysis.
EXPERIMENT 4: Test of the inhibitory effect of the compounds according to the present invention on the tube formation of HUVEC
HUVEC (Human umbilical vein endothelial cells) having been used within passage 5 were cultured at 370C in a 5% CO2 incubator to 70-80% confluence in a
100 mm culture dish, treated with trypsin, neutralized in M 199 medium supplemented with 0.2% BSA (Sigma), then seeded at a concentration of 4x104 cells/well into the media containing compounds diluted at graded concentrations in a 24-well plate coated with 10 mg/ml of Matrigel (R&D systems), followed by the addition of 5% FBS. After 17 hours, the media were removed, and adherent material was fixed with
100 μl of 3.7% Paraformaldehyde/PBS and placed under a microscope, then the lengths of formed tubes were quantified using KS Lite software
EXPERIMENT 5: SRB (Sulforhodamine B) assay of HCT116 by the compounds according to the present invention
100 μl of HCTl 16 cells (3x103 cells/well:KCLB) were seeded into 96-well plates and allowed to grow in RPMI 1640 medium (supplemented with 5% FBS, IX Penicillin/Streptomycin and 0.5 mM Glutamine; Gibco BRL) at 37°C in a 5% CO2 incubator for one day. Thereafter, the medium was treated with compounds diluted at graded concentrations. After incubation for two days, cells were fixed with 4% formaldehyde (Sigma) for 3-4 hours, washed five times with PBS, then dried in an oven set to 55°C for 10 minutes. 50 μl of 0.4% (w/v) SRB (Sigma) dissolved in 1% acetic acid was added into each well and maintained at room temperature for 30 minutes, then washed with 1% acetic acid. The plate was again dried in the oven set to 55°C for 10 minutes, then placed in 100 ml of 10 mM Tris-HCl (pH 10.5) on a shaker for 20 minutes, and the surviving cells were quantified photometrically at 530 nm. GI50, the concentration of compounds of inhibiting 50% of the total cell growth, was determined using mean values from three experiments using Linear regression analysis.
In TABLE 9 below, summarized are the representative compounds of Formula 1 and their IC50 values showing the enzyme activity-inhibiting ability measured for KDR and HUVEC.
[TABLE 9]
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Note: N.D. means that No experimental Data are available.
In TABLE 10 below, summarized are IC5O values of some compounds of Formula 1 showing the ability to inhibit the cell growth of HCTl 16 cells and bFGF- and PDGF-dependent HUVEC cells.
[TABLE 10]
Figure imgf000189_0001
Note: N.D. means that No experimental Data are available.
From the above results, it is clear that the compounds according to the present invention are very effective in inhibiting KDR activity and also inhibiting HUVEC growth.
Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope of particular embodiments of the invention indicated by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula 1
Figure imgf000190_0001
or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof,
where
A) R1 is one selected from the group consisting of
I) hydrogen;
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl;
HI) optionally substituted alkenyl;
IV) ptionally substituted aryl;
V) optionally substituted heterocycle;
VI) perhaloalkyl;
VII) a substituent of formula -CY1Y2(Y3)H-Y4, where Y1 and Y2 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl; Y3 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl; Y4 is selected from the group consisting of hydrogen, lower alkoxy, pyrrolidinone, pyrrolidine, piperidine, thiophene, optionally substituted piperazine, morpholine, aziridine, lower alkylamine, carboxy, sulfide, hydroxy, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl; and n is an integer from 0 to 3;
VIII) a substituent of formula -NZ1(Z^n1-Z3, where
Z1 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, aryl and heteroaryl, or two substituents are combined to form a cyclic saturated alkyl or a cyclic saturated alkyl interrupted by N, O or S;
Z2 is selected from the group consisting of lower alkylene, lower alkenylene, lower alkinylene, aryl and heteroaryl;
Z3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furane, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl; and n is an integer from 0 to 3;
B) R2 is selected from the group consisting of cyclic alkyl, aryl, heteroaryl, optionally substituted cyclic alkyl, aryl and heteroaryl;
C) R3 is selected from the group consisting of hydrogen, optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl; and
D) X is selected from the group consisting of O, S and NR', where R' is hydrogen or lower alkyl.
2. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 1 , wherein R1 is selected from the substituents I) - IX) as follows:
I) lower alkyl;
II) lower alkyl substituted with one or more substituents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, thiophene, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfoneamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
III) cyclic alkyl or heterocycle;
IV) cyclic alkyl or heterocycle substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
V) alkenyl;
VI) alkenyl substituted with one or more substitutents selected from the group consisting of optionally substituted lower alkyl, halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amine, lower alkylamine, cyclic alkyl, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime, trifluoromethyl, aryl and heteroaryl;
VII) aryl or heteroaryl;
VIII) aryl or heteroaryl substituted with one or more substitutents selected from the group consisting of halogen, amide, carbonyl, carbamate, carboxy, lower alkyl, lower alkoxy, amine, lower alkylamine, pyrrole, pyridine, pyrazine, pyrazole, pyrrolidine, pyrrolidinone, piperidine, piperidinone, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl;
IX) a substituent of formula -NZi(Z2)-Z3, where
Z1 is selected from the group consisting of hydrogen and optionally substituted lower alkyl;
Z2 is optionally substituted lower alkylene;
Z3 is selected from the group consisting of hydrogen, hydroxy, optionally substituted lower alkoxy, amino, imidazole, thiophene, furan, pyrazole, pyrazine, pyrrole, pyrrolidinone, pyrrolidine, pyridine, piperidine, piperazine, morpholine, aziridine, lower alkylamine, carbonyl, carboxy, sulfide, lower alkyl, cycloalkyl, aryl and heteroaryl.
3. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 2, wherein among R1, Zi is hydrogen and Z2 is alkylene having 1 to 3 carbon atoms.
4. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 1, wherein R2 is selected from the substituents I) - IV) as follows:
I) cyclic alkyl;
II) cyclic alkyl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carbonyl, carbamate, carboxy, acetyl, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl;
III) heteroaryl;
IV) heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, optionally substituted amide, carbonyl, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
5. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 4, wherein R2 is aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amide, carboxylic acid, carbamate, carboxy, lower alkyl, perhaloalkyl, lower alkoxy, amine, lower alkylamine, pyrrolidine, piperidine, piperazine, morpholine, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
6. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 5, wherein R2 is aryl substituted with halogen.
7. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 1, wherein R3 is selected from the substituents I) - III) as follows:
I) hydrogen;
H) lower alkyl;
III) lower alkyl substituted with one or more substituents selected from the group consisting of halogen, amide, carboxylic acid, carbamate, carboxy, lower alkoxy, amino, lower alkylamino, cyano, hydroxy, sulfonyl, sulfoxy, sulfonamide, amidine, amideoxime and trifluoromethyl.
8. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 7, wherein R3 is hydrogen or lower alkyl.
9. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 1, wherein X is O or S.
10. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 9, wherein X is S.
11. The compound or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof according to claim 1, wherein the compound of Formula 1 is selected from the group consisting of
1. iV-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl] cyclopentanecarboxamide
2. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
3. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-έ]ρyridine-2-yl]-2-(thiophene-2-yl) acetamide
4. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-ό]pyridine-2-yl]-3- cyclopentylpropaneamide
5. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-δ]pyridine-2-yl]-2-(4- morpholinyl)acetamide 6. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-2-(l- pyrrolidinyl)acetamide
7. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl]-2- (diethylamino)acetamide
8. Λf-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl]acetamide
9. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-δ]pyridine-2-yl]-2- methylpropaneamide
10. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine-2- yl] cyclobutanecarboxamide
11. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]-3-(4- morpholinyl)propaneamide
12. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-2-(4-methyl-l- piperazinyl) acetamide
13. ethyl l-({[5-(4-chloroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]amino} carbonyl) cyclopropanecarboxylate
14. l-({[5-(4-chloroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]amino}carbonyl) cyclopropanecarboxylic acid
15. N-[5-(4-chloro-2-fluoromethylanilino)[l ,3]thiazolo[5,4-ό]pyridine-2-yl]-iV'- [2-(4-morpholinyl)ethyl]urea
16. N-[5-(4-fluoro-2-hydroxymethylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl cyclopropanecarboxyamide
17. iV-[5-(cyclohexylamino)[l ,3]thiazolo[5,4-έ]pyridine-2- yl] cyclopropanecarboxamide
18. iV-[5-(cyclopentylamino)[l ,3]thiazolo[5,4-6]pyridine-2- yl] cyclopropanecarboxamide
19. N-[5-(4-chloroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-3- (diethylamino)propaneamide
20. N-[5-(4-chloroanilino)[l ,3]thiazolo[5,4-6]pyridine-2-yl]-3-(l -piperidinyl) propaneamide
21. iV-[5-(3-chloroanilino)[l,3]thiazolo[5,4-ό]pyridine-2- yl] cyclopropanecarboxamide
22. N-[5-(2-chloroanilino)[l ,3]thiazolo[5,4-Z>]pyridine-2- yljcycloproanecarboxamide
23. iV-[5-(2-fluoroanilino)[l ,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
24. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
25. iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-2-(4- morpholinyl)acetamide
26. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-Z>]pyridine-2-yl]-3-(4- morpholinyl)propaneamide
27. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
28. 2-({[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl] amino } carbonyl)cyclopropanecarboxylic acid
29. N-[5-(4-bromo-2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
30. iV-[5-(3-fluoro-4-methylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
31. iV-[5-(4-chloro-2-fluoroanilino)[l ,3]thiazolo[5,4-ό]pyridine-2-yl] cyclopropanecarboxamide
32. N-[5-(2,4-difluoroanilino)[l ,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
33. N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]-2-[(4- methyl- 1 -piperazinyl)carbonyl]cyclopropanecarboxamide
34. N1-[2-(diethylamino)ethyl]-N2-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4- δ]pyridine-2-yl]- 1 ^-cyclopropanedicarboxamide
35. (E)-N-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-Z>]pyridine-2-yl]-3- phenyl-2-propeneamide
36. iV-[5-(2-fluoro-4-methylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]acrylamide
