Title of Invention

NITROGEN-CONTAINING AROMATIC DERIVATIVES

Abstract Compounds represented by the following general formula, salts thereof, or hydrates of both: wherein X1 is nitrogen or a group represented by the general formula: -CR10=; X2 is nitrogen or a group represented by the general formula: -CR11=; Y is oxygen or the like; R1 is C1-6 alkoxy, optionally substituted C6-10 aryloxy, a group represented by the general formula: -NR12aR12b, or the like; R2 is hydrogen, optionally substituted C1-6 alkyl, or the like; R3, R4, R5, R6, R7, R8, R10, and R11 are each independently hydrogen, halogeno, optionally substituted C1-6 alkyl, or the like; R9 is a group represented by the general formula: -NR16aR16b, or the like; and R12a, R12b, R16a, and R16b are each independently hydrogen, optionally substituted C1-6 alkyl, or the like.
Full Text

Description
NITROGEN-CONTAINING AROMA.TIC DERIVATIVES Technical Field
[0001]
The present invention relates to novel compounds effective for prevention and treatment of various diseases associated with abnormal angiogenesis^ and to the medical compositions such as angiogenesis inhibitors and antitumor agents containing the novel compounds. Background Art
[0002]
Angiogenesis is an essential biological phenomenon for fetal vascular formation and morphological and functional development of organs. New blood vessels are assembled through several processes including endothelial cell migration, proliferation and tube formation, and the participation of mast cells, lymphocytes, interstitial cells and the like has been shown to be important in this process (non-patent literature 1) .
[0003] .
A multiple in vivo angiogenesis-stimulating factors have been identified, particularly Vascular Endothelial Growth Factor (hereinafter abbreviated as "VEGF") and Fibroblast Growth Factor (hereinafter

abbreviated as "FGF") are reported to enhance angiogenesis (non-patent literature 2 and 3).
[0004]
Although physiological angiogenesis occurs at the time of healing of wound or in a female estrous cycle in adult individuals, it is known that pathological increase in angiogenesis in adult individuals is involved in onset or progression of various disease. Specific diseases associated with abnormal angiogenesis include cancer, rheumatoid arthritis, atherosclerosis, diabetic retinopathy, angioma, psoriasis, and the like (non-patent literature 4) . In particular, a literature has indicated angiogenesis dependency for solid tumor growth, and angiogenesis inhibitors are therefore promising as new therapeutic agents for intractable solid tumors (nonpatent literature 5).
[0005]
Patent literature 1 and 2 are provided as prior arts with regard to 6-membered nitrogen-containing aromatic derivatives bonded with substituted indole.
[0006]
Although patent literature 1 describes indole derivatives which suppress VEGF-stimulated angiogenesis based on a selective tyrosine kinase inhibition, the pharmacological test results on their inhibition action

are not disclosed. Although patent literature 2 describes pyridine derivatives bonded with indole ring via an oxygen atom at the 4-position, neither the compound according to the present invention nor their inhibiting actions on FGF-stimulated angiogenesis are disclosed.
[0007]
[patent literature 1] WO 02/16348
[patent literature 2] WO 02/32872
[non-patent literature 1] J. Biol. Chem. , 2 67;. 10931, 1992.
[non-patent literature 2] Endocrinology, 133, 848, 1993.
[non-patent literature 3] Biochem. Biophys. Res. Commun., 147, 876, 1987.
[non-patent literature 4] N. Engl. J. Med., 333, 1757, 1995.
[non-patent literature 5] J. Natl. Cancer Inst., 82, 4, 1990. Disclosure OF Invention
[0008]
It is an object of the present invention to investigate and discover angiogenesis-inhibiting compounds which: (1) exhibit antitumor activity by strongly suppressing both of angiogenesis included by VEGF and FGF which are major in vivo angiogenesis

factors, (2) are highly useful as drug materials in terms of their properties, biokinetics and safety, and (3) are useful for amelioration, prevention and treatment of various diseases associated with abnormal increase in angiogenesis. [0009]
As a result of much diligent research in light of the circumstances described above, the present inventors have succeeded in synthesizing novel pyridine derivatives and pyrimidine derivatives represented by the following general formula (I) , salts thereof, or hydrates of the foregoing. At the same time, the inventors have completed the present invention upon discovering that these compounds, the salts thereof, or the hydrates of the foregoing exhibit an excellent angiogenesis-inhibiting effect.


represented by the formula -CR10=, X2 represents a nitrogen atom or a group represented by the formula -CR11, and X1 and X2 do not represent a nitrogen atom at the same time;
Y represents an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, or a group represented by the formula -NRy- (wherein Ry represents a hydrogen atom or a C1-6 alkyl group) ;
Ri represents an optionally substituted C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NRi2aRi2bf a group represented by the formula:



(wherein Tl represents an optionally substituted 5- to 10- membered aromatic heterocycle which may have X in the ring or an optionally substituted 3- to 10-membered heterocycle which may have X in the ring); R3, R4, Rsf R6, R7, R8, R10 and R11 each independently represent a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, a group represented by the formula -CO-R13, a group represented by the formula -NR14-CO-R13, a group represented by the formula -S02-R15, a group represented by the formula -NR14-SO2-


(wherein T2 represents an optionally substituted 5- to 10- mexnbered aromatic heterocycle or an optionally substituted 3- to 10- meinbered heterocycle) ; Ri2a and Ri2b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 alkenyl group, an optionally substituted C3-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted 3- to 10- membered heterocyclic group, or an optionally substituted C1-6 alkoxy group; Ri3 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5- to 10- membered heteroaryl group, an optionally substituted 3- to 10- membered heterocyclic group, an optionally substituted C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12b, or a group represented by the formula:


(wherein T2 represents an optionally substituted 5- to 10- membered aromatic heterocycle or an optionally substituted 3- to 10- membered heterocycle); R2 and R14 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, or a group represented by the formula -CO-R13;
R15 represents an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5- to 10- membered heteroaryl group, or an optionally substituted 3- to 10- membered heterocyclic group; R16a and R16b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 alkenyl group, an optionally substituted C3-6 alkynyl group, an optionally substituted C3-6 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5- to 10- membered heteroaryl group, an optionally substituted 3- to 10- membered heterocyclic group, or

an optionally substituted C1-6 alkoxy group; and X represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, a group represented by the formula -CRx1Rx2- or a group represented by the formula -NRx3- (wherein Rx1, Rx2 and Rx3 each independently represent a hydrogen atom or a group represented by the formula -A1-A2-A3 (wherein A1 and A2 each independently represent a single bond, an optionally substituted C1-6 alkylene group or a carbonyl group; and A3 represents a hydrogen atom, a C3-8 cycloalkyl group, a group represented by the formula -NRAIRA2, or the formula -0RA3 (wherein, RA1, RA2 and RA3 each independently represent a hydrogen atom or a C1-6 alkyl group), or an optionally substituted group represented by the formula:


R4, R5, R6, R7, R8 and R9 in , respectively,
a salt thereof, or a hydrate of the foregoing;
a compound according to or , a salt of the
compound, or a hydrate of the foregoing, wherein Y
represents an oxygen atom, a group represented by the
formula -NH-, or a group represented by the formula -
N(CH3)-;
a compound according to or , a salt of the
compound, or a hydrate of the foregoing, wherein Y
represents an oxygen atom;
a compound according to any of to , a salt
of the compound, or a hydrate of the foregoing, wherein
one of X1 and X2 represents a group represented by the
formula -CH= and the other represents a nitrogen atom;
a compound according to any of to , a salt
of the compound, or a hydrate of the foregoing, wherein
both X1 and X2 represent a group represented by the
formula -CH=;
a compound according to any of to , a salt
of the compound, or a hydrate of the foregoing^ wherein
R3, R4, R5, R6 and R8 each represent a hydrogen atom,
and R7 represents a hydrogen atom, a halogen atom or an
optionally substituted C1-6 alkyl group;
a compound according to any of to , a salt
of the compound, or a hydrate of the foregoing, wherein
R9 represents a group represented by the formula -NHR17

(wherein R17 represents an optionally substituted C1-6 alkyl group, a C3-6 alkynyl group, a C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group or an optionally substituted 5- to 10- membered heteroaryl group);
a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula -NR18aR18b (wherein R18a and R18b each independently represent a C-6 alkyl group) ;
a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula:


a compound according to any of to r a salt of the compound^ or a hydrate of the foregoing, wherein R2 represents a hydrogen atom;
a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula -NHR20 (wherein R20 represents a methyl group, an ethyl group or a cyclopropyl group);
a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula -NH(CH3) ;
a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R1 represents a further optionally substituted group represented by the formula:


a compound according to , a salt of the
compound/ or a hydrate of the foregoing, wherein X in
the formula (IV) represents an oxygen atom;
a compound according to " , a salt of the
compound, or a hydrate of the foregoing, wherein X in
the formula (IV) represents a group represented by the
formula:


A7-A8-A9 (wherein A? and AB each independently represent a single bond, an optionally substituted C1-6 alkylene group or a carbonyl group; and A9 represents a hydrogen atom, a C3-8 cycloalkyl group, a group represented by the formula -NRA7RA8, or the formula -0RA9 (wherein RA7, RABT and RA9 each independently represent a hydrogen atom or a C1-6 alkyl group) , or a group represented by the formula:



(wherein Rx51 and Rx61 each independently represent a hydrogen atom or a group represented by the formula -A71-A81-A91 (wherein A71 and A81 each independently represent a single bond,- an optionally substituted C1-6 alkylene group or a carbonyl group; and A91 represents a hydrogen atom,. a C3-8 cycloalkyl group, a group represented by the formula -NRA71RA81 or the formula -0RA91 (wherein RA71, RA81, and RA91 each independently represent a hydrogen atom or a C1-6 alkyl group) , or a group represented by the formula:


bond, an oxygen atom, a carbonyl group, or a sulfonyl group; and A12 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a group represented by the formula -NRAioRAiir or the formula -0RAI2 (wherein, RAiOf RAH and RA12 each independently represent a hydrogen atom, a C1-6 alkyl group or a C3-8 cycloalkyl group) , or a group represented by the formula:


independently represent a hydrogen atom, a C1-6 alkyl group or a C3-8 cycloalkyl group), or a group represented by the formula:

wherein Substituent Group Alpha is a group consisting of a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a carboxyl group, an amino group, a C1-6 alkyl group, a Ca-e cycloalkyl group, and a group represented by the formulas:


a compound according to any of to ;. a salt of the compound, or a hydrate of the foregoing,, wherein Ri represents a group represented by the formulas:


a compound according to any of to , a salt of the compound, or a hydrate of the foregoing, wherein R1 represents a group represented by the formulas:



(each of the foregoing members being optionally substituted with a group selected from Substituent Group Beta,
wherein Substituent Group Beta is a group consisting of a hydroxyl group, a C1-6 alkyl group, a C3-8 cycloalkyl group, and a group represented by the formulas:


(1) Nl-ethyl-5-(2-((methoxylamino)carbonyl)amino-4-
pyrimidyl)oxy-lH-indolecarboxamider
(2) 5-(6-(3-(3-
diethylaminopropylaiaino) ureido)pyrimidin-4-yloxy) -IH-
indole-1-carboxylic acid laethylamide,
(3) 5-(6-(((4-hydroxypiperidin-l-yl)carbonyl)amino)-
pyrimidin-4-yloxy)-lH-indole-1-carboxylic acid
methylamide^
(4) 5- (6-((4-pyrrolidin-l-yl)piperidin-1-
yl)carbonylamino)pyrimidin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(5) 5-(2-(3-((IR)-l-carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(6) 5-(2-(3-((lS)-l-carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(7) 5-(2-(3-(2-0X0-2-(pyrrolidin-1-
yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;.
(8) 5-(2-(3-(2-(4-hydroxy-4-methylpiperidin-l-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(9) 5-(2-(3-((IS)-1-carbamoylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(10) 5-(2-(3-((IS)-l-carbamoyl-3-

I
methylbutyl)ureido) pyridin-4-yloxy) -lH-indole-1-carboxylic acid methylamide,
(11) 5-(2- (3-carbamoylmethylureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide,
(12) 5- (2- (3-cyclopropylcarbamoylmethylureido)pyridin-
4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(13) 5- (2-(3-((IS)-l-carbamoyl-2-
hydroxyethyl) -areido) pyridin-4-yloxy) -lH-indole-1-
carboxylic acid methylamide,
(14) 5-(2-(3-((lR)-l-carbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(15) (2S)-2-(3-(4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)ureido)-1,5-pentanedicarboxylic acid diamide,
(16) (2S)-2- (3-(4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)ureido)succinamide,
(17) 5- (2- (3- ( (IS)-l-cyclopropylcarbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(18) 5-(2- (3-((IS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(19) 5-(2-(3-((IR)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide.

