WO2007058482A1 - Inhibiteurs de la proteine kinase - Google Patents

Inhibiteurs de la proteine kinase Download PDF

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Publication number
WO2007058482A1
WO2007058482A1 PCT/KR2006/004822 KR2006004822W WO2007058482A1 WO 2007058482 A1 WO2007058482 A1 WO 2007058482A1 KR 2006004822 W KR2006004822 W KR 2006004822W WO 2007058482 A1 WO2007058482 A1 WO 2007058482A1
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Prior art keywords
pyridine
methyl
thiazolo
amino
ylamino
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PCT/KR2006/004822
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English (en)
Inventor
Seung-Hyun Yoon
Hyun Woo Joo
Jeong Uk Song
Young Kwan Kim
Sun-Young Koo
So Yeun Yang
Kyoung-Hee Kim
Jin-A Hwang
Heung Soo Cho
Hwan Geun Choi
Dongchul Lim
Ji Soo Song
Hae-Seong Yoon
Sang-Yong Hong
Min-Jeong Kim
Seihyun Choi
Kiwon Jo
Min-Hyeung Kim
Jieun Kim
Jung In Kim
Tae Kyo Park
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Lg Life Sciences, Ltd.
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Publication of WO2007058482A1 publication Critical patent/WO2007058482A1/fr

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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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to novel compounds having aminothiazole structure, more specifically, novel compounds for inhibition of VEGF receptor 2 kinase (hereinafter, referred to as "VEGFR2 kinase” or “KDR”) activity, as will be illustrated in Formula 1 later, or a pharmaceutically acceptable salt thereof.
  • VEGFR2 kinase VEGF receptor 2 kinase
  • KDR VEGF receptor 2 kinase
  • the compounds according to the present invention is useful for the treatment and prevention of diseases resulting from the undesired KDR, particularly angiogenesis-related diseases activity,
  • Angiogenesis referring to the physiological mechanism that makes new blood vessels for providing nutrients and oxygen necessary for cell survival and eliminating waste materials therefrom, allows only 0.01 % of blood vessel cells to proliferate under a normal condition, thereby recovering wounded parts in blood vessels (Carmeliet et al.,
  • 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 that nutrients or oxygen can reach cells by diffusion (so-called, diffusion limit) (Carmeliet et ah, 2000, Nature 407:249-257).
  • cancer cells distant from blood vessels become under the hypoxia condition due to the deficiency of oxygen.
  • cancer cells or stromal cells secrete various pro-angiogenic factors to induce angiogenesis toward a solid cancer.
  • 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 refers to the disease that capillary vessels created newly while arthritis proceeding to chronic inflammatory disease invade articulation to destroy cartilaginous tissues.
  • 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 the diabetic retinopathy. Since eyes are tissues with most rarely blood vessels in body, angiogenesis results in directly 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, draw an attention as a target for development of anti-angiogenesis drugs.
  • anti-angiogenesis drugs exhibit the effect of inhibiting the activity of VEGFR2 (KDR) and simultaneously also inhibiting the activity of other angiogenesis RTK families. This combined inhibiting effect is known as one mechanism of significantly increasing the angiogenesis inhibiting effect (Adams et al., 2002, Current Opinion in Chemical Biology, 5:486-492). Therefore, many researches are being carried out to find 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 researches and many experiments, could synthesize novel compounds capable of inhibiting the KDR activity and, after measuring their inhibition abilities, found that they can be used in treatment or prevention of diseases resulting from the undesired activation of KDR, for example, angiogenesis-related diseases, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • angiogenesis-related diseases such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • the present invention was achieved on the basis of such finding.