37. N1-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-N2-[2-(4- morpholinyl)ethyl] - 1 ^-cyclopropanedicarboxamide
38. N1-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-N2-[2-(2- pyridiny l)ethy 1] - 1 ^-cyclopropanedicarboxamide
39. Λr-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl]acrylamide
40. N-[5-(4-chloro2-fluoroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-3-methyl-3- buteneamide
41. iV-[5-(4-chloro2-fluoroanilino)[l,3]thiazolo[5,4-δ]pyridine-2-yl]-3-methyl-2- buteneamide
42. N-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-3- buteneamide
43. (E)-N-[5-(4-chloro-2-fluoroanilino)[l,3]thiazolo[5,4-ό]pyridine-2-yl]-2- buteneamide
44. N-[5-(2,6-difluoroanilino)[l,3]thiazolo[5,4-&]pyridine-2-yl] cyclopropanecarboxamide
45. N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
46. JV- {5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-6]pyridine-2-yl} acrylamide
47. 7V-{5-[4-chloro(ethyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
48. 7V-{5-[4-chloro(ethyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl}acrylamide
49. ethyl 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6] pyridine-5-yl}anilino)acetamide
50. 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl}anilino)acetic acid
51. 2-(4-chloro{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-δ]pyridine-5- yl} anilino)ethyl cyclopropanecarboxylate
52. N-{5-[4-chloro(2-hydroxyethyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
53. N-[5-(4-chloro-2-fluromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
54. N-{5-[2,4-difluoro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
55. N-{5-[2,6-difluoro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
56. N-[5-(4-bromo-2-fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl] cyclopropanecarboxamide
57. N-{5-[2-methoxy(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
58. N-{5-[3,4-difluoro(methyl)anilino][l,3]thiazolo[5,4-δ]pyridine-2-yl} cyclopropanecarboxamide
59. iV-{5-[methyl-4-(trifluoromethyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl} cyclopropanecarboxamide
60. iV-{5-[4-methoxy(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl} cyclopropanecarboxamide
61. iV-{5-[4-cyano(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
62. N-{5-[4-isopropyl(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl} cyclopropanecarboxamide
63. N-{5-[2,3-dihydro-lH-indene-5-yl(methyl)anilino][l,3]thiazolo[5,4- 6]pyridine-2-yl } cyclopropanecarboxamide
64. N- {5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-ό]pyridine-2-yl} - 1 -methyl- 1 - H-pyrrole-2-carboxamide
65. ethyl 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-ό]pyridine-5-yl} (methyl)amino]benzoate
66. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-ό]pyridine-5-yl} (methyl)amino]benzoic acid
67. (E)-iV-[5-(4-bromo-2-fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]- 3 -(4-piperidinyl)-2-propeneamide
68. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-Z)]pyridine-2-yl}-3-(l- ethyl-4-piperidinyl)-2-propeneamide
69. (E)-N- { 5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-%yridine-2-yl} -3-( 1 - methyl-4-piperidinyl)-2-propeneamide
70. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl}-4-(4- morpholinyl)-2-buteneamide
71. 4[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl } (methyl)amino] -N, iV-dimethylbenzamide
72. 4[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl}(methyl)amino]-iV-[2-(dimethylamino)ethyl]benzainide
73. N-IS-^-chloroCmethyOanil^tl^JthiazoloES^-^pyridine^-ylJ-l-methyl- 1 H-imidazole-4-carboxamide
74. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-&]pyridine-5- yl } (methyl)amino] -iV-methylbenzamide
75. N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2-yl}-l-methyl-l- H-iniidazole-5-carboxamide
76. (E)-N- {5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo[5,4-%yridine-2-yl } -3-( 1 - (methylsulfonoyl)-4-piperidinyl)-2-propeneamide
77. 4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl } (methyl)amino]benzamide
78. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-&]pyridine-2-yl}-4-(l- piperidinyl)-2-buteneamide
79. (E)-N- { 5-[4-chloro(methyl)anilino] [ 1 ,3]thiazolo [5 ,4-6]pyridine-2-yl } -4-( 1 ,4- dioxa-8-azaspiro[4.5]de-8-cyl]-2-buteneamide
80. (E)-N-{5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-δ]ρyridine-2-yl}-4- (dimethylamino)-2-buteneamide
81. ethyl 2-{4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-6]pyridine-5- yl } (methyl)amino]phenyl } acetamide
82. 2-{4-[{2-[(cyclopropylcarbonyl)amino][l,3]thiazolo[5,4-έ]pyridine-5- yl}(methyl)amino]phenyl}acetic acid
83. N-{5-[4-[2-(dimethylamino)-2-oxoethyl](methyl)anilino][l,3]thiazolo[5,4- όJpyridine-S-ylJcyclopropanecarboxamide
84. ethyl 4-[(E)-3-({5-[4-chloro(methyl)anilino][l ,3]thiazolo[5,4-ό]pyridine-2- yl} amino)-3 -oxo- 1 -propenyl] - 1 -piperidinecarboxylate
85. methyl 4-[(E)-3-({5-[4-chloro(methyl)anilino][l,3]thiazolo[5,4-ό]pyridine-2- yl } amino)-3 -oxo- 1 -propenyl] - 1 -piperidinecarboxylate
86. (£)-3-(l-acetyl-4-piperidinyl)-JV-{5-[4- chloro(methyl)anilino][l,3]thiazolo[5,4-6]pyridine-2-yl}-2-propeneamide
87. N-[5-(4-chloro-2-fluoromethylanilino)[l,3]thiazolo[5,4-6]pyridine-2-yl]-iV'- [2-(4-morpholinyl)ethyl] -urea
88. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl} -3 -ethyl-urea
89. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-diethylamino-ethyl)-urea
90. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 -hydroxy-propyl)-urea
91. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-(3-morpholine-4-yl-propyl)-urea
92. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-methoxy-ethyl)-urea
93. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-pyrrolidine- 1 -yl-ethyl)-urea
94. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl}-3-[3-(4-methyl-piperazine-l-yl)-propyl]-urea
95. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-(3-dimethylamino-propyl)-urea
96. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 -diethylamino-propyl)-urea
97. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-δ]pyridine-2- yl } -3 - [2-( 1 -methyl-pyrrolidine-2-yl)-ethyl]-urea
98. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-pyridine-2-yl-ethyl)-urea
99. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-hydroxy-ethyl)-urea
100. l-{5- [(4-chloro-2-fluoro-phenyl)-methylamino] -thiazolo [5,4-Z>] pyridine-2- yl } -3 -(2-hydroxy- 1 -methyl-ethyl)-urea
101. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(2-hydroxy-propyl)-urea
102. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(2-dimethylamino-ethyl)-urea
103. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -cyclopentyl-urea
104. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-cyclohexyl-urea
105. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2-yl}- 3 -(2-piperidine- 1 -yl-ethyl)-urea
106. l-{5- [(4-chloro-2-fluoro-phenyl)-methylamino] -thiazolo [5,4-6] pyridine-2- yl } -3 -(5 -methyl-pirazine-2-ylmethyl)-urea
107. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl}-3-(2-pyridine-4-yl-ethyl)-urea
108. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -pyridine-4-yl-urea
109. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-έ]pyridine-2- yl } -3 -( 1 ,5 -dimethyl- 1 H-pyrrole-3 -ylmethyl)-urea
110. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2-yl}- 3 -thiophene-3 -ylmethyl-urea
111. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-έ]pyridine-2- yl}-3-furan-3ylmethyl-urea
112. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl } - 1 -(2-hydroxy-ethyl)- 1 -methyl-urea
113. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -((R)- 1 -(hydroxymethyl-propyl)-urea
114. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -pyridine-4-ylmethyl-urea
115. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -pyridine-3 -ylmethyl-urea
116. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -pyridine-2-ylmethyl-urea
117. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl} -3 -pyridine-3 -yl-urea
118. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl} -3-pyridine-2-yl-urea
119. 4-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-ureido)-piperidine-l-carboxylic acid tert-butyl ester
120. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-b]pyridine-2-yl}- 3 -cyclopropylmethyl-urea
121. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -cyclohexylmethyl-urea
122. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-&]pyridine-2- yl}-3-phenyl-urea
123. l-benzyl-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl} -urea
124. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-6]pyridine-2- yl } -3 -phenethyl-urea
125. 4-(3-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-Z>]pyridine-2- yl } -ureidomethyl)-piperidine- 1 -carboxylic acid tert-butyl ester
126. l-{5-[(4-chloro-2-fluoro-phenyl)-methylamino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(4-hydroxy-butyl)-urea
127. 3 -(3 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-ό]pyridine-2- yl}-ureidomethyl)-piperidine-l -carboxylic acid tert-butyl ester
128. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -[2-(3 -hydroxy-propoxy)-ethyl] -urea
129. l-{5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 , 4-6]pyridine-2- yl } -3 -(( R)-2-hydroxy- 1 -methyl-ethyl)-urea
130. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-b]pyridine-2- yl } -3 - { 2- [(2-hydroxy-ethyl)-methyl-amino]-ethyl} -urea
131. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-{2- [(4-hydroxy-piperidine- 1 -yl)-ethyl] -urea
132. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - { 3- [(2-hydroxy-ethyl)-methyl-amino] -propyl} -urea
133. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-[3-(4-hydroxy-piperidine-l-yl)-propyl]-urea
134. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-{3- [4-(2-hydroxy-ethyl)-piperidine- 1 -yl)-propyl] -urea
135. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-ό]pyridine-2- yl } -3 -hydroxy-urea
136. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -methoxy-urea
137. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(carboxymethyloxy)-urea
138. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl } - ureido)-ethyl] -acetamide
139. l-{5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo [5 ,4-6]pyridine-2- yl } -3 -(methyl-amino)-urea
140. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}- 3 -(2-hydroxyethylamino)-urea
141. 1 -(4-aminomethyl-benzyl)-3- { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-δ]pyridine-2-yl}-urea
142. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 -pyridine- 1 -yl-propyl)-urea
143. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-Z>]pyridine-2- yl}-3-[3 -(4-hydroxymethyl-piperidine- 1 -yl)-propyl] -urea
144. {(S)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- δ]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-3-yl}-carbamic acid tert-butyl ester
145. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(3 ,4-dihydroxy-benzyl)-urea
146. l-(4-amino-benzyl)-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-6]pyridine-2-yl}-urea
147. l-(3-aminobenzyl)-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-6]pyridine-2-yl}-urea
148. l-(2-amino-benzyl)-3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-ό]pyridine-2-yl}-urea
149. l-{5- [(4-chloro-2-fluoro-phenyl)-methyl-amino] -thiazolo[5,4-Z>]pyridine-2- yl } -3 -(tetrahydrofuran-2-ylmethyl)-urea
150. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(3 -imidazole- 1 -yl-propyl)-urea
151. 1 -(4-amino-cyclohexyl)-3- { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-δ]pyridine-2-yl}-urea
152. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(4-hydroxy-cyclohexyl)-urea
153. (S)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- ό]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester
154. (R)-l-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- έ]pyridine-2-yl}-ureido)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester
155. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 - [3 -(4-oxo-piperidine- 1 -yl)-propyl] -urea
156. 3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl} - 1 -(2-hydroxy-ethyl)- 1 -methyl-urea
157. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-(2-piperidine-4-yl-ethyl)-urea
158. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}- 3 -piperidine-4-yl-urea
159. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -piperidine-4-ylmethyl-urea
160. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-/b]pyridine-2- yl}-3-piperidine-3-ylmethyl-urea
161. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(3 -piperazine- 1 -yl-propyl)-urea
162. 1 -{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(S)-pyrrolidine-3 -yl-urea
163. l-[3-((S)-3-amino-pyrrolidine-l-yl)-propyl]-3-{5-[(4-chloro-2-fluoro-phenyl)- methyl-amino] -thiazolo [5 ,4-&]pyridine-2-yl } -urea
164. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-(2-methyl-amino-ethyl)-urea
165. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 - [3 -(4-hydroxyimino-piperidine- 1 -yl)-propyl] -urea
166. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-[3-(R)-2-hydroxymethyl-pyrrolidine-l-yl]-propyl]-urea
167. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}- 3-[3-((S)-2-hydroxymethyl-pyrrolidine-l-yl)-propyl]-urea
168. 4-[3-(3-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4- 6]pyridine-2-yl}-ureido)-propyl]-piperazine-l-carboxylic acid ethyl ester
169. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 - [3 -(4-methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
170. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}- 3 - [3 -(4-ethanesulfonyl-piperazine- 1 -yl)-propyl] -urea
171. 1 -[3-(4-acetyl-piperazine- 1 -yl)-propyl]-3-{5-[(4-chloro-2-fluoro-phenyl)- methyl-amino] -thiazolo [5 ,4-&]pyridine-2-yl } -urea
172. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl}-3-[3 -(4-cyclopropyl-piperazine- 1 -yl)-propyl] -urea
173. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 - { 3 - [4-(2-fluoro-ethyl)-piperazine- 1 -yl)-propyl] -urea
174. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-[3-(4-propionyl-piperazine-l-yl)-propyl]-urea
175. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 - [3 -(4-cyclopropionyl-piperazine- 1 -yl)-propy 1] -urea
176. 1 -[2-(4-acetyl-piperazine- 1 -yl)-ethyl] -3 - { 5- [(4-chloro-2-fluoro-phenyl)- methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl} -urea
177. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-Z)]pyridine-2- yl}-3-[2-(l -methyl-piperidine-4-yl)-ethyl] -urea
178. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}- 3-[2-(l-ethyl-piperidine-4-yl)-ethyl]-urea
179. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl } -3 -( 1 -methyl-piperidine-4-yl)-urea
180. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3-( 1 -ethyl-piperidine-4-yl)-urea
181. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -( 1 -methyl-piperidine-4-ylmethyl)-urea
182. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -( 1 -ethyl-piperidine-4-ylmethyl)-urea
183. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -( 1 -methyl-piperidine-3 -ylmethyl)-urea
184. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -( 1 -ethyl-piperidine-3 -ylmethyl)-urea
185. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -((S)- 1 -methyl-ρyrrolidine-3 -yl)-urea
186. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl}-3-((S)-l -ethyl-pyrrolidine-3 -yl)-urea
187. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -[3 -((S)-3 -dimethyl-amino-pyrrolidine- 1 -yl)-propyl]-urea
188. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(4-dimethyl-amino-cyclohexyl)-urea
189. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 - [3 -(4-ethyl-piperazine- 1 -yl)-propyl] -urea
190. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-έ]pyridine-2- yl } -3 - [3 -(4-isopropyl-piperazine- 1 -yl)-propyl] -urea
191. 1 - { 5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl}-3-[3-(4-isobutyl-piperazine-l-yl)-propyl]-urea
192. l-[3-(4-sec-butyl-piperazine-l-yl)-propyl]-3-{5-[(4-chloro-2-fluoro-phenyl)- methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
193. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2- yl}-3-[3-(4-methyl-piperazine-l-yl)-3-oxo-propyl]-urea
194. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-b]pyridine-2- yl } -3 - [4-(4-methyl-piperazine- 1 -yl)-butyl] -urea
195. l-{5-[(4-chloro-2-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 - [2-(4-methyl-piperazine- 1 -yl)-ethyl]-urea
196. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-Z)]pyridine-2-yl} -3-(2-morpholine-4- yl-ethyl)-urea
197. l-ethyl-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-urea
198. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(3-morpholine-4- yl-propyl)-urea
199. 1 -(2-diethylamino-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine- 2-yl]-urea
200. l-[3-(4-methyl-piperazine-l-yl)-propyl-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
201. l-(3-hydroxy-propyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2- yl]-urea
202. 1 -(3-diethylamino-propyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-έ] pyridine-2-yl] -urea
203. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-pyridine-2-yl methyl-urea
204. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-pyridine-3-yl methyl-urea
205. 1 -[5-(methyl-p-tolyl-amino)-thiazolo [5 ,4-ό]pyridine-2-yl] -3 -pyridine-4- ylmethyl-urea
206. l-(5-methyl-pyrazine-2-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
207. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(2-pyridine-2-yl- ethyl)-urea
208. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(2-pyridine-4-yl- ethyl)-urea
209. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(2-pyrrolidine-l- yl-ethyl)-urea
210. l-(l,5-dimethyl-lH-pyrrole-3-ylmethyl)-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-&]pyridine-2-yl]-urea
211. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-(2-pyridine-3-yl- ethyl)-urea
212. l-(4-hydroxy-butyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2- yl]-urea
213. l-(2-hydroxy-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2- yl]-urea
214. l-((R)-2-hydroxy-l-methyl-ethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
215. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-Z>]pyridine-2-yl]-3-[3-(2-oxo- pyrrolidine- 1 -yl)-propyl] -urea
216. 1 -[2-(2-hydroxy-ethyoxy)-ethyl]-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- δ]pyridine-2-yl]-urea
217. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-(3-pyrrolidine-l- yl-propyl)-urea
218. l-[2-(4-hydroxy-piperidine-l-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
219. l-{3-[(2-hydroxy-ethyl)-methyl-amino]-propyl}-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
220. l-{3-[(4-hydroxy-piperidine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-&]pyridine-2-yl]-urea
221. l-fS-CC^-S-hydroxy-pyrrolidine-l-y^-propy^-S-ES-Cmethyl-p-tolyl-amino)- thiazolo[5,4-δ]pyridine-2-yl]-urea
222. 1 -[3-(4-hydroxymethyl-piperidine- 1 -yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
223. (R)-2-{3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]- ureidomethyl} -pyrrolidine- 1-carboxylic acid tert-butyl ester
224. 1 -[2-(4-acetyl-piperazine- 1 -yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-ό]pyridine-2-yl]-urea
225. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-piperidine-4-yl- urea
226. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-piperidine-4- ylmethyl-urea
227. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-piperidine-3- ylmethyl-urea
228. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine-2-yl]-3-(2-piperidine-4- yl-ethyl)-urea
229. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(3-piperazine-l-yl- propyl)-urea
230. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(S)-pyrrolidine- 3-yl-urea
231. 1 -[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]ρyridine-2-yl]-3-(R)-l - pyrrolidine-2-ylmethyl-urea
232. l-[2-(l-methyl-piperidine-4-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-δ]pyridine-2-yl]-urea
233. l-[2-(l-methyl-piperidine-4-yl)-ethyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-ό]pyridine-2-yl]-urea
234. 1 -(I -methyl-piperidine-3-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- ό]pyridine-2-yl] -urea
235. l-(l-ethyl-piperidine-3-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
236. 1 -(I -methyl-piperidine-4-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl] -urea
237. 1 -(I -ethyl-piperidine-4-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl]-urea
238. l-(l-methyl-piperidine-4-ylmethyl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- 6]pyridine-2-yl]-urea
239. l-[3-(4-ethyl-piperazine-l-yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-6]pyridine-2-yl]-urea
240. 1 -[3-(4-isopropyl-piperazine- 1 -yl)-propyl]-3-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-δ]pyridine-2-yl]-urea
241. l-((S)-methyl-pyrrolidine-3-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- £]pyridine-2-yl]-urea