(20) 5- (2- (3- ( (1S) -l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(21) 5-(2-(3-((lR)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;.
(22) 5- (2- (3- ( (IS) -l-hydroxyiaethyl-2- (4-
hydroxypiperidin-1-yl) -2-oxoethyl) ureido) pyridin-4-
yloxy)-lH-indole-1-carboxylic acid methylamide,
(23) 5- (2- (3- ( (IS) -l-hydroxymethyl-2- (inorpholin-4-yl) -
2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(24) 5-(2-(3-(2-
cyclopropylcarbamoylethyl)ureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide,
(25) 5- (2-(3-(3-OXO-3-(pyrrolidin-1-
yl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(26) 5- (2-(3-(3-(4-hydroxy-4-methylpiperidin-l-yl)-3-
oxopropyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(27) Nl-ethyl-5-(2-(((2-
ethoxyethyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(28) Nl-methyl-5-(2-((4-(2-hydroxy-2-
methylpropionyl ) piperazin-l-yl)carbonyl)amino-4-

pyridyl)oxy-lH-1-indolecarboxamider
(29) Nl-methyl-S-(2-((3-
(diethylamino)propylamino)carbonyl)amino-4-pyridyl)oxy-
lH-1-indolecarboxamide,
(30) Nl-methyl-5-(2-(((3-(4-
hydroxypiperidino)propyl)amino)carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(31) Nl-methyl-5-(2-(((3-(4-methylpiperazin-l-
yl)propyl) amino)carbonyl) amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(32) 5-(2-(3-(4-OXO-4-(pyrrolidin-1-
yl)butyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(33) 5-(2-(3-(3-
(cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy) -
lH-indole-1-carboxylic acid methylamide,
(34) 5- (2- (3-(4-(4-hydroxy-4-methylpiperidin-l-yl)-4-
oxobutyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(35) 5-(2-(3-(3-
(diethylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide,
(36) 5-(2-(3-(3-(methylcarbamoyl)propyl)ureido)pyridin-
4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(37 ) Nl-methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide.

(38) Nl-methyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamider
(39) Nl-methyl-5-(2- ( (4-
hydroxypiperidino) carbonyl) ainino-4-pyridyl) oxy-lH-1-
indolecarboxamide.
(40) Nl-raethyl-5- (2- (4-oxopiperidin-l-ylcarbonyl) aiaino-
4-pyridyl)oxy-lH-l-indolecarboxamide,
(41) 5- (2-(((4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(42) Nl-methyl-5-(2-((4-(1-hydroxy-l-
methylethyl)piperidino)carbonyl) amino-4-pyridyl)oxy-lH-
1-indolecarboxamide,
(43) 5-(2-(((4- (3-methylcarbamoylpropyl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(44) 5- (2-( ( (4-(3-carbamoylpropyl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(45) 5-(2-((4-((pyrrolidin-1-yl)carbonyl)piperidin-1-
yl)carbonylamino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(46) Nl-methyl-5-(2-{((4-(pyrrolidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide.
(47) Nl-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-

yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide,
(48) Nl-methyl-5-(2-((4-ethylpipera2in-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-l-indolecarboxamide,
(49) Nl-methyl-5-(2-((4-(2-hydroxyethyl)piperazin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide,
(50) Nl-methyl-5-(2-((3-
methylsulfonylpropylamino)carbonyl)amino-4-pyridyl)oxy-
lH-1-indolecarboxamide,
(51) Nl-methyl-5-(2-( (4- (2-
dimethylaminoacetyl)piperazin-l-yl)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(52) Nl-methyl-5-(2-((4-cyclohexylpiperazin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide^
(53) N4-(4-(l-(methylamino)carbonyl-lH-5-indolyl)oxy-2-
pyridyl)-4-morpholinecarboxamide,
(54) Nl-methyl-5-(2-((1,l-dioxothiomorpholin-4-
ylcarbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(55) 5-(2-(3-((IR)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide,
(56) 5-(2-(3-((IS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide^.
(57) 5-(2- (3-((IR)-l-hydroxymethyl-2-oxo-2-piperidin-l-

ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide,
(58) 5- (2- (3- ( (IS) -l-hydroxy.ethyl-2-oxo-2-piperidin-l-
ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid ethylamide.
(59) 5-(2-(3-(2-(4-hydroxy-4-methylpiperidin-l-yl)-2-
oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid ethylamide,
(60) Nl-ethyl-5-(2-((((l-methyl-4-
piperidyl)methyl)amino)carbonyl) amino-4-pyridyl)oxy-lH-
1-indolecarboxamide,
(61) Nl-ethyl-5-(2-(((2-
diethylamino)ethyl)amino)carbonyl) amino-4-pyridyl)oxy-
IH-l-indolecarboxamide^
(62) Nl-ethyl-5-(2-(((2-(morpholin-4-
yl)ethyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(63) Nl-ethyl-5-(2-( ( (2-(4-
hydroxypiperidino) ethyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(64) Nl-methyl-5-(2- ( ((2- (4-
hydroxypiperidino)ethyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(65) Nl-ethyl-5-(2-((3-
(diethylamino)propylamine)carbonyl) amino-4-pyridyl)oxy-
lH-1-indolecarboxamide,

(66) Nl-ethyl-5-(2-(((3-(morpholin-4-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(67) Nl-ethyl-5-(2-( ( (3-(4-xnethylpiperazin-l-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(68) Nl-cyclopropyl-5-(2-(((4-(pyrrolidin-1-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(69) 5-(2-(3-((IR)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide,
(70) 5- (2- (3- ( (IS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide,

(71) 5-(2-(3-(2-OXO-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide,
(72) 5-(2-(3-(3-OXO-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide,

(73) 5-(2-(3-((lR)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide,
(74) 5-(2-(3-((lS)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic

acid cyclopropylamide.
(75) Nl-phenyl-5-(2-( ( (3-
(diethylaiaino) propyl) amino) carbonyl) ainino-4-
pyridyl) oxy-lH-1-indolecarboxamide;-
(76) Nl-phenyl-5-(2-(((3-(4-methylpiperazin-l-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(77) Nl-ethyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(78) 5-(2-(((4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole~l-
carboxylic acid ethylamide.
(79) Nl-ethyl-5-(2-((4-hydroxypiperidin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide,
(80) Nl-ethyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(81) Nl-ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-
pyridyl)oxy)-lH-1-indolecarboxamide,
(82) N4- (4-((l-(ethylamino)carbonyl-lH-5-indolyl)oxy)-
2-pyridyl)-4-morpholinecarboxamide,
(83) Nl-ethyl-5-(2-((1,l-dioxothiomorpholin-4-
ylcarbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide.
(84) Nl-ethyl-5-(2-((methoxylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,

(85) Nl-cyclopropyl-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxainide,
(86) Nl-cyclopropyl-5-(2-(((4-hydroxy-4-
methylpiperidin-l-yl)carbonyl)amino)pyridin-4-yloxy)-
lH-1-indolecarbox-amide,
(87) N4-(4-(l-(cyclopropylamino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,
(88) Nl-cyclopropyl-5-(2-((pyrrolidin-1-
ylcarbonyl)amino)-4-pyridyl)oxy-lH-1-indolecarboxamide,
(89) Nl-cyclopropyl-5-(2-(piperidin-1-ylcarbonyl)amino-
4-pyridyl)oxy-lH-1-indolecarboxamide,
(90) N4-(4-(1-(cyclopentylamino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,
(91) 5- (2-(((4-hydroxypiperidin-l-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid cyclopentylamide,
(92) Nl-cyclopentyl-5-(2-((4-(pyrrolidin-1-
yl)piperidin-1-ylcarbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(93) Nl-(3-methylbutyl)-5-(2-(((4-(pyrrolidin-1-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(94) Nl-(3-methylbutyl)-5-(2-( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamider

(95) N4-(4-(l-((3-methylbutyl)amino)carbonyl-lH-5-
indolyl) oxy-2-pyridyl) -4-morpholinecarboxamide,
(96) Nl-(1-ethylpropyl)-5-(2-(((4-(pyrrolidin-1-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(97) Nl-(1-ethylpropyl)-5-(2- ( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(98) N4-(4-(1-((1-ethylpropyl) amino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,
(99) N4-(4-(1-((1-pentyl) amino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,
(100) Nl-(1-pentyl)-5-(2-(((4-hydroxypiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;.
(101) Nl-(1-pentyl)-5-(2-((4-(pyrrolidin-1-
yl)piperidin-l-ylcarbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide.
(102) Nl-methyl-3-chloro-5-(2-(((3-
(diethylamino)propyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-l-indolecarboxamide,
(103) Nl-methyl-3-chloro-5-(2-((4-(pyrrolidin-1-
yl)piperidino)carbonyl) amino-4-pyridyl)oxy-lH-1-
indolecarboxamider
(104) Nl-methyl-3-chloro-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-

indolecarboxamide.
(105) Nl-methyl-3-chloro-5-(2-(((3-(4-
hydroxypiperidino)propyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(106) Nl-methyl-3-chloro-5-(2-((4-(2-
hydroxyethyl) piperazin-1-yl) carbonyl) ainino-4 -
pyridyl)oxy-lH-l-indolecarboxamide,
(107) N4-(4-(3-chloro-l-(methyl amino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide,
(108) Nl-methyl-3-chloro-5-(2-((4-(ethylpiperazin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide,
(109) Nl-ethyl-3-chloro-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(110) Nl-ethyl-3-chloro-5-(2-(((3- (4-
hydroxypiperidino)propyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamider
(111) Nl-ethyl-3-chloro-5-(2-(((3-
(diethylamino)propyl)amino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(112) Nl,3-dimethyl-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(113) Nl,3-dimethyl-5-(2-((4-(pyrrolidin-1-
yl)piperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide^

(114) Nl-cylopropyl-5- (2- ( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-3-
methyl-lH-1-indolecarboxamide,
(115) Nl-cylopropyl-5-(2-((4-(2-hydroxyethyl)piperazin-
1-yl) carbonyl) amino-4-pyridyl) oxy-3-inethyl-lH-l-
indolecarboxamide,
(116) Nl-methyl-5-(2-((methylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamider
(117) Nl-methyl-5-(2-((diethylamino)carbonyl)amino-4-
pyridyl) oxy-lH-1-indolecarboxamide;.
(118) Nl-(2-propynyl)-5-(2-{(pyrrolidin-1-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(119) Nl-methyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamider
(120) Nl-ethyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(121) Nl-cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-
4-pyridyl) oxy-lH-1-indolecarboxamide;-
(122) Nl-methyl-5-(2-(((4-(morpholin-4-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(123) Nl-methyl-5-(2-(((4-(azetidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(124) Nl-methyl-5-(2-(((4-(diethylamino)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-

indolecarboxamide,
(125) Nl-methyl-5-(2- ( ( (4-(4-hydroxypiperidin-l-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide, and
(12 6) Nl-propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4" pyridyl)oxy-lH-1-indolecarboxamide;
a compound according to , a salt of the compound, or a hydrate of the foregoing, wherein the compound is a compound selected from a group consisting of
(1) 5- (2- (3-(2-OXO-2-(pyrrolidin-1-
yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(2) 5-(2- (3-carbamoylmethylureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide,
(3) 5-(2-(3-((IS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-l-
ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(4) Nl-methyl-5-(2-((4-(2-hydroxy-2-
methylpropionyl)piperazin-l-yl)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(5) 5- (2- (3- (4-OXO-4-(pyrrolidin-1-
yl)butyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(6) 5-(2-(3-(3-
(cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-

lH-indole-1-carboxylic acid methylamide,
(7) 5-(2-(3-(4- (4-hydroxy-4-inethylpiperidin-l-yl) -4-
oxobutyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide,
(8) 5-(2-(3-(3-(methylcarbamoyl)propyl)ureido)pyridin-
4-yloxy)-lH-indole-1-carboxylic acid methylamide,
(9) Nl-methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(10) Nl-methyl-5-(2- ( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(11) Nl-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-
4-pyridyl)oxy-lH-1-indolecarboxamide,
(12) 5-(2-(((4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(13) 5-(2-(((4-(3-methylcarbamoylpropyl)piperidin-1-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(14) 5-(2-(((4-(3-carbamoylpropyl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(15) Nl-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(16) Nl-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-

yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide,
(17) Nl-methyl-5-(2-( (3-
methylsulfonylpropylamino)carbonyl) amino-4-pyridyl)oxy-
lH-1-indolecarboxamide,
(18) N4- (4- (1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-
pyridyl)-4-morpholinecarboxamide,
(19) Nl-cyclopropyl-5-(2-(((4-(pyrrolidin-1-
yl)piperidin-1-yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide r
(20) 5- (2- ( ( (4-hydroxy-4-inethylpiperidin-l-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid ethylamide,
(21) Nl-ethyl-5-(2-((4-hydroxypiperidin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide,
(22) Nl-ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-
pyridyl)oxy)-lH-1-indolecarboxamide,
(23) N4- (4-((1-(ethylamino)carbonyl-lH-5-indolyl)oxy)-
2-pyridyl)-4-morpholinecarboxamide,
(24) Nl-cyclopropyl-5-(2-((pyrrolidin-1-
ylcarbonyl)amino)-4-pyridyl)oxy-lH-1-indolecarboxamide,
(25) Nl-methyl-3-chloro-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;.
(26) Nl-methyl-5-(2-((methylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide.