  • R 1 is a hydrogen, or C 1 -CiO alkyl
  • a 1 and A 2 are each independently carbon or nitrogen;
  • R. 2 is selected from the group consisting of hydrogen, halogen, cyano, -CF 3 and Ci-Cio alkyl;
  • Ari is 5-membered or 6-membered aromatic or heteroaromatic group
  • R 7 and R 8 are each independently hydrogen, optionally substituted C 1 -CiO alkyl, optionally substituted aryl, optionally substituted sulfone, or optionally substituted amine, and R 7 and Rg may be mutually combined to form cyclic structures;
  • R 9 is hydrogen or optionally substituted C 1 - C 10 alkyl, and ni is 0 to 1, n 2 is 1 to 5;
  • R 5 and R 6 are each independently hydrogen, hydroxyl, optionally substituted C 1 -C 10 alkyl, optionally substituted aryl, optionally substituted sulfone alkyl, or optionally substituted amine; two substituents as selected from R 4 , R 5 and R ⁇ may be mutually combined to form cyclic structures;
  • n is 0 or an integer of 1 ⁇ 5;
  • G) E is oxygen or sulfur
  • Ar 2 is hydrogen or 5-membered or 6-membered aromatic group represented by the below formula 2,
  • Q is selected from the group consisting of carbon, nitrogen, oxygen and sulfur
  • I) m is 0 or an integer of 1 ⁇ 4,
  • n] is 0 or an integer of 1 ⁇ 5;
  • J 2 and J 3 are each independently selected from the group consisting of -N-, -0-, -CR'- and -S-, or are a direct bond, wherein R' is the same as defined above;
  • n 2 and n 6 are O or an integer of 1 ⁇ 3 ;
  • 11 3 and 1I 4 are each independently selected from O or an integer of 1 ⁇ 3, and when n 3 or ru are O, they are nothing or a direct bond;
  • n 5 is selected from O or an integer of 1 ⁇ 3, and when n 5 is O, it is nothing or a direct bond;
  • 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.
  • 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, 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, hydro
  • Pharmaceutical salts can also be prepared by treating 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.
  • the substituent group(s) is(are) substituted with one or more group(s) individually and independently selected from alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, oxo, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, optionally substituted sulfonyl, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, isothiocyanato, isothiocyanato, isothiocyana
  • 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.
  • a lower alkyl of 1 to 10 carbon atoms in the present disclosure includes linear, branched, cyclic and partial cyclic forms.
  • the partial cyclic alkyl group is a general term including substituents having the cyclic structure in any part(s) among alkyl groups, for example, methylcyclopropylmethyl, cyclopropyvinyl, 2,2- dimethylcyclopropylmethyl, etc.
  • the lower alkyl is intended to include alkyl structures having 1 to 5 of double bond or triple bond.
  • halogen refers to -F, -Cl, -Br and -I.
  • the substitent X which binds to Ar 1 of 5-membered or 6-membered aromatic or heteroaromatic group, is one or more.
  • X is two or more, they may be the same or different substituents.
  • R 1 in Formula 1 is preferably hydrogen or methyl, and more preferably methyl.
  • a 1 and A 2 are preferably carbon.
  • R 2 is preferably hydrogen or halogen, and more preferably hydrogen.
  • Ar 1 is preferably 6-membered cyclic aromatic or heteroaromatic group, and more preferably phenyl.
  • n is preferably 0 or an integer of 1 ⁇ 4, more preferably 0 or an integer of 1 ⁇ 3.
  • E is preferably sulfur.
  • Q is preferably carbon or nitrogen
  • 1 (L) is preferably 3 or 4 and more preferably 4.
  • cyclic structure or group is not particularly limited; for example, they are 3-membered through 8-membered cyclic structures, and more preferably optionally substituted aziridine, pyrrolidine, piperazine, piperidine or morpholine.
  • Representative compounds of the present invention include, for example, but are not limited to the following compounds:
  • 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 present invention is not limited to the below processes.
  • the compound of Formula 1 can be prepared by reacting the aromatic cyclic compound of Formula 2 and the compound of Formula 3 in the presence of palladium catalyst.