242. l-((S)-ethyl-pyrrolidine-3-yl)-3-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- Z>]pyridine-2-yl]-urea
243. 1 -((R)- 1 -furan-2-ylmethyl-pyrrolidine-2-ylmethyl)-3 -[5 -(methyl-p-tolyl- amino)-thiazolo[5,4-έ]pyridine-2-yl]-urea
244. l-[(R)-l-(l-methyl-li/-pyrrole-2-ylmethyl)-pyrrolidine-2-ylmethyl]-3-[5- (methyl-p-tolyl-amino)-thiazolo[5,4-δ]pyridine-2-yl]-urea
245. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-ό]pyridine-2-yl]-3-[3-(4-propionyl- piperazine- 1 -yl)-propyl] -urea
246. l-[5-(methyl-p-tolyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-[3-(4-propionyl- piperazine-l-yl)-propyl]-urea
247. l-[3-(4-methanesulfonyl-piperazine-l-yl)-propyl]-3-[5-(methyl-p-tolyl- amino)-thiazolo[5,4-δ]pyridine-2-yl]-urea
248. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-Z)]pyridine-2-yl]-3-[3- (4-methyl-piperazine- 1 -yl)-propyl] -urea
249. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
250. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
251. 1 - {5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl} -3- [2-(4-methyl-piperazine- 1 -yl)-ethyl]-urea
252. 1 - { 5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5 ,4-δ]pyridine-2-yl } -3- ( 1 -methyl-piperidine-4-y lmethyl)-urea
253. 1 - { 5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5 ,4-6]pyridine-2-yl } -3 - [3 - (4-isopropyl-piperazine- 1 -yl)-propyl] -urea
254. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-Z)]pyridine-2-yl}-3- [3 -(4-ethyl-piperazine- 1 -yl)-propyl] -urea
255. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [3 -(4-methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
256. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [2-(4-ethyl-piperazine- 1 -yl)-ethyl]-urea
257. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(2,4-difluoro-phenyl)-methyl- amino]-thiazolo[5,4-Z>]pyridine-2-yl}-urea
258. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- (3 -pyrazole- 1 -yl-propyl)-urea
259. l-{5-[(2,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3- (4-propionyl-piperazine- 1 -yl)-propyl]-urea
260. l-[3-(4-cyclopropanecarbonyl-piperazine-l-yl)-propyl]-3-{5-[(2,4-difluoro- phenyl)-methyl-amino]-thiazolo[5,4-£]pyridine-2-yl}-urea
261. 1 - [3 -(4-ethyl-piperazine- 1 -yl)-propyl] -3 - [5 -(methyl-phenyl-amino)- thiazolo[5,4-6]pyridine-2-yl}-urea
262. 1 -[3-(4-isopropyl-piperazine- 1 -yl)-propyl]-3-[5-(methyl-phenyl-amino)- thiazolo [5 ,4-6]pyridine-2-yl } -urea
263. l-[5-(methyl-phenyl-atnino)-thiazolo[5,4-&]pyridine-2-yl]-3-[3-(4-methyl- piperazine- 1 -yl)-propyl] -urea
264. l-[5-(methyl-phenyl-amino)-thiazolo[5,4-6]pyridine-2-yl]-3-(3-morpholine-4- yl-propyl)-urea
265. 1 -[5-(methyl-phenyl-amino)-thiazolo[5,4-b]pyridine-2-yl]-3-(2-morpholine-4- yl-ethyl)-urea
266. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-[5-(methyl-phenyl-amino)- thaizolo[5,4-6]pyridine-2-yl]-urea
267. l-[5-(methyl-phenyl-amino)-thiazolo[5,4-&]pyridine-2-yl]-3-[3-(4-propionyl- piperazine-l-yl)-propyl]-urea
268. l-[3-(4-cyclopropanecarbonyl-piperazine-l-yl)-propyl]-3-[5-(methyl-phenyl- amino)-thiazolo[5,4-ό]pyridine-2-yl}-urea
269. l-[3-(4-methyl-piperazine-l-yl)-propyl]-3-{5-[methyl-(4-trifluoromethyl- phenyl-amino)-thiazolo [5 ,4-έ]pyridine-2-yl } -urea
270. l-{5-[methyl-(4-trifluoromethyl-phenyl)-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(2-morpholine-4-y l-ethyl)-urea
271. l-{5-[methyl-(4-trifluoromethyl-phenyl)-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(3 -morpholine-4-yl-propyl)-urea
272. l-[3-(4-ethyl-piperazine-l-yl-propyl]-3-{5-[methyl-(4-trifluoromethyl-phenyl- amino)-thiazolo [5,4-ό]pyridine-2-yl } -urea
273. l-[3-(4-isopropyl-piperazine-l-yl-propyl]-3-{5-[methyl-(4-trifluoromethyl- phenyl)-amino] -thiazolo [5,4-6]pyridine-2-yl } -urea
274. l-[2-(4-methyl-piperazine-l-yl)-ethyl]-3-{5-[methyl-(4-trifluoromethyl- phenyl)-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
275. 1 -( 1 -methyl-piperidine-4-ylmethyl)-3 - { 5- [methyl-(4-trifluoromethyl-phenyl)- amino] -thiazolo [5 ,4-6]pyridine-2-yl } -urea
276. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
277. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
278. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]ρyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl] -urea
279. l-{5-[(4-cyano-ρhenyl)-methyl-amino]-thiazolo[5,4-ό]ρyridine-2-yl}-3-[2-(4- methyl-piperazine- 1 -yl)-ethyl]-urea
280. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}-3-(l- methyl-piperidine-4-ylmethyl)-urea
281. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3-(4- ethyl-piperazine- 1 -yl)-propyl] -urea
282. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
283. l-{5- [(4-cyano-phenyl)-methyl-amino] -thiazolo [5 ,4-Z>] pyridine-2-yl } -3 - [3 -(4- isopropyl-piperazine- 1 -yl)-propyl]-urea
284. 1 - { 5-[(4-cyano-phenyl)-methyl-amino] -thiazolo [5 ,4-6]pyridine-2-yl } -3 - [2-(4- ethyl-piperazine- 1 -yl)-ethyl] -urea
285. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-cyano-phenyl)-methyl- amino]-thiazolo[5,4-&]pyridine-2-yl}-urea
286. l-{5-[(4-cyano-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(3- pyrazole- 1 -yl-propyl)-urea
287. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl]-urea
288. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
289. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
290. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[2-(4- methyl-piperazine- 1 -yl)-ethyl]-urea
291. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(l- methyl-piperidine-4-ylmethyl)-urea
292. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -y l)-propyl] -urea
293. 1 - [3 -(4-ethyl-piperazine- 1 -yl)-propyl] -3 - { 5 - [(4-fluoro-phenyl)-methyl- amino]-thiazolo[5,4-ό]pyridine-2-yl}-urea
294. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3-(4- methanesulfonyl-piperazine- 1 -yl)-propyl] -urea
295. 1 -[2-(4-ethyl-piperazine- 1 -yl)-propyl] -3 - { 5- [(4-fluoro-phenyl)-methyl- amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
296. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-fluoro-phenyl)-methyl-amino]- thiazolo[5,4-&]pyridine-2-yl}-urea
297. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methyl-piperazine- 1 -yl)-propyl]-urea
298. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
299. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-(l- methyl-piperidine-4-yl-methyl)-urea
300. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-(2- moφholine-4-yl-ethyl)-urea
301. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-δ]pyridine-2-yl}-3-[2-(4- methyl-piperazine- 1 -yl)-ethyl] -urea
302. 1 -[3-(4-ethyl-piperazine- 1 -yl)-propyl]-3- { 5-[(2-fluoro-4-methoxy-phenyl)- ethyl-amino]-thiazolo[5,4-b]pyridine-2-yl}-urea
303. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-b]pyridine-2-yl}-3-[3-(4- isopropyl-piperazine- 1 -yl)-propyl] -urea
304. l-{5-[(4-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3-(4- methylsulfonyl-piperazine- 1 -yl)-propyl]-urea
305. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 - [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
306. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl } -3 -(3 -hydroxy-propyl)-urea
307. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2- yl}-3-(3-morpholine-4-yl-propyl)-urea
308. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(3 -diethylamino-propyl)-urea
309. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2- yl } -3 -(2-morpholine-4-y l-ethyl)-urea
310. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2- yl } -3 -(3 -pyrrolidine- 1 -yl-propyl)-urea
311. l-{5-[(4-chloro-2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine- 2-yl}-3-[2-(4-methyl-piperazine-l-yl)-ethyl]-urea
312. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-chloro-2-hydroxy-phenyl)- methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-urea
313. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3-[3- (4-ethyl-piperazine- 1 -yl)-propyl]-urea
314. l-{5- [(4-bromo-phenyl)-methyl-amino] -thiazolo [5,4-6] pyridine-2-yl }-3-[3-(4- isopropyl-piperazine- 1 -yl)-propyl]-urea
315. 1 - { 5-[(4-bromo-phenyl)-methyl-amino] -thiazolo[5 ,4-έ]pyridine-2-yl } -3 - [3 -(4- methyl-piperazine- 1 -yl)-propyl] -urea
316. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(3- morpholine-4-yl-propyl)-urea
317. l-{5-[(4-bromo-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-(2- morpholine-4-yl-ethyl)-urea
318. l-[3-(4-acetyl-piperazine-l-yl)-propyl]-3-{5-[(4-bromo-phenyl)-methyl- amino]-thiazolo[5,4-δ]pyridine-2-yl}-urea
319. l-{5-[(3,4-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3- [3-(4-methyl-piperazine-l-yl)-propyl]-urea
320. 1 -{5-[(2,6-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl} -3- [3-(4-methyl-piperazine-l-yl)-propyl]-urea
321. l-{5-[(4-chloro-3-fluoro-phenyl)-methyl-amino]-thiazolo[5,4-&]pyridine-2-yl}- 3-[3-(4-methyl-piperazine- 1 -yl)-propyl]-urea
322. l-{5-[(2,3-difluoro-phenyl)-methyl-amino]-thiazolo[5,4-6]pyridine-2-yl}-3- [3 -(4-methyl-piperazine- 1 -yl)-propyl] -urea
323. 1 - { 5-[(2-fluoro-ρhenyl)-methyl-amino] -thiazolo [5 ,4-δ]pyridine-2-yl } -3 -[3 -(4- methyl-piperazine- 1 -yl)-propyl] -urea
324. l-{5-[(2-hydroxy-phenyl)-methyl-amino]-thiazolo[5,4-ό]pyridine-2-yl}-3-[3- (4-methyl-piperazine- 1 -yl)-propyl]-urea
325. l-[3-(4-methyl-piperazine-l-yl)-propyl]-3-{5-[methyl-(2,3,4-trifluoro- phenyl)-amino] -thiazolo [5 ,4-6]pyridine-2-yl } -urea
12. Use of the compound of Formula 1 as defined in claim 1 for manufacture of a medicament for the treatment or prevention of diseases resulting from an unregulated or undesired KDR activity.
13. The method according to claim 12, wherein said diseases are cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis, Kaposi's sarcoma, etc.
14. A pharmaceutical composition comprising (a) a therapeutically effective amount of a compound according to claim 1, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
PCT/KR2005/004524 2004-12-31 2005-12-26 Novel ([1,3]thiazolo[5,4-b]pyridin-2-yl)-2-carboxamide derivatives WO2006071035A1 (en)

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WO2008043183A1 (en) * 2006-10-13 2008-04-17 Neuromed Pharmaceuticals Ltd. Cyclopropyl-piperazine compounds as calcium channel blockers
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CN114437113A (en) * 2022-03-18 2022-05-06 西安交通大学 Thiazolopyridine ring-linked triazole compound and preparation method and application thereof

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