WO2006068410A1 - Novel 3-(2-amino-6-pyridinyl)-4-hydroxyphenyl amine derivatives - Google Patents

Novel 3-(2-amino-6-pyridinyl)-4-hydroxyphenyl amine derivatives Download PDF

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WO2006068410A1
WO2006068410A1 PCT/KR2005/004418 KR2005004418W WO2006068410A1 WO 2006068410 A1 WO2006068410 A1 WO 2006068410A1 KR 2005004418 W KR2005004418 W KR 2005004418W WO 2006068410 A1 WO2006068410 A1 WO 2006068410A1
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Prior art keywords
amino
hydroxyphenyl
methyl
pyridinyl
chloro
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PCT/KR2005/004418
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French (fr)
Inventor
Jinho Lee
Yun Sik Kim
Seihyun Choi
Hwan Geun Choi
Seunghyun Yoon
Young Kwan Kim
Kiwon Jo
Min-Hyeung Kim
Sun-Young Koo
Jieun Kim
Jung In Kim
Dongchul Lim
Kyoung-Hee Kim
Ji Soo Song
Hae-Seong Yoon
Heung-Soo Cho
Joonghoon Park
Jin-A Hwang
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Lg Life Sciences, Ltd.
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Publication of WO2006068410A1 publication Critical patent/WO2006068410A1/en

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to novel compounds having 3-(2-amino-6- pyridinyl)-4-hydroxyphenyl amine 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, hydrate, solvate, isomer, and prodrug thereof.
  • VEGFR2 kinase ase activity
  • KDR VEGF receptor 2 kinase
  • the compounds according to the present invention is useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • 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., 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 that nutrients or oxygen can reach cells by diffusion (so-called, diffusion limit) (Carmeliet et al., 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, 6:486- 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 angiogenesis-related diseases, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc., resulting from the undesired activation of KDR.
  • angiogenesis-related diseases for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
  • R 1 is an aryl, heteroaryl, or optionally substituted aryl or heteroaryl;
  • R 2 is one selected from the group consisting of
  • R 3 is selected from the group consisting of
  • X 1 is a direct bond, oxygen, optionally substituted amino, optionally substituted alkyl, or optionally substituted aryl;
  • X 2 is selected from the group consisting of hydrogen, pyrrolidine, piperazine, morpholine, lower alkyl amine, hydroxyl, halogen, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl, optionally substituted piperidine and optionally substituted thiazole; and
  • X 3 is selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl
  • X 4 and X 5 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted sulfone and alkyl carbamate, or X 4 and X 5 are together taken to form optionally substituted cyclic or heterocyclic group;
  • n 1 to 5;
  • R 4 is selected from the group consisting of
  • substituent group(s) may be covalently bonded to the primary molecule.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkyl, cycloalkyl, 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,
  • 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. Therefore, wherever a substituent is described as being "optionally substituted” that substituent may be substituted with one of the above substituents.
  • 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, 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, ethanesulfonic acid or p-
  • 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.
  • 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.
  • 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.
  • the compounds of Formula 1 in the present invention may have an asymmetric carbon center according to the kind of substituents, and in this case, they can be present in the form of optical isomers such as enantiomers or diastereomers.
  • 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.
  • Formula 1 is intended to include the compound itself, and/or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof.
  • 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, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • 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.
  • substituent is described as being "optionally substituted", that substituent may be substituted with one of the above substituents.
  • R refers to a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and 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.
  • N-sulfonamido refers to a RS( ⁇ O) 2 NH- group wherein R is as defined herein.
  • perhaloalkyl refers to an alkyl group in which all of the hydrogen atoms are replaced by halogen atoms.
  • R 1 is preferably an aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, lower alkyl, amino and lower alkoxy.
  • R 1 is more preferably a phenyl substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, C 1 -C 5 alkyl, amino and C 1 -C 5 alkoxy.
  • R 2 is preferably hydrogen or lower alkyl, and more preferably hydrogen or C 1 -C 5 alkyl.
  • X 3 is preferably hydrogen, and n is 1 or 2, and more preferably 1.
  • R 4 is preferably hydrogen or cyclic lower alkyl containing N or O.
  • 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 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 NRjR 2 as defined in Formula 1 into 5- bromo-2-hydroxyacetophenone of Formula 2 below as a starting material, (ii) a step of introducing a pyrimidine substituent thereto, and (iii) a step of introducing R 3 by the conversion of nitrile group.
  • the step of performing the conversion of the carboxyl group after the introduction of the pyrimidine substituent comprises,
  • PG means a protecting group and includes, for example, but is not limited to t-butyl, alkyl ether, substituted or unsubstituted benzyl group, and the like,
  • the process for introducing various substituents by the conversion of the cyano group as defined in Formula 8 comprises,
  • the process also comprise,
  • the compound of Formula 4 may be prepared from p-anisidine as defined in the compound of Formula 11 below as a starting material, as shown in Reaction Scheme 1.
  • Bn means a benzyl group as a protecting group.
  • Reaction Scheme 2 illustrates the preparation of a compound in which R 1 is 4-chloro-2-fluorobenzene, R 2 is methyl, R 3 is cyano and R 4 is hydrogen in Formula 1.
  • Bn means a benzyl group as a protecting group.
  • 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 as defined in claim 1 for manufacture of a medicament for the treatment or prevention of these diseases.
  • 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, ethanesulfonic 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.
  • 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.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
  • 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.
  • 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, 8% 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. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50 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 50 .
  • 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 50 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 judgment of the prescribing physician.
  • the solid compound was dissolved in 1500 ml of toluene, then 200 ml of ethylene glycol and catalytic amount (3 g) of p-toluenesulfonic acid were added thereto, followed by stirring under Dean-Stark reflux for 48 hours. After completion of the reaction, 300 ml of ethyl acetate was added thereto, and the reaction mixture was washed 3 times with water, then the residue was concentrated to obtain 533 g (0.999 mol) of the title compound in a yield of 94%.
  • PREPARATION 2 4-(benzyloxy)-N-(4-chlorophenyl)-N-methyl-3-(2-methyl-l,3- dioxolane-2-yl)aniline
  • PREPARATION 3 l- ⁇ 2-(benzyloxy)-5-[4-chloro(methyl)anilino]phenyl ⁇ -l- ethanone 6.59 g (16.1 mmol) of the compound obtained in PREPARATION 2 was dissolved in 100 ml of methanol, and 20 ml of aqueous 6 N hydrochloride was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was cooled and neutralized with aqueous 6 N sodium hydroxide. The methanol was removed by evaporation in vacuo, and 100 ml of water was added thereto. The precipitated solids were filtered and dried to obtain 5.78 g (15.6 mmol) of the title compound in a yield of 97%.
  • reaction mixture was allowed to stir at room temperature for 1 hour. After completion of the reaction, 20 ml of water added thereto, the reaction solution was extracted twice with 20 ml of ethyl acetate. The residue was concentrated and purified by the column chromatography to obtain 17 mg (0.040 mmol) of the title compound in a yield of 24%.
  • EXAMPLE 11 tert-butyl (2-amino-6- ⁇ 5-[4-chloro(methyl)anilino]-2- hydroxyphenyl ⁇ -3-pyridinyl)methyl carbamate 34 mg (0.096 mmol) of the compound obtained in EXAMPLE 2 was dissolved in 10 ml of dichloromethane, and 23 mg of di-t-butyl dicarbonate was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the residue was purified by the column chromatography to obtain 41 mg (0.091 mmol) of the title compound in a yield 95%.
  • EXAMPLE 13 iV-[(2-amino-6- ⁇ 5-[4-chloro(methyl)anilino]-2-hydroxyphenyI ⁇ -3- py ridinyl)methyl] acetamide
  • the title compound was obtained from the compound obtained in EXAMPLE 2 in the same manner as Process B.
  • This compound was dissolved in 700 ml of N,N-dimethylformamide, then 144 g (1.04 mol) of potassium carbonate and 106 ml (0.92 mol) of benzyl bromide were added thereto in sequence, followed by stirring at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, and 800 ml of water added thereto, then a solid compound thus obtained were filtered and dried to obtain 17O g (0.60 mol) of a compound. This compound was dissolved in 700 ml of dichloromethane, and 170 g (0.78 mol) of di-t- butyl dicarbonate was added thereto, followed by stirring at room temperature for 4 hours.
  • reaction solution was concentrated, and 500 ml of methanol was added and dissolved thereto.
  • 500 ml of aqueous 2 N sodium chloride was added thereto followed by stirring at room temperature for 30 minutes.
  • solvent was removed by evaporation in vacuo, 700 ml of water was added thereto, then a solid compound thus obtained was filtered and dried to obtain 199 g (0.58 mol) of a compound.
  • This compound was dissolved in 1 / of N,N-dimethylformamide, and the solution was allowed to cool to 0°C.
  • PREPARATION 7 4-(benzyloxy)-iV-(4-bromophenyl)-iV-methyI-3-(2-methyl-l,3- dioxolane-2-yl)aniline
  • the title compound was obtained from the compound obtained in PERPARATION 6 and 4-iodinebromobenzene in the same manner as in PREPARATION 2.
  • EXAMPLE 36 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]- nicotinamide 47 mg (0.14 mmol) of the compound obtained in EXAMPLE 35 was dissolved in 3 ml of 6 N potassium hydroxide and 2 ml of ethanol, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was concentrated and neutralized with aqueous 2 N hydrochloric acid then exatrcted twice by 10 ml of ethyl acetate. The product was concentrated and purified by the column chromatography to obtain 23 mg (0.066 mmol) of the title compound in a yield of 47%.
  • the title compound was obtained from the compound obtained in EXAMPLE 41 in the same manner as in EXAMPLE 3 and 4 in sequence.
  • the title compound was obtained from the compound obtained in EXAMPLE 101 in the same manner as in EXAMPLE 65.
  • EXAMPLE 104 2-(6-amino-5- ⁇ [(3-hydroxypropyl)ammo]methyl ⁇ -2-pyridinyl)-4- (2-fluoro-4-dimethylanilino)phenol
  • the title compound was obtained from the compound obtained in EXAMPLE 79 in the same manner as in EXAMPLE 103.
  • EXAMPLE 110 JV-( ⁇ 2-6-amino-6-[5-(2-fluoro-4-dimethyIanilino)-2- hydroxyphenyl]-3-pyridinyl ⁇ methyl)-l-ethanesulfonamide
  • EXAMPLE 111 Ethyl l-( ⁇ 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl ⁇ methyl)-2-aziridinecarboxyIate
  • PREPARATION 8 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-iV-methyl-iV-methoxynicotmamide
  • EXAMPLE 284 4-[( ⁇ 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hy droxyphenyl] -3-py ridinyl ⁇ methyl)amino] -4-oxobutanoic acid
  • the title compound was obtained from the compound obtained in EXAMPLE 300 in the same manner as in EXAMPLE 42.
  • EXAMPLE 339 (2S)-N-[(2-amino-6- ⁇ 5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl ⁇ -3-pyridinyl)methyl]-2,3-dihydroxypropanamide 23 mg (0.0475 mmol) of the compound obtained in EXAMPLE 337 was dissolved in 10 ml of methanol, 1 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with aqueous 2 N sodium hydroxide and concentrated in vacuo. The residue was extracted twice with 20 ml of ethyl acetate to obtain 18 mg (0.0405 mmol) of the title compound in a yield of 85%.
  • EXAMPLE 341 N-[(2-amino-6- ⁇ 5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyI ⁇ -3-pyridinyl)methyl]-4-methyl-l-piperazinecarboxyamide Using 4-methyl-l-piperazinecarbonyl chloride instead of 4- morpholinecarbonyl chloride in EXAMPLE 340, the title compound was obtained in the same manner as in EXAMPLE 294.
  • EXPERIMENT 1 Test of the inhibitory effect of the compounds according to the present invention on the activity of various RTKs (Receptor Tyrosine Kinases)
  • the reaction was carried out in a total reaction volume of 20 ⁇ l, 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).
  • IC 50 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.
  • EXPERIMENT 2 Test of the inhibitory effect of the compounds according to the present invention on VEGF-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 5X10 3 cells per well, and cultured in M 199 media (Gibco BRL; supplemented with 10% FBS, 30 ⁇ g/ml ECGS, 50 ⁇ g/ml Heparin, IX Penicillin/Streptomycin and 0.5 mM Glutamine) at 37°C in a 5% CO 2 incubator for one day. Thereafter, serum starvation was performed in M 199 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.
  • M 199 media Gibco BRL; supplemented with 10% FBS, 30 ⁇ g/ml ECGS, 50 ⁇ g/ml Heparin, IX Penicillin/Streptomycin and 0.5 mM Glutamine
  • VEGF vascular endothelial growth factor
  • HUVEC Human umbilical vein endothelial cells having been used within passage 5 were cultured at 37°C in a 5% CO 2 incubator to 70-80% confluence in a
  • HCTl 16 cells 3X10 3 cells/well:KCLB
  • RPMIl 640 medium supplemented with 5% FBS, IX Penicillin/Streptomycin and 0.5 mM Glutamine; Gibco BRL
  • the medium was treated with compounds diluted at graded concentrations.
  • 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.
  • GI 50 the concentration of compounds of inhibiting 50% of the total cell growth, was determined using mean values from three experiments using Linear regression analysis.
  • EXPERIMENT 5 Test of the inhibitory effect of the compounds according to the present invention on cancer cell growth in vivo
  • B ALB/c nude mice (5 - 6 weeks age, female) purchased from Harlan (USA) were raised in a cage equipped with a clean room HEPA filter and adapted to the cage for a week.
  • Human cancer cells selected for test were cultured at each suitable condition and then subcutaneously administered to the nude mice at the amount of 5 ⁇ 10 X 10 5 cells/100 ⁇ l.
  • the compounds according to the present invention were orally administered at a predetermined amount once a day.
  • the size of tumor and the weight of mice were measured three times a day, and the clinical manifestation was investigated and recorded once or twice a day.
  • the size of tumor was recorded as a volume value by measuring the width, length and height of tumor and then calculating the volume value on the basis of (width x length x height)/6 formula. The test continued for 15 ⁇ 18 days.
  • the inhibitory effect on the tumor growth was determined by two factors, i.e., IR% (Inhibition Rate %) and %T/C.
  • IR% (1 - Average tumor size of administration group / Average tumor size of control group) X 100
  • %T/C ⁇ (Average tumor size of administration group at a certain day - Average tumor size of administration group at an administration starting day) / (Average tumor size of control group at a certain day - Average tumor size of control group at an administration starting day) ⁇ X 100
  • IC 50 values of some compounds of Formula 1 showing the ability to inhibit the cell growth of HCTl 16 cells, bFGF-dependent HUVEC and PDGF-dependent PASMC.
  • Some compounds of Formula 1 showed a significant inhibitory effect in the in vivo test regarding the inhibitory effect on the cancer cell growth using nude mice.

Abstract

The present invention relates to novel compounds having 3-(2-amino-6-pyrimidinyl)-4-hydroxyphenyl amine structure, as being illustrated in Formula 1, and preparations for preparation of them, and the use of them, and pharmaceutical compositions containing them at a therapeutically effective amount. The compounds according to the present invention are useful for the treatment and prevention of diseases resulting from the undesired KDR activity, for example, angiogenesis-related diseases such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.

Description

NOVEL 3-(2-AMINO-6-PYRIDINYL)-4-HYDROXYPHENYL
AMINE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to novel compounds having 3-(2-amino-6- pyridinyl)-4-hydroxyphenyl amine 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, hydrate, solvate, isomer, and prodrug thereof. The compounds according to the present invention is useful for the treatment and prevention of angiogenesis-related diseases, particularly resulting from the undesired KDR activity, such as cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc.
BACKGROUND OF THE INVENTION
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., 2000, Nature 407:249-257).
However, fast-growing tissues such as solid tumors need further many 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 that nutrients or oxygen can reach cells by diffusion (so-called, diffusion limit) (Carmeliet et al., 2000, Nature 407:249-257).
Cancer cells distant from blood vessels become under the hypoxia condition due to the deficiency of oxygen. In such condition, cancer cells or stromal cells secrete various pro-angiogenic factors to induce angiogenesis toward a solid cancer. 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 is activated by these growth factors to result in the proliferation of cancer cells (Carmeliet P., 2000, Nature Medicine 5:389-395, Yancopoulos et ah,
2000, Nature 407:242-248).
Rheumatoid arthritis, as other angiogenesis-related disease than cancers, refers to the disease that capillary vessels created newly while arthritis proceeding to chronic inflammatory disease invade articulation to destroy cartilaginous tissues.
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 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 (RTKs) as receptors of pro-angiogenic factors, such as VEGFR2 (KDR), FGFRl, PDGFR-β and the like, draw an 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 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, 6:486- 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.
As representative examples of compounds of inhibiting KDR kinase activity, known are 2-indolinone derivatives (WO 9850356), qunazoline derivatives (EP 0566266 Al), triazole derivatives (WO 02057240), diaminothiazole derivatives (WO 0075120), benzothiazole derivatives (WO 0157008), and, but these compounds do not 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 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 angiogenesis-related diseases, for example, cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, etc., resulting from the undesired activation of KDR. The present invention was achieved on the basis of such finding.
According to the present invention there is provided a compound of Formula
Figure imgf000005_0001
or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof,
where
A) R1 is an aryl, heteroaryl, or optionally substituted aryl or heteroaryl;
B) R2 is one selected from the group consisting of
I) hydrogen; and
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl;
C) R3 is selected from the group consisting of
I) cyano;
II) optionally substituted alkyl;
III) a substituent of formula -CC=O)-X1-X2, where
X1 is a direct bond, oxygen, optionally substituted amino, optionally substituted alkyl, or optionally substituted aryl;
X2 is selected from the group consisting of hydrogen, pyrrolidine, piperazine, morpholine, lower alkyl amine, hydroxyl, halogen, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl, optionally substituted piperidine and optionally substituted thiazole; and
IV) a substituent of formula -C(CH(-X3))NnX4X5, where
X3 is selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl;
X4 and X5 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted sulfone and alkyl carbamate, or X4 and X5 are together taken to form optionally substituted cyclic or heterocyclic group;
n is 1 to 5;
D) R4 is selected from the group consisting of
I) hydrogen; and
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl.
DETAILED DESCRIPTION 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 means that a substituent group(s) may be covalently bonded to the primary molecule. The substituent group(s) is(are) one or more group(s) individually and independently selected from alkyl, cycloalkyl, 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, nitro, silyl, trihalomethanesulfonyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, morphorinyl, furyl, thiazolidine, isooxazole, azetidinyl, dioxolane, pyrazinyl, thienyl, aziridine, oxazolidine, imidazole, alkanoic acid, alkanoate, amino including mono- and di-subsitituted amino groups, and the protected derivatives thereof. In some cases, 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. Therefore, wherever a substituent is described as being "optionally substituted" that substituent may be substituted with one of the above substituents.
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, 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 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.