  • the compound in Formula 1-1 below can be prepared by reacting the compound of Formula 3 with the compound of Formula
  • dba is dibenzylideneacetone and Xanphos is 9,9-dimethyl-4,5- bis(diphenylphosphino)xanthine.
  • the compound of Formula 3 having aminothiazole structure can be prepared from the method in Korean applicaton No. 2004-117617, wherein Ar is the same aromatic compound as defined above.
  • the above application is incorporated into the present invention as a reference.
  • the preparation process of the compound in Formula 1 comprises, as seen in Reaction Scheme 2 below, (a) reaction of the compound of Formula 3 with the compound of Formula 2-2 as obtained in Reaction Scheme 3 below in the presence of palladium catalyst to produce the compound of Formula 4 below, (b) removal of benzylalcohol (OTBDMS) protecting group using ammonium fluoride (NH 4 F), and then reaction of the residue compound with phosphorousoxychloride (POCI 3 ) to produce the compound of Formula 5, and (c) amidation using various amines to produce the compound of Formula 1-2.
  • Reaction Scheme 2 Reaction Scheme 2 below, (a) reaction of the compound of Formula 3 with the compound of Formula 2-2 as obtained in Reaction Scheme 3 below in the presence of palladium catalyst to produce the compound of Formula 4 below, (b) removal of benzylalcohol (OTBDMS) protecting group using ammonium fluoride (NH 4 F), and then reaction of the residue compound with phosphorousoxychloride (POCI 3 ) to produce the compound of Formula 5,
  • the compound of Formula 2-2 can be prepared by the process including (a) esterification of 2-chloro-isonicotinic acid of Formula 2-2-1 as a starting material to produce the compound of Formula 2-2-2, (b) reduction using lithiumalumiumhydride (LiAlH 4 ) to produce the compound of Formula
  • the preparation process of the compound of Formula 1 comprises, as seen in Reaction Scheme 4, (a) reaction of the compound of Formula 3 with methylbenzoate of Formula 2-3 in the presence of palladium catalyst to produce the compound of Formula 6, (b) hydrolyzation of the compound of Formula 6 using lithium hydroxide to produce the compound of Formula 7, and (c) amidation of the compound of Formula 7 using various amines to produce the compound of Formula 1-3.
  • Formula 1 comprises, as seen in Reaction Scheme 5 below, (a) reaction of the compound of Formula 5 obtained from Reaction Scheme 2 with carbon monoxide in the presence of palladium acetate [Pd(OAc) 2 ] and triphenylphosphine (PPh 3 ) to produce the compound of Formula 8, (b) hydrolyzation of the compound of Formula 8 using lithium hydroxide to produce the compound of Formula 9, and (c) amidation of phenylacetic acid of Formula 9 using various amines to produce the compound of Formula 1-4.
  • Reaction Scheme 5 Reaction Scheme 5 below, (a) reaction of the compound of Formula 5 obtained from Reaction Scheme 2 with carbon monoxide in the presence of palladium acetate [Pd(OAc) 2 ] and triphenylphosphine (PPh 3 ) to produce the compound of Formula 8, (b) hydrolyzation of the compound of Formula 8 using lithium hydroxide to produce the compound of Formula 9, and (c) amidation of phenylacetic acid of Formula 9 using various amines to produce
  • the compound according the present invention is in particular effective for the treatment and prevention of diseases associated with unregulated or undesired KDR activity such as diseases associated with angiogenesis.
  • diseases associated with unregulated or undesired KDR activity such as diseases associated with angiogenesis.
  • diseases associated with angiogenesis 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 method for the treatment and prevention of diseases resulted from an unregulated or undesired KDR activity comprising using the compound of Formula 1. 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.
  • 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, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • 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.
  • PREPARATION 4 Preparation of N 2 -[3-(tert-butyl-dimethyl-silanyloxymethyl)- pyridine-2-yl]-N 5 -methyl-N 5 -p-tolyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • the title compound was synthesized from using N 5 -methyl-N 5 -p-tolyl- thiazole[5,4-b]pyridine-2,5-diamine synthesized in Korean patent application No. 2004- 117617 and the compound as obtained in PREPARATION 3 in the same manner as in EXAMPLE 1.