(27) Nl-methyl-5-(2-((diethylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(28) Nl-(2-propynyl)-5-(2-( (pyrrolidin-1-
yl)carbonyl)amino-4-pyridyl)oxy-lH-l-indolecarboxamide,
(2 9) Nl-methyl-5-(2-(azetidin-l-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide,
(30) Nl-ethyl-5-(2-(azetidin-l-ylcarbonyl)amino-4-
pyridyl)oxy-lH-l-indolecarboxamide,
(31) Nl-cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-
4-pyridyl)oxy-lH-1-indolecarboxamide,
(32) Nl-methyl-5-(2-(((4-(morpholin-4-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide^.
(33) Nl-methyl-5-(2-(((4-(azetidin-l-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(34 ) Nl-methyl-5-(2-(((4-(diethylamino)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide,
(35) Nl-methyl-5-(2-(((4-(4-hydroxypiperidin-l-
yl)piperidin-1-yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide and
(36) Nl-propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
a compound according to ,' a salt of the compound, or a hydrate of the foregoing, wherein the

compound is a compound selected from a group consisting of
(1) 5-(2-(((4-hydroxy-4-methylpiperidin-l-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide,
(2) Nl-methyl-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide,
(3) Nl-methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide,
(4) Nl-methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide, and
(5) N4-(4- (1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-
pyridyl)-4-morpholinecarboxamide;
a pharmaceutical composition comprising a compound
according to any of to and a pharmaceutical
adjuvant;
a prophylactic or therapeutic agent for a disease
for which angiogenesis inhibition is effective,
comprising as an active ingredient, a compound
according to any of to , a salt thereof, or a
hydrate of the foregoing;
an angiogenesis inhibitor comprising as an active
ingredient, a compound according to any of to ,

a salt thereof, or a hydrate of the foregoing;
an antitumor agent comprising as an active
ingredient, a compound according to any of to ,
a salt thereof, or a hydrate of the foregoing;
an antitumor agent according to , wherein the
tumor is a pancreatic cancer, a gastric cancer, a colon
cancer, a breast cancer, a prostate cancer, a lung
cancer, a renal cancer, a brain tumor, a blood cancer,
or an ovarian cancer;
a therapeutic agent for hemangioma comprising as
an active ingredient , a compound according to any of
to , a salt thereof, or a hydrate of the
foregoing;
a cancer metastasis inhibitor comprising as an
active ingredient, a compound according to any of
to , a salt thereof, or a hydrate of the foregoing;
a therapeutic agent for retinal neovascularization
or diabetic retinopathy comprising as an active
ingredient, a compound according to any of to ,
a salt thereof, or a hydrate of the foregoing;
a therapeutic agent for an inflammatory disease
comprising as an active ingredient, a compound
according to any of to , a salt thereof, or a
hydrate of the foregoing;
a therapeutic agent for an inflammatory disease
according to , wherein the inflammatory disease is

deformant arthritis, rheumatoid arthritis, psoriasis or
delayed hypersensitivity reaction;
a therapeutic agent for atherosclerosis comprising
as an active ingredient, a compound according to any of
to , a salt thereof, or a hydrate of the
foregoing;
an angiogenesis inhibition-based antitumor agent
comprising as an active ingredient, a compound
according to any of to , a salt thereof, or a
hydrate of the foregoing;
a prophylactic or therapeutic method for a disease
for which angiogenesis inhibition is effective,
comprising administering to a patient, a
pharmacologically effective dose of a compound
according to any of to , a salt thereof, or a
hydrate of the foregoing; and
use of a compound according to any of to ,
a salt thereof, or a hydrate of the foregoing for the
manufacture of a prophylactic or therapeutic agent for
a disease for which angiogenesis inhibition is
effective.
Best mode for carrying out the Invention
[0011]
The meanings of the terms, symbols or the like used in the specification are described and the present invention is described in detail below.

It should be noted that, although the structural formula of a compound may indicate a certain isomer for convenience's sake in this specification, the present invention include all geometrical isomers generated in the structures of compounds, isomers such as optical isomers based on asymmetric carbon atom, stereoisomers and tautomers, and a mixture of isomers, which are not limited to the descriptions of formulas for convenience's sake, either of isomers or mixtures may be included- Therefore, although optically active compounds and racemic compounds may be existent when they have asymmetric carbon atoms in a molecule;, they are not particularly limited in the present invention and any cases are included. In addition, although a variety of crystal morphism are existent, these are not limited similarly. Specifically, any of a single crystal form or mixtures may be included, in addition, anhydrates, hydrates or solvates may be included.
[0013]
In addition, compounds according to the present invention also include compounds which still indicate a desired activity after they are subjected to metabolism such as oxidation, reduction, hydrolysis and conjugation in an organism, and the present invention

according to the present invention after they are subjected to metabolism such as oxidation, reduction and hydrolysis.
[0014]
The term 'Xi-e alkyl group" as described in the specification represents a linear or branched alkyl group of 1 to 6 carbon atoms, which is a monovalent group derived by removing a hydrogen atom from an aliphatic hydrocarbon of 1 to 6 carbon atoms. As specific examples there may be mentioned methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, n-pentyl group, i-pentyl group, sec-pentyl group, neopentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, i-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, l-ethyl-2-methylpropyl group or the like, and preferably methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group and t-butyl group.

The term 'C2-6 alkenyl group" as described in the specification represents a linear or branched alkenyl group of 2 to 6 carbon atoms which may contain 1 to 2 double bonds. As specific examples there may be mentioned ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-l-propenyl group, pentenyl group, hexenyl group, hexandienyl group or the like, and preferably ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-methyl-l-propenyl group.
[0016]
The term "C3-6 alkenyl group" as described in the specification represents a linear or branched alkenyl of 3 to 6 carbon atoms which may contain 1 to 2 double bonds. As specific examples there may be mentioned 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-l-propenyl group, pentenyl group, hexenyl group, hexandienyl group or the like, and preferably 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group and 2-methyl-l-propenyl group. [0017]
The term 'C2-6 alkynyl group" as described in the specification represents a linear or branched alkynyl

group of 2 to 6 carbon atoms which may contain 1 to 2 triple bonds- As specific examples there may be menti oned ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group, hexandiynyl group or the like, and preferably ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynyl group.
[0018]
The term 'C3-6 alkynyl group" as described in the specification represents a linear or branched alkynyl group of 3 to 6 carbon atoms which may contain 1 to 2 triple bonds. As specific examples there may be mentioned 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group, hexynyl group, hexandiynyl group or the like, and preferably 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group and 3-butynyl group.
[0019]
The term 'C3-8 cycloalkyl group" as described in the specification represents a cyclic aliphatic hydrocarbon group of 3 to 8 carbon atoms, and as specific examples there may be mentioned cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group or the like, and preferably cyclopropyl group, cyclobutyl group and

cyclopentyl group.
[0020]
The term 'C1-6 alkylene group" as described in the specification represents a divalent group derived by further removing a hydrogen atom from the aforementioned definition of 'C1-6 alkyl group." As specific examples there may be mentioned methylene group, ethylene group, methylethylene group, propylene group, ethylethylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, tetramethylene group, pentamethylene group, hexamethylene group or the like, and preferably methylene group and ethylene group.
[0021]
The term "C1-6 alkoxy group" as described in the specification represents' an oxy group bonded with the aforementioned definition of 'C1-6 alkyl group." As specific examples there may be mentioned methoxy group, ethoxy group, n^propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxy group, i-pentyloxy group, sec-pentyloxy group, neopentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,1-dimethylpropoxy group, 1,2-dimethylpropoxy group, n-hexyloxy group, i-hexyloxy group, 1-methylpentyloxy group, 2-menthylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy

group, 1,3-dimethylbutoxy group, 2, S-dimethylbutoxy group, 3,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1,1,2-triinethylpropoxy group, 1,2,2-triraethylpropoxy group, 1-ethyl-l-methylpropoxy group, l-ethyl-2-methylpropoxy group or the like, and preferably methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, and t-butoxy group.
[0022]
The term C1-6 alkylthio group" as described in the specification represents a thio group bonded with the aforementioned definition of "^C1-6 alkyl group." As specific examples there may be mentioned methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group, t-butylthio group, n-pentylthio group, i-pentylthio group, sec-pentylthio group, neopentylthio group, 1-methylbutylthio group, 2-methylbutylthio group, 1,1-dimethylpropylthio group, 1,2-dimethylpropylthio group, n-hexylthio group, i-hexylthio group, 1-methylpentylthio group, 2-methylpentylthio group, 3-methylpentylthio group, 1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group, 2,3-dimethylbutylthio group, 3,3-dimethyIbutylthio group, 1-ethylbutylthio group, 2-

ethylbutylthio group, 1,1,2-triiuethylpropylthio group, 1,2,2-trimethylpropylthio group, 1-ethyl-l^ methylpropylthio group, l-ethyl-2-methylpropylthio group or the like, and preferably methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, sec-butylthio group and t-butylthio group.
[0023]
The term "C6-10 aryl group" as described in the specification represents an aromatic hydrocarbon ring group of 6 to 10 carbon atoms. As specific examples there may be mentioned phenyl group, 1-naphthyl group, 2-naphthyl group, indenyl group, azulenyl group, heptalenyl group or the like, and preferably phenyl group, 1-naphthyl group and 2-naphthyl group.
[0024]
The term ^^C6-10 aryloxy group" as described in the specification represents an oxy group bonded with the aforementioned definition of 'C6-10 aryl group." As specific examples there may be mentioned phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group, indenyloxy group, azulenyloxy group, heptalenyloxy group or the like, and preferably phenoxy group, 1-naphthyloxy group and 2-naphthyloxy group.
[0025]
The term 'halogen atom" as described in the

specification represents fluorine atom, chlorine atom, bromine atom or iodine atom, and preferably fluorine atom, chlorine atom and bromine atom.
[0026]
The term ""'heteroatom" as described in the specification represents nitrogen atom, sulfur atom, or oxygen atom.
[0027]
The term "5- to 10- membered aromatic heterocycle" as described in the specification represents an aromatic ring in which the number of atoms forming the ring is 5 to 10, and 1 to a plurality of heteroatoms are contained in the atoms forming the ring. Specific examples are pyrrole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, pyrazole ring, imidazole ring, triazole ring, tetrazole ring, indole ring, isoindole ring, indazole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxaline ring, naphthyridine ring, phthalazine ring, carbazole ring, purine ring, furan ring, thiophene ring, benzimidazole ring, imidazopyridine ring, imidazotriazine ring, pyrrolopyridine ring, pyrrolopyrimidine ring, pyridopyrimidine ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, phenoxazine ring, phenothiazine ring, .furopyrrole ring, imidazothiazole

ring, benzoxazole ring, benzthiazole ring, pyrazoloxazole ring, pyridoxazine ring, benzofuran ring, benzothiophene ring or the like, and preferably furan ring, thiophen ring, and thiazole ring.
[0028]
The term "5- to 10- membered heteroaryl group" as described in the specification represents a monovalent group derived by removing a hydrogen atom from the aforementioned definition of '5- to 10-membered aromatic heterocycle."
[0029]
The term '3- to 10- membered heterocycle" as described in the specification represents,
(1) a monocyclic or bicyclic non-aromatic ring
(2) having 3 to 10 atoms in the ring,
(3) containing 1 to 2 hetero atoms among the atoms of the ring,
(4) optionally including 1 to 2 double bonds in the
ring, and
(5) optionally including 1 to 3 carbonyl groups or 1 to
3 sulfonyl groups in the ring.
Specific examples are aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, 4-oxopiperidine ring, homopiperidine ring, piperazine ring, homopiperazine ring, morpholine ring, thiomorpholine ring, 1,1-dioxothiomorpholine ring, pyridone ring, phthalimide

ring, succinimide ring or the like, and preferably azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring and thiomorpholine ring.
[0030]
The term 3- to 10- membered heterocyclic group" as described in the specification represents a monovalent group derived by removing a hydrogen atom from the aforementioned definition of '5- to 10-membered heterocycle."
[0031]
The term 'optionally substituted" as described in the specification is equivalent in the meaning as in "which may have 1 or a plurality of substituents by arbitrarily combining them at substitutable positions". As specific examples of such substituents there may be mentioned the following:
(1) a halogen atom,
(2) a hydroxyl group,
(3) a thiol group,
(4) a nitro group,
(5) a cyano group,
(6) an azido group,
(7) a formyl group,
{8) a carboxyl group, (9) an amino group.