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. For examples, the compounds of Formula 1 in the present invention may have an asymmetric carbon center according to the kind of substituents, and in this case, they can be present in the form of optical isomers such as enantiomers or diastereomers.
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.
One skilled in the art to which the present invention pertains would readily appreciate the meaning of the above terms and be easily able to replicate them, for example, various hydrates, solvates, isomers and prodrugs of the compound of
Formula 1 , on the basis of prior art, thus the detailed descriptions of the preparation methods thereof is omitted in the present disclosure.
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, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. 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. Wherever a substituent is described as being "optionally substituted", that substituent may be substituted with one of the above substituents.
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 alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and 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 -Q=C))CH3 group.
A "trihalomethanesulfonyl" group refers to a Y3CS(=O)2 group wherein Y 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 RS(^O)2NH- group wherein R is as defined herein.
A "trihalomethanesulfonamido" group refers to a Y3CS(=O)2NR- group wherein Y and R are as defined herein, respectively.
An "O-carbamyl" group refers to a -OC(=O)-NR group wherein R is as defined herein.
An "N-carbamyl" group refers to a ROC(=O)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(=0)-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 Formula 1 above, R1 is preferably an aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, lower alkyl, amino and lower alkoxy. R1 is more preferably a phenyl substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, C1-C5 alkyl, amino and C1-C5 alkoxy.
R2 is preferably hydrogen or lower alkyl, and more preferably hydrogen or C1-C5 alkyl.
In R3, X3 is preferably hydrogen, and n is 1 or 2, and more preferably 1.
R4 is preferably hydrogen or cyclic lower alkyl containing N or O.
Representative compounds of the present invention include, for example, but are not limited to the following compounds:
1) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinonitrile
2) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-[4-chloro(methyl)anilino]-phenol
3) Ethyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinate
4) 2-amino-6- { 5- [4-chloro(methyl)anilino] -2-hydroxyphenyl } nicotinic acid 5) 2-[6-amino-5-(hydroxymethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino]phenol
6) 2-{6-amino-5-[(dimethylaniino)methyl]-2-pyridinyl}-4-[4- chloro(methyl)anilino]phenol
7) 2-{6-amino-5-[(dimethylamino)methyl]-2-pyridinyl}-4-[4- chloro(methyl)anilino]phenol
8) 2-[6-amino-5-(4-morpholinylmethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino]phenol
9) l-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2-pyrrolidinone
10) Methyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinate
11) tørt-butyl (2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methylcarbamate
12) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-iV-(3- furylmethyl)nicotinamide
13) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] acetamide
14) 2-amino-6-{5-[4-chloro(niethyl)anilino]-2-hydroxyphenyl}-iV-[3-(4-methyl-l- piperazinyl)propyl] nicotinamide
15) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-iV-[3-(4- morpholinyl)propyl]nicotinamide 16) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-[3- (dimethylamino)propyl]nicotinamide
17) Ethyl 4-{[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)carbonyl] amino } butanoate
18) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-(4- hydroxybutyl)nicotinamide
19) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
20) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2-hydroxyacetamide
21) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-cyanoacetamide
22) N- [(2-amino-6- { 5 - [4-chloro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl] -3 -methoxypropanamide
23) N-[(2-amino-6-{5-[4-chloro(niethyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]nicotinamide
24) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]tetrahydro-2-furancarboxyamide
25) (2i?)-N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2-hydroxypropanamide
26) iV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-(4-morpholinyl)acetamide
27) 4-{[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)carbonyl] amino } butanoic acid
28) 2-amino-6- { 5- [4-bromo(methyl)anilino] -2-hydroxyphenyl } nicotinic acid
29) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
30) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-[3-(4- morpholinyl)propyl] nicotinamide
31) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-[2- (diethylamino)ethyl]nicotinamide
32) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-(2- furylmethyl)nicotinamide
33) 2-amino-6- { 5-[4-bromo(methyl)anilino] -2-hydroxyphenyl } -N-(3 - furylmethyl)nicotinamide
34) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-iV-(2- pyridinylmethyl)nicotinamide
35) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinonitrile
36) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinamide
37) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinic acid
38) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-jV-[3-(4- morpholiyl)propyl]nicotinamide 39) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-(2- furylmethyl)nicotinamide
40) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-(2- pyridinylmethyl)nicotinamide
41) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinonitrile
42) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -nicotinic acid
43) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxyethyl)nicotinamide
44) Ethyl 4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } carbonyl)amino]butanoate
45) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- furylmethyl)nicotinamide
46) 2-amino-6-[5-(2-fluoro-4-dimethylamlino)-2-hydroxyphenyl]-N-(3- furylmethyl)nicotinamide
47) 2-amino-N-[3-(dimethylamino)propyl]-6-[5-(2-fluoro-4-diniethylanilino)-2- hydroxyphenyl] nicotinamide
48) 2-amino-iV-[2-(diethylamino)ethyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
49) 2-amino-N-[2-(dimethylamino)ethyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
50) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-dimethylanilino]-2- hydroxyphenyl] -N-(3 -hydroxypropyl)nicotinamide
51) 2-amino-N-[(l,5-dimethyl-lH-pyrrole-2-yl)methyl]-6-[5-(2-fluoro-4- dimethylanilino)-2-hydroxyphenyl]nicotinamide
52) 2-amino-6-[5-(2-fluoro-4-dimethylanilmo)-2-hydroxyphenyl]-iV-[3-(4- morpholinyl)propyl] nicotinamide
53) 2-amino-N-[4-(aminosulfonyl)benzyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
54) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-[4- (methylsulfonyl)benzyl]nicotinamide
55) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-jV-(2- pyridinylmethyl)nicotinamide
56) tert-butyl-4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } carbonyl)amino] - 1 -piperidinecarboxylate
57) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-[(5-methyl-2- pyrazinyl)methyl] nicotinamide
58) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-jV-(4- piperidinylmethyl)nicotinamide
59) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(3- piperidinylmethyl)nicotinamide
60) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-[2-hydroxy- l-(hydroxymethyl)ethyl]nicotinamide 61) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- methoxyethyl)-iV-methylnicotinamide
62) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxyethyl)-jV-methylnicotinamide
63) tert-butyl-2-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]- 3-pyridinyl}carbonyl)amino]ethyl(methyl)carbamate
64) 4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } carbonyl)amino]butanoic acid
65) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(4- piperidinyl)nicotinamide
66) 2-amino-N-(l-ethyl-4-piperidinyl)-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]nicotinamide
67) 2-amino-iV-[(l-ethyl-4-piperidinyl)methyl]-6-[5-(2-fluoro-4-dimethylanilino)- 2-hydroxyphenyl]nicotinamide
68) 2-amino-N-[(l-ethyl-3-piperidinyl)methyl]-6-[5-(2-fluoro-4-dimethylanilino)- 2-hydroxyphenyl]nicotinamide
69) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-[2- (methylamino)ethyl] nicotinamide
70) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(2-fluoro-4- dimethylanilino)phenol
71) tert-butyl-4-{[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3 -pyridinyl } methyl)amino] carbonyl } - 1 -piperidincarboxylate
72) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-(2-thienyl)acetamide
73) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(4-morpholinyl)propanamide
74) tert-butyl-4-{2-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] -2-oxoethyl } - 1 - piperidinecarboxylate
75) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)acetamide
76) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)propanamide
77) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
78) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(I -piperidinyl)propanamide
79) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -hydroxypropanamide
80) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-(4-morpholinyl)acetamide
81) Λ/-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 -piperidinyl)acetamide
82) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 -pyrrolidinyl)acetamide
83) N-({2-aniino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclopropanecarboxyamide
84) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclohexanecarboxyamide
85) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxy-2-methylpropanamide
86) (25)-N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
87) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)isonicotinamide
88) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
89) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(3 -pyridinyl)acetamide
90) N-( { 2-amino-6- [5 -(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-( 1 H-imidazole-4-yl)acetamide
91) N-( { 2-amino-6-[5 -(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-(2-pyridinyl)acetamide 92) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
93) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-methoxyacetamide
94) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 H-imidazole-4-carboxyamide
95) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methyl-2-butenamide
96) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(methylsulfonyl)acetamide
97) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-oxo-2-pyrrolidinecarboxyamide
98) 2-(acetylamino)-N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)acetamide
99) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [2-(2-methoxy)ethoxy] acetamide
100) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyanoacetamide
101) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
102) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-piperidinyl)acetamide
103) 2-{6-amino-5-[(propylamino)methyl]-2-pyridinyl}-4-(2-fluoro-4- dimethylanilino)phenol
104) 2-(amino-6-{[(3-hydroxypropyl)amino]methyl}-2-pyridinyl)-4-(2-fluoro-4- dimethylanilino)phenol
105) 2-[amino-5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2-pyridinyl]-4-(2-fluoro-4- dimethylanilino)phenol
106) 2-[6-amino-5-({[3-(4-morpholinyl)propyl]amino}methyl)-2-pyridinyl]-4-(2- fluoro-4-dimethylanilino)phenol
107) Ethyl {2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl} methylcarbamate
108) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)methansulfonamide
109) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)(phenyl)methansufonamide
110) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethansulfonamide
111) Ethyl l-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-aziridincarboxylate
112) Ethyl 3-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-oxo- 1 ,3 -oxazolidine-5 -carboxylate 113) 2-(6-amino-5-{[2-(hydroxymethyl)-l-aziridinyl]methyl}-2-pyridinyl)-4-(2- fluoro-4-dimethylanilino)phenol
114) 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyl } nicotinonitrile
115) 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyl} nicotinic acid
116) 2-amino-6-{5-[l ,3-benzodioxol-5-yl(methyl)amino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
117) 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2-hydroxyphenyl}-N-[2- (dimethylamino)ethyl]nicotinamide
118) 2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl} nicotinonitrile
119) 2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}nicotinic acid
120) 2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-N-[(5-methyl- 2-pyrazinyl)methyl]nicotinamide
121) 2-amino-N-(2-hydroxyethyl)-6-{2-hydroxy-5-[4- methoxy(methyl)anilino]phenyl } nicotinamide
122) 2-amino-6- {2-hydroxy-5 -[4-methoxy(methyl)anilino]phenyl } -N- [3 -( 1 H- imidazole-4-yl)propyl]nicotinamide
123) 2-amino-6-{2-hydroxy-5-[4-hydroxy(methyl)anilino]phenyl}-jV-[(5-methyl-2- pyrizinyl)methyl]nicotinamide
124) 2-[6-amino-5-(ammomethyl)-2-pyridinyl]-4-[4- methoxy(methyl)anilino]phenol
125) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]-2-(4-morpholinyl)acetamide
126) N- [(2-amino-6- { 2-hydroxy-5- [4-methoxy(methyl)anilino]phenyl } -3 - pyridinyl)methyl]tetrahydro-3 -furancarboxyamide
127) (25)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-5-oxo-2-pyrrolidincarboxyamide
128) N-[(2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl} -3- pyridinyl)methyl] ] isonicotinamide
129) N-[(2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl} -3- pyridinyl)methyl]]-2-(2-pyridinyl)acetamide
130) N- [(2-amino-6- { 2-hydroxy-5- [4-methoxy(methyl)anilino]phenyl } -3 - pyridinyl)methyl]]-3-methoxypropanamide
131) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-(l/f-imidazole-4-yl)acetamide
132) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]] -2- [2-(2-methoxyethoxy)ethoxy] acetamide
133) (25)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl] ] -2-hydroxypropanamide
134) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-hydroxyacetamide 135) iV-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-cyanoacetamide
136) (25)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl] ] -2-hydroxypropanamide
137) jV-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl] ] -2-( 1 H-imidazole-4-yl)acetamide
138) 2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2- hydroxyphenyl] nicotinonitrile
139) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(2-fluoro-4- methoxymethylanilino)phenyl
140) iV-({2-aniino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
141) iV-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
142) iV-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyanoacetamide
143) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
144) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahydro-2-furancarboxyamide
145) (2S)-N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)-2-hydroxypropanamide
146) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-morpholinyl)acetamide
147) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinonitrile
148) Ethyl 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinate
149) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]nicotinic acid
150) 2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-N-(2- hydroxyethyl)nicotinamide
151) Ethyl 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3-pyridinyl}carbonyl)amino]butanoate
152) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- furylmethyl)nicotinamide
153) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- piperidinylmethyl)nicotinamide
154) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(5- methyl-2-pyrazinyl)methyl]nicotinamide
155) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[4- (methylsulfonyl)benzyl]nicotinamide 156) 2-amino-N-[4-(aminosulfonyl)benzyl]-6-[5-(4-chloro-2-fluoromethylanilino)- 2-hydroxyphenyl]nicotinamide
157) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2- (dimethylamino)ethyl]nicotinamide
158) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2- (diethylamino)ethyl]nicotinamide
159) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[3-(4- morpholinyl)propyl] nicotinamide
160) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[3-(4- methyl- 1 -piperazinyl)propyl]nicotinamide
161) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[3-(l//- imidazole-4-yl)propyl]nicotinamide
162) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-7V-(4- piperidinyl)nicotinamide
163) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(l -ethyl - 4-piperidinyl)nicotinamide
164) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- (cyclohexylmethyl)nicotinamide
165) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- isobutylnicotinamide
166) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- hydroxypropyl)nicitinamide
167) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxy- 1 -methylethyl)nicotinamide
168) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(li?)-l- (hydroxymethyl)propyl] nicotinamide
169) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(l1S)-l- (hydroxymethyl)propyl]nicotinamide
170) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- methoxybenzyl)nicotinamide
171) 2-amino-N-(4-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
172) 2-amino-N-(4-aminobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]nicotinamide
173) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- methoxyethyl)nicotinamide
174) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- methoxypropyl)nicotinamide
175) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- hydroxy- 1 , 1 -dimethylethyl)nicotinamide
176) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2- hydroxy- 1 -(hydroxymethyl)- 1 -methyl ethyl] nicotinamide 177) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(15)-l- (hydroxymethyl)-3-(methylsulfonyl)propyl]nicotinamide
178) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-jV-[(15)-2- hydroxy- 1 -methylethyl] nicotinamide
179) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(l1S')-2- hydroxy- 1 -( 1 H-imidazole-4-ylmethyl)ethyl]nicotinamide
180) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[3-(2- methyl- 1 -piperidinyl)propyl]nicotinamide
181) 2-aniino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-jV-[2-(l- methyl-2-pyrrolidinyl)ethyl]nicotinamide
182) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- (tetrahydro-2-furanylmethyl)nicotinamide
183) 2-amino-N-benzyl-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
184) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- methoxybenzyl)nicotinamide
185) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(3- methoxybenzyl)nicotinamide
186) 2-amino-iV-(2-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyljnicotinamide
187) 2-amino-N-(3-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
188) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- fluorobenzyl)nicotinamide
189) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxybenzyl)nicotinamide
190) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-7V-(3- hydroxybenzyl)nicotinamide
191) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(2S)-2- hydroxy- 1 -methyl-2-phenylethyl]nicotinamide
192) Methyl (2R)-2-[({2-amino-6-[5-(4-chloro-2-fluoromethylanylino)-2- hydroxyphenyl] -3 -pyridinyl } carbonyl)amino]propanoate
193) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(li?)-2- hydroxy- 1 -methyl ethyl] nicotinamide
194) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- (cyclopropylmethy^nicotinamide
195) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- methyl- 1 ,3-thiazole-2-yl)nicotinamide
196) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- hydroxy-2,2-dimethylpropyl)nicotinamide
197) Ethyl 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } carbonyl)amino] - 1 -piperidinecarboxylate 198) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- isopropylnicotinamide
199) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- cyclopropylnicotinamide
200) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- cyclopentylnicotinamide
201) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-#- cyclohexylnicotinamide
202) 2-amino-6-[5-(4-chloro-2-fluoromethylanilmo)-2-hydroxyphenyl]-N-(3- pyridinylmethyl)nicotinamide
203) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- pyridinylmethyl)nicotinamide
204) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- pyridinyl)nicotinamide
205) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(4- morpholinyl)ethyl] nicotinamide
206) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- hydroxycyclohexyl)nicotinamide
207) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2-(4- pyridinyl)ethyl] nicotinamide
208) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(3- pyridinyl)ethy 1] nicotinamide
209) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2-(2- pyridinyl)ethyl]nicotinamide
210) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-{2-[(5- nitro-2-pyridinyl)amino] ethyl } nicotinamide
211) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[3-(2- oxo- 1 -pyrrolidinyl)propyl]nicotinamide
212) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(l- pyrrolidinyl)ethyl]nicotinamide
213) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2-(l - piperidinyl)ethyl] nicotinamide
214) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2,3- dihydroxypropyl)nicotinamide
215) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[l- (hydroxymethyl)cyclopentyl]nicotinamide
216) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- pyridinylmethyl)nicotinamide
217) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-jV-[(l R)- 1 - (hydroxymethyl)-3-(methylsulfonyl)propyl]nicotinamide
218) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(l- ethyl-2-pyπOlidinyl)methyl]nicotinamide 219) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(l - ethyl-4-piperidinyl)methyl]nicotinamide
220) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- morpholinyl)nicotinamide
221) 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } carbonyl)amino]butanoic acid
222) l-{2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } - 1 -propanone
223) {2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } (4-chlorophenyl)methanone
224) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- hydroxybenzyl)nicotinamide
225) 2-hydroxyethyl 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinate
226) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(4-chloro-2- fluoromethylanilino)phenol
227) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-morpholinyl)acetamide
228) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-(4-methyl-l-piperazinyl)acetamide
229) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-[(2-hydroxyethyl)(methyl)amino]acetamide
230) iV-({2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(diethylamino)acetamide
231) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)benzamide
232) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
233) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
234) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methylbutanamide
235) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-hydroxybutanamide
236) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -hydroxypropanamide
237) Methyl-4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amide] -4-oxobutanoate
238) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-(l-methyl-4-piperidinyl)acetamide
239) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -( 1 -piperidinyl)propanamide 240) N-( { 2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-3 -pyridinyl } methyl)acetamide
241) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)propanamide
242) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(4-morpholinyl)propanamide
243) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(diethylamide)propanamide
244) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclobutanecarboxyamide
245) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahydro-3 -furancarboxyamide
246) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-[4-(dimethylamino)phenyl]acetamide
247) tert-butyl-2-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] -2-oxoethylcarbamate
248) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyclopentene- 1 -carboxyamide
249) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-oxo-l,3-thiazolidine-4-carboxyamide
250) jV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-anilinoacetamide
251) (E)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(3 -pyridinyl)-2-propenamide
252) 7V-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-methylcyclopropanecarboxyamide
253) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-oxohexanamide
254) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-5 -isooxazolecarboxyamide
255) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-pyrazinecarboxyamide
256) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -hydroxy-2,2-dimethylpropanamide
257) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)isonicotinamide
258) (25)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
259) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclopropanecarboxyamide
260) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 //-imidazole-4-yl)acetamide 261) jV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [2-(2-methoxyethoxy)ethoxy] acetamide
262) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
263 ) N-( { 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)- 5 -hydroxypentanamide
264) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-oxo-2-azetidinecarboxyamide
265) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyclopropylacetamide
266) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2,3 -dihydroxypropanamide
267) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [bis(2 -hydroxy ethyl)amino] acetamide
268) 4-amino-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)benzamide
269) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
270) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-cyanoacetamide
271) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(methylsulfonyl)acetamide
272) (25)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-oxo-2-pyrrolidinecarboxyamide
273) iV-({2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(2-pyridinyl)amide
274) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahy dro-2-furancarboxyamide
275) (25)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
276) 7V-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -furamide
277) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-methyl-2-pyrazinecarboxyamide
278) N-({2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-anilinoacetamide
279) tert-butyl-4{[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino]carbonyl } - 1 -piperidinecarboxylate
280) 3-amno-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)benzamide
281) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-hydroxybenzamide 282) tert-butyl-(2S)-2- { [({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino]carbonyl } - 1 - pyrrolidinecarboxylate
283) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethyl -4-piperidinecarboxyamide
284) 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-amino] -4-oxobutanoic acid
285) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)acetamide
286) 2-(6-amino-5-{ [(3-hydroxypropyl)amino]methyl} -2-pyridinyl)-4-(4-chloro-2- fluoromethylanilino)phenol
287) 2-(6-amino-5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-4-(4-chloro-2- fluoromethylailino)phenol
288) 2-[6-amino-5-({[2-(4-morpholinyl)ethyl]amino}methyl)-2-pyridinyl]-4-(4- chloro-2-fluoromethylanilino)phenol
289) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
290) 2-(6-amino-5-{[(2-anilinoethyl)amino]methyl}-2-pyridinyl)-4-(4-chloro-2- fluoromethylanilino)phenol
291) (2i?)-iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } methyl)-2-pyrrolidincarboxyamide 292) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)methansulfonamide
293) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethansulfonamide
294) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-morpholinecarboxyamide
295) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -piperidinecarboxyamide
296) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-methyl- 1 -piperazinecarboxyamide
297) 2-{6-amino-5-[(cyclopentylamino)methyl]-2-pyridinyl}-4-(4-chloro-2- fluoromethylanilino)phenol
298) Ethyl-{2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methylcarbamate
299) Ethyl- 1 - {2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl-2-aziridincarboxylate
300) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}nicotinonitrile
301) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}nicotinic acid
302) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
303) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[(5-methyl- 2-pyrazinyl)methyl]nicotinamide
304) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino] -2-hydroxyρhenyl } -N- [3 -( 1 H- imidazole-4-yl)propyl]nicotinamide
305) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[(li?)-l- (hydroxymethyl)propyl] nicotinamide
306) 2-amino-6- { 5- [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -N- [( 1 R)-2- hydroxy- 1 -methylethyl] nicotinamide
307) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[3-(2- methyl- 1 -piperidinyl)propyl]nicotinamide
308) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[2-(l- methyl-2-pyrrolidinyl)-ethyl]nicotinamide
309) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-(tetrahydro- 2-furanylmethyl)nicotinamide
310) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-(3-hydroxy- 2,2-dimethylpropyl)nicotinamide
311) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(2,3- dihydroxypropyl)nicotinamide
312) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[2-(4- morpholinyl)ethyl]nicotinamide
313) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV- isopropylnicotinamide 314) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[3-(2-oxo- 1 -pyrrolidinyl)propyl] nicotinamide
315) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(2- pyridinylmethyl)nicotinamide
316) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(3- pyridinylmethyl)nicotinamide
317) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(4- pyridinylmethyl)nicotinamide
318) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[2-(2- pyridinyl)ethyl]nicotinamide
319) 2-amino-6-{5-[2,4-difluoro(memyl)anilino]-2-hydroxyphenyl}-ΛL[2-(3- pyridinyl)ethyl]nicotinamide
320) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[2-(4- pyridinyl)ethyl]nicotinamide
321) 2-amino-7V-cyclopropyl-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl } nicotinamide
322) 2-amino-5-(aminomethyl)-2-pyridinyl]-4-[2,4-difluoro(methyl)anilino]phenol
323) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxyacetamide
324) J/V-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] nicotinamide 325) J/V-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-cyanoacetamide
326) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -3 -methoxypropanamide
327) N- [(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]tetrahydro-2-furancarboxyamide
328) (2i?)-N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxypropanamide
329) N- [(2-amino-6- { 5- [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl] -2-(4-morpholinyl)acetamide
330) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-isonicotinamide
331) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-pyrazinecarboxyamide
332) N- [(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]-5-methyl-2-pyrazinecarboxylamide
333) jV-[(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl] -3 -furamide
334) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -tetrahydro-3 -furancarboxyamide
335) iV-[(2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl} -3 - pyridinyl)methyl] acetamide
336) (25)-iV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxypropanamide
337) (4S)-N-[(2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl} -3 - pyridinyl)methyl]-2,2-dimethyl-l ,3-dioxolane-4-carboxyamide
338) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2,3-dihydroxypropanamide
339) (25)-J/V-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2,3-dihydroxypropanamide
340) N- [(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]-4-morpholinecarboxyamide
341) iV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-4-methyl- 1 -piperazinecarboxyamide
342) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-[2-(lH- imidazole-4-yl)ethyl]nicotinamide
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 NRjR2 as defined in Formula 1 into 5- bromo-2-hydroxyacetophenone of Formula 2 below as a starting material, (ii) a step of introducing a pyrimidine substituent thereto, and (iii) a step of introducing R3 by the conversion of nitrile group.