  • PREPARATION 5 Preparation of N 5 -(chloromethyl-pyridine-2-yl)-N 5 -methyl-N 5 - p-tolyl-thiazole [5,4-b] py ridine-2,5-diamine
  • the title compound was synthesized using 6-chloroisonicotinic acid instead of 6-chloropyridine-2-carboxylic acid in PREPARATION 1 in the same manner as in PREPARATION 1, 2 and 3 in sequence.
  • PREPARATION 8 Preparation of piperazine-1-carboxylic acid methylamide 11 g (59 mmol) of N-butyloxycarbonylpiperazine was dissolved in 250 ml of anhydrous tetrahydrofuran, and then 20.6 ml (118 mmol) of N,N-diisopropylethylamine and 13.1 g (64.9 mmol) of 4-nitrophenylchloroformate were added thereto, followed by stirring under reflux for 1 hour. 177 ml of methylamine (2 M tetrahydrofuran solution) was added to the reaction, followed by stirring under reflux for 30 minutes.
  • reaction solution was concentrated, after addition of 100 ml of water, and then extracted twice with 100 ml of dichloromethane. 30 ml of 4 N hydrochloric acid/l,4-dioxane solution was added thereto, followed by stirring for 5 hours at room temperature. A solid, which was produced from completion of the reaction, was filtered off and dried to obtain 9.53 g (53 mmol, yield of 90%) of the title compound as hydrochloride salt.
  • PREPARATION 10 Preparation of N 2 -(4-chloromethyl-pyridine-2-yl)-N 5 -methyl- N 5 -p-toly 1-thiazolo [5,4-b] py ridine-2,5-diamine
  • the title compound was prepared from the compound as obtained in PREPARATION 12 and N 5 -methyl-N 5 -p-tolyl-thiazolo[5,4-b]pyridine-2,5-diamine in
  • PREPARATION 16 in the same manner as in PREPARATION 12.
  • the title compound was prepared from the compound as obtained in PREPARATION 16 and N 5 -methyl-N 5 -p-tolyl-thiazolo[5,4-b]pyridine-2,5-diamine in the same manner as in EXAMPLE 1.
  • EXAMPLE 46 Preparation of l-(4-methyl-piperazine-l-yl)-2- ⁇ 6-[5-(methyl-p- tolyl-amino)-thiazolo [5,4-b] py ridine-2-y lamino] -py ridine-3-y 1 ⁇ -ethanone
  • PREPARATION 17 Preparation of N 2 -(4-chloromethyl-pyridine-2-yl)-N 5 -(4- fluoro-phenyl)-N 5 -methyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • EXAMPLE 48 Preparation of N 5 -(4-fluoro-phenyl)-N 5 -methyl-N 2 -(4-morpholine- 4-ylmethl-pyridine-2-yl)-thiazolo[5,4-b]pyridine-2,5-diamine
  • EXAMPLE 64 Preparation of cyclopropyl-[4-(2- ⁇ 5-[(4-fluoro-phenyl)-methyl- amino]-thiazolo[5,4-b]pyridine-2-ylamino ⁇ -pyridine-4-ylmethyl)-piperazine-l-yl]- methanone
  • EXAMPLE 65 Preparation of l-[4-(2- ⁇ 5-[(4-fhioro-phenyl)-methyl-amino]- thiazolo[5,4-b]pyridine-2-ylamino ⁇ -pyridine-4-ylmethyl)-piperazine-l-yl]-propan- 1-one
  • PREPARATION 18 Preparation of N 2 -(5-chloromethyl-pyridine-2-yl)-N s -(4- fluoro-phenyl)-N 5 -methyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • N 5 -(4-fiuoro-phenyl)-thiazolo[5,4-b]pyridine-2,5-diamine instead of N 5 -methyl-N 5 - phenyl-thiazolo[5,4-b]pyridine-2,5-diamine in PREPARATION 7 and the compound as obtained in PREPARATION 12 instead of in PREPARATION 6 to give the title compound.