(10) an oxo group or
(11) a group represented by the formula -T1-T2-T3,
wherein T1 represents a single bond or a C1-6 alkylene
group; T2 represents a single bond, a C1-6 alkylene
group, an oxygen atom, an sulfur atom, a sulfinyl group,
a sulfonyl group, a carbonyl group, or a group
represented by the formula -0-C0-, the formula -C0-0-,
the formula -NRT1-, the formula -CO-NRT1-, the formula -
NR'T1-CO-, the formula -S02-NRT1-, or the formula -NRT1-
SO2-; TT3 represents a hydrogen atom, a C1-6 alkyl group,
a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8
cycloalkyl group, a C6-10 aryl group, a 5- to 10-
membered heteroaryl group, a 3- to 10- membered
heterocyclic group or a group represented by the
formula -N (RT2) (RT3) ; RT1 RT2 or RT3 each independently
represent a hydrogen atom or a C1-6 alkyl group; wherein
a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl
group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5-
to 10- membered heteroaryl group and a 3- to 10-
membered heterocyclic group in T"^ may each
independently have 1 to 3 groups selected from a group
of the below-mentioned Siibstituent Group;

a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl

group, a C6-10 aryl group, a 5- to 10- membered heteroaryl group, a 3- to 10- membered heterocyclic group, a C1-6 alkoxy group and a C1-6 alkylthio group.
[0032]
The term ''leaving group" as described in the specification may be any group commonly known as a leaving group in organic synthesis, with no special restrictions, and as specific examples there may be mentioned a halogen atom such as a chlorine atom, a bromine atom, an iodine atom; a nitro group; an alkylthio group such as a methylthio group, an ethylthio group and a propylthio group; an arylthio group such as a phenylthio group, a toluylthio group and a 2-pyridylthio group; an alkylsulfonyloxy group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy; an arylsulfonyloxy group such as a benzenesulfonyloxy group, a p-toluenesulfonyloxy group; an alkanoyloxy group such as an acetoxy group and a trifluoroacetoxy group; an alkoxy group such as a methoxy group, an ethoxy group and a propoxy group; an alkylamino group such as a methylamino group, an ethylamino group, a propylamine group and a butylamino group; a dialkylamino group such as a dimethylamino group, a diethylamino group, a dipropylamino group, a methylethylamino group, an

ethylpropylamino group and a methylpropylamino group; a substituted phosphoryloxy group such as diphenoxyphosphoryloxy group or the like, and preferably a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, a trifluoromethanesulfonyl group or the like. [0033]
As a ''salt" described in the specification, there may be mentioned, for example, a salt with inorganic acid, a salt with organic acid, a salt with inorganic base, a salt with organic base, a salt with acidic or basic amino acid or the like, preferably a pharmacologically acceptable salt. A salt is formed in an appropriate ratio of 0.1 to 5 molecules of acid or base to one molecule of the compound-[0034]
As preferable examples of a salt with inorganic acid, there may be mentioned, for example, a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like, and as preferable examples of a salt with organic acid, there may be mentioned, for example, a salt with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid or the like.

As preferable examples of a salt with inorganic base, there may be mentioned, for example, an alkali metal salt such as a sodium salt and a potassium salt, an alkali earth metal salt such as a calcium salt and a magnesium salt, an aluminum salt, an ammonium salt or the like. As preferable examples of a salt with organic base, there may be mentioned, for example, a salt with diethylamine, diethanolamine, meglumine, N,N'-dibenzylethylenediamine or the like. [0036]
As preferable examples of a salt with acidic amino acid, there may be mentioned, for example, a salt with aspartic acid, glutamic acid or the like, and as preferable examples of a salt with basic amino acid, there may be mentioned, for example, a salt with arginine, lysine, ornithine or the like. [0037]
As a "adjuvant" described in the specification, there may be mentioned, for example, a excipient, a binder, a disintegrator, a lubricant, a coloring agent, a corrective coating, a stabilizer, a emulsifier, a absorbefacient, a surfactant, a pH adjuster, a preservative, an antioxidant or the like. [0038]
Production methods for the compounds of the

invention will now be described. Various methods may be considered for production of compounds of the invention represented by the general formulas (I) and (II) with synthesis carried out by ordinary organic synthesis means^ and the following are representative examples of methods for their production.
[0039] [General synthesis method] [Production method 1]
A typical production method of the compound represented by the formula (la)


[Production method 1-A]
A typical production method of the compound (le), which is the compounds represented by the formula (la), wherein Y represents an oxygen atom, a sulfur atom or a group represented by the formula -NRy- (Ry represents a hydrogen atom or a C1-6 alkyl group)


methylpyrrolidone, N,N-dimethylformamide^ dimethyl sulfoxide, 2-ethoxyethanol, chlorobenzene or the like can be used. A base or an acid may be added thereto, specifically, an organic base such as diisopropylethylamine, an inorganic base such as potassium carbonate, cesium carbonate and sodium hydride and an acid such as pyridine hydrochloride and hydrochloric acid can be used. The reaction can be performed at a temperature ranging from room temperature to reflux temperature for a reaction time ranging from 10 minutes to 30 hours. In addition, a compound where a halogen atom which is not as a leaving group is bonded on pyrimidine or pyridine ring may be used as a starting material, and the halogen atom can be reduced by the catalytic reduction method or the like after this step.
[0042]
This is a step for obtaining a compound (Id) by carboxamidating the 1-position of indole in compound (Ic) . As a reagent, a carbamate derivative, an isocyanate derivative, a halogenated carbamoyl derivative or the like can be used. As a reaction solvent, chloroform, toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, chlorobenzene can be used. A base may be added thereto, specifically.

an organic base such as pyridine, triethylamine and diisopropylethylamine, an inorganic base such as potassium carbonate^ cesium carbonate and sodium hydride can be used^ for example. The reaction can be performed for a time of 10 minutes to 30 hours at a
temperature of 0 ^C to reflux temperature.
[0043]
This is a step for converting a compound (Id) into a urea derivative (1e) . Carbamate ester derivative is prepared by using phenyl chlorocarbonate or the like as a reagent, for example. After this intermediate is isolated, or not isolated, the intermediate is allowed to react with an amine, thereby a urea derivative can be obtained. Alternatively, by reacting a carbamate derivative or an isocyanate derivative as a reagent, a corresponding urea derivative can be converted into. As a reaction solvent, chloroform, toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, chlorobenzene or the like can be used. A base may be added thereto, specifically, an organic base such as pyridine, triethylamine, and diisopropylethylamine, an inorganic base such as potassium carbonate, cesium carbonate and sodium hydride can be used, for example. The reaction can be performed for a time of 10 minutes to 30 hours

at a temperature of 0 °C to reflux temperature.
[0044]
It should be noted that a substituent conversion in R2, R101. R102 can be also performed by suitably using an oxidation reaction, a reduction reaction, a reductive amination reaction, an ester formation reaction, an amide formation reaction, a protecting group introduction reaction, a deprotection reaction, a hydrolysis reaction or the like which are generally used before and/or after each process. Specifically, for example, in the case that R2 is a hydrogen atom in the compounds (la), (Ic) and (Id), the following methods come under the above-mentioned substituent conversions; that is, a method for converting R2 into a C1-6 alkyl group by performing a reductive amination reaction with aldehyde or ketone, a method in which, after a corresponding urea derivative is obtained as in from the compound (Ic) and an amine having ketone or aldehyde, an amine side chain is introduced into R101, R102 by further performing a reductive amination reaction with an amine, or the like. In these cases, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium triacetoxyborohydride or the like can be used as a reducing agent, and methanol, tetrahydrofuran, dichloromethane, dichloroethane or the like can be used as a reaction solvent. In addition, a

method that a benzotriazole derivative is prepared and
the derivative is reduced by sodium borohydride as
reported in Tetrahedron 47, 2683 (1991), or the like is
useful. Alternatively, a corresponding urea is formed
as in from the compound (Ic) and an amine
having an ester. After the ester is hydrolyzed by
bases such as lithium hydroxide, sodium hydroxide or
potassium hydroxide in aqueous ethanol, an amide
derivative can be also obtained by using a condensing
agent. In this case, N,N-dimethylformamide,
tetrahydrofuran or the like can be used as a reaction
solvent, and l-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride, (lH-1,2,3-benzotriazole-1-yloxy)(tri(dimethylamino))phosphonium hexafluorophosphate can be used as a condensing agent. The reaction can be performed for a time of 10 minutes to 30 hours at a temperature of 0 °C to reflux temperature. [0045] [Production method 1-B]
A production method of the compound (Ig), which is the compound represented by the formula (la), wherein Y is a sulfinyl group or a sulfonyl group



This is a step for oxidation of a compound (If) to a compound (Ig). Hydrogen peroxide^ peracetic acid, methaperiodate, S-chloroperbenzoic acid or the like can be used as an oxidizing agent. Methanol, water, dichloromethane, chloroform or the like can be used as a solvent. The reaction can be performed for a time of 10 minutes to 30 hours at a temperature of 0 °C to reflux temperature. [Production method 2]
Another production method of the compound (2c), which is the compound (Ic) having a halogen atom, a formyl group, or a cyano group as a substituent at the 3-position in the indole ring


This is a step for obtaining a compound (2b) by
the condensation of a pyrimidine or pyridine derivative
(la) and a indole derivative (2a) not having a
substituent on the 3-position. The compound (2b) can
be obtained under the same conditions as .
[0048]
This is a step in which a substituent is introduced into 3-position of indole in a compound (2b) to obtain a compound substituted at the 3-position of indole (2c) . A compound (2c) substituted with a halogen atom, a formyl group, an amino group or the like as the 3-position substituent can be obtained by reacting a compound (2b) with halogenation agents such as N-chlorosuccinimide, N-bromosuccinimide or a mixed reagent of phosphorous oxychloride or thionyl chloride

with N^ N-dimethylformamide, or after converting the compound into a N-chlorosulfonylcarbamoyl derivative by allowing chlorosulfonyl isocyanate to react with the compound, followed by allowing triethylamine to react with the derivative or the like as reported in Tetrahedron _50, 6549 (1994). As a reaction solvent, 2-propanol, N,N-dimethylformamide, tetrahydrofuran, acetonitrile or the like can be used, and the reaction can be performed for a time of 10 minutes to 30 hours at a temperature of 0 °C to reflux temperature.
[0049] [Production method 3]
Another production method of the compound (Id) via the compounds (3c), (3d), (3g) or (3h)