Figure imgf000046_0001
In an embodiment, the step of performing the conversion of the carboxyl group after the introduction of the pyrimidine substituent comprises,
(a) a step of conducting the formation of two protecting groups to the compound of Formula 2 sequently to produce the compound of Formula 3 below;
Figure imgf000046_0002
where PG means a protecting group and includes, for example, but is not limited to t-butyl, alkyl ether, substituted or unsubstituted benzyl group, and the like,
(b) a step of reacting the compound of Formula 3 with aryl amine by catalyst reaction of palladium and sequently with alkylhalide to produce the compound of Formula 4 below;
Figure imgf000047_0001
where R1 and R2 are the same as in Formula 1,
(c) a step of hydrolyzing the compound of Formula 4 by acid catalyst to produce the compound of Formula 5 below;
Figure imgf000047_0002
(d) a step of reacting the compound of Formula 5 with N,N-dimethylformamide diethyl acetal to produce the compound of Formula 6 below;
Figure imgf000047_0003
(e) a step of reacting the compound of Formula 6 with 3,3-diaminacrylonitrile to produce the compound of Formula 7; and
Figure imgf000047_0004
(f) a step of removing the protecting group ('PG') from the compound of Formula 7 to produce the compound of Formula 8.
Figure imgf000048_0001
In an embodiment, the process for introducing various substituents by the conversion of the cyano group as defined in Formula 8 comprises,
(al) a step of reducing the cyano group in the compound of Formula 8 to produce the compound of Formula 9 below; and
Figure imgf000048_0002
(b 1 ) a step of introducing a substituent to the compound of Formula 9.
In another embodiment, the process also comprise,
(a2) a step of reacting the cyano group in the compound of Formula 8 with sulfuric acid to produce the compound of Formula 10 below; and
Figure imgf000048_0003
(b2) a step of introducing a substituent to the compound of Formula 10.
The compound of Formula 4 may be prepared from p-anisidine as defined in the compound of Formula 11 below as a starting material, as shown in Reaction Scheme 1.
Figure imgf000049_0001
Reaction Scheme 1
Figure imgf000049_0002
where Bn means a benzyl group as a protecting group.
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.
Reaction Scheme 2 below illustrates the preparation of a compound in which R1 is 4-chloro-2-fluorobenzene, R2 is methyl, R3 is cyano and R4 is hydrogen in Formula 1.
Reaction Scheme 2
Figure imgf000050_0001
Figure imgf000050_0002
where Bn means a benzyl group as a protecting group.
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 as defined in claim 1 for manufacture of a medicament for the treatment or prevention of these diseases. 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, ethanesulfonic 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) Compo sition/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, 8% 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 IC50 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 ED50. 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 ED50 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 judgment 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.
Most of compounds in the present disclosure are synthesized by PROCESS A and B below. PRCESS A
Figure imgf000061_0001
PRCESS B
R
Figure imgf000061_0002
PREPARATION 1: 2-[2-(benzyloxy)-5-bromophenyl]-2-methyl-l,3-dioxolane
350 g (1.63 mmol) of 5-bromo-2-hydroxyacetophenone was dissolved in 800 ml of N,N-dimetylformamide, and 320 g (2.44 mol) of potassium carbonate was added, then 234 ml (1.96 mol) of benzyl bromide was added thereto, followed by stirring at room temperature for 20 hours. After completion of the reaction, the reaction mixture was concentrated, and 800 ml of water was added thereto, then the precipitated solids were filtered and dried. The solid compound was dissolved in 1500 ml of toluene, then 200 ml of ethylene glycol and catalytic amount (3 g) of p-toluenesulfonic acid were added thereto, followed by stirring under Dean-Stark reflux for 48 hours. After completion of the reaction, 300 ml of ethyl acetate was added thereto, and the reaction mixture was washed 3 times with water, then the residue was concentrated to obtain 533 g (0.999 mol) of the title compound in a yield of 94%.
1H NMR (CDCl3, ppm); δ 7.64(1H, s), 7.37~7.25(5H, m), 6.89(1H, d), 6.79(1H, d), 5.15(2H, s), 4.06(2H, t), 3.85(2H, t), 1.78(3H, s)
FAB MS(m/e) = 349 [M+l]
PREPARATION 2: 4-(benzyloxy)-N-(4-chlorophenyl)-N-methyl-3-(2-methyl-l,3- dioxolane-2-yl)aniline
10.3 g (29.6 mmol) of the compound obtained in PREPARATION 1, 3.22 g (22.7 mmol) of N-methyl-4-chloroaniline, 207 mg (0.226 mmol) of bis(dibenzylidene acetone)dipalladium, 102 mg (0.341 mmol) of 2-(di-t-butylphosphino)biphenyl and 3.28 g (34.1 mmol) of sodium t-butoxide were dissolved in 150 ml of toluene, followed by heating to 800C with stirring. After completion of the reaction, 100 ml of ethyl acetate was added thereto, and the reaction mixture was washed twice with 100 ml of water and then subjected to concentration. The crude compound thus obtained was purified by column chromatography to give 6.60 g (16.1 mmol) of the title compound at 71% yield.
1H NMR (CDCl3, ppm); δ 7.6O(1H, s), 7.27~7.15(5H, m), 7.10(2H, d), 6.89(1H, d), 6.79(1H, d), 6.65(2H, d), 5.14(2H, s), 4.05(2H, t), 3.83(2H, t), 1.79(3H, s)
FAB MS(m/e) = 410 [M+l]
PREPARATION 3: l-{2-(benzyloxy)-5-[4-chloro(methyl)anilino]phenyl}-l- ethanone 6.59 g (16.1 mmol) of the compound obtained in PREPARATION 2 was dissolved in 100 ml of methanol, and 20 ml of aqueous 6 N hydrochloride was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was cooled and neutralized with aqueous 6 N sodium hydroxide. The methanol was removed by evaporation in vacuo, and 100 ml of water was added thereto. The precipitated solids were filtered and dried to obtain 5.78 g (15.6 mmol) of the title compound in a yield of 97%.
1H NMR (CDCl3, ppm); δ 7.62(1H, s), 7.27~7.15(5H, m), 7.11(2H, d), 6.89(1H, d), 6.79(1H, d), 6.64(2H, d), 5.15(2H, s), 2.61(3H, s)
FAB MS(m/e) = 366[M+1]
PREPARATION 4: (E)-l-{2-(benzyloxy)-5-[4-chloro(methyl)anilino]phenyl}-3- (dimethylamino)-2-propene-l-one
50 g of N,N-dimethylformamidediethyl acetal was added to 5.70 g (15.6 mmol) of the compound obtained in PREPARATION 3, followed stirring under reflux for 24 hours. After completion of the reaction, the reaction mixture was concentrated, and after addition of 150 ml of water, extracted two times with 100 ml of ethyl acetate, then again concentrated to give 5.80 g (13.8 mmol) of the title compound at 89% yield.
1H NMR (CDCl3, ppm); δ 7.62(1H, s), 7.27~7.15(5H, m), 7.11(2H, d), 6.89(1H, d), 6.79(1H, d), 6.64(2H, d), 5.15(2H, s), 3.19(1H, d), 2.62(1H, d), 2.48(3H, s), 2.43(3H, s)
FAB MS(m/e) = 421[M+1] PREPARATION S: 2-amino-6-{2-(benzyloxy)-5-[4-chloro(methyl)anilino]phenyI} -nicotinonitrile
5.75 g (13.7 mmol) of the compound obtained in PREPARATION 4 and 1.71 g (20.5 mmol) of 3,3-diamineacrylonitrile were dissolved in 80 ml of glacial acetic acid, followed stirring twice under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and after addition of 200 ml of water, extracted twice with 100 ml of ethyl acetate. An organic layer was washed twice with 50 ml of water and concentrated. The crude compound thus obtained was purified by column chromatography to give 3.31 g (7.52 mmol) of the title compound at 55% yield.
1H NMR (CDCl3, ppm); δ 8.1O(1H, d), 7.8O(1H, s), 7.34(1H, d), 7.30-7.19(5H, m), 7.15(2H, d), 7.11(1H, d), 6.91(1H, d), 6.67(2H, d), 6.51(2H, s), 5.15(2H, s), 3.22(3H,
s)
FAB MS(m/e) = 441 [M+ 1]
EXAMPLE 1 : 2-amino-6- {5- [4-chIoro(methy l)anilino] -2-hydroxy phenyl}- nicotinonitrile
3.20 g (7.27 mmol) of the compound obtained in PREPARATION 5 was dissolved in 100 ml of dichloromethane, and 15 ml of born tribromide (1 M dichloromethane solution) was added thereto, followed by stirring at room temperature. After completion of the reaction, the reaction solution was neutralized with aqueous 1 N sodium hydroxide, then concentrated in vacuo. The residue was partitioned between 100 ml of water and 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was triturated with 30 ml of diethylether by stirring for 10 minutes. The resulting solid was filtered and dried to obtain 2.40 g (6.86 mmol) of the title compound in a yield of 94%.
1U NMR (CDCl3, ppm); δ 8.11(1H, d), 7.81(1H, s), 7.33(1H, d), 7.13(2H, d), 7.1O(1H, d), 6.91(1H, d), 6.67(2H, d), 6.50(2H, s), 3.21(3H, s)
FAB MS(m/e) = 351[M+l]
EXAMPLE 2: 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino] phenol
1.0 g (2.86 mmol) of the compound obtained in EXAMPLE 1 was dissolved in 30 ml of tetrahydrofuran, and 0.434 g (11.4 mmol) of lithiumaluminiumhydride was added thereto, followed by stirring at room temperature for 15 hours. After completion of the reaction, the reaction mixture was cooled to 0°C, and 0.43 ml of water was slowly added thereto, then 0.43 ml of aqueous 15% sodium hydroxide, 1.3 ml of water were added in sequence thereto, followed by stirring for 10 minutes. The mixture was filtered through Celite, and the filtrate concentrated in vacuo. The residue was triturated with 20 ml of diethylether by stirring for 5 minutes. The resulting solid was filtered and dried to obtain 0.76 g (2.14 mmol) of the title compound in a yield of 75%.
1H NMR (DMSO-d6, ppm); δ 13.62(1H, s), 8.31(2H, t), 8.11(1H, d), 7.81(1H, s), 7.33(1H, d), 7.13(2H, d), 7.1O(1H, d), 6.91(1H, d), 6.67(2H, d), 6.50(2H, s), 4.08(2H, t), 3.21(3H, s) FAB MS(m/e) = 355 [M+ 1]
EXAMPLE 3: Ethyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2- hydroxyphenyljnicotinate
1.35 g (3.86 mmol) of the compound obtained in EXAMPLE 1 was dissolved in 20 ml of ethanol, and 8 ml of sulfuric acid was added thereto, followed by stirring under reflux for one hour and thirty minutes. After completion of the reaction, methanol was removed by evaporation in vacuo, 50 ml of ethyl acetate was added thereto, followed by cooling to 0°C. When the reaction solution was neutralized to pH 4-5 with aqueous 2 N sodium hydroxide, the reaction solution was separated to two layers. The resulting solution was moved to a separatory funnel, and a water layer was removed, then an organic layer was washed 3 times with 50 ml of water. The residue was concentrated and purified by column chromatography to give 1.33 g (3.35 mmol) of the title compound at 87% yield.
1H NMR (CDCl3, ppm); δ 13.55(1H, s), 8.11(1H, d), 7.81(1H, s), 7.33(1H, d), 7.13(2H, d), 7.1O(1H, d), 6.91(1H, d), 6.67(2H, d), 6.50(2H, s), 3.78(2H, q), 3.21(3H, s), 1.34(3H, t)
FAB MS(m/e) = 398[M+1]
EXAMPLE 4: 2-amino-6-{5-[4-chloro(methyI)anilino]-2-hydroxyphenyl}nicotinic acid
0.50 g (1.26 mmol) of the compound obtained in EXAMPLE 3 was dissolved in 90 ml of tetrahydrofuran and 30 ml of methanol, 0.21 g (5.03 mmol) of lithium hydroxide (1 hydrate) which was dissolved in 30 ml of water was added thereto. After stirring at room temperature for 3 hours, the reaction was completed. And tetrahydrofuran and methanol were removed by evaporation in vacuo, then 50 ml of water was added thereto. When the reaction solution was neutralized to pH 5-6 with aqueous 1 N hydrochloric acid, a solid compound were obtained. The solid compound was filtered and dried to provide 0.44 g of the title compound (1.20 mmol, 95% yield).
1R NMR (DMSO-d6, ppm); δ 13.71(1H, s), 8.09(1H, d), 7.78(1H, s), 7.32(1H, d), 7.11(2H, d), 7.07(1H, d), 6.9O(1H, d), 6.65(2H, d), 6.50(2H, s), 3.22(3H, s)
FAB MS(m/e) = 370 [M+ 1 ]
EXAMPLE 5: 2-[6-amino-5-(hydroxymethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino] phenol
0.64 g (1.80 mmol, yield: 89%) of the title compound was obtained from 0.80 g (2.02 mmol) of the compound obtained in EXAMPLE 3 in the same manner as in EXAMPLE 2.