  • PREPARATION 19 Preparation of N 2 -(4-chloromethyl-pyridine-2-yl)-N 5 -(2,4- difluoro-phenyl)-N 5 -methyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • the title compound was synthesized using N 5 -methyl-N 5 -(4-fluorophenyl)- thiazolo[5,4-b]pyridine-2,5-diamine instead of N 5 -methyl-N 5 -phenyl-thiazolo[5,4- b]pyridine-2,5-diamine in PREPARATION 7 in the same manner as in PREPARATION 7.
  • EXAMPLE 80 Preparation of 4-(2- ⁇ 5-[(2,4-difluoro-phenyl)-methyl-amino]- thiazolo[5,4-b]pyridine-2-ylamino ⁇ -pyridine-4-ylmethyl)-piperazine-l-carboxylic acid dimethylamide
  • the title compound was synthesized using N 5 -methyl-N 5 -(2,4-difluoro-phenyl)- thiazolo[5,4-b]pyridine-2,5-diamine instead of N 5 -methyl-N 5 -phenyl-thiazolo[5,4- b]pyridine-2,5-diamine in PREPARATION 7 and the compound as obtained in
  • PREPARATION 21 Preparation of 4-(6- ⁇ 5-[(2,4-difluoro-phenyl)-methyl-amino]- thiazolofS ⁇ -bJpyridine ⁇ -ylaminoJ-pyridine-S-ylmethylJ-piperazine-l-carboxylic acid tert-butyl ester
  • PREPARATION 22 Preparation of (6- ⁇ 5-[(2,4-difluoro-phenyl)-methyl-amino]- thiazolo[5,4-b]pyridine-2-ylamino ⁇ -nicotinic acid methyl ester
  • the title compound was obtained from N 5 -methyl-N 5 -(2,4-difluorophenyl)- thazolo[5,4-b]pyridine-2,5-diamine and methyl 6-chloronicotinate in the same manner as in EXAMPLE l.
  • PREPARATION 23 Preparation of 6- ⁇ 5-[(2,4-difluoro-phenyl)-methyI-amino]- thiazolo[5,4-b]pyridine-2-ylamino ⁇ -nicotinic acid
  • PREPARATION 24 Preparation of N 5 -(4-chloro-2-fluoro-phenyl)-N 2 -(4- chloromethyl-pyridine-2-yl)-N 5 -methyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • the title compound was synthesized using N 5 -methyl-N 5 -(4-chloro-2- fluoro)phenyl-thiazolo[5,4-b]pyridine-2,5-diamine instead of N 5 -methyl-N 5 -phenyl- thiazolo[5,4-b]pyridine-2,5-diamine in PREPARATION 7 in the same manner as in PREPARATION 7.
  • EXAMPLE 110 Preparation of N 5 -(4-chloro-2-fluoro-phenyl)-N 5 -methyI-N 2 -(4- morpholme-4-yImethyI-pyridine-2-yl)-thiazolo[5,4-b]pyridine-2,5-diamine
  • EXAMPLE 112 Preparation of l-[4-(2- ⁇ 5-[(4-chloro-2-fluoro-phenyl)-methyl- amino]-thiazolo[5,4-b]pyridine-2-ylamino ⁇ -pyridine-4-ylmethyl)-piperazine-l-yl]-
  • PREPARATION 25 Preparation of N 5 -(4-chloromethyl-pyridine-2-yl)-N 5 -(4- chloro-pheny l)-N 5 -methy 1-thiazolo [5,4-b] py ridine-2,5-diamine
  • the title compound was synthesized using N 5 -methyl-N 5 -(4-chlorophenyl)- thiazolo[5,4-b]pyridine-2,5-diamine instead of N 5 -methyl-N 5 -phenyl-thiazolo[5,4- b] ⁇ yridine-2,5-diamine in PREPARATION 7 in the same manner as in PREPARATION 7.