[0050]
These are steps for obtaining an indole derivative (3c) or an indoline derivative (3d), both being introduced a carboxamide group at the 1-position, via a compound (3b) from an indole derivative (3a).

is a step for conducting carboxamidation of the 1-position of an indole derivative (3a) to obtain a compound (3b), and can be performed in a similar way as . A methyl group, a benzyl group, a substituted benzyl group, a benzyloxycarbonyl group can be used as a protecting group, for example.
[0052]
is a step for obtaining a compound (3c) by deprotecting an indole derivative (3b) . Specifically, for example, in the case that Yi is an oxygen atom, the methods used for ordinary deprotection such as demethylation by using boron tribromide, debenzylation by using trifluoroacetic acid-thioanisole, debenzylation or the debenzyoxycarbonylation by catalytic reduction can be used.
[0053]
is a step for reduction of an indole derivative (3c) to an indoline derivative (3d). Catalytic hydrogenation reaction in the presence of palladium catalyst under ordinary pressure or under pressurization or the like can be applied. Methanol, N,N-dimethylformamide, tetrahydrofuran or the like can be used as a reaction solvent, and the reaction can be performed for a time of 10 minutes to 30 hours at a

temperature of 0 °C to reflux temperature.
[0054]
These are steps for obtaining an aminoindole derivative (3g) or an aininoindoline derivative (3h) having a carboxamide group at the 1-position via a compound (3f) from a nitroindole derivative (3e).
[0055]
is a step conducting carboxamidation of the 1-position of a indole derivative (3e) to obtain a compound (3f) ^ and can be performed in the same way as in ,
[0056]
is a step for reducing a nitroindole derivative (3f) to an aminoindole derivative (3g). The conditions used for reduction reaction of a nitro group to an amino group generally utilized, specifically, for example, reduction by iron-ammonium chloride or iron-acetic acid or the like, catalytic reduction by palladium hydroxide-hydrogen or the like can be applied. Methanol, ethanol, water, N,N-dimethylformamide, tetrahydrofuran or the like can be used as a reaction solvent, and the reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 30 hours.

is a step for reducing an indole derivative (3g) to an indoline derivative (3h) and can be performed in the same way as in .
[0058]
These are steps for condensing an indole derivative (3c or 3g) or an indoline derivative (3d or 3h) and a compound (la) to obtain an indole derivative
(Id) or an indoline derivative (3i), and can be performed in the same way as in -
[0059]
This is a step for oxidizing an indoline derivative (3i) to an indole derivative (Id) . For example, 2, 3-dichloro-5,6-dicyano-l, 4-benzoquinone
(DDQ) or the like can be used as an oxidizing agent, and 1,4-dioxane, toluene, benzene or the like can be used as a solvent. Alternatively, a method in which manganese acetate (III) is used as an oxidizing agent or the like as reported in Tetrahedron Lett. _29_^ 2151
(1988) can be applied.
In addition, in the case that Y1 is the formula -NRy1-
and Ry1 is a hydrogen atom in compounds (3g) , (3h) ,
(3c) or (3d), a compound (Id), wherein Y1 is the formula -NRy1- and Ry1 is a C1-6 alkyl group, can be also obtained by converting the hydrogen atom into a C1-6

alkyl group by a reductive ainination reaction with
aldehyde or ketone, and by using these for the
respective following reactions. In addition, in the
case that Y1 is the formula -NRy1- and Ry1 is a hydrogen
atom in compounds (3i) or (Id) , thr compounds can be
also similarly converted into the compounds (3i) or
(Id), wherein Yl is the formula -NRyl- and Ryl is a C1-6
alkyl group. In this case, sodium cyanoborohydride,
sodium trimethoxyborohydride, sodium
triacetoxyborohydride or the like can be used as a reducing agent, and methanol, tetrahydrofuran, dichloromethane, dichloroethane or the like can be used as a reaction solvent. In addition, a method in which a benzotriazole derivative is prepared and is reduced by sodium borohydride as reported in Tetrahedron _47,2683 (1991) or the like can be applied.



This is a step for converting a compound (Ic) to a compound (4a), and can be performed in the same way as in -
[0062]
This is a step for conducting carboxamidation of the 1-position of indole in a compound (4a) to obtain a compound (le), and can be performed in the same way as in .
It is to be noted that, as described in [Production method 1-A], a substituent conversion can be also performed in R2, R9, R101 and R102 by properly performing oxidation reaction, reduction reaction, reductive amination reaction, ester formation reaction, amide formation reaction, protecting group introduction reaction, deprotection reaction, hydrolysis reaction or the like generally utilized after these steps.
[0063]


the aforementioned definition.
[0064]
This is a step for converting a pyrimidine or pyridine derivative (la) into a corresponding urea derivative (5a), and can be performed in the same way as in .
[0065]
This is a step for obtaining a compound (le) from a pyrimidine or pyridine derivative (5a) having urea. A method in which the same operations as in and are sequentially performed, a method in which the same operations as in , and are sequentially performed, a method as in , a method in which the same operations as in and are sequentially performed or the like can be applied.
[0066]
It is to be noted that, as described in [Production method 1-A] , a substituent conversion can be also performed in R2, R9, R101 and R102 by properly performing oxidation reaction, reduction reaction, reductive amination reaction, ester formation reaction, amide formation reaction, protecting group introduction reaction, deprotection reaction;, hydrolysis reaction or


[0068]
These are steps for condensing a pyrimidine or pyridine derivative having leaving groups L1 and L2 and an indole or indoline derivative. In these steps;- it is preferable that L1 is a substituent having higher

reactivity than that of L2- Specifically, for example, a combination of L1 being a nitro group and L2 being a chlorine atom or the like comes under the category. By using an indole derivative (lb), indole derivatives (3c), (3g) having a carboxamide group at the 1-position, indoline derivatives (3d), (3h) having a carboxamide group at the 1-position, each compound (6b), (6c) and (6d) can be obtained under the same conditions as in .
[0069]
This is a step for conducting carboxamidation of the 1-position of indole in a compound (6b) to obtain a compound (5c), and can be performed in the same way as in .
[0070]
This is a step for oxidizing an indoline derivative (6d) to an indole derivative (6c). The same method as in can be used.
[0071]
These are steps in which the leaving group L2 of pyrimidine or pyridine derivatives (6b), (6c), or (6d) is converted into a group represented by the formula -NHR2, wherein R2 represents the same definition as the

aforementioned definition, to obtain compounds (Ic) ,
(Id), or (3i), respectively. For example, an ammonia-
ethanol solution or a corresponding primary amine is
used, and the reaction can be perfoanned in a sealed
tube for a time of 10 minutes to 100 hours at a
temperature of 60 °c to reflux temperature. [0072]
[Production method 7]
Another production method of a compound (7j), which is the compound represented by the formula (la), wherein Y is an oxygen atom and both 2- and 3-positions of indole
(R8, R7) are hydrogen atoms
[production method 7-A]



This is a step for obtaining a compound (7a) by introducing an aminophenoxy group into a compound (6a). It is preferable that in the compound {6a), L1 is a substituent having higher reactivity than that of L2-Specifically, for example, a combination of Li being a nitro group and L2 being a chlorine atom comes under the category. A compound (7a) can be obtained by using a compound (6a) and an aminophenol derivative in the same method as in . In addition, after these compounds are condensed by using a nitrophenol derivative in the same way as in , a method for reducing a nitro group by catalytic hydrogenation reaction using palladium catalyst or the like, or metal reduction reaction using iron-ammonium chloride, iron-acetic acid or the like can be applied. In the reduction reaction of the nitro group, methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide or the like can be used as a reaction solvent, and the catalytic hydrogenation reaction can be performed at ordinary pressure or under pressurization. The reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 30 hours.
[0074]

This is a step for protecting amino group of a compound (7a) to obtain a compound (7b). As a protecting group, for example, a benzyloxycarbonyl group or the like can be introduced by using a corresponding chlorocarbonate ester.
[0075]
This is a method for obtaining a compound (7c) from a compound (7b), t-Butyl bromoacetate as a reagent, sodium hydride or the like as a base, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide or the like as a reaction solvent can be used. The reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 30 hours.
[0076]
This is a step for deprotecting a compound (7c) to obtain a compound (7d). There may be mentioned, for example, deprotection reaction by the catalytic hydrogenation reaction of benzyloxycarbonyl group or the like.
[0077]
This is a step for obtaining a compound (7e) by introducing a carboxamide group to a compound (7d). As

a reagent, an isocyanate derivative, a carbamate derivative or the like can be used. As a reaction solvent, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene or the like can be used, and organic bases such as triethylamine or pyridine can be added thereto as requested- The reaction can be performed for a time of 10 minutes to 30 hours and at a
temperature of 0 "c to reflux temperature. [0078]

This is a step for obtaining a compound (7f) from a compound (7e) by cyclization reaction. The reaction is performed in an acidic condition, specifically, for example, in trifluoroacetic acid-trifluoroacetic anhydride or the like. The reaction can be performed for a time of 10 minutes to 30 hours
and at a temperature of 0 °C to reflux temperature.
[0079]
These are steps for converting into an indole derivative (7h) via a compound (7g) from a 3-oxoindoline derivative (7f). A 3-hydroxyindoline derivative (7g) is prepared by reduction of a carbonyl group using sodium borohydride as a reagent, in tetrahydrofuran, methanol, ethanol or the like as a reaction solvent, thereafter a compound (7h) can be

obtained by performing dehydration by using camphor sulfonic acid or the like as a reagent, and toluene, dichloroethane or the like as a reaction solvent.
[0080]
Thereafter, it is possible to lead to a step in which a compound (7j) is prepared under the same conditions in each of , [Production method 7-B]



This is a step for protecting an amino group of a compound (7k) to obtain a compound (71), and can be performed in the same way as in -
[0083]
This is a method for obtaining a compound (7m) from a compound (71);- and can be performed in the same way as in .
[0084]
This is a step for deprotecting a compound (7m) to obtain a compound (7n) ;. and can be performed in the same way as in .
[0085]
This is a step for introducing a carboxamide group to a compound (7n) to obtain a compound (7o), and can be performed in the same way as in ,
[0086]
This is a step for obtaining a cyclized compound (7p) from a compound (7o), and can be performed in the same way as in .
[0087]


These are steps for converting into an indole derivative (7j) via a compound (7q) from a 3-oxoindoline derivative (7p), and can be performed in the same as in .
[0088] [Production method 8]
Another production method of a compound (8g), which is the compound represented by the formula (la) ;. wherein both 2- and 3-positions of indole (Re, R7) are hydrogen atoms


This is a coupling reaction of a compound (6a) with a nitrobenzene derivative. A compound (8a) can be obtained under the same conditions as in .
[0090]
This is a step for obtaining a compound (8b) from a compound (8a) . The reaction can be performed under the conditions as described in Tetrahedron Lett. 39, 71 (1998)- Specifically, a dimethylacetal compound can be derived by condensing a nitrotoluene derivative and dimethyl formamide dimethylacetal in N,N-dimethylformamide at a temperature of room temperature to reflex temperature for 10 minutes to 30 hours, and by sequentially performing the reaction of the compound in methanol under acidic condition at a temperature of room temperature to reflex temperature for 10 minutes to 30 hours.
[0091]
This is a step for reducing a compound (8b) to a compound (8c) . Reduction by iron-ammonium chloride, iron-acetic acid or the like can be used. As a reaction solvent, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide or the like can be used. The reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 30

hours -
[0092]
This is a step for converting a compound (8c) into a urea derivative to obtain a compound (8d) , and can be performed in the same way as in . Alternatively, tetrahydrofuran or N,N-dimethylformamide is used as a reaction solvent, for example, after a carbamate derivative is prepared by using phenyl chlorocarbonate or the like, and urea can be also introduced by allowing the derivative to react with an amine at a temperature of room temperature to reflux temperature for 10 minutes to 30 hours, while N,N-dimethylformamide, dimethyl sulfoxide are used as a reaction solvent.
[0093]
This is a step for cyclizing a compound (8d) to obtain a compound (8e). The reaction can be performed under the conditions as described in Tetrahedron Lett, 39, 71 (1998). Specifically, there may be mentioned a method in which reflux is performed in solvents such as benzene in the presence of catalytic amounts of camphor sulfonic acid and quinoline.
[0094]

This is a step for obtaining a compound (8f) from a compound (8e), and can be performed in the same way as in .
[0095]
This is a step for obtaining a compound (Bg) from a compound (8f), and can be performed in the same way as in .
[0096]


This is a step for obtaining a compound (8h) by performing coupling reaction of a compound (la) with a nitrobenzene derivative, and can be performed in the same way as in .
[0098]
This is a step for introducing urea to a compound (8h) to obtain a compound (8i), and can be performed in the same way as in .
[0099]
This is a step for condensing a nitrotoluene derivative (8i) and dimethylformamide dimethylacetal, subsequently, for deriving the compound to dimethylacetal compound (8j) . The step can be performed in the same way as in ,
[0100]
This is a step for reducing a nitro group of a compound (8j) to obtain a compound (8k) , and can be performed in the same way as in .
[0101]
This is a step for obtaining a compound (81) from a compound (8k) by introducing urea, and can be performed in the same way as in .