1H NMR (DMSOd6, ppm); δ 13.52(1H, s), 8.09(1H, d), 7.78(1H, s), 7.32(1H, d), 7.11(2H, d), 7.07(1H, d), 6.9O(1H, d), 6.65(2H, d), 6.37(2H, s), 5.22(1H, t), 4.36(2H, d), 3.22(3H, s)
FAB MS(m/e) = 356 [M+l]
EXAMPLE 6 : 2- {6-amino-5- [(dimethy lamino )methy I ] -2-py ridinyl}-4- [4- chloro(methyl)anilino] phenol
50 mg (0.14 mmol) of the compound obtained in EXAMPLE 5 was dissolved in 10 ml of dichloromethane, 0.1 ml (1.37 mmol) of thionylchloride was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated, and 10 ml of tetrahydrofuran was added again, then 1.0 ml of dimethylamine (1 M tetrahydrofuran solution), followed by stirring at room temperature for 2 hours. After completion of the reaction, the residue was concentrated and purified by the column chromatography to obtain 23 mg (0.060 mmol) of the title compound in a yield of 43%.
1H NMR (CDCl3, ppm); δ 13.53(1H, s), 8.12(1H, d), 7.76(1H, s), 7.3O(1H, d), 7.10(2H, d), 7.05(1H, d), 6.92(1H, d), 6.63(2H, d), 6.31(2H, s), 3.60(2H, s), 3.22(3H, s), 2.43(6H, s)
FAB MS(m/e) - 383 [M+ 1]
EXAMPLE 7: 2-{6-amino-5-[(diethylamino)methyl]-2-pyridinyl}-4-[4- chloro(methyl)anilino] phenol
Diethylamine instead of dimethylamine was used in EXAMPLE 6 to produce the title compound.
1H NMR (CDCl3, ppm); δ 13.51(1H, s), 8.12(1H, d), 7.76(1H, s), 7.3O(1H, d), 7.10(2H, d), 7.05(1H, d), 6.92(1H, d), 6.63(2H, d), 6.31(2H, s), 3.58(2H, s), 3.21(3H, s), 2.88(4H, q), 1.69(6H, t)
FAB MS(m/e) = 411 [M+ 1] EXAMPLE 8: 2-[6-amino-5-(4-morpholinylmethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino] phenol
Morpholine instead of dimethylamine was used in EXAMPLE 6 to produce the title compound.
1R NMR (CDCl3, ppm); δ 13.41(1H, s), 8.11(1H, d), 7.75(1H, s), 7.31(1H, d), 7.11(2H, d), 7.03(1H, d), 6.91(1H, d), 6.63(2H, d), 6.35(2H, s), 3.55(4H, s, broad), 3.48(2H, s), 3.21(3H, s), 2.32(4H, s, broad)
FAB MS(m/e) = 425 [M+ 1]
EXAMPLE 9: 2-[6-amino-5-(4-morpholinylmethyI)-2-pyridinyl]-4-[4- chloro(methy l)anilino] phenol
58 mg (0.68 mmol) of pyrrolidinone was dissolved in 10 ml of tetrahydrofuran, and 27 mg (0.68 mmol) of sodium hydride (60%) was added thereto, followed by stirring at room temperature for 30 minutes. In the other reaction flask, 60 mg (0.17 mmol) of the compound obtained in EXAMPLE 5 was dissolved in 10 ml of dichloromethane, 0.1 ml (1.37 mmol) of thionylchloride was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with 10 ml of tetrahydrofuran. The resulting solution was added to the reaction mixture that was prepared above. The reaction mixture was allowed to stir at room temperature for 1 hour. After completion of the reaction, 20 ml of water added thereto, the reaction solution was extracted twice with 20 ml of ethyl acetate. The residue was concentrated and purified by the column chromatography to obtain 17 mg (0.040 mmol) of the title compound in a yield of 24%.
1H NMR (CD3OD, ppm); δ 7.6O(1H, s), 7.47(1H, d), 7.12(1H, d), 7.08(2H, d), 7.01(1H, d), 6.88(1H, d), 6.65(2H, d), 4.34(2H, s), 3.37(2H, t), 3.22(3H, s), 2.43(2H, t), 2.02(2H, quin)
FAB MS(m/e) = 423 [M+ 1]
EXAMPLE 10: Methyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2- hydroxyphenyljnicotinate
45 mg (0.12 mmol) of the compound obtained in EXAMPLE 4 was dissolved in 10 ml of methanol, and 0.05 ml (0.685 mmol) of thionyl chloride was added thereto, followed by stirring under reflux for 2 hours. After completion of the reaction, the residue was purified by the column chromatograpy to obtain 39 mg (0.10 mmol) of the title compound in a yield of 85%.
1H NMR (CDCl3, ppm); δ 13.52(1H, s), 8.10(1H, d), 7.82(1H, s), 7.31(1H, d), 7.12(2H, d), 7.11(1H, d), 6.93(1H, d), 6.62(2H, d), 6.41(2H, s), 3.21(3H, s), 3.11(3H,
s)
FAB MS(m/e) = 384 [M+ 1]
EXAMPLE 11: tert-butyl (2-amino-6-{5-[4-chloro(methyl)anilino]-2- hydroxyphenyl}-3-pyridinyl)methyl carbamate 34 mg (0.096 mmol) of the compound obtained in EXAMPLE 2 was dissolved in 10 ml of dichloromethane, and 23 mg of di-t-butyl dicarbonate was added thereto, followed by stirring at room temperature for 1 hour. After completion of the reaction, the residue was purified by the column chromatography to obtain 41 mg (0.091 mmol) of the title compound in a yield 95%.
1H NMR (DMSOd6, ppm); δ 13.61(1H, s), 8.21(1H, t), 8.11(1H, d), 7.81(1H, s), 7.33(1H, d), 7.13(2H, d), 7.1O(1H, d), 6.91(1H, d), 6.67(2H, d), 6.50(2H, s), 4.08(2H, d), 3.21(3H, s), 1.47(9H, s)
FAB MS(m/e) = 455 [M+l]
EXAMPLE 12: 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-iV-(3- furylmethyl)nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 4 in the same manner as Process A.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 8.89(1H, t), 8.07(1H, d), 7.79(1H, s), 7.74(2H, s), 7.59-7.57(2H, m), 7.31(1H, d), 7.16(2H, d), 7.12(1H, d), 6.91(1H, d), 6.65(2H, d), 6.46(1H, s), 4.26(2H, d), 3.22(3H, s)
FAB MS(m/e) = 449 [M+l]
EXAMPLE 13: iV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyI}-3- py ridinyl)methyl] acetamide The title compound was obtained from the compound obtained in EXAMPLE 2 in the same manner as Process B.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 8.82(1H, t), 8.01(1H, d), 7.74(1H, s), 7.70(2H, s), 7.31(1 H, d), 7.12(2H, d), 7.05(1H, d), 6.91(1 H, d), 6.62(2H, d), 4.24(2H, d), 3.22(3H, s), 1.89(3H, s)
FAB MS(m/e) = 397 [M+l]
The title compounds in EXAMPLES 14 to 26 of TABLE 1 below were obtained using the compound obtained in EXAMPLE 4 in the same manner as PROCESS A or using the compound obtained in EXAMPLE 2 in the same manner as PROCESS B.
[TABLE 1]
Figure imgf000072_0001
Figure imgf000073_0001
EXAMPLE 27: 4-{[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyI}-3- pyridinyl)carbonyl]amino}butanoic acid
The title compound was obtained from hydrolysis for the compound obtained in EXAMPLE 17 in the same manner as EXAMPLE 4.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 13.21(1H, s), 8.82(1H, t), 8.01(1H, d), 7.74(1H, s), 7.70(2H, s), 7.31(1H, d), 7.12(2H, d), 7.05(1H, d), 6.91(1H, d), 6.62(2H, d), 3.24(2H, t), 3.21(3H, s), 2.33(2H, t), 1.75(2H, quin)
FAB MS(m/e) = 455 [M+l] PREPARATION 6: iV-[4-(benzyloxy)-3-(2-methyl-l,3-dioxolane-2-yl)phenyl]-N- methylamine
209 g (1.70 mol) of p-anisidine was dissolved in 1 / of dichloromethane, and 355 ml (2.55 mol) of triethylamine was added thereto, followed by cooling to 0°C. 127 ml (1.78 mol) of acetyl chloride was added dropwise over 1 hour thereto, and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated, and 1 / of water added thereto, then a solid compound thus obtained was filtered and dried to obtain 167 g (1.01 mol) of a compound. 500 g (3.75 mol) of aluminium chloride was added to this compound, and 1.5 / of carbon disulfate was added dropwise thereto over 30 minutes. After stirring under reflux for 3 hours, the reaction was cooled to room temperature. The solvent, carbon disulfate was removed by decantation, and the residue was cooled to 0°C. To the residue was slowly added 700 ml of water over 40 minutes, and the resulting solid was filtered, dried to give 118.3 g (0.61 mol) of a compound. This compound was dissolved in 700 ml of N,N-dimethylformamide, then 144 g (1.04 mol) of potassium carbonate and 106 ml (0.92 mol) of benzyl bromide were added thereto in sequence, followed by stirring at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated, and 800 ml of water added thereto, then a solid compound thus obtained were filtered and dried to obtain 17O g (0.60 mol) of a compound. This compound was dissolved in 700 ml of dichloromethane, and 170 g (0.78 mol) of di-t- butyl dicarbonate was added thereto, followed by stirring at room temperature for 4 hours. After completion of the reaction, the reaction solution was concentrated, and 500 ml of methanol was added and dissolved thereto. 500 ml of aqueous 2 N sodium chloride was added thereto followed by stirring at room temperature for 30 minutes. After completion of the reaction, solvent was removed by evaporation in vacuo, 700 ml of water was added thereto, then a solid compound thus obtained was filtered and dried to obtain 199 g (0.58 mol) of a compound. This compound was dissolved in 1 / of N,N-dimethylformamide, and the solution was allowed to cool to 0°C. 26.8 g (0.70 mol) of sodium hydride was added dropwise thereto, and stirred for 5 minutes, then 38 ml (0.61 ml) of iodomethane was added dropwise thereto over 30 minutes, followed by stirring for 1 hour. After completion of the reaction, 30 ml of water was added thereto and the reaction solution was concentrated. The residue was partitioned between 600 ml of water and 700 ml of ethyl acetate, then the organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to obtain 219 g (0.58) of a compound. This compound was dissolved in 700 ml of methanol, and 400 ml of 6 N hydrochloric acid-methanol solution was added thereto, then stirred for 1 hour. After completion of the reaction, the reaction solution was cooled to 0°C, neutralized with aqueous 6 N sodium hydroxide. Methanol was removed by evaporation in vacuo, 800 ml of water was added thereto, a solid compound thus obtained was filtered and dried to give 167 g (0.56 mol) of the title compound.
1H NMR (CDCl3, ppm); δ 7.45-7.21(5H, m), 6.86(1H, d), 6.61(1H, s), 6.38(1H, d), 5.25(1H, q), 4.92(2H, s), 3.91(2H, t), 3.70(2H, t), 2.60(3H, d), 1.62(3H, s)
FAB MS(m/e) = 300 [M+l]
PREPARATION 7: 4-(benzyloxy)-iV-(4-bromophenyl)-iV-methyI-3-(2-methyl-l,3- dioxolane-2-yl)aniline The title compound was obtained from the compound obtained in PERPARATION 6 and 4-iodinebromobenzene in the same manner as in PREPARATION 2.
1H NMR (CDCl3, ppm); δ 7.82(1H, s), 7.34(2H, d), 7.27~7.15(5H, m), 7.12(1H, d), 6.92(1H, d), 6.61(2H, d), 5.25(2H, s), 4.01(2H, t), 3.82(2H, t), 3.21(3H, s), 1.79(3H, s)
FAB MS(m/e) = 454 [M+l]
EXAMPLE 28: 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}- nicotinic acid
The title compound was obtained from the compound obtained in
PERPARATION 7 in the same manner as in PREPARATION 3, 4, 5, EXAMPLE 1, 3, and 4 in sequence.
1H NMR (CDCl3, ppm); δ 13.52(1H, s), 13.41(1H, s), 8.11(1H, d), 7.82(1H, s), 7.74(2H, s), 7.35(1H, d), 7.29(2H, d), 7.12(1H, d), 6.92(1H, d), 6.61(2H, d)
FAB MS(m/e) = 414 [M+l]
The title compounds in EXAMPLES 29 to 34 of TABLE 2 below were obtained using the compound obtained in EXAMPLE 28 in the same manner as PROCESS A.
[TABLE 2]
Figure imgf000077_0001
EXAMPLE 35 : 2-amino-6- [5-(2-fluoro-4-methylanilino)-2-hy droxyphenyl] - nicotinic acid
2-fluoro-4-methylaniline was used instead of N-methyl-4-chloroaniline in PREPARATION 2, and the title compound was obtained in the same manner as in PREPARATIONS 2, 3, 4 and 5 in sequence.
1H NMR (CDCl3, ppm); δ 13.53(1H, s), 8.05(1H, s), 7.65(2H, s), 7.32(H, s), 7.17(1H, d), 7.11(1H, t), 7.05(1H, d), 7.00(1H, d), 6.72(1H, d), 6.68(1H, d), 6.62(1H, s), 2.29(3H, s)
FAB MS(m/e) = 335[M+1]
EXAMPLE 36: 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]- nicotinamide 47 mg (0.14 mmol) of the compound obtained in EXAMPLE 35 was dissolved in 3 ml of 6 N potassium hydroxide and 2 ml of ethanol, followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was concentrated and neutralized with aqueous 2 N hydrochloric acid then exatrcted twice by 10 ml of ethyl acetate. The product was concentrated and purified by the column chromatography to obtain 23 mg (0.066 mmol) of the title compound in a yield of 47%.
1H NMR (DMSOd6, ppm); δ 13.51(1H, s), 8.32(2H, s), 8.02(1H, s), 7.64(2H, s), 7.30(H, s), 7.15(1H, d), 7.11(1H, t), 7.02(1H, d), 7.00(1H, d), 6.72(1H, d), 6.68(1H, d), 6.62(1H, s), 2.30(3H, s)
FAB MS(m/e) = 352[M+1]
EXAMPLE 37: 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxy phenyl] - nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE
35 in the same manner as in EXAMPLE 3 and 4 in sequence.
1H NMR (DMSOd6, ppm); δ 13.5O(1H, s), 13.12(1H, s), 8.03(1H, s), 7.67(2H, s), 7.32(H, s), 7.17(1H, d), 7.11(1H, t), 7.06(1H, d), 7.00(1H, d), 6.71(1H, d), 6.65(1H, d), 6.6O(1H, s), 2.30(3H, s)
FAB MS(m/e) = 354 [M+l]
The title compounds in EXAMPLES 38 to 40 of TABLE 3 below were obtained using the compound obtained in EXAMPLE 37 in the same manner as PROCESS A.
[TABLE 3]
Figure imgf000079_0001
EXAMPLE 41: 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxy phenyl] - nicotinonitrile
iV-methyl-2-fluoro-4-methylaniline instead of 2-fluoro-4-methylaniline was used in EXAMPLE 35 to produce the title compound.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 8.05(1H, s), 7.65(2H, s), 7.32(H, s), 7.17(1H, d), 7.11(1H, t), 7.05(1H, d), 7.00(1H, d), 6.72(1H, d), 6.68(1H, d), 6.62(1H, s), 3.21(3H, s), 2.28(3H, s)
FAB MS(m/e) = 349 [M+ 1]
EXAMPLE 42: 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]- nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE 41 in the same manner as in EXAMPLE 3 and 4 in sequence.
1H NMR (DMSO-(I6, ppm); δ 13.63(1H, s), 13.12(1H, s), 8.05(1H, s), 7.65(2H, s), 7.32(H, s), 7.17(1H, d), 7.11(1H, t), 7.05(1H, d), 7.00(1H, d), 6.72(1H, d), 6.68(1H, d), 6.62(1H, s), 3.21(3H, s), 2.28(3H, s)
FAB MS(m/e) = 368 [M+ 1]
The title compounds in EXAMPLES 43 to 63 of TABLE 4 below were obtained using the compound obtained in EXAMPLE 42 in the same manner as PROCESS A.
[TABLE 4]
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
EXAMPLE 64: 4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -3-pyridinyl}carbonyl)amino] butanoic acid
The title compound was obtained from hydrolysis for the compound obtained in EXAMPLE 44 in the same manner as EXAMPLE 4.
1H NMR (DMSO-d6, ppm); δ 13.52(1H, s), 13.21(1H, s), 8.49(1H, t), 8.05(1H, d), 7.65(2H, s), 7.32(1H, s), 7.18(1H, d), 7.11(1H, t), 7.05(1H, d), 7.00(1H, d), 6.72(1H, d), 6.68(1H, d), 3.27(2H, t), 3.21(3H, s), 3.32(2H, t), 2.29(3H, s), 1.76(2H, quin)
FAB MS(m/e) = 453 [M+l]
EXAMPLE 65: 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxy phenyl] -N- (4-piperidinyl)nicotinamide
100 mg (0.182 mmol) of the compound obtained in EXAMPLE 56 was dissolved in 10 ml of dichloromethane, and 5 ml of trifluoroacetic acid was added thereto, followed by stirring for 30 minutes. After completion of the reaction, the reaction solution was neutralized with saturated sodium hydrogen carbonate solution, and dichloromethane was removed by evaporation in vacuo. The residue was extracted twice with 20 ml of ethyl acetate and concentrated to obtain 74 mg (0.165 mmol) of the title compound in a yield of 91%.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 7.71(1H, d), 7.18(1H, s), 7.06-6.99(2H, m), 6.93-6.83(4H, m), 6.53(2H, s), 6.24(1H, t), 3.78-3.74(1H, m), 3.26(3H, s), 3.05- 3.00(2H, m), 2.34(3H, s), 2.02-1.97(2H, m), 1.79-1.75(2H, m), 1.50-1.46(2H, m)
FAB MS(m/e) = 450 [M+l]
EXAMPLE 66: 2-amino-N-(l-ethyl-4-piperidinyl)-6-[5-(2-fluoro-4-dimethyl- anilino)-2-hydroxyphenyl]nicotinamide
26 mg (0.058 mmol) of the compound obtained in EXAMPLE 65 was dissolved in 10 ml of 1 ,2-dichloromethane, and 8.1 ul (0.144 mmol) of acetaldehyde was added thereto, followed by stirring for 10 minutes. And 25 mg (0.116 mmol) of sodium triacetoxyborohydride was added thereto, then stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and 20 ml of water added, then extraction was performed twice with 20 ml of ethyl acetate. The residue was purified by the column chromatography to obtain 18 mg (0.038 mmol) of the title compound in a yield of 65%.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 7.75(1H, d), 7.26(1H, s), 7.17(1H, s), 7.11- 6.93(5H, m), 6.40(2H, s), 6.38(1H, t), 4.02-3.99 (IH, m), 3.26(3H, s), 3.16(2H, q), 2.62(2H, t), 2.33-2.30(5H, m), 2.20-2.17(2H, m), 1.85-1.82(2H, m), 1.17(3H, t)
FAB MS(m/e) = 478 [M+l]
EXAMPLE 67: 2-amino-iV-[(l-ethyl-4-piperidinyl)methyl]-6-[5-(2-fluoro-4- dimethylanilino)-2-hydroxyphenyl]nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 58 in the same manner as in EXAMPLE 66.