  • PREPARATION 27 Preparation of N 2 -(6-chloro-pyrimidine-4-yI)-N 5 -(2,4- difluoro-phenyl)-N 5 -methyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • the title compound was synthesized using N 5 -(2,4-difluorophenyl)-N 5 -methyl- thiazolo[5,4-b]pyridine-2,5-diamine and 4,6-dichloropyrimidine in the same manner as in EXAMPLE l.
  • EXAMPLE 120 Preparation of 2-[4-(6- ⁇ 5-[(2,4-difhioro-phenyl)-methyl-amino]- thiazolo[5,4-b]pyridine-2-ylamino ⁇ -pyrimidine-4-yI)-piperazine-l-yl]-ethanol
  • EXAMPLE 120 Preparation of 4- ⁇ 2-[5-(methlyl-p-tolyl-amino)-thiazolo[5,4- b]pyridine-2-yIamino]-pyrimidine-4-ylmethyl ⁇ -piperaziiie-2-one
  • EXAMPLE 152 Preparation of l- ⁇ 2-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- b] py ridine-2-y lamino] -py ridine-4-y lmethy 1 ⁇ -piperidine-4-one O-methy 1-oxime
  • the title compound was obtained in the same manner as in EXAMPLE 151, except for using methoxyamine hydrochloric acid instead of hydroxylamine hydrochloric acid.
  • PREPARATION 10 was added thereto, and then stirred for 1 hour at room themperature.
  • EXAMPLE 154 Preparation of 2-hydroxy-l-(4 ⁇ 2-[5-(methyl-p-tolyI-amino)- thiazolo [5,4-b] py ridine-2-y lamino] -py ridine-4-y lmethy 1 ⁇ -piperazine-1 -y l)-ethanone
  • PREPARATION 28 Preparation of (S)-l- ⁇ 2-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-ylmethyl ⁇ -pyrrolidine-2-carboxylic acid methyl ester
  • the reaction was filtered through Celite to remove a solid, and the filterate was concentrated to obtain a solid, then 20 ml of diethylether and 50 ml of n-hexane were added to the solid, followed by stirring for 20 minutes. The resulting solution was filtered and dried to obtain 1.90 g (5.05 mmol, yield of 89%) of the title compound.
  • PREPARATION 29 Preparation of 2-( ⁇ 2-[5-(methyl-p-tolyl-amino)-thiazoIo[5,4- b]pyridine-2-ylamino]-pyridine-4-ylmethyl ⁇ -carbamoyl)-pyrrolidine-l-carboxylic acid t-butyl ester
  • the title compound was prepared from using the compound as obtained in PREPARATION 29 in the same manner as in EXAMPLE 62.
  • EXAMPLE 176 Preparation of N 2 -[4-(l,l-dioxo-l ⁇ 6 -thiomorpholine-4-yImethyl)- py ridine-2-y 1] -N 5 -methyl-N 5 -p-tolyl-thiazolo [5,4-b] py ridine-2,5-diamine
  • EXAMPLE 178 Preparation of l-cyclopropyl-3- ⁇ 2-[5-(methyl-p-tolyl-amino)- thiazolo [5,4-b] py ridine-2-y lamino] -py ridine-4-y lmethy 1 ⁇ -urea
  • EXAMPLE 181 Preparation of l-(4-acetyl-piperazine-l-yl)-2- ⁇ 2-[5-(methyI-p- tolyl-amino)-thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-yl ⁇ -ethanone
  • PREPARATION 30 Preparation of [(S)-l- ⁇ 2-[5-(methyI-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-yl ⁇ -acetyI]-pyrrolidine-3-yl]-
  • the title compound was synthesized using the compound as obtained in PERPARATION 30 in the same manner as in EXAMPLE 62.