This is a step for obtaining a compound (9a) by
coupling of a compound (6a) with a phenol derivative.
Specifically, for example, a corresponding condensed
compound can be obtained under the same conditions as
in , by using 4-amino-3-iodophenol obtained
from t-butyl (2-iodo-4-

( (triisopropylsilyl)oxy)phenyl)carbamate obtained by a method as described in J. Org. chem. , S2^r 6507 (19 97) by allowing n-butylammonium fluoride or the like to react therewith.
[0105]
This is a step for converting a compound (9a) into a urea derivative to obtain a compound (9b), and can be performed in the same way as in .
[0106]
This is a step for obtaining an acetylene
derivative (9c) from an iodo compound (9b) using
trimethylsilylacetylene. The condensation can be
performed in the presence of
tetrakis(triphenylphosphine)palladium or
dichlorobis(triphenylphosphine)palladium, cuprous iodide. N,N-dimethylformamide or the like can be used as a reaction solvent, and the reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 30 hours.
[0107]
This is a step for performing cyclization by heating an acetylene derivative (9c) in the presence of cuprous iodide to obtain an indole derivative (7h) .

N^N-dimethylformamide or the like can be used as a reaction solvent, and the reaction can be performed at
a temperature of 80 ° C to reflux temperature for 5 minutes to 10 hours.
Subsequently, a compound (7h) can be converted into a compound (7j) as described in , . [0108]


into a urea derivative to obtain a compound (9e), and can be performed in the same way as in .
[0111]
This is a step for obtaining an acetylene derivative (9f) from an iodo compound (9e) by using trimethylsilylacetylene, and can be performed in the same way as in .
[0112]
This is a step for cyclizing an acetylene derivative (9f) by heating in the presence of cuprous iodide to obtain an indole derivative (7j), The same conditions as in can be applied.
[0113] [Production method 10]
A typical production method of a compound (lOg), which is the compound represented by the formula (la), wherein Y is an oxygen atom,, a sulfur atom or a group represented by the formula -NRy- (wherein Ry represents a hydrogen atom or a C1-6 alkyl group) , X1 is a group represented by the formula -C(CN)=, X2 is a group represented by the formula -CH=, R2 is a hydrogen atom, R3 is a hydrogen atom, an optionally substituted C1-6 alkyl group or an optionally substituted C3-8 cycloalkyl group


atom, X202 represents a bromine atom or an iodine atom; R301 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or an optionally substituted C3-8 cycloalkyl group; it is preferable that as a combination of X201 and X202, X202 is an iodine atom or a bromine atom if X201 is a chlorine atom, X202 is an iodine atom if X201 is a bromine atom; other symbols represent the same definition as the aforementioned definition.
[0114]
This is a step for bromination or iodination of

the 5-position of a 2-aminopyridine derivative (10a) having a chlorine atom or a bromine atom at the 4-position to obtain a compound (10b). For example, halogenation agents such as iodine, N-bromosuccinimide, bromine, N-iodosuccinimide can be used. As a reaction solvent, for example, N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride and acetonitrile can be used. The reaction can be performed at a temperature of 0 "C to reflux temperature for 10 minutes to 4 8 hours.
[0115]
This is a step for converting X202 of a compound (10b) into a cyano group to obtain a compound (10c).
For example, 6,5 to 0.6 equivalent of zinc
cyanide, 1.0 to 1.2 equivalent of potassium cyanide, or
trimethylsilylcyanide is reacted with a compound (10b)
in the presence of a palladium catalyst such as
tetrakis (triphenylphosphine)palladium or
dichlorobis(triphenylphosphine)palladium. As a reaction solvent, for example, N,N-dimethylformamide, dioxane and tetrahydrofuran can be used. The reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 10 hours.
[0116]

These are steps for condensing a pyridine derivative (10c) and an indole or indoline derivative. Compounds (lOd), (lOe) and (lOf) can be obtained, respectively, by using an indole derivative (lb), indole derivatives (3c), (3g) having a carboxamide group at the 1-position, and indoline derivatives (3d), (3h) having a carboxamide group at the 1-position under the same conditions as in .
[0117]
This is a step for conducting carboxamidation of 1-position of indole of a compound (lOd) to obtain a compound (lOe), and can be performed in the same way as in .
[0118]
This is a step for oxidizing an indoline derivative (lOf) to an indole derivative (lOe), and can be performed in the same way as in .
[0119]
This is a step for converting a compound (lOe) into a compound (lOg) , and can be performed in the same way as in .
[0120] [Production method 11]


[0121]
These are steps for converting aminopyridine derivatives (10c), (10a) into corresponding urea derivatives (lle) , (lle) , respectively, and can be performed in the same way as in .
[0122]
This is a step for iodination or bromination of the 5-position of a 2-ureidopyridine derivative (lie) having a chlorine atom or a bromine atom at the 4-position to obtain a compound (lid), and can be performed in the same way as in .
[0123]
This is a step for converting X202, of a compound

(lid) into a cyano group to obtain a compound (lie) , and can be performed in the same way as in ,
[0124]
This is a step for obtaining a compound (lOg) from a pyridine derivative (lle) having urea, and can be performed in the same way as in .
[Production method 12]
A production method of a compound (12b), which is the compound represented by the formula (la), wherein Y is a sulfinyl group or a sulfonyl group, X1 is a group represented by the formula -C(CN)=, and R2 is a hydrogen atom


A production method of a compound (131), which is the compound represented by the formula (la), wherein Y is an oxygen atom, a sulfur atom or the formula -NRy-(wherein Ry represents a hydrogen or a C1 to C6 alkyl group), and X1 is a group represented by the formula -C(CN)=


wherein, X203 represents a chlorine atom, a bromine atom or an iodine atom; other symbols represent the same definition as the aforementioned definition.
[0127]
This is a step for converting X203 of 4,6-
dihalogenated nicotinic acid or its analogous compound
(13a) such as 4,6-dichloronicotinic acid as reported in
Acad- Nauk Ukr. SSSR, 1986, page 36 into an amino group
to obtain a compounds {13b) . The reaction can be
performed at a temperature of 0 °C to reflux temperature for 10 minutes to 100 hours by using, for example, an ammonia-ethanol solution or the like.
[0128]
This is a step for obtaining a compound {13c) by converting a carboxyl group of a compound (13b) into a carbamoyl group. For example, a method in which, after oxalyl chloride or thionyl chloride is allowed to react
with the compound at a temperature of 0 °C to reflux temperature for 10 minutes to 24 hours, ammonia is allowed to react with the compound, or a method in which diethylcyanophosphate, ammonium chloride, triethylamine are employed as disclosed in Synthesis [SYNTBF], 1998, 1467 - 1475 or the like can be used. [0129]


These are steps for condensing a pyridine or pyrimidine derivative (13c) and an indole or indoline derivative. Compounds (13d), (13e), (13f) can be obtained, respectively, by using an indole derivative (lb) , indole derivatives (3c), (3g) having a carboxamide group at the 1-position, or indoline derivatives (3d), (3h) having a carboxamide group at the 1-position under the same conditions as in .
[0130]
These are steps for conducting carboxamidation of the 1-position of indole of compounds (13d), (13g) to obtain compounds (13e) , (13j) and can be performed in the same way as in ,
[0131]
These are steps for converting a carbamoyl group of compounds (13d), (13h), (131 [0132]


These are steps for converting aminopyridine or aminopyriiaidine derivatives (13e) , (13f) , (13j) into corresponding urea derivatives (13h), (13i), (131), and can be performed in the same way as in .
[0133]
These are steps for oxidizing indoline derivatives (13f), (13i) to indole derivatives (13e)r (13k), and can be performed in the same way as in .


wherein, each symbol represents the same definition as the aforementioned definition.
[0135]
These are steps for substituting a substituent in 6-membered heterocycle from a hydrogen atom to a halogen atom. A compound can be obtained from a corresponding compound respectively: a compound (14d) from a compound (14a), a compound (14e) from a compound
(14b) and a compound (14f) from a compound (14c) as in . [0136]
[Production method 15] A typical production method of compounds (15a), (15b),
(15c) by substituting a halogen atom in 6-membered heterocycle of compounds (14d), (14e), (14f) to a cyano group



These are steps for obtaining a compound from a corresponding compound respectively: a compound (15a) from a compound (14d), a compound (15b) from a compound
(14e) and a compound (15c) from a compound (14f) by-substituting a substituent in 6-membered heterocycle from a halogen atom to a cyano group. 0.5 to 2.0 equivalent of zinc cyanide or 1.0 to 3.0 equivalent of copper(I) cyanide, potassium cyanide, sodiim cyanide, trimethylsilylcyanide or the like to compounds (14d),
(14e) and (14f) can be used. In order to accelerate the reaction, as a catalyst, for example, a palladium

catalyst such as tetrakis(triphenylphosphine)palladium or dichlorobis(triphenylphosphine)palladium, copper (I) iodide, copper(0) or the like can be used. As a reaction solvent, for example, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, dioxane, tetrahydrofuran or the like can be used. The reaction can be performed at a temperature of room temperature to reflux temperature for 10 minutes to 2 days.
[0138]-
After completing the aforementioned reactions, purification can be performed by an ordinary treatment method, for example, column chromatography using silica gel or adsorbent resins or the like, or recrystallization from a suitable solvent.
[0139]
The compounds of the invention, salts thereof or hydrates of the foregoing may be formulated as tablets, powders, fine particles, granules, coated tablets, capsules, syrups, lozenges, inhalants, suppositories, injections, ointments, eye salves, eye drops, nasal drops, ear drops, paps, lotions and the like, by any common methods. The formulation may employ any commonly used excipients, binders, lubricants, coloring agents, corrective coatings, and if necessary, stabilizers, emulsifiers, absorbefacients, surfactants, pH adjustors, preservatives, antioxidants, or the like.

in combination with various components that are ordinarily used as raw materials for phazmaceutical formulations. For example, an oral formulation may be prepared by combining a compound of the invention or pharmacologically acceptable salt thereof with an excipient, if necessary adding a binder, disintegrator, lubricant, coloring agent, corrective coating or the like, and forming a powder, fine particles, granules, tablets, coated tablets, capsules, etc. by a common method. As such components there may be mentioned animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethy1cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol.