1FI NMR (CDCl3, ppm); δ 13.73(1H, s), 7.7O(1H, d), 7.18(1H, s), 7.06-6.99(2H, m), 6.94-6.83(4H, m), 6.53(2H, s), 6.24(1H, t), 3.34(2H, t), 3.26(3H, s), 3.05-3.02(2H, m), 2.48(2H, q), 2.34(3H, s), 2.02-1.97(2H, m), 1.79-1.76(2H, m), 1.72-1.65(1H, m), 1.50- 1.41(2H, m), l,12(3H, t)
FAB MS(m/e) - 492 [M+l]
EXAMPLE 68 : 2-amino-JV- [(I -ethyl-3-piperidiny l)methy I] -6- [5-(2-fluoro-4- dimethylanilino)-2-hydroxyphenyl]nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE
59 in the same manner as in EXAMPLE 66.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 7.67(1H, d), 7.18(1H, s), 7.06-6.99(2H, m), 6.93-6.89(2H, m), 6.83-6.81(2H, m), 6.58(2H, s), 3.48-3.33(2H, m), 3.25(3H, s), 2.80- 2.78(1H, m), 2.67-2.65(1H, m), 2.44(2H, q), 2,33(3H, s), 2.28-1.96(3H, m), 1.77- 1.57(3H, m), 1.25-1.2O(1H, m), 1.10(3H, t)
FAB MS(m/e) = 492[M+1]
EXAMPLE 69: 2-amino-6[5-(2-fluoro-4-dimethyIanilino)-2-hydroxyphenyl]-iV- [2-(methyIamino)ethyl]nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE
63 in the same manner as in EXAMPLE 65. 1H NMR (CDCl3, ppm); δ 13.72(1H, s), 8.07(1H, d), 7.63(1H, s), 7.36(1H, s), 7.2O(1H, d), 7.14-6.99(3H, m), 6.76(1H, d), 6.68(1H, d), 3.39(2H, t), 3.22(3H, s), 2.75(2H, t), 2.37(3H, s), 2.30(3H, s)
FAB MS(m/e) = 424[M+1]
EXAMPLE 70 : 2- [6-amino-5-(aminomethy l)-2-py ridiny I] -4-(2-fluoro-4-dimethyl- anilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 41 in the same manner as in EXAMPLE 2.
1H NMR (DMSO-d6, ppm); δ 13.52(1H, s), 8.59(2H, s), 8.08(1H, d), 7.20-7.15(2H, m), 7.05(1H, d), 7.03-6.99(3H, m), 6.92(1H, d), 6.67(1H, d), 4.07(2H, t), 3.22(3H, s), 2.23(3H, s)
FAB MS(m/e) = 353[M+l]
The title compounds in EXAMPLES 71 to 100 of TABLE 5 below were obtained from the compound obtained in EXAMPLE 70 in the same manner as PROCESS B.
[TABLE 5]
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
EXAMPLE 101 : iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxy- pheny 1] -3-py ridiny 1} methyl)-4-piperidinecarboxy amide
The title compound was obtained from the compound obtained in EXAMPLE 71 in the same manner as in EXAMPLE 65.
1H NMR (DMSOd6, ppm); δ 13.52(1H, s), 8.41(1H, d), 7.39(1H, d), 7.2O(1H, s),
7.09-7.06(3H, m), 7.01(1H, d), 6.96(1H, d), 6.67(1H, d), 6.6O(1H, d), 6.45(2H, s),
4.09(2H, d), 3.13(3H, s), 3.07(1H, s, broad), 2.76(2H, t), 2.46(2H, t), 2.26(3H, s), 1.91(1H, m), 1.70(2H, m), 1.22(2H, m)
FAB MS(m/e) = 464[M+1]
EXAMPLE 102: iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxy- phenyl]-3-pyridinyl}methyl)-2-(4-piperidinyl)acetamide
The title compound was obtained from the compound obtained in EXAMPLE 101 in the same manner as in EXAMPLE 65.
1H NMR (DMSO-de, ppm); δ 13.52(1H, s), 8.41(1H, d), 7.39(1H, d), 7.2O(1H, s), 7.09-7.06(3H, m), 7.01(1H, d), 6.96(1H, d), 6.67(1H, d), 6.71(2H, s), 6.6O(1H, d), 4.09(2H, d), 3.13(3H, s), 3.07(1H, s, broad), 2.76(2H, t), 2.46(2H, t), 2.26(3H, s), 2.08(2H, d), 1.91(1H, m), 1.70(2H, m), 1.22(2H, m)
FAB MS(m/e) = 478 [M+l]
EXAMPLE 103: 2-{6-amino-5-[(propylamino)methyl]-2-pyridinyl}-4-(2-fluoro-4- dimethylanilino)phenol
50 mg (0.12 mmol) of the compound obtained in EXAMPLE 76 was dissolved in 0.5 ml of tetrahydrofuran, and 61 ul of 10 M borane dimethylsulfide [BH3S(CH3)2] which was dissolved in tetrahydrofuran was added thereto, followed by heating under reflux with stirring for 3 hours. 1 ml of methanol and 0.2 ml of aqueous 4 N sodium hydroxide were added to the reaction mixture, followed by heating under reflux with stirring for 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature, and the crude compound, obtained after concentration in vacuo, was purified by a preparative TLC to give 15.1 g of the title compound in a yield of 31%.
1H NMR (CD3OD, ppm); δ 7.44(1H, d), 7.18(1H, s), 7.05-7.02(1H, m), 6.99(1H, d), 6.93-6.89(2H, m), 6.71-6.68(2H, m), 3.69(2H, s), 3.20(3H, s), 2.57(2H, t), 2.30(3H, s), 1.54(2H, sex), 0.92(2H, t)
FAB MS(m/e) = 395[M+1]
EXAMPLE 104: 2-(6-amino-5-{[(3-hydroxypropyl)ammo]methyl}-2-pyridinyl)-4- (2-fluoro-4-dimethylanilino)phenol The title compound was obtained from the compound obtained in EXAMPLE 79 in the same manner as in EXAMPLE 103.
1H NMR (CD3OD, ppm); δ 7.45(1H, d), 7.31(1H, s), 7.12-7.09(3H, m), 7.01(1H, d), 6.68(1H, d), 6.63(1H, d), 3.75(2H, s), 3.62(2H, t), 3.23(3H, s), 2.73(2H, t), 2.31(3H, s), 1.75(2H, quin)
FAB MS(m/e) - 480[M+l]
EXAMPLE 105: 2-[6-amino-5-({[2-(2-pyridinyl)ethyl]amino}methyl)-2- pyridinyl]-4-(2-fluoro-4-dimethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE
89 in the same manner as in EXAMPLE 103.
1H NMR (CD3OD, ppm); δ 8.39(1H, d), 7.75-7.72(1H, m), 7.43(1H, d), 7.31(1H, d), 7.25-7.22(1H, m), 7.17(1H, s), 7.06-7.03(1H, m), 7.17(1H, s), 7.06-7.03(1H, m), 6.97(1H, d), 6.93-6.91(3H, m), 6.72-6.70(2H, m), 3.74(2H, s), 3.30(3H, s), 2.97- 2.95(4H, m), 2.31(3H, s)
FAB MS(m/e) = 458 [M+ 1]
EXAMPLE 106: 2-[6-amino-5-({[3-(4-morphorinyl)propyl]amino}methyl)-2- pyridinyl]-4-(2-fluoro-4-dimethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE
78 in the same manner as in EXAMPLE 103. 1H NMR (DMSOd6, ppm); δ 13.65(1H, s), 7.61(1H, t), 7.41(1H, d), 7.25(1H, s), 7.25-6.98(4H, m), 6.72(1H, d), 6.67(1H, d), 6.42(2H, s), 4.04-4.02(4H, m), 3.58(4H, s, broad), 3.22(3H, s), 2.53(2H, t), 2.34(4H, s, broad), 2.29(3H, s), 1.73(2H, quin)
FAB MS(m/e) = 480[M+l]
EXAMPLE 107: Ethyl {2-amino-6-[5-(2-fluoro-4-dimethyIaniIino)-2- hydroxyphenyl]-3-pyridinyl}methylcarbamate
35 mg (0.099 mmol) of the compound obtained in EXAMPLE 70 was dissolved in 20 ml of dichloromethane, and 13 mg (0.106 mmol) of N ,N- dimethylaminopyridine was dissolved thereto. After stirring for 10 minutes, 9.5 ul (0.099 mmol) of ethyl chloroformate was added thereto, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was concentrated, and 20 ml of water was added thereto. The crude compound was extracted twice with 20 ml of ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, concentrated and purified by the column chromatography to obtain 31 mg (0.073 mmol) of the title compound in a yield of 74%.
1H NMR (DMSOd6, ppm); δ 13.67(1H, s), 7.55(1H, t), 7.45(1H, d), 7.22(1H, s), 7.1O(1H, t), 7.06-7.03(2H, m), 6.97(1H, d), 6.68(1H, d), 6.63(1H, d), 6.42(2H, s), 4.01(2H, d), 3.32(2H, q), 3.20(3H, s), 2.32(3H, s), 1.20(3H, t)
FAB MS(m/e) = 425 [M+ 1] EXAMPLE 108: iV-({2-6-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)methanesulfonamide
Methanesulfonyl chloride instead of ethyl chloroformate was used in EXAMPLE 107 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.65(1H, s), 7.56(1H, d), 7.46(1H, t), 7.25(1H, s), 7.19-6.98(4H, m), 6.71(1H, d), 6.63(1H, d), 6.36(2H, s), 4.03(2H, d), 3.20(3H, s), 2.94(3H, s), 2.29(3H, s)
FAB MS(m/e) = 431[M+l]
EXAMPLE 109: iV-({2-6-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)(phenyl)methanesulfonamide
Benzylsulfonyl chloride instead of methanesulfonyl chloride was used in EXAMPLE 108 to produce the title compound.
1H NMR (DMSOd6, ppm); δ 13.65(1H, s), 7.56(1H, d), 7.46(1H, t), 7.40-7.29(5H, m), 7.25(1H, s), 7.19-6.98(4H, m), 6.71(1H, d), 6.63(1H, d), 6.36(2H, s), 4.21(2H, s), 4.03(2H, d), 3.20(3H, s), 2.29(3H, s)
FAB MS(m/e) = 507 [M+ 1]
EXAMPLE 110: JV-({2-6-amino-6-[5-(2-fluoro-4-dimethyIanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-l-ethanesulfonamide
Ethanesulfonyl chloride instead of methanesulfonyl chloride was used in EXAMPLE 108 to produce the title compound.
1H NMR (DMSOd6, ppm); δ 13.65(1H, s), 7.56(1H, d), 7.46(1H, t), 7.25(1H, s), 7.19-6.98(4H, m), 6.71(1H, d), 6.63(1H, d), 6.36(2H, s), 4.03(2H, d), 3.20(3H, s), 3.06(2H, q), 2.29(3H, s), 1.21(3H, t)
FAB MS(m/e) = 445 [M+ 1]
EXAMPLE 111: Ethyl l-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-2-aziridinecarboxyIate
215 mg (0.610 mmol) of the compound obtained in EXAMPLE 70 was dissolved in 20 ml of N,N-dimethylformamide, and 252 mg (1.83 mmol) of potassium carbonate and 159 mg (0.610 mmol) of ethyl 2,3-dibromopropionate were added thereto, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction solution was concentrated, and 30 ml of water was added, then extraction was performed twice with 30 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by the column chromatography to obtain 105 mg (0.233 mmol) of the title compound in a yield of 38% and 76 mg (0.153 mmol) of the compound of EXAMPLE
112 in a yield of 25%.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 7.25(1H, d), 7.19(1H, d), 7.05-6.99(2H, m), 6.90-6.79(4H, m), 5.53(2H, s), 4.17(2H, q), 3.48(1H, d), 3.35(1H, d), 3.25(3H, s), 2.32(3H, s), 2.23(1H, d), 1.25(3H, t)
FAB MS(m/e) = 451[M+l] EXAMPLE 112: Ethyl 3-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-2-oxo-l,3-oxazolidine-5-carboxylate
The title compound was obtained in the same manner as in EXAMPLE 111.
1H NMR (CDCl3, ppm); δ 13.74(1H, s), 7.35(1H, d), 7.17(1H, s), 7.06-7.00(2H, m), 6.92-6.80(4H, m), 5.25(2H, s), 4.93-4.89(1H, m), 4.28(2H, q), 3.73-3.68(1H, m), 3.54- 3.52(1H, m), 3.25(3H, s), 2.33(3H, s), 1.29(3H, t)
FAB MS(m/e) = 495 [M+ 1]
EXAMPLE 113: 2-(6-amino-5-{[2-(hydroxymethyl)-l-aziridinyl]methyl}-2- pyridinyl)-4-(2-fluoro-4-dimethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 111 in the same manner as in EXAMPLE 2.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 7.29(1H, d), 7.19(1H, d), 7.03-7.01(2H, m), 6.91-6.79(4H, m), 5.46(2H, s), 3.75(1H, dd), 3.49(1H, d), 3.38(1H, dd), 3.30(1H, d), 3.24(3H, s), 2.32(3H, s), 1.82-1.78(2H, m), 1.46(1H, d)
FAB MS(m/e) - 409 [M+ 1]
EXAMPLE 114: 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyljnicotinonitrile
N-methyl-3,4-methylenedioxyaniline instead of 2-fluoro-4-methylaniline was used in EXAMPLE 35 to produce the title compound.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 7.7O(1H, d), 7.52(1H, s), 7.09-7.06(2H, m), 6.96(1H, d), 6.71(1H, d), 6.62(2H, s), 6.46(1H, s), 6.32(1H, d), 5.88(2H, s), 3.25(3H,
s)
FAB MS(m/e) = 361 [M+l]
EXAMPLE 115: 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxy phenyl} nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE 114 in the same manner as in EXAMPLE 42.
1H NMR (DMSOd6, ppm); δ 13.72(1H, s), 13.11(1H, s), 7.72(1H, d), 7.5O(1H, s), 7.09-7.06(2H, m), 6.97(1H, d), 6.74(1H, d), 6.62(2H, s), 6.46(1H, s), 6.32(1H, d), 5.88(2H, s), 3.25(3H, s)
FAB MS(m/e) = 380 [M+l]
EXAMPLE 116: 2-amino-6-{5-[l,3-benzodioxol-5-yI(methyl)amino]-2- hydroxyphenyl}-Λr-(2-hydroxyethyl)nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 115 in the same manner as in PROCESS A.
1H NMR (CDCl3, ppm); δ 13.72(1H, s), 7.7O(1H, d), 7.52(1H, s), 7.09-7.06(2H, m), 6.96(1H, d), 6.71(1H, d), 6.62(2H, s), 6.46(1H, s), 6.32(1H, d), 5.88(2H, s), 3.86(2H, t), 3.63(2H, t), 3.25(3H, s)
FAB MS(m/e) = 423 [M+ 1]
EXAMPLE 117: 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyl}-N-[2-(dimethylamino)ethyl]nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 115 in the same manner as in PROCESS A.
1H NMR (CDCl3, ppm); δ 13.75(1H, s), 7.82(1H, d), 7.44(1H, s), 7.07-7.03(2H, m), 6.95(1H, d), 6.71(1H, d), 6.61(2H, s), 6.45(1H, s), 6.31(1H, d), 5.95(2H, s), 3.52(2H, t), 3.22(3H, s), 2.60(2H, t), 2.33(6H, s)
FAB MS(m/e) - 450 [M+ 1]
EXAMPLE 118: 2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}- nicotinonitrile
N-methyl-4-methoxyaniline instead of 2-fluoro-4-methylaniline was used in
EXAMPLE 35 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.56(1H, s), 7.49(1H, s), 7.45(1H, d), 7.15(1H, d), 6.91(1H, d), 6.83-6.79(5H, m), 6.58(2H, s), 3.71(3H, s), 3.20(3H, s)
FAB MS(m/e) = 347 [M+l] EXAMPLE 119: 2-amino-6- {2-hydroxy-5- [4-methoxy(methy l)anilino] phenyl}- nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE 118 in the same manner as in EXAMPLE 42.
1H NMR (DMSOd6, ppm); δ 13.72(1H, s), 13.12(1H, s), 7.48(1H, s), 7.44(1H, d), 7.14(1H, d), 6.9O(1H, d), 6.83-6.78(5H, m), 6.21(2H, s), 3.71(3H, s), 3.21(3H, s)
FAB MS(m/e) = 366 [M+l]
The title compounds in EXAMPLES 120 to 122 of TABLE 6 below were obtained using the compound obtained in EXAMPLE 119 in the same manner as PROCESS A.
[TABLE 6]
Figure imgf000097_0001
EXAMPLE 123: 2-amino-6-{2-hydroxy-5-[4-hydroxy (methyI)anilino]phenyl}-N- [(5-methyl-2-pyrazinyl)methyl]nicotinamide
15 mg (0.032 mmol) of the compound obtained in EXAMPLE 120 was dissolved in 20 ml of dichloromthane, then 0.3 ml of borontribromide (1.0 M dichloromethane solution) was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, 2 ml of methanol was added thereto to concentrate. The crude compound was purified by the column chromatography to obtain 9.8 mg (0.021 mmol) in a yield of 67%.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 8.56(1H, s), 8.41(1H5 s), 7.76(1H, d), 7.37(1H, s), 7.01-7.00(2H, m), 6.92(1H, d), 6.80-6.75(4H, m), 6.60(2H, s), 4.72(2H, d), 3.21(3H, s), 2.58(3H, s)
FAB MS(m/e) = 457 [M+l]
EXAMPLE 124 : 2- [6-amino-5-(aminomethy l)-2-py ridinyl] -4- [4-methoxy- (methy l)anilino] phenol
The title compound was obtained from the compound obtained in EXAMPLE
118 in the same manner as in EXAMPLE 2.
1H NMR (DMSOd6, ppm); δ 13.7O(1H, s), 7.48(1H, s), 7.44(1H, d), 7.39(2H, s, broad), 7.14(1H, d), 6.9O(1H, d), 6.83-6.78(5H, m), 6.55(2H, s), 3.71(3H, s), 3.21(3H,
s)
FAB MS(m/e) = 351 [M+l] The title compounds in EXAMPLES 125 to 136 of TABLE 7 below were obtained from the compound obtained in EXAMPLE 124 in the same manner as PROCESS B.
[TABLE 7]
Figure imgf000099_0001
Figure imgf000100_0001
EXAMPLE 137: N-[(2-amino-6-{2-hydroxy-5-[4-hydro(methyI)aniline]phenyl}-3- py ridinyl)methy 1] ] -2-(l H-imidazole-4-yl)acetamide
The title compound was obtained from the compound obtained in EXAMPLE 131 in the same manner as in EXAMPLE 123.