  • PREPARATION 31 Preparation of [(R)-l-(2- ⁇ 2-[5-(methyI-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-yl ⁇ -acetyl)-pyrrolidine-3-yl]- carbarmic acid tert-butyl ester
  • the title compound was synthesized using the compound as obtained in PERPARATION 30 in the same manner as in EXAMPLE 62.
  • PREPARATION 32 Preparation of 2-[5-(methyl-p-tolyl-amino)-thiazoIo[5,4- bjpyridine-l-ylaminoj-isonicotinic acid methyl ester
  • PREPARATION 33 Preparation of 2-[5-(methyl-p-tolyl-amino)-thiazolo[5,4- b] py ridine-2-ylamino] -isonicotinic acid
  • PREPARATION 34 Preparation of (l- ⁇ 2-[5-(methyl-p-toIyl-amino)-thiazolo[5,4- b]pyridine-2-ylamino]-pyridine-4-carbonyl ⁇ -pipelidine-4-yl)-carbarmic acid tert- butyl ester
  • PREPARATION 35 Preparation of ((S)-l- ⁇ 2-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-carbonyI ⁇ -pyrroHdine-3-yl)- carbarmic acid tert-butyl ester
  • PREPARATION 36 Preparation of ((R)-l- ⁇ 2-[5-(methyl-p-tolyl-amino)- thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-carbonyl ⁇ -pyrrolidine-3-yl)- carbarmic acid tert-butyl ester
  • the obtained aldehyde was dissolved in 15 ml of dichloroethane, then 98 mg (0.766 mmol) of acetylpiperazine and 162 mg (0.766 mmol) of sodium triacetoxyborohydride were added thereto, and after stirring for 12 hours at room temperature, the reaction was completed with methanol.
  • the resulting solution was extracted with 30 ml of dichloromethane, and the combined organic layer was concentrated, then purified by column chromatography to obtain 129 mg (0.257 mmol, yield of 67%) of the title compound.
  • EXAMPLE 215 Preparation of N 5 -methyl-N 2 - ⁇ 4-[2-(4-methyl-pi ⁇ erazine-l-yl)- ethyl]-pyridine-2-yl ⁇ -N 5 -p-tolyl-thiazolo[5,4-b]pyridine-2,5-diamine
  • EXAMPLE 224 Preparation of 2-hydroxy-2-methyl-l-[4-(2- ⁇ 2-[5-(methyI-p-toIyl- amino)-thiazolo[5,4-b]pyridine-2-ylamino]-pyridine-4-yl ⁇ -ethyl)-piperazine-l- yl] propane-1 -one

Abstract

L'invention porte sur des composés permettant d'inhiber des kinases de tyrosine du récepteur d'angiogenèse, notamment l'activité de la kinase 2 (« KDR ») du récepteur VEG et sur des procédés de préparation et d'utilisation afférents. L'invention porte également sur des compositions pharmaceutiques les renfermant en une dose thérapeutiquement efficace. Les composés selon l'invention sont utiles pour traiter et prévenir des maladies provoquées par une activité KRD non désirée, notamment des maladies liées à l'angiogenèse, telles que des cancers, le psoriasis, la polyarthrite rumatoïde, la rétinopathie diabétique, etc.