dipropylene glycol and sorbitol; sugars such as glucose
and sucrose; inorganic powders such as silicic acid
anhydride, magnesium aluminina silicate and aluminum
silicate, purified water, and the like. Examples of
excipients which may be used include lactose, corn
starch, white soft sugar, glucose, mannitol, sorbit,
crystalline cellulose and silicon dioxide, examples of
binders which may be used include polyvinyl alcohol,
polyvinyl ether, methylcellulose, ethylcellulose, gum
arable, tragacanth, gelatin, shellac,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone, polypropylene
glycol/polyoxyethylene block polymer and meglumine, examples of disintegrators which may be used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium, examples of lubricants which may be used include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oils, examples of coloring agents which may be used include those approved for addition to drugs, and examples of corrective coatings which may be used include cocoa powder, menthol, aromatic powders, mentha oil, borneol and powdered cinnamon. The tablets or granules may also be sugar coated or provided with another type of suitable

coating if necessary. For preparation of a liquid formulation such as a syrup or injection, a common method may be used to formulate a compound of the invention or a pharmacologically acceptable salt thereof with a pH adjuster, solubilizer, isotonizing agent or the like, as well as a solubilizing aid, stabilizer etc. if necessary. There are no particular restrictions on the method of preparing an external agent, and any common method may be employed. That is, it may be prepared using as base materials any of various raw materials which are ordinarily used in drugs, quasi drugs, cosmetics and the like. As examples of specific base materials there may be mentioned raw materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water and the like, and if necessary pH adjusters, antioxidants, chelating agents, antiseptics and fungicides, coloring agents, aromas and the like may also be added, although the base materials for external agents according to the invention are not limited to these. If necessary, there may also be included components such as ingredients having differentiation-inducing activity, circulation promoters, microbicides, antiphlogistic agents, cell

activators, vitamins, amino acids, humectants,
keratolytic agents and the like. The amounts of the aforementioned base materials may be the concentrations established for preparation of ordinary external agents.
[0140]
There are no particular restrictions on the compound of the invention, the salt thereof or the hydrate thereof when administered, and either oral or parenteral administration may be carried out according to ordinary methods. For example, it may be prepared and administered in the form of a tablet, powder, a granule, a capsule, syrup, lozenge, inhalant, suppository, injection, ointment, eye salve, eye drop, nasal drop, ear drop, pap, lotion or the like.
[0141]
Although the dosage of a drug according to the invention will differ depending on severity of symptoms, age, gender, body weight, form of administration, type of disease, etc., it will be generally 100 pg - 10 g per day for an adult and such dosages may be administered once or divided over several.
[0142]
The administration form of the medicine according to the present invention is not particularly restricted, and can be an oral administration or a parenteral administration by a generally employed

method.
[0143]
The biochemical activity and actions and effects (angiogenesis inhibition activity, antitumor activity or the like) as a medicine of the compounds according to the present invention can be evaluated by the following methods.
[0144]
The following is a list of abbreviations used in the phairmacological test examples described below. DNA (deoxyribonucleic acid)
VEGFR2 (vascular endothelial growth factor receptor 2)
Hepes (N-[2-Hydroxyethyl]piperazine-N'- [2-
ethanesulfonic acid];. HEPES (buffer solution)) MgCl2 (Magnesium Chloride) MnCl2 (Manganese Chloride) Na3V04 (Sodium Orthovanadate (V) ) ATP (Adenosine 5 -Triphosphate) EDTA (Ethylenediaminetetraacetic acid) HTRF (Homogenous Time-Resolved Fluorescence) FGFRl (Fibroblast growth factor receptor 1) PDGFR3 (Platelet derived growth factor receptor [3) HGFR (Hepatocyte growth factor receptor) EGFR (Epidermal growth factor receptor) Tris (Tris (hydroxymethyl)aminomethane, Tris (buffer

solution))
NaCl (sodium Chloride)
BSA (Bovine Serum Albumin)
HRP (Horseradish peroxidase)
EGTA (Ethylene glycol bis(2-aminoethyl ether)-
N,N,N',N'-tetraacetic acid)
SDS (Sodium Dodecylsulphate)
NP-40 (Nonidet P-40)
PCR: polymerase chain reaction
RT-PCR: reverse transcription-polymerase chain reaction
RNA: ribonucleic acid
cDNA: complementary DNA
cRNA: complementary RNA
dNTP: a mixture composed of dATP, dCTP, dGTP, and dTTP
UTP: Uridine 5 -triphosphate
CTP: Cytidine 5 -triphosphate
dATP: 2 -Deoxyadenosine 5 -triphosphate
dCTP: 2 -Deoxycytidine 5 -triphosphate
dGTP: 2 -Deoxyguanosine 5 -triphosphate
dUTP: 2 -Deoxyuridine 5 -triphosphate
GAPDH: glyceraldehyde 3-phosphate dehydrogenase
FBS: Fetal bovine serum
PBS: Phosphate buffered saline
MTT: (3-[4,5-Dimethylthio2ol-2-yl]-2,5-
diphenyltetrazolium bromide; Thiazolyl blue)
DMSO: Dimethyl sulfoxide

PDGF: Platelet derived growth factor
EGF: Epidermal growth factor
FGF2: Fibroblast growth factor 2
VEGF: Vascular endothelial growth factor
HGF: Hepatocyte growth factor
TNF-a: Tumor Necrosis factor alpha
FCS: Fetal Calf Serum
EGM-2: Endothelial Cell Growth Medium-2
[0145] Pharmacological Test Example 1: Inhibition against sandwich tube formation by vascular endothelial cells in response to stimulation by angiogenesis factor
Human Umbilical Vein Endothelial Cells (HUVECs) were isolated according to a reported method (Shinseikagaku Jikken Koza [New Biochemistry Experiment Lectures], "Saibo Baiyo Gijutsu" [Cell Culturing Techniques], p.197-202),
and were cultured in a 5% CO2 incubator (37°C) using EGM-2 medium (purchased from Clonetics Corp.) until the cells reached confluency. [0146]
An ice-cooled mixture of collagen: 5x RPMI 1640: reconstitution buffer (all purchased from Nitta Gelatin, Inc.) at 7:2:1 was dispensed at 0.4 ml into each well of a 24-well plate. After the solution was gelled by being stationed for 40 minutes in a 5% CO2 incubator

(37°C), HUVEC cell suspension was added at 0.4 ml to each well (using 1 to 1.2 x 10^ cells^ though the numbers of cells differ slightly according to the HUVEC lot), the HUVEC cell suspension being in human endothelial serum free medium (SFM, purchased from GIBCO BRL) containing added angiogenesis factors [20 ng/ml FGF2 (purchased from GIBCO BRL) and 10 ng/ml EGF (purchased from GIBCO BRL)r or 25 ng/ml VEGF (purchased from Wako Pure Chemical Industries Co., Ltd.) and 10 ng/ml EGFr or 30 ng/ml HGF (purchased from R&D Co.) and 10 ng/ml EGF] , and cultured overnight in a 5% CO2
incubator (37°C) . On the following day, the medium on the upper layer was aspirated off, and then 0.4 ml of an ice-cooled mixture of collagen: 5x RPMI 164 0: reconstitution buffer (all purchased from Nitta Gelatin, Inc. ) at 7:2:1 was superposed into each well prior to
stationing for 4 hours in a 5% CO2 incubator (37°C) for gelling. After adding 1.5 ml of an SFM solution containing each of the aforementioned angiogenesis factors and a diluted test substance onto the upper layer, culturing was performed in a 5% CO2 incubator
(37°C) . Upon aspirating off the culture supernatant in each well on the 4th day after addition of the test substance, 0.4 ml of a 3.3 mg/ml MTT solution dissolved in PBS (purchased from Sigma Corp. ) was added to each well and culturing was performed for approximately 2

hours in a 5% CO2 incubator (37°C) . The tubes formed in the collagen gel of each well were stained by MTT, the tube images were loaded into a computer (Macintosh) r and the total length of the tubes was determined by image analysis software "MacScope" (purchased from Mitani Corp.). The ratio of the total length of the tubes formed in the well containing the test substance with respect to the total length of the tubes formed in the well containing no test substance was expressed as a percentage, and the concentration of each test substance required for 5 0% inhibition of tube formation (IC50) was determined from the ratio value. The results are shown in Table 1.


inhibition against receptor tyrosine kinase activity
This assay is used to determine inhibition of a test substance on tyrosine kinase activity. DNA coding for the cytoplasmic domain of VEGFR2 is obtained by total cDNA synthesis (Edwards M^ International Biotechnology Lab 5(3), 19-25, 1987) or by cloning. Expression in an appropriate expression system can produce a polypeptide with tyrosine kinase activity. The cytoplasmic domain of VEGFR2 obtained by expression of recombinant protein in, for example, insect cells have been found to exhibit intrinsic tyrosine kinase activity. For VEGFR2 (GenBank Accession No. L04947), the 1.7 kb DNA fragment described by Terman et al. (Oncogene, 6(9), 1677-1683, 1991), coding for the cytoplasmic domain, beginning with lysine 7 91 and including the termination codon, was isolated from a human placental cDNA library (purchased from Clontech Laboratories, Inc.) and cloned in a Baculovirus expression vector (pFastBacHis, purchased from GIBCO BRL) . The recombinant construct was transfected into insect cells {Spondoptea frugiperdaS (Sf9)) to prepare a recombinant Baculovirus. (Instructions for preparation and use of recombinant Baculovirus may be found in standard texts, such as "Bac-To-Bac Baculovirus Expression System" (GIBCO BRL).) The cytoplasmic fragment starting from lysine 398 (FGFRl,

GenBank Accession No. X52833), the cytoplasmic fragment starting from lysine 558 (PDGFRP, GenBank Accession No. M21616) or the cytoplasmic fragment starting from lysine 974 (HGFR, GenBank Accession No. J02958) may be cloned and expressed by the same method for use in assays for other tyrosine kinases. EGFR was purchased from Sigma Co. (Product No. E-2645),
[0149]
For expression of the VEGFR2 tyrosine kinase, Sf 9 cells were infected with the VEGFR2 recombinant virus and collected after 48 hours. The collected cells were rinsed with ice-cooled phosphate buffered saline (PBS) and then re suspended using 20 ml of ice-cooled Lysis Buffer (50 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 1 mM phenylmethylsulfonyl fluoride, 1% (v/v) NP-40) per 1.5 x 10^ cells. The suspension was centrifuged at 12,000 rpm for 30 minutes
at 4°C and the supernatant was obtained. The supernatant was added to a Ni-NTA agarose column (3 ml, purchased from Qiagen) equilibrated with Buffer A {20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 500 mM KCl, 20 mM imidazole, 10% (v/v) glycerol}. The column was washed with 30 ml of Buffer A, and then with 6 ml of Buffer B {20 mM Tris-HCl (pH 8,5), 5 mM 2-mercaptoethanol, IM KCl, 10% (v/v) glycerol}, and finally with 6 ml of Buffer A. After washing, it was

eluted with 6 ml of Buffer C {20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 100 mM imidazole;-10% (v/v) glycerol}- The eluate was placed on a dialysis membrane (purchased from Spectrum Laboratories) and dialyzed with a dialysis buffer {20 mM Tris-HCl (pH 7.5), 10% (v/v) glycerol, 1 mM dithiothreitol, 0.1 mM NasVO4, 0.1 mM EGTA} . After dialysis, it was supplied for SDS-electrophoresis, and the recombinant protein (His6-VEGFR2, cytoplasmic domain of VEGFR2 fused with 6 histidine residues at the N-terminus) detected at a molecular weight of approximately 100 kDa with Coumassie Brilliant Blue staining was assayed using BSA (bovine serum albumin, purchased from Sigma Co. ) as the standard substance,
and stored at -8 0°C until use - Using the same method for the cytoplasmic domains of FGFRl, PDGFRp and HGFR yielded respective recombinant proteins fused with 6 histidine residues at the N-terminal (His6-FGFR1, His6-PDGFRp or His6-HGFR).
[0150]
The tyrosine kinase reaction was conducted as follows- In the case of VEGFR2, for example, 10 ]il of a kinase reaction solution {200 mM Hepes (pH 7.4),. 80 mM MgCl2, 16 mM MnCl2, 2 mM Na3V04}, 250 ng of biotin-bound poly(Glu4:Tyrl) (biotin-poly(GT) , purchased from CIS Diagnostics Co.) (6 ^1 of a 15-fold dilution with

distilled water), 15 ng of His6-VEGFR2 (10 µl of a 240-fold dilution with 0.4% BSA solution) and the test substance dissolved in dimethyl sulfoxide (4 µl of a 100-fold dilution with 0.1% BSA solution) were added into each well of a 9 6-well round-bottom plate (NUNC Co. Product No. 163320), to a total of 30 µl. Next, 10 µl of 4 µM ATP (diluted with distilled water) was
added prior to incubation at 30°C for 10 minutes, and then 10 ]il of 500 mM EDTA (pH 8.0) was added. [0151]
The tyrosine phosphorylated biotin-poly(GT) was measured by the Homogenous Time-Resolved Fluorescence
(HTRF) method (Analytical Biochemistry, 269, 94-104, 1999) . Specifically, the kinase reaction solution was transferred to a 9 6-well black half-plate (Product No. 3694, Coster, Inc.), 7.5 ng of europium cryptate-labeled anti-phosphotyrosine antibody (Eu(K)-PY20, purchased from CIS Diagnostics Co.) (25 µl of a 250-fold dilution with 20 mM Hepes (pH 7.0), 0.5 M KF, 0.1% BSA solution) and 250 ng of XL665-labeled streptavidin
(XL665-SA, purchased from CIS Diagnostics Co.) (25 µl of a 62.5-fold dilution with 20 mM Hepes (pH 7.0), 0.5 M KF and 0.1% BSA solution) were added thereto, the mixture was allowed to stand at room temperature for 30 minutes, and then the fluorescent intensity was measured at 665 nm and 620 nm under irradiation with an