1H NMR (DMSO-d6, ppm); δ 8.94(1H, s), 8.38(1H, t), 7.95(1H, s), 7.52(1H, s), 7.44(1H, d), 7.35(1H, s), 7.08(1H, d), 6.82(1H, s), 6.79-6.75(2H, m), 6.63(2H, d), 6.43-6.39(3H, m), 4.13(2H, d), 3.69(2H, s), 3.14(3H, s)
FAB MS(m/e) = 445 [M+ 1]
EXAMPLE 138 : 2-amino-6- [5-(2-fluoro-4-methoxy anilino)-2-hydroxyphenyl] - nicotinonitrile
N-methyl-2-fluoro-4-methylaniline instead of 2-fluoro-4-methylaniline was used in EXAMPLE 35 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.72(1H, s), 7.45(1H, d), 7.21(1H, t), 7.12(1H, s), 7.06(1H, d), 6.9O(1H, d), 6.88(1H, d), 6.8O(1H, d), 6.56(1H, d), 6.47(2H, s), 3.77(3H, s), 3.17(3H, s) FAB MS(m/e) = 365 [M+l]
EXAMPLE 139 : 2- [6-amino-5-(aminomethyl)-2-py ridinyl] -4-(2-fluoro-4- methoxymethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE
138 in the same manner as in EXAMPLE 2.
1H NMR (DMSO-d6, ppm); δ 13.72(1H, s), 7.56(2H, t), 7.45(1H, d), 7.21(1H, t), 7.12(1H, s), 7.06(1H, d), 6.9O(1H, d), 6.88(1H, d), 6.8O(1H, d), 6.56(1H, d), 6.47(2H, s), 4.01(2H, t), 3.77(3H, s), 3.17(3H, s)
FAB MS(m/e) = 369 [M+l]
The title compounds in EXAMPLES 140 to 146 of TABLE 8 below were obtained using the compound obtained in EXAMPLE 139 in the same manner as PROCESS B.
[TABLE 8]
Figure imgf000101_0001
Figure imgf000102_0001
EXAMPLE 147: 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinonitrile
N-methyl-4-chloro-2-fluoroaniline instead of 2-fluoro-4-methylaniline was used in EXAMPLE 35 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.74(1H, s), 7.44(1H, d), 7.37-7.35(2H, m), 7.23- 7.18(2H, m), 7.1O(1H, d), 6.75-6.72(2H, m), 6.52(2H, s), 3.21(3H, s)
FAB MS(m/e) = 369 [M+l]
EXAMPLE 148: 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hy droxyphenyl] nicotinate
The title compound was obtained from the compound obtained in EXAMPLE 147 in the same manner as in EXAMPLE 3.
1U NMR (CDCl3, ppm); δ 13.62(1H, s), 7.45(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.11(1H, d), 6.75-6.72(2H, m), 6.42(2H, s), 3.74(2H, q), 3.21(3H, s), 1.32(3H, t) FAB MS(m/e) = 416 [M+l]
EXAMPLE 149: 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxy phenyl] nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE
147 in the same manner as in EXAMPLE 42.
1H NMR (DMSOd6, ppm); δ 13.74(1H, s), 13.12(1H, s), 7.45(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.11(1H, d), 6.75-6.72(2H, m), 6.42(2H, s), 3.21(3H, s)
FAB MS(m/e) = 388 [M+l]
The title compounds in EXAMPLES 150 to 220 of TABLE 9 below were obtained using the compound obtained in EXAMPLE 149 in the same manner as PROCESS A.
[TABLE 9]
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
EXAMPLE 221 : 4-[({2-amino-6-[5-(4-chloro-2-fluoromethyIaniIino)-2- hydroxyphenyl]-3-pyridinyl}carbonyl)amino]butanoic acid
The title compound was obtained from hydrolysis for the compound obtained in EXAMPLE 151 in the same manner as EXAMPLE 42.
1H NMR (DMSO-d6, ppm); δ 13.64(1H, s), 13.12(1H, s), 8.28(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 6.91(1H, d), 6.75-6.72(2H, m), 6.37(2H, s), 3.32(2H, t), 3.21(3H, s), 2.31(2H, t), 1.78(2H, quin)
FAB MS(m/e) = 473 [M+l]
PREPARATION 8: 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-iV-methyl-iV-methoxynicotmamide
The title compound was obtained from the compound obtained in EXAMPLE 149 in the same manner as in PROCESS A.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 8.12(1H, d), 7.27(1H, s), 7.12-7.03(4H, m), 6.96-6.89(2H, m), 3.41 (3H, s), 3.21(3H, s), 3.01(3H, s)
FAB MS(m/e) = 431 [M+l]
EXAMPLE 222: l-{2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-3-pyridinyl}-l-propanone
65 mg (0.156 mmol) of the compound obtained in PREPARATION 8 was dissolved in 20 ml of tetrahydrofuran, followed by cooling to 0°C. 0.16 ml of ethyl magnesium bromide (I M tetrahydrofuran solution) was added thereto, and stirred for 1 hour. After completion of the reaction, 20 ml of water was added, and extraction was performed twice with 20 ml of ethyl acetate. An organic layer was concentrated and purified by the column chromatography to obtain 47 mg (0.118 mmol) of the title compound in a yield of 76%.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 8.12(1H, d), 7.27(1H, s), 7.12-7.03(4H, m), 6.96-6.89(2H, m), 3.21(3H, s), 2.96(2H, q), 1.22(3H, t)
FAB MS(m/e) = 400 [M+l]
EXAMPLE 223: {2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3-py ridinyl} (4-chlorophenyl)methanone
4-chlorophenylmagnesium bromide instead of ethyl magnesium bromide was used in EXAMPLE 222 to produce the title compound.
1H NMR (CDCl3, ppm); δ 13.73(1H, s), 7.83(1H, d), 7.58(2H, d), 7.54(2H, d), 7.29(1H, s), 7.23(1H, d), 7.17-7.08(2H, m), 7.03(1H, d), 6.97-6.91(2H, m), 3.27(3H,
s)
FAB MS(m/e) = 482 [M+ 1]
EXAMPLE 224: 2-amino-6-[5-(4-chIoro-2-fluoromethylanilino)-2- hydroxyphenyl]-N-(4-hydroxybenzyl)nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 170 in the same manner as in EXAMPLE 123.
1H NMR (CDCl3, ppm); δ 13.69(1H, s), 7.66(1H, d), 7.23-7.21(3H, m), 7.10-7.01(3H, m), 6.97(1H, d), 6.93-6.90(2H, m), 6.83(2H, d), 6.58(2H, s), 6.23(1H, t), 4.53(2H, d), 3.26(3H, s)
FAB MS(m/e) = 493 [M+l]
EXAMPLE 225: 2-hydroxy ethyl 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)- 2-hy droxyphenyl] nicotinate
45 mg (0.116 mmol) of the compound obtained in EXAMPLE 149 was dissolved in 3 ml of ethyleneglycol, and a drop of concentrated hydrochloric acid was added, followed by stirring under reflux for 3 hours. After completion of the reaction, 30 ml of water was added, and extraction was performed twice with 20 ml of ethyl acetate. The combined organic layers were washed twice with 20 ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by the column chromatography to obtain 36 mg (0.0835 mmol) of the title compound in a yield of 72%.
1H NMR (CDCl3, ppm); δ 13.74(1H, s), 8.21(1H, d), 7.26(1H, s), 7.11-7.02(4H, m), 6.92-6.89(2H, m), 4.44(2H, t), 3.99(2H, t), 3.26(3H, s)
FAB MS(m/e) = 432 [M+l]
EXAMPLE 226 : 2- [6-amino-5-(aminomethyl)-2-py ridinyl] -4-(4-chloro-2- fluoromethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 147 in the same manner as in EXAMPLE 2.
1H NMR (DMSO-d6, ppm); δ 13.74(1H, s), 8.12(2H, t), 7.53(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.11(1H, d), 6.75-6.72(2H, m), 6.42(2H, s), 3.67(2H, t), 3.21(3H, s)
FAB MS(m/e) = 373 [M+l]
The title compounds in EXAMPLES 227 to 286 of TABLE 10 below were obtained using the compound obtained in EXAMPLE 226 in the same manner as PROCESS B.
[TABLE 10]
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
EXAMPLE 283: N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-l-ethyl-4-piperidinecarboxyamide
The title compound was obtained from the compound obtained in EXAMPLE 232 in the same manner as in EXAMPLE 66.
1U NMR (DMSOd6, ppm); δ 13.72(1H, s), 8.3O(1H, t), 7.52(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.11(1H, d), 6.75-6.72(2H, m), 6.42(2H, s), 4.11(2H, d), 3.21(3H, s), 2.95-2.79(4H, m), 2.30(2H, q), 2.14-2.O8(1H, m), 1.70-1.62(4H, m), 0.97(3H, t)
FAB MS(m/e) = 512 [M+l]
EXAMPLE 284: 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hy droxyphenyl] -3-py ridinyl} methyl)amino] -4-oxobutanoic acid
The title compound was obtained from hydrolysis for the compound obtained in EXAMPLE 237 in the same manner as in EXAMPLE 42.
1H NMR (DMSOd6, ppm); δ 13.72(1H, s), 13.12(1H, s), 8.12(1H, t), 7.41(1H, d), 7.34-7.30(2H, m), 7.19-7.14(2H, m), 7.07(1H, d), 6.71-6.69(2H, m), 6.46(2H, s), 4.06(2H, d), 3.19(3H, s), 2.20(2H, t), 2.04(2H, t)
FAB MS(m/e) = 473 [M+ 1] EXAMPLE 285: 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)acetamide
The title compound was obtained from the compound obtained in EXAMPLE 247 in the same manner as in EXAMPLE 65.
1H NMR (DMSO-d6, ppm); δ 13.7O(1H, s), 8.49(1H, t), 7.46(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.1O(1H, d), 6.76-6.63(2H, m), 6.57(2H, s), 4.16(2H, d), 3.25(2H, t), 3.21(3H, s)
FAB MS(m/e) = 430 [M+ 1]
EXAMPLE 286: 2-(6-amino-5-{[(3-hydroxypropyl)amino]methyl}-2-pyridinyl)-4- (4-chloro-2-fluoromethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 236 in the same manner as in EXAMPLE 103.
1H NMR (DMSOd6, ppm); δ 13.69(1H, s), 8.54(1H, t), 8.09(1H, d), 7.74(2H, s), 7.34(1H, d), 7.20-7.14(3H, m), 6.94(1H, d), 6.70-6.68(2H, m), 4.05(2H, t), 3.30(2H, t), 3.21(3H, s), 2.53(2H, t), 1.62(2H, quin)
FAB MS(m/e) = 431 [M+l]
EXAMPLE 287: 2-(6-amino-5-{[(2-hydroxyethyl)amino]methyI}-2-pyridinyl)-4- (4-chloro-2-fluoromethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 233 in the same manner as in EXAMPLE 103.
1H NMR (CD3OD, ppm); δ 7.48(1H, d), 7.31(1H, s), 7.14-7.10(3H, m), 7.04(1H, d), 6.81(1H, d), 6.75(1H, d), 3.76(2H, s), 3.63(2H, t), 3.28(3H, s), 2.73(2H, t)
FAB MS(m/e) = 417 [M+l]
EXAMPLE 288: 2-[6-amino-5-({[2-(4-morpholinyl)ethyl]amino}methyl)-2- pyridinyl]-4-(4-chloro-2-fluoromethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 227 in the same manner as in EXAMPLE 103.
1H NMR (CD3OD, ppm); δ 7.45(1H, d), 7.3O(1H, s), 7.14-7.10(3H, m), 7.03(1H, d), 6.83(1H, d), 6.72(1H, d), 3.76(2H, s), 3.63(2H, t), 3.55(4H, t), 3.31(4H, t), 3.28(3H, s), 2.73(2H, t)
FAB MS(m/e) = 486 [M+ 1]
EXAMPLE 289: iV-({2-amino-6-[5-(4-chIoro-2-fluoromethylanilino)-2- hydroxyphenyI]-3-pyridinyI}methyl)-4-piperidinecarboxy amide
The title compound was obtained from the compound obtained in EXAMPLE 283 in the same manner as in EXAMPLE 65.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 8.21(1H, t), 7.45(1H, d), 7.37-7.35(2H, m), 7.23-7.18(2H, m), 7.1O(1H, d), 6.76-6.63(2H, m), 6.46(2H, s), 4.11(2H, d), 3.21(3H, s), 3.07(1H, s, broad), 2.76(2H, t), 2.46(2H, t), 1.93-1.9O(1H, m), 1.70-1.67(2H, m), 1.22-1.19(2H, m)
FAB MS(m/e) = 484 [M+l]
EXAMPLE 290: 2-(6-amino-5-{[(2-anilinoethyl)amino]methyl}-2-pyridinyl)-4-(4- chloro-2-fluoromethylanilino)phenol
The title compound was obtained from the compound obtained in EXAMPLE 282 in the same manner as in EXAMPLE 103.
1H NMR (CD3OD, ppm); δ 7.85(1H, d), 7.4O(1H, s), 7.21(1H, d), 7.14-6.93(7H, m), 6.83(1H, d), 6.72(1H, d), 6.62(1H, d), 4.82(2H, s), 3.76(2H, t), 3.20(3H, s), 2.97(2H, t)
FAB MS(m/e) - 492 [M+l]
EXAMPLE 291: (2R)-iV-({2-amino-6-[5-(4-chloro-2-fluoromethyIanilino)-2- hydroxyphenyl] -3-py ridinyl} methyl)-2-py rrolidinecarboxy amide
The title compound was obtained from the compound obtained in EXAMPLE
282 in the same manner as in EXAMPLE 65.
1H NMR (DMSO-dg, ppm); δ 13.73(1H, s), 8.52(1H, t), 7.41(1H, d), 7.36-7.34(2H, m), 7.22-7.18(2H, m), 7.11(1H, d), 6.75-6.72(2H, m), 6.53(2H, s), 4.12(2H, d), 3.64(1H, quin), 3.21(3H, s), 2.9O-2.88(1H, m), 2.81-2.78(1H, m), 1.99-1.96(1H, m), 1.69- 1.65(1H, m), 1.61-1.59(2H, m)
FAB MS(m/e) = 470[M+l] EXAMPLE 292: iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3-py ridinyl} methyl)methanesulfonamide
The title compound was obtained from the compound obtained in EXAMPLE 226 in the same manner as in EXAMPLE 108.
1H NMR (DMSOd6, ppm); δ 13.72(1H, s), 7.56(1H, d), 7.47(1H, t), 7.40-7.37(2H, m), 7.26-7.18(3H, m), 6.80-6.76(2H, m), 6.41(2H, s), 4.03(2H, d), 3.24(3H, s), 2.94(3H, s)
FAB MS(m/e) = 451 [M+l]
EXAMPLE 293: iV-({2-amino-6-[5-(4-chloro-2-fluoromethylaniliiio)-2- hydroxyphenyl]-3-pyridinyl}methyl)-l-ethanesulfonamide
Ethane sulfonyl chloride instead of methane sulfonyl chloride was used in EXAMPLE 292 to produce the title compound.
1H NMR (DMSOd6, ppm); δ 13.72(1H, s), 7.56(1H, d), 7.47(1H, t), 7.40-7.37(2H, m), 7.26-7.18(3H, m), 6.80-6.76(2H, m), 6.41(2H, s), 4.02(2H, d), 3.21(3H, s), 3.05(2H, q), 1.17(3H, t)
FAB MS(m/e) = 465 [M+l]
EXAMPLE 294: iV-({2-amino-6-[5-(4-chloro-2-fluoromethylaniIino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-l- morpholinecarboxyamide
Using the compound obtained in EXAMPLE 226 and 4-morpholinecarbonyl chloride instead of ethyl chloroformate, the title compound was obtained in the same manner as in EXAMPLE 107.
1H NMR (DMSOd6, ppm); δ 13.7O(1H, s), 7.42(1H, d), 7.38-7.36(2H, m), 7.24- 7.18(2H, m), 7.1O(1H, d), 7.07(1H, t), 6.79-6.76(2H, m), 6.60(2H, s), 4.11(2H, d), 3.55(4H, t), 3.31(4H, t), 3.21 (3H, s)
FAB MS(m/e) = 486 [M+ 1]
EXAMPLE 295: iV-({2-amino-6-[5-(4-chloro-2-fluoromethylaniIino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-l-pipelidinecarboxyamide
1 -pipelidinecarbonyl chloride instead of 4-morpholinecarbonyl chloride was used in EXAMPLE 294 to produce the title compound.
1H NMR (DMSOd6, ppm); δ 13.71(1H, s), 7.39(1H, d), 7.37-7.35(2H, m), 7.24- 7.18(2H, m), 7.1O(1H, d), 6.93(1H, t), 6.79-6.76(2H, m), 6.62(2H, s), 4.08(2H, d), 3.31(4H, t), 3.21(3H, s), 1.53-1.50(2H, m), 1.42-1.38(4H, m)
FAB MS(m/e) = 484 [M+l]
EXAMPLE 296: iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl)-4-methyl-l-piperazinecarboxyamide
4-methyl-l-piperazinecarbonyl chloride instead of 4-morpholinecarbonyl chloride was used in EXAMPLE 294 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.71(1H, s), 7.41(1H, d), 7.38-7.36(2H, m), 7.24- 7.18(2H, m), 7.12(1H, d), 7.02(1H, t), 6.79-6.76(2H, m), 6.61(2H, s), 4.10(2H, d), 3.31(4H, t), 3.21(3H, s), 2.25(4H, t), 2.17(3H, s)
FAB MS(m/e) = 499 [M+ 1]
EXAMPLE 297: 2-{6-amino-5-[(cyclopentylamino)methyl]-2-pyridinyl}-4-(4- chloro-2-fluoromethylanilino)phenol
Using the compound obtained in EXAMPLE 226 and cyclopentanone instead of acetaldehyde, the title compound was obtained in the same manner as in EXAMPLE 66.
1H NMR (DMSOd6, ppm); δ 13.71(1H, s), 7.6O(1H, t), 7.39(1H, d), 7.38-7.36(2H, m), 7.24-7.18(2H, m), 7.1O(1H, d), 6.79-6.76(2H, m), 6.62(2H, s), 3.95(2H, d), 3.32- 3.28(1H, m), 3.22(3H, s), 2.58-2.54(2H, m), 1.81-1.76(1H, m), 1.67-1.60(2H, m), 1.53-1.47(3H, m)
FAB MS(m/e) = 441 [M+ 1]
EXAMPLE 298: Ethyl {2-amino-6-[5-(4-chloro-2-fluoromethylaniIino)-2- hydroxyphenyl]-3-pyridinyl}methylcarbamate
The title compound was obtained from the compound obtained in EXAMPLE 226 in the same manner as in EXAMPLE 107.