PCT/KR2006/004822 2005-11-16 2006-11-15 Inhibiteurs de la proteine kinase WO2007058482A1 (fr)

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WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
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WO2007117381A2 (fr) * 2006-03-24 2007-10-18 Array Biopharma Inc. Activateurs de glucokinase
WO2007117381A3 (fr) * 2006-03-24 2008-02-14 Array Biopharma Inc Activateurs de glucokinase
US8883828B2 (en) 2006-03-24 2014-11-11 Array Biopharma Inc. 2-aminopyridine analogs as glucokinase activators
US8354540B2 (en) 2006-03-24 2013-01-15 Array Biopharma Inc. 2-aminopyridine analogs as glucokinase activators
EP2543667A1 (fr) * 2006-03-24 2013-01-09 Array Biopharma, Inc. Analogues de 2-aminopyridine en tant qu'activateurs de la glucokinase
US8022223B2 (en) 2006-03-24 2011-09-20 Array Biopharma, Inc. 2-aminopyridine analogs as glucokinase activators
AU2007235558B2 (en) * 2006-03-24 2011-12-01 Array Biopharma Inc. 2 -aminopyridine analogs as glucokinase activators
JP2010527909A (ja) * 2007-06-05 2010-08-19 武田薬品工業株式会社 キナーゼ阻害剤としての二環式複素環化合物
US8304557B2 (en) 2007-06-05 2012-11-06 Takeda Pharmaceutical Company Limited Fused heterocycle derivatives and use thereof
US8324395B2 (en) 2007-08-23 2012-12-04 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8344135B2 (en) 2007-08-29 2013-01-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9079890B2 (en) 2007-09-21 2015-07-14 Array Biopharma Inc. Intermediates for the preparation of pyridin-2-yl-amino-1,2,4-thiadiazole derivatives
US8853409B2 (en) 2007-09-21 2014-10-07 Array Biopharma Inc. Pyridin-2yl-amino-1, 2, 4-thiadiazole derivatives as glucokinase activators for the treatment of diabetes mellitus
US8697874B2 (en) 2008-12-01 2014-04-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
JP5579619B2 (ja) * 2008-12-01 2014-08-27 武田薬品工業株式会社 複素環化合物およびその用途
WO2010064611A1 (fr) 2008-12-01 2010-06-10 武田薬品工業株式会社 Composé hétérocyclique et applications
US8143258B2 (en) 2008-12-02 2012-03-27 Takeda Pharmaceutical Company Limited Benzothiazole compounds useful for Raf inhibition
WO2010064722A1 (fr) 2008-12-02 2010-06-10 Takeda Pharmaceutical Company Limited Dérivés de benzothiazole convenant comme agents anticancéreux
US8497274B2 (en) 2008-12-02 2013-07-30 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2012035055A1 (fr) * 2010-09-17 2012-03-22 Glaxo Group Limited Nouveaux composés
US20160347767A1 (en) * 2010-11-19 2016-12-01 Ligand Pharmaceuticals Incorporated Heterocycle amines and uses thereof
US10030034B2 (en) * 2010-11-19 2018-07-24 Ligand Pharmaceuticals Incorporated Heterocycle amines and uses thereof
CN108864151A (zh) * 2010-11-19 2018-11-23 利亘制药公司 杂环胺及其用途
US11773110B2 (en) 2010-11-19 2023-10-03 Ligand Pharmaceuticals Incorporated Heterocycle amines and uses thereof
WO2016029218A1 (fr) * 2014-08-22 2016-02-25 The Arizona Board Of Regents On Behalf Of The University Of Arizona Dérivés de 1-aryléthyl-4-acylaminopipéridine substitués à titre de modulateurs des récepteurs d'opioïdes/adrénorécepteur alpha et leur procédé de préparation
US9765027B2 (en) 2014-08-22 2017-09-19 Arizona Board Of Regents On Behalf Of The University Of Arizona Substituted 1-arylethyl-4-acylaminopiperidine derivatives as opioid/alpha-adrenoreceptor modulators and method of their preparation
US10617681B2 (en) 2014-08-22 2020-04-14 Arizona Board Of Regents On Behalf Of The University Of Arizona 1-arylalkyl-4-acylaminopiperidine compounds
US10807983B2 (en) 2015-03-16 2020-10-20 Ligand Pharmaceuticals, Inc. Imidazo-fused heterocycles and uses thereof
US11858938B2 (en) 2015-03-16 2024-01-02 Ligand Pharmaceuticals, Inc. Imidazo-fused heterocycles and uses thereof

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