1H NMR ((DMSOd6, ppm); δ 13.74(1H, s), 7.6O(1H, t), 7.41-7.35(3H, m), 7.25- 7.14(3H, m), 6.77-6.73(2H, m), 6.44(2H, s), 4.04-3.99(4H, m), 3.22(3H, s), 1.18(3H, t)
FAB MS(m/e) = 445 [M+l]
EXAMPLE 299: Ethyl l-{2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl]-3-pyridinyl}methyl-2-aziridinecarboxylate
The title compound was obtained from the compound obtained in EXAMPLE 226 in the same manner as in EXAMPLE 111.
1H NMR (CDCl3, ppm); δ 13.71(1H, s), 7.24(1H, d), 7.2O(1H, d), 7.05-6.99(2H, m), 6.90-6.79(4H, m), 5.53(2H, s), 4.17(2H, q), 3.42(1H, d), 3.31(1H, d), 3.21(3H, s), 2.22(lH, d), 1.25(3H, t)
FAB MS(m/e) = 471 [M+l]
EXAMPLE 300: 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl}nicotinonitrile
N-methyl-2,4-difluoroaniline instead of 2-fluoro-4-methylaniline was used in
EXAMPLE 35 to produce the title compound.
1H NMR (DMSO-d6, ppm); δ 13.71(1H, s), 7.43(1H, d), 7.31-7.23(3H, m), 7.10- 7.06(2H, m), 6.73(1H, d), 6.64(1H, d), 6.48(2H, s), 3.20(3H, s)
FAB MS(m/e) = 353 [M+l] EXAMPLE 301: 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxy phenyl} nicotinic acid
The title compound was obtained from the compound obtained in EXAMPLE 300 in the same manner as in EXAMPLE 42.
1H NMR (DMSOd6, ppm); δ 13.67(1H, s), 13.12(1H, s), 7.41(1H, d), 7.31-7.23(3H, m), 7.10-7.06(2H, m), 6.72(1H, d), 6.63(1H, d), 6.52(2H, s), 3.21(3H, s)
FAB MS(m/e) = 372 [M+l]
The title compounds in EXAMPLES 302 to 321 of TABLE 11 below were obtained using the compound obtained in EXAMPLE 301 in the same manner as PROCESS A.
[TABLE I l]
Figure imgf000124_0001
Figure imgf000125_0001
EXAMPLE 322: 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-[2,4-
(lifluoro(methyl)aniline] phenol
The title compound was obtained from the compound obtained in EXAMPLE 300 in the same manner as in EXAMPLE 2.
1H NMR (DMSO-d6, ppm); δ 13.67(1H, s), 8.02(2H, t), 7.4O(1H, d), 7.31-7.23(3H, m), 7.10-7.06(2H, m), 6.72(1H, d), 6.62(1H, d), 6.47(2H, s), 4.01(2H, t), 3.22(3H, s)
FAB MS(m/e) = 357 [M+ 1]
The title compounds in EXAMPLES 323 to 338 of TABLE 12 below were obtained using the compound obtained in EXAMPLE 322 in the same manner as PROCESS B.
[TABLE 12]
Figure imgf000126_0001
Figure imgf000127_0001
EXAMPLE 339: (2S)-N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl}-3-pyridinyl)methyl]-2,3-dihydroxypropanamide 23 mg (0.0475 mmol) of the compound obtained in EXAMPLE 337 was dissolved in 10 ml of methanol, 1 ml of concentrated hydrochloric acid was added, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with aqueous 2 N sodium hydroxide and concentrated in vacuo. The residue was extracted twice with 20 ml of ethyl acetate to obtain 18 mg (0.0405 mmol) of the title compound in a yield of 85%.
1H NMR (DMSOd6, ppm); δ 13.71(1H, s), 8.35(1H, t), 7.47(1H, d), 7.30-7.24(3H, m), 7.08-7.05(2H, m), 6.73(1H, d), 6.64(1H, d), 6.51(2H, s), 5.66(1H, d), 4.73(1H, t), 4.15(2H, d), 3.94-3.92(1H, m), 3.64-3.59(1H, m), 3.52-3.47(1H, m), 3.20(3H, s)
FAB MS(m/e) = 445 [M+l]
EXAMPLE 340: iV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl}-3-pyridinyl)methyl]-4-morpholinecarboxyamide
The title compound was obtained from the compound obtained in EXAMPLE 322 in the same manner as in EXAMPLE 294.
1H NMR (DMSOd6, ppm); δ 13.71(1H, s), 7.4O(1H, d), 7.28-7.22(3H, m), 7.08- 7.04(3H, m), 6.7O(1H, d), 6.63(1H, d), 6.52(2H, s), 4.09(2H, d), 3.55(4H, t), 3.31(4H, t), 3.20(3H, s)
FAB MS(m/e) = 470 [M+l]
EXAMPLE 341: N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyI}-3-pyridinyl)methyl]-4-methyl-l-piperazinecarboxyamide Using 4-methyl-l-piperazinecarbonyl chloride instead of 4- morpholinecarbonyl chloride in EXAMPLE 340, the title compound was obtained in the same manner as in EXAMPLE 294.
1H NMR (DMSO-d6, ppm); δ 13.73(1H, s), 7.41(1H, d), 7.29-7.23(3H, m), 7.08- 7.04(3H, m), 6.71(1H, d), 6.62(1H, d), 6.49(2H, s), 4.10(2H, d), 3.40(4H, t), 3.20(3H, s), 2.25(4H, t), 2.17(3H, s)
FAB MS(m/e) - 483 [M+ 1]
EXAMPLE 342: 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyI]-iV- [2-(lH-imidazole-4-yl)ethyl] nicotinamide
The title compound was obtained from the compound obtained in EXAMPLE 42 in the same manner as in PROCESS A.
1H NMR (DMSO-d6, ppm); δ 13.71(1H, s), 8.6O(1H, t), 8.04(1H, d), 7.68(2H, s),
7.55(1H, s), 7.34(1H, s), 7.19(1H, d), 7.13-7.11(2H, m), 7.07(1H, d), 7.02(1H, d), 6.82(1H, s), 6.74(1H, d), 6.67(1H, d), 3.47(2H, t), 3.21(3H, s), 2.76(2H, t), 2.30(3H, s)
FAB MS(m/e) = 461[M+l]
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 mM MgCl2, 1 mM MnCl2, 2 mM DTT, 0.1 mM sodium orthovanadate, 10 μM ATP, 0.2 μCi [γ- P32J-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 niM 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:FGFR1 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-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 M 199 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). 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, 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 the tube formation of HUVEC
HUVEC (Human umbilical vein endothelial cells) having been used within passage 5 were cultured at 37°C 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 4: 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 RPMIl 640 medium (supplemented with 5% FBS, IX Penicillin/Streptomycin and 0.5 mM Glutamine; Gibco BRL) at 370C 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.
EXPERIMENT 5: Test of the inhibitory effect of the compounds according to the present invention on cancer cell growth in vivo
B ALB/c nude mice (5 - 6 weeks age, female) purchased from Harlan (USA) were raised in a cage equipped with a clean room HEPA filter and adapted to the cage for a week. Human cancer cells selected for test were cultured at each suitable condition and then subcutaneously administered to the nude mice at the amount of 5 ~ 10 X 105 cells/100 μl. When the size of tumor grew to the extent of 90 ~ 120 mm2 suitable for Regression model, the compounds according to the present invention were orally administered at a predetermined amount once a day. The size of tumor and the weight of mice were measured three times a day, and the clinical manifestation was investigated and recorded once or twice a day. The size of tumor was recorded as a volume value by measuring the width, length and height of tumor and then calculating the volume value on the basis of (width x length x height)/6 formula. The test continued for 15 ~ 18 days.
The inhibitory effect on the tumor growth was determined by two factors, i.e., IR% (Inhibition Rate %) and %T/C.
IR% = (1 - Average tumor size of administration group / Average tumor size of control group) X 100
%T/C = {(Average tumor size of administration group at a certain day - Average tumor size of administration group at an administration starting day) / (Average tumor size of control group at a certain day - Average tumor size of control group at an administration starting day)} X 100
In TABLE 13 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 13]
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Note: N.D. means that No experimental Data are available.
In TABLE 14 below, summarized are IC50 values of some compounds of Formula 1 showing the ability to inhibit the cell growth of HCTl 16 cells, bFGF- dependent HUVEC and PDGF-dependent PASMC.
[TABLE 14]
Figure imgf000144_0002
Note: N.D. means that No experimental Data are available.
Some compounds of Formula 1 showed a significant inhibitory effect in the in vivo test regarding the inhibitory effect on the cancer cell growth using nude mice.
From the above results, it is clear that the compounds according to the present invention are very effective in inhibiting KDR activity, inhibiting HUVEC growth and inhibiting cancer cell growth in vivo. 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 imgf000146_0001
or a pharmaceutically acceptable salt, hydrate, solvate, isomer, or prodrug thereof,
where
A) Ri is an aryl, heteroaryl, or optionally substituted aryl or heteroaryl;
B) R2 is one selected from the group consisting of
I) hydrogen; and
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alky 1;
C) R3 is selected from the group consisting of
I) cyano;
II) optionally substituted alkyl;
III) a substituent of formula -C(=O)-Xi-X2, where
X1 is a direct bond, oxygen, optionally substituted amino, optionally substituted alkyl, or optionally substituted aryl;
X2 is selected from the group consisting of hydrogen, pyrrolidine, piperazine, morpholine, lower alkyl amine, hydroxyl, halogen, optionally substituted lower alkyl, optionally substituted aryl and heteroaryl, optionally substituted piperidine and optionally substituted thiazole; and
IV) a substituent of formula -C(CH(-X3))NnX4X5, where
X3 is selected from the group consisting of hydrogen, halogen and optionally substituted lower alkyl;
X4 and X5 are each independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted sulfone and alkyl carbamate, or X4 and X5 are together taken to form optionally substituted cyclic or heterocyclic group;
n is 1 to 5;
D) R4 is selected from the group consisting of
I) hydrogen; and
II) optionally substituted straight-chain, branched, or cyclic saturated or unsaturated alkyl.
2. The compound according to claim 1, wherein R1 is preferably an aryl substituted with one or more substituents selected from the group consisting of halogen, hydroxy, lower alkyl, amino and lower alkoxy.
3. The compound according to claim 2, wherein R1 is a phenyl substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, C1-C5 alkyl, amino and C1-C5 alkoxy.
4. The compound according to claim 1, wherein R2 is hydrogen or lower alkyl.
5. The compound according to claim 1, wherein X3 is hydrogen, and n is 1 or 2.
6. The compound according to claim 2, wherein R4 is hydrogen or cyclic lower alkyl containing N or O.
7. The compound according to claim 2, wherein the compound of Formula 1 is selected from the group consisting of
1) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinonitrile
2) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-[4-chloro(methyl)anilino]-phenol
3) Ethyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinate
4) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinic acid
5) 2-[6-amino-5-(hydroxymethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino]phenol
6) 2-{6-amino-5-[(dimethylamino)methyl]-2-pyridinyl}-4-[4- chloro(methyl)anilino]phenol
7) 2- {6-amino-5-[(dimethylamino)methyl]-2-pyridinyl} -4-[4- chloro(methyl)anilino]phenol
8) 2-[6-amino-5-(4-morpholinylmethyl)-2-pyridinyl]-4-[4- chloro(methyl)anilino]phenol
9) 1 - [(2-amino-6- { 5 - [4-chloro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]-2-pyrrolidinone
10) Methyl 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}nicotinate
11) ter t-b\xtyl (2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methylcarbamate
12) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-(3- furylmethyl)nicotinamide
13) Λr-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] acetamide
14) 2-amino-6- { 5-[4-chloro(methyl)anilino] -2-hydroxyphenyl } -N- [3 -(4-methyl- 1 - piperaziny l)propy 1] nicotinamide
15) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-[3-(4- morpholinyl)propyl] nicotinamide
16) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-[3- (dimethylamino)propyl]nicotinamide
17) Ethyl 4-{[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)carbonyl] amino } butanoate
18) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-(4- hydroxybutyl)nicotinamide
19) 2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
20) iV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)niethyl]-2-hydroxyacetamide
21) iV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-cyanoacetamide
22) iV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -3 -methoxypropanamide
23) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] nicotinamide
24) N-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]tetrahydro-2-furancarboxyamide
25) (2i?)-jV-[(2-amino-6-{5-[4-chloro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxypropanamide
26) N- [(2-amino-6- { 5 - [4-chloro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]-2-(4-morpholinyl)acetamide
27) 4- { [(2-amino-6- { 5 - [4-chloro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)carbonyl] amino } butanoic acid 28) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}nicotinic acid
29) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-7V-(2- hydroxyethyl)nicotinamide
30) 2-amino-6- { 5- [4-bromo(methyl)anilino] -2-hydroxyphenyl } -N- [3 -(4- morpholinyl)propyl]nicotinamide
31) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-[2- (diethylamino)ethyl]nicotinamide
32) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-(2- furylmethyl)nicotinamide
33) 2-amino-6-{5-[4-bromo(methyl)anilino]-2-hydroxyphenyl}-N-(3- furylmethyl)nicotinamide
34) 2-amino-6- { 5-[4-bromo(methyl)anilino]-2-hydroxyphenyl} -N-(2- pyridinylmethyl)nicotinamide
35) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinonitrile
36) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinamide
37) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinic acid
38) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-[3-(4- morpholiyl)propyl] nicotinamide
39) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-(2- furylmethyl)nicotinamide
40) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-(2- pyridinylmethyl)nicotinamide
41) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-nicotinonitrile
42) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-nicotinic acid
43) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxyethyl)nicotinamide
44) Ethyl 4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}carbonyl)amino]butanoate
45) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- furylmethyl)nicotinamide
46) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(3- furylmethyl)nicotinamide
47) 2-amino-iV-[3-(dimethylamino)propyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
48) 2-amino-N-[2-(diethylamino)ethyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
49) 2-amino-N-[2-(dimethylamino)ethyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
50) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-dimethylanilino]-2- hydroxyphenyl] -N-(3 -hy droxypropyl)nicotinamide
51) 2-amino-iV-[(l,5-dimethyl-lH-pyrrole-2-yl)methyl]-6-[5-(2-fluoro-4- dimethylanilino)-2-hydroxyphenyl]nicotinamide 52) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-J/V-[3-(4- morpholinyl)propyl]nicotinamide
53) 2-amino-N-[4-(aminosulfonyl)benzyl]-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] nicotinamide
54) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-7V-[4- (methylsulfonyl)benzyl]nicotinamide
55) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- pyridinylmethyl)nicotinamide
56) tert-butyl-4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } carbonyl)amino] - 1 -piperidinecarboxylate
57) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-[(5-methyl-2- pyrazinyl)methyl]nicotinamide
58) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(4- piperidinylmethyl)nicotinamide
59) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-iV-(3- piperidinylmethyl)nicotinamide
60) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-jV-[2-hydroxy- l-(hydroxymethyl)ethyl]nicotinamide
61) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- methoxyethyl)-iV-methylnicotinamide
62) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(2- hydroxyethyl)-iV-methylnicotinamide
63) tert-butyl-2-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } carbonyl)amino] ethyl(methyl)carbamate
64) 4-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl }carbonyl)amino]butanoic acid
65) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-(4- piperidinyl)nicotinamide
66) 2-amino-iV-(l-ethyl-4-piperidinyl)-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl]nicotinamide
67) 2-amino-N-[(l-ethyl-4-piperidinyl)methyl]-6-[5-(2-fluoro-4-dimethylanilino)- 2-hydroxyphenyl]nicotinamide
68) 2-amino-iV-[(l-ethyl-3-piperidinyl)methyl]-6-[5-(2-fluoro-4-diinethylanilino)- 2-hydroxyphenyl] nicotinamide
69) 2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-N-[2- (methylamino)ethyl]nicotinamide
70) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(2-fluoro-4- dimethylanilino)phenol
71) tert-butyl-4-{[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] carbonyl } - 1 -piperidincarboxylate
72) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(2-thienyl)acetamide 73) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-3-(4-morpholinyl)propanamide
74) tert-butyl-4-{2-[({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] -2-oxoethyl } - 1 - piperidinecarboxylate
75) N-({2-amino-6-[5-(2-fluoro-4-diniethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)acetamide
76) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)propanamide
77) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
78) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -( 1 -piperidinyl)propanamide
79) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -hydroxypropanamide
80) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-morpholinyl)acetamide
81) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 -piperidinyl)acetamide
82) J/V-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 -pyrrolidinyl)acetamide 83) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methytycyclopropanecarboxyamide
84) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methytycyclohexanecarboxyamide
85) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxy-2-methylpropanamide
86) (25)-N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
87) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)isonicotinamide
88) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
89) N-( { 2-amino-6- [5 -(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-(3 -pyridinyl)acetamide
90) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 H-iniidazole-4-yl)acetamide
91) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(2-pyridinyl)acetamide
92) N-({2-aniino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
93) N-( { 2-amino-6- [5 -(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-methoxyacetamide
94) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 //-imidazole-4-carboxyamide
95) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methyl-2-butenamide
96) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(methylsulfonyl)acetamide
97) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-oxo-2-pyrrolidinecarboxyamide
98) 2-(acetylaniino)-N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)acetamide
99) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [2-(2-methoxy)ethoxy]acetamide
100) jV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyanoacetamide
101) Λr-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
102) iV-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-(4-piperidinyl)acetamide
103) 2-{ 6-amino-5- [(propylamino)methyl] -2-pyridinyl } -4-(2-fluoro-4- dimethylanilino)phenol 104) 2-(amino-6-{[(3-hydroxypropyl)amino]methyl}-2-pyridinyl)-4-(2-fluoro-4- dimethylanilino)phenol
105) 2- [amino-5 -( { [2-(2-pyridinyl)ethyl]amino } methyl)-2-pyridinyl] -4-(2-fluoro-4- dimethylanilino)phenol
106) 2- [6-amino-5-( { [3 -(4-morpholinyl)propyl] amino } methyl)-2-pyridinyl] -4-(2- fluoro-4-dimethylanilino)phenol
107) Ethyl {2-amino-6-[5-(2-fluoro-4-dimethylaπilino)-2-hydroxyphenyl]-3- pyridinyl} methylcarbamate
108) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)methansulfonamide
109) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)(phenyl)methansufonamide
110) N-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethansulfonamide
111) Ethyl l-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-aziridincarboxylate
112) Ethyl 3-({2-amino-6-[5-(2-fluoro-4-dimethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-oxo- 1 ,3 -oxazolidine-5 -carboxylate
113) 2-(6-amino-5-{[2-(hydroxymethyl)-l-aziridinyl]methyl}-2-pyridinyl)-4-(2- fluoro-4-dimethylanilino)phenol
114) 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyl } nicotinonitrile
115) 2-ammo-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2- hydroxyphenyl} nicotinic acid
116) 2-amino-6-{5-[l,3-benzodioxol-5-yl(methyl)amino]-2-hydroxyphenyl}-iV-(2- hydroxyethyl)nicotinamide
117) 2-amino-6- { 5-[ 1 ,3 -benzodioxol-5-yl(methyl)amino]-2 -hydroxyphenyl } -N-[2- (dimethylamino)ethyl]nicotinamide
118) 2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}nicotinonitrile
119) 2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}nicotinic acid
120) 2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-N-[(5-methyl- 2-pyrazinyl)methyl]nicotinamide
121) 2-amino-iV-(2-hydroxyethyl)-6- {2-hydroxy-5-[4- methoxy(methyl)anilino]phenyl } nicotinamide
122) 2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl} -N- [3 -( 1 H- imidazole-4-yl)propyl]nicotinamide
123) 2-amino-6-{2-hydroxy-5-[4-hydroxy(methyl)anilino]phenyl}-N-[(5-methyl-2- pyrizinyl)methyl] nicotinamide
124) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-[4- methoxy(methyl)anilino]phenol
125) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]-2-(4-morpholinyl)acetamide 126) iV-[(2-amino-6- {2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl} -3- pyridinyl)methyl]tetrahydro-3-furancarboxyamide
127) (2S)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-5-oxo-2-pyrrolidincarboxyamide
128) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]isonicotinamide
129) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-(2-pyridinyl)acetamide
130) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-3-methoxypropanamide
131) iV-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-(lH-imidazole-4-yl)acetamide
132) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-[2-(2-methoxyethoxy)ethoxy]acetamide
133) (21S)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-hydroxypropanamide
134) iV-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-hydroxyacetamide
135) N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-cyanoacetamide
136) (25)-N-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]]-2-hydroxypropanamide
137) iV-[(2-amino-6-{2-hydroxy-5-[4-methoxy(methyl)anilino]phenyl}-3- pyridinyl)methyl]] -2-( 1 H-imidazole-4-yl)acetamide
138) 2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2- hydroxyphenyl]nicotinonitrile
139) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(2-fluoro-4- methoxymethylanilino)phenyl
140) iV-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
141) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
142) iV-({2-aniino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyanoacetamide
143) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
144) N-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahydro-2-furancarboxyamide
145) (25)-iV-({2-amino-6-[5-(2-fluoro-4-methoxymethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)-2-hydroxypropanamide
146) iV-({2-ainino-6-[5-(2-fluoro-4-methoxymethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-morpholinyl)acetamide 147) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinonitrile
148) Ethyl 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinate
149) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]nicotinic acid
150) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- hydroxyethyl)nicotinamide
151) Ethyl 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3-pyridinyl}carbonyl)amino]butanoate
152) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(3- furylmethyl)nicotinamide
153) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- piperidinylmethyl)nicotinamide
154) 2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-N-[(5- methyl-2-pyrazinyl)methyl]nicotinamide
155) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-jV-[4- (methylsulfonyl)benzyl]nicotinamide
156) 2-amino-N-[4-(aminosulfonyl)benzyl]-6-[5-(4-chloro-2-fluoromethylanilino)- 2-hydroxyphenyl]nicotinamide
157) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2- (dimethylamino)ethyl]nicotinamide
158) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2- (diethylamino)ethyl]nicotinamide
159) 2-amino-6- [5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -N- [3 -(4- morpholinyl)propyl] nicotinamide
160) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[3-(4- methyl- 1 -piperazinyl)propyl] nicotinamide
161) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[3-(lH- imidazole-4-yl)propyl]nicotinamide
162) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-7V-(4- piperidinyl)nicotinamide
163) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(l -ethyl- 4-piperidinyl)nicotinamide
164) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- (cyclohexylmethyl)nicotinamide
165) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N- isobutylnicotinamide
166) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- hydroxypropyl)nicitinamide
167) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- hydroxy- 1 -methylethyl)nicotinamide 168) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-J/V-[(li?)-l- (hydroxymethyl)propyl]nicotinamide
169) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(15)-l- (hydroxymethyl)propyl]nicotinamide
170) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-7V-(4- methoxybenzyl)nicotinamide
171) 2-amino-N-(4-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
172) 2-amino-iV-(4-aminobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
173) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- methoxyethyl)nicotinamide
174) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(3- methoxypropyl)nicotinamide
175) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxy- 1 , 1 -dimethylethyl)nicotinamide
176) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-Λr-[2- hydroxy- 1 -(hydroxymethyl)- 1 -methylethyl] nicotinamide
177) 2-amino-6- [5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -N- [( 1 S)- 1 - (hydroxymethyl)-3 -(methylsulfonyl)propyl]nicotinamide
178) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(15)-2- hydroxy- 1 -methylethyl]nicotinamide
179) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(lS)-2- hydroxy-l-(lH-imidazole-4-ylmethyl)ethyl]nicotinamide
180) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[3-(2- methyl- 1 -piperidinyl)propyl]nicotinamide
181) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(l- methyl-2-pyrrolidinyl)ethyl]nicotinamide
182) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- (tetrahydro-2-furanylmethyl)nicotinamide
183) 2-amino-N-benzyl-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
184) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- methoxybenzyl)nicotinamide
185) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- methoxybenzyl)nicotinamide
186) 2-amino-N-(2-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
187) 2-amino-N-(3-chlorobenzyl)-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinamide
188) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- fluorobenzyl)nicotinamide 189) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2- hydroxybenzyl)nicotinamide
190) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- hydroxybenzyl)nicotinamide
191) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(2S)-2- hydroxy- 1 -methyl-2-phenylethyl]nicotinamide
192) Methyl (2R)-2-[({2-amino-6-[5-(4-chloro-2-fluoromethylanylino)-2- hydroxyphenyl] -3 -pyridinyl } carbonyl)amino] propanoate
193) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-jV-[(li?)-2- hydroxy- 1 -methylethyl]nicotinamide
194) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- (cyclopropylmethyl)nicotinamide
195) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- methyl- 1 ,3 -thiazole-2-yl)nicotinamide
196) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(3- hydroxy-2,2-dimethylpropyl)nicotinamide
197) Ethyl 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } carbonyl)amino] - 1 -piperidinecarboxylate
198) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- isopropylnicotinamide
199) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- cyclopropylnicotinamide
200) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV- cyclopentylnicotinamide
201) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-Λf- cyclohexylnicotinamide
202) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-7V-(3- pyridinylmethyl)nicotinamide
203) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(2- pyridinylmethyl)nicotinamide
204) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(3- pyridinyl)nicotinamide
205) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(4- morpholinyl)ethyl]nicotinamide
206) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- hydroxycyclohexy^nicotinamide
207) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(4- pyridinyl)ethyl]nicotinamide
208) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[2-(3- pyridinyl)ethy 1] nicotinamide
209) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(2- pyridinyl)ethyl] nicotinamide 210) 2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-N-{2-[(5- nitro-2-pyridinyl)amino]ethyl}nicotinamide
211) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[3-(2- oxo- 1 -pyrrolidinyl)propyl]nicotinamide
212) 2-amino-6- [5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -N- [2-( 1 - pyrrolidinyl)ethyl]nicotinamide
213) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[2-(l- piperidinyl)ethyl]nicotinamide
214) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(2,3- dihydroxypropyl)nicotinamide
215) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[ 1 - (hydroxymethyl)cyclopentyl]nicotinamide
216) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- pyridinylmethyl)nicotinamide
217) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-[(l R)- 1 - (hydroxymethyl)-3-(methylsulfonyl)propyl]nicotinamide
218) 2-amino-6-[5-(4-chloro-2-fluoroniethylanilino)-2-hydroxyphenyl]-iV-[(l - ethyl-2-pyrrolidinyl)methyl]nicotinamide
219) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-[(l - ethyl-4-piperidinyl)methyl]nicotinamide
220) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-iV-(4- morpholinyl)nicotinamide
221) 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl} carbonyl)amino]butanoic acid
222) 1 - { 2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } - 1 -propanone
223) {2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } (4-chlorophenyl)methanone
224) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-N-(4- hydroxybenzyl)nicotinamide
225) 2-hydroxyethyl 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] nicotinate
226) 2-[6-amino-5-(aminomethyl)-2-pyridinyl]-4-(4-chloro-2- fluoromethylanilino)phenol
227) Λr-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-(4-moφholinyl)acetamide
228) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(4-methyl- 1 -piperazinyl)acetamide
229) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [(2-hydroxyethyl)(methyl)amino] acetamide
230) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(diethylamino)acetamide 231) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)benzamide
232) 7V-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
233) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxyacetamide
234) 7V-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methylbutanamide
235) N-( {2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-4-hydroxybutanamide
236) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -hydroxypropanamide
237) Methyl-4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amide] -4-oxobutanoate
238) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 -methyl-4-piperidinyl)acetamide
239) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -( 1 -piperidinyl)propanamide
240) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -pyridinyl } methyl)acetamide
241) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)propanamide
242) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(4-morpholinyl)propanamide
243) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(diethylamide)propanamide
244) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclobutanecarboxyamide
245) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahydro-3 -furancarboxyamide
246) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [4-(dimethylamino)phenyl] acetamide
247) tert-butyl-2-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl} methyl)amino] -2-oxoethylcarbamate
248) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl }methyl)-2-cyclopentene- 1 -carboxyamide
249) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-2-oxo-l,3-thiazolidine-4-carboxyamide
250) N-( { 2-amino-6- [5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-anilinoacetamide
251) (E)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -(3 -pyridinyl)-2-propenamide 252) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-methylcyclopropanecarboxyamide
253 ) N-( { 2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)- 5 -oxohexanamide
254) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-isooxazolecarboxyamide
255) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-pyrazinecarboxyamide
256) N-( { 2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-3 -hydroxy-2,2-dimethylpropanamide
257) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)isonicotinamide
258) (25)-7V-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
259) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methy^cyclopropanecarboxyamide
260) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-( 1 //-imidazole-4-yl)acetamide
261) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [2-(2-methoxyethoxy)ethoxy] acetamide
262) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -methoxypropanamide
263) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl}methyl)-5-hydroxypentanamide
264) jV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-oxo-2-azetidinecarboxyamide
265) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyclopropylacetamide
266) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2,3 -dihydroxypropanamide
267) JV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2- [bis(2-hydroxyethyl)amino] acetamide
268) 4-amino-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)benzamide
269) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)nicotinamide
270) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-cyanoacetamide
271) Λr-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(methylsulfonyl)acetamide
272) (25)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-5 -oxo-2-pyrrolidinecarboxyamide 273) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-(2-pyridinyl)amide
274) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)tetrahy dro-2-furancarboxyamide
275) (25)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-2-hydroxypropanamide
276) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-3 -furamide
277) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-methyl-2-pyrazinecarboxyamide
278) N-( { 2-amino-6- [5 -(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl] -3 - pyridinyl } methyl)-2-anilinoacetamide
279) tert-butyl-4{[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] carbonyl } - 1 -piperidinecarboxylate
280) 3-amno-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)benzamide
281) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-hydroxybenzamide
282) tert-butyl-(25)-2-{[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2- hydroxyphenyl] -3 -pyridinyl } methyl)amino] carbonyl } - 1 - pyrrolidinecarboxylate 283) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethyl-4-piperidinecarboxyamide
284) 4-[({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-amino] -4-oxobutanoic acid
285) 2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)acetamide
286) 2-(6-amino-5-{[(3-hydroxypropyl)amino]methyl}-2-pyridinyl)-4-(4-chloro-2- fluoromethylanilino)phenol
287) 2-(6-amino-5-{[(2-hydroxyethyl)amino]methyl}-2-pyridinyl)-4-(4-chloro-2- fluoromethylailino)phenol
288) 2-[6-amino-5-({[2-(4-morpholinyl)ethyl]amino}methyl)-2-pyridinyl]-4-(4- chloro-2-fluoromethylanilino)phenol
289) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-piperidinecarboxyamide
290) 2-(6-amino-5- { [(2-anilinoethyl)amino]methyl} -2-pyridinyl)-4-(4-chloro-2- fluoromethylanilino)phenol
291) (2i?)-N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]- 3 -pyridinyl } methyl)-2-pyrrolidincarboxyamide
292) Λr-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)methansulfonamide
293) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -ethansulfonamide
294) iV-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-morpholinecarboxyamide
295) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)- 1 -piperidinecarboxyamide
296) N-({2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl)-4-methyl- 1 -piperazinecarboxyamide
297) 2-{6-amino-5-[(cyclopentylamino)methyl]-2-pyridinyl}-4-(4-chloro-2- fluoromethylanilino)phenol
298) Ethyl- {2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methylcarbamate
299) Ethyl-l-{2-amino-6-[5-(4-chloro-2-fluoromethylanilino)-2-hydroxyphenyl]-3- pyridinyl } methyl-2-aziridincarboxylate
300) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}nicotinonitrile
301) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}nicotinic acid
302) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(2- hydroxyethyl)nicotinamide
303) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[(5-methyl- 2-pyrazinyl)methyl]nicotinamide
304) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl } -N- [3-( 1 H- imidazole-4-yl)propyl]nicotinamide 305) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[(li?)-l- (hydroxymethyl)propyl]nicotinamide
306) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -N- [( 1 R)-2- hydroxy- 1 -methylethyl] nicotinamide
307) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[3-(2- methyl- 1 -piperidinyl)propyl]nicotinamide
308) 2-amino-6-{ 5- [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl} -N- [2-(l- methyl-2-pyrrolidinyl)-ethyl]nicotinamide
309) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-(tetrahydro- 2-furanylmethyl)nicotinamide
310) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl} -7V-(3 -hydroxy - 2,2-dimethylpropyl)nicotinamide
311) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-(2,3- dihydroxypropyl)nicotinamide
312) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-[2-(4- morpholinyl)ethyl]nicotinamide
313) 2-amino-6- { 5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl} -N- isopropylnicotinamide
314) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[3-(2-oxo- 1 -pyrrolidinyl)propyl]nicotinamide
315) 2-amino-6-{ 5- [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl }-JV-(2- pyridinylmethyl)nicotinamide
316) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-(3- pyridinylmethyl)nicotinamide
317) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-(4- pyridinylmethyl)nicotinamide
318) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-N-[2-(2- pyridinyl)ethyl] nicotinamide
319) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-jV-[2-(3- pyridinyl)ethyl]nicotinamide
320) 2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-iV-[2-(4- pyridinyl)ethy 1] nicotinamide
321) 2-amino-N-cyclopropyl-6-{5-[2,4-difluoro(methyl)anilino]-2- hydroxyphenyl } nicotinamide
322) 2-amino-5-(aminomethyl)-2-pyridinyl]-4-[2,4-difluoro(methyl)anilino]phenol
323) jV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxyacetamide
324) JV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] nicotinamide
325) J/V-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2-cyanoacetamide
326) N- [(2-amino-6- { 5 -[2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl] -3 -methoxypropanamide
327) N- [(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]tetrahydro-2-furancarboxyamide
328) (2i?)-N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2-hydroxypropanamide
329) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-(4-morpholinyl)acetamide
330) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-isonicotinamide
331) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyρhenyl}-3- pyridinyl)methyl]-2-pyrazinecarboxyamide
332) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-5-methyl-2-pyrazinecarboxylamide
333) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -3 -furamide
334) N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -tetrahydro-3 -furancarboxyamide
335) 7V-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] acetamide
336) (25)-N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-2-hydroxypropanamide 337) (4S)-N- [(2-amino-6- { 5- [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl]-2,2-dimethyl-l,3-dioxolane-4-carboxyamide
338) iV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2,3 -dihydroxypropanamide
339) (25)-N-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl] -2,3 -dihydroxypropanamide
340) iV-[(2-amino-6-{5-[2,4-difluoro(methyl)anilino]-2-hydroxyphenyl}-3- pyridinyl)methyl]-4-morpholinecarboxyamide
341) N- [(2-amino-6- { 5 - [2,4-difluoro(methyl)anilino] -2-hydroxyphenyl } -3 - pyridinyl)methyl] -4-methyl- 1 -piperazinecarboxyamide
342) 2-amino-6-[5-(2-fluoro-4-methylanilino)-2-hydroxyphenyl]-N-[2-(lH- imidazole-4-yl)ethyl]nicotinamide
8. A process for preparation of the compound of Formula 1 as defined in claim 1 comprising (i) a step of introducing NR1R2 as defined in Formula 1 into 5-bromo-2- hydroxyacetophenone of Formula 2 below as a starting material, (ii) a step of introducing a pyrimidine substituent thereto, and (iii) a step of introducing R3 by the conversion of nitrile group.
Figure imgf000180_0001
9. The process according to claim 8, wherein
the step of performing the conversion of the carboxyl group after the introduction of the pyrimidine substituent comprises,
(a) a step of conducting the formation of two protecting groups to the compound of Formula 2 sequently to produce the compound of Formula 3 below;
Figure imgf000181_0001
where PG means a protecting group and includes, for example, but is not limited to t-butyl, alkyl ether, substituted or unsubstituted benzyl group, and the like,
(b) a step of reacting the compound of Formula 3 with aryl amine by catalyst reaction of palladium and sequently with alkylhalide to produce the compound of Formula 4 below;
Figure imgf000181_0002
where R1 and R2 are the same as in Formula 1 ,
(c) a step of hydrolyzing the compound of Formula 4 by acid catalyst to produce the compound of Formula 5 below;
Figure imgf000182_0001
(d) a step of reacting the compound of Formula 5 with N,N-dimethylformamide diethyl acetal to produce the compound of Formula 6 below;
Figure imgf000182_0002
(e) a step of reacting the compound of Formula 6 with 3,3-diaminacrylonitrile to produce the compound of Formula 7; and
Figure imgf000182_0003
(f) a step of removing the protecting group ('PG') from the compound of Formula 7 to produce the compound of Formula 8.
Figure imgf000182_0004
10. The process according to claim 9, wherein the process for introducing various substituents (R3) by the conversion of the cyano group as defined in Formula 8 comprises,
(al) a step of reducing the cyano group in the compound of Formula 8 to produce the compound of Formula 9 below; and
Figure imgf000183_0001
(b 1 ) a step of introducing a substituent to the compound of Formula 9.
11. The process according to claim 9, wherein the process for introducing various substituents (R3) by the conversion of the cyano group as defined in Formula 8 comprises,
(a2) a step of reacting the cyano group in the compound of Formula 8 with sulfuric acid to produce the compound of Formula 10 below; and
Figure imgf000183_0002
(b2) a step of introducing a substituent to the compound of Formula 10.
12. A process for preparation of the compound of Formula 1 as defined in claim 1 comprising, (i) a step of introducing R1 and R2 as defined in Formula 1 using p- anisidine of Formula 11 below as a starting material, (ii) a step of introducing a pyrimidine substituent thereto, and (iii) a step of introducing R3 by the conversion of nitrile group:
Figure imgf000184_0001
13. Use of the compound of Formula 1 as defined in claim 1 for manufacture of a medicament for the treatment or prevention of diseases involving the undesired KDR activity.
14. The use according to claim 13, wherein the diseases include cancers, psoriasis, rheumatoid arthritis, diabetic retinopathy, ischemic cardiovascular disease, atherosclerosis and Kaposi's sarcoma.
15. A pharmaceutical composition comprising (a) a therapeutically effective amount of the compound of Formula 1 as defined in claim 1, and (b) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
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