excitation wavelength of 337 nm using a Discovery HTRF Microplate Analyzer (Packard Co.). The tyrosine phosphorylation rate for the biotin-poly(GT) was expressed as the delta F% value as described in the HTRF Standard Experiment Methods text by CIS Diagnostics Co. The delta F% value in the presence of the test substance was determained as a ratio (%) with the delta F% value with addition of His6-VEGFR2 in the absence of the test substance defined as 100% and the delta F% value in the absence of both the test substance and His6-VEGFR2 defined as 0%. This ratio (%) was used to calculate the test substance concentration required for 50% inhibition of VEGFR2 kinase activity (IC50) -
[0152]
Measurement of inhibition against FGFRl, EGFR and HGFR kinase activity was conducted using 15 ng of His6-FGFR1, 23 ng of EGFR and 30 ng of His6-HGFR, respectively, according to the tyrosine kinase reaction and HTRF method described above. Measurement of inhibition against PDGFRp kinase activity was conducted using 50 ng of His6-PDGFRβ according to the tyrosine kinase reaction described above, followed by detection of tyrosine phosphorylated biotin-poly(GT) by the following method. Specifically, the kinase reaction solution was added to a 96-well streptavidin-coated

plate (Product No. 15129, Pierce Chemical) and incubated at room temperature for 30 minutes. After rinsing 3 times with 150 µl of a rinsing solution {20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20, 0.1% BSA}, 70 µl of anti-phosphotyrosine (PY20) -HRP conjugate (Product No. P-11625, Transduction Laboratories) {2000-fold dilution with 20 mM Tris-HCl (pH 7.6) , 137 mM NaCl, 0.05% Tween-20, 1% BSA} was added thereto and incubation was performed at room temperature for 1 hour. After incubation, it was rinsed 3 times with 150 ]il of the rinsing solution, and 100 µl of TMB Membrane Peroxidase Substrate (Product No. 50-5077-03, Funakoshi Co., Ltd.) was added to initiate the reaction. After stationing at room temperature for 10 minutes, 100 µl of 1 M phosphoric acid was added to suspend the reaction, and the absorbance at 4 50 nm was measured with a microplate reader (BIO KINETICS READER EL304, Bio-Tek Instruments),. The absorbance ratio in the presence of the test substance was determined with respect to 100% as the absorbance with addition of His6-PDGFRP and no test substance, and 0% as the absorbance without addition of both the test substance and His6-PDGFR(3. This absorbance ratio was used to calculate the test substance concentration required for 50% inhibition of PDGFRβ kinase activity (IC50) - The results are shown in Table 2.



angiogenesis-inducing activity using mouse dorsal air sac model
(1) Construction of VEGF (Vascular Endothelial
Growth Factor) expression vector
PCR was conducted using a human placenta cDNA library (Toyobo Co., Ltd.) as the template and the SEQ ID N0:1 (5'CCGGATCCATGAACTTTCTGCTG3') and SEQ ID NO: 2 (5'GTGAATTCTGTATCGATCGTT3') of VEGF as primers. After completion of the PCR reaction, the 5' ends were phosphorylated and an approximately 600 bp DNA band was separated by 1.2% agarose gel electrophoresis. After polymerization by self-ligation, the cDNA was cut with EcoRI and BamHI and inserted into the EcoRI and BamHI sites of vector pUC19. This was used to transform E. coli JM83, and plasmids were recovered from the transformed clones. A VEGF cDNA fragment was cut out of the plasmids with Hindi 11 and EcoRI and then inserted into pIRES2-rsGFP vector to yield pIRES2-rsGFP/VEGF for protein expression. [0155]
(2) Preparation of VEGF high-expressing strain
After overnight culturing of KP-1 human
pancreatic cancer cells (3 x 106 cells) with 10% FCS-containing RPMI 1640 medium, an Effectene Transfection Reagent Kit (Qiagen) was used for introduction of 3 µg of pIRES2-rsGFP/VEGF into the KP-1 cells. After

culturing in 10% FCS-containing RPMI 1640 medium containing 600 pg/ml of Geneticin, drug-resistant cells were selected. Furthermore, GFP high-expressing cells were collected by cell sorter (Becton Dickinson) as VEGF high-expressing KP-1 cells (KP-1/VEGF). [0156]
(3) Measurement of VEGF level in culture
supernatant
The KP-1/VEGF cells were prepared to 5 x 10^ cells/ml, and 0.5 ml thereof was dispensed into each
well of a 24-well plate and cultured at 37°C for 24 hours. The culture supernatants were collected and the VEGF levels thereof measured using a VEGF measuring kit (IBL Co., Ltd-) for confirmation of high expression. [0157]
(4) Evaluation of in vivo angiogenesis-inducing
activity using mouse dorsal air sac model
Millipore rings (Nihon Millipore) were sealed with 0.45 ym Durapore filter membranes (Nihon Millipore) to create chambers. KP-1/VEGF hiiman pancreatic cancer cells (3 x 106) suspended in 0.17 ml of collagen gel were injected into each chamber through the injection port, and the chambers were sealed. Approximately 10 ml of air was then injected in the dorsal skin of 6-week-old C57BL/6N female mice under anesthesia to produce pouches, and the prepared

chambers were transplanted therein. About 6 hours after completing transplantation, a test substance suspended in 0.5% methyl cellulose was orally administered (0.1 ml/10 g body weight), and this was continued once a day for the next 4 days.
[0158]
On the 4th day after transplanting the chambers, 0.2 ml of 51Cr (Amersham Pharmacia)-labeled mouse erythrocytes (2.5 x 106 cpm/ml) were injected through the caudal veins of each of the mice with the transplanted chambers. After a prescribed period, the skin in contact with the chamber was excised and frozen, the section in direct contact with the chamber was precisely cut off, and the radioactivity was measured with a Y~counter- The blood volume was calculated from the radioactivity and used as an index of the in vivo angiogenesis-inducing activity. The angiogenesis volume was recorded as this measured blood volume minus the blood volume obtained with transplantation of a chamber containing only collagen gel. The experiment was conducted using 10 mice in the control (solvent-administered) group and 5 mice in each compound-administered group. The proportions (%) of the angiogenesis amount after administering a test substance to that of control are shown in Table 3.
[0159]


Pharmacological Test Example 4: Evaluation of antituinor activity on KP-1/VEGF cells in subcutaneous xenograft models
VEGF high-expressing pancreatic cancer cells (KP-1/VEGF) suspended in PBS at a concentration of 1 x lO"^ cells/ml were transplanted under the right flank skin of 6-week-old female Balb/c (nu/nu) mice in a volume of 0.1 ml. When the tumor volume reached approximately 100 mm3, the test substance was orally administered twice a day over a period of 2 weeks with a schedule of 5 days per week. The test substance was suspended in 0.5% methyl cellulose for an administered volume of 0.1 ml/10 g body weight. The tumor size was measured twice a week using a micrometer caliper. The tumor volume was determined by measuring the long and short diameters of the tumor with a micrometer caliper, and calculating 1/2 x (long diameter x short diameter x short diameter). The experiment was conducted using 10 mice in the control (solvent-


The experiment was performed according to the method as already reported in the method (Lab- Invest., 67_(4), 519 - 528, 1992). Specifically, 10 pg/ml of recombinant FGF-2 (purchased from Invitrogen Corporation) dissolved in PBS was added to Matrigel Matrix (purchased from BD Biosciences) to prepare 1 ]ag/ml. After that, a 300 µl of this mixture of Matrigel Matrix and Recombinant FGF-2 was injected into a subcutaneous tissue on the median line of the abdomen of a 6-week-old Balb/c (nu/nu) mouse.
[0163]

Subsequently, the test substance suspended in a 0.5% methyl cellulose or the like had been orally administered in succession once a day or twice a day for 7 days.
[0164]
After 7 days, the implanted Matrigel was taken out, 300 pi of water was added thereto, and cut into pieces with scissors. The resultant substance was allowed to stand at a cool dark place overnight. After hemoglobin in Matrigel was fully extracted, 100 ]il of the supernatant obtained by centrifugation and 100 ]il of Drabkin's solution (purchased from Sigma Chemical Co. , Ltd) were allowed to react at room temperature at a dark place for 1 hour. After that, the absorbance of the reaction solution was measured with wavelength of 550nm and reference wavelength of 660 nm. The hemoglobin quantity (g/ml) in Matrigel was calculated from the calibration curve established by use of hemoglobin as a standard.
[0165]
The experiment was conducted using 8 mice in the control (solvent-administered) group and 6 mice in each compound-administered group -[Examples]
[0166]
The compounds according to the present invention

can be prepared by the methods as described in the following examples, for example. These are, however, exemplary, and the compounds according to the present invention are not limited to the specific examples mentioned below in any cases.
[0167] Example 1
Nl-Ethyl-5-(2-((methoxylamino)carbonyl)amino-4-pyrimidyl)oxy-lH-1-indolecarboxamide
Similarly to Production example 27-2, a crude product of phenyl N-(4-(1-(ethylamino)carbonyl-lH-5-indolyl) oxy-2-pyrimidyl) carbamate (54 6 mg, 1. 31 mmol, 56.3%) was obtained as pale brown powder from Nl-ethyl-5- (2-amino-4-pyrimidyl)oxy-lH-1-indolecarboxamide (691 mg, 2.32 mmol) and phenyl chlorocarbonate. The crude carbamate product (273 mg, 0.65 mmol) was dissolved in tetrahydrofuran (7,0 ml); and triethylamine (0.91 ml, 6.53 mmol) and methoxylamine hydrochloride (273 mg, 3.27 mmol) was added thereto while stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 1) .

The crystals were precipitated from ethyl acetate-hexane (1: 10), filtered off, and dried under aeration to yield the title compound (52.5 mg, 0.14 mmol, 21,7%) as white crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.17 (3H, t, J=7.2 Hz) , 3.20-3.4 0 (2H, m) , 3.68 (3H, s) , 6.4 5 (1H, d, J-5.6HZ), 6.67 (1H, d, J-3.6H2), 7.09 (1H, dd, J=2.4, 8.8 Hz), 7.43 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=5.6 Hz), 7.8 9 (1H, d, J=3.6 Hz) , 8.21 (1H, m) , 8,26 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=5.6 Hz), 9,31 (1H, d, J-10.0 Hz) .
[0168]
The starting materials were synthesized by the following methods. Production example 1-1 4-Chloro-6-(lH-5-indolyloxy)-2-pyrimidinamine
Sodium hydride (1,0 g, 25 mmol) was suspended in dimethyl sulfoxide (40 ml) under nitrogen atmosphere, and 5-hydroxyindole (3.33 g, 25 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 20 minutes, 2-amino-4,6-dichloropyrimidine (3,28 g, 20 mmol) was added. The
reaction mixture was heated at 100 °C and was stirred for 3 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 10% aqueous ammonia solution.

The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate: hexane = 2: 1) . The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.15 g, 4.41 mmol, 22.0%) as white crystals.
1H-NMR Spectrum (CDCI3) 5{ppm): 5.09 (2H, brs), 6.07 (1H, s) , 6.57 (1H, m) , 6.95 (1H, dd, J=2. 4, 8.8 Hz) , 7.2 9 (1H, m) , 7.37 (1H, m) , 7.41 (1H, d, J=8.8 Hz) , 8.28 (1H, brs).
[0169] Production example 1-2 4-(lH-5-Indolyloxy)-2-pyrimidinamine
4-Chloro-6-(lH-5-indolyloxy)-2-pyrimidinamine
(1.15 g, 4.41 mmol) was dissolved in tetrahydrofuran
(50 ml)-triethylamine (3.07 ml), 10% palladium on
carbon (5 0% wet, 500 mg) was added, and the reaction
mixture was stirred overnight under hydrogen atmosphere
at atmospheric pressure.
The reaction was purged with nitrogen. After methanol (50 ml) was added and stirred, the catalyst was filtered out. The resultant solution was concentrated under reduced pressure, thus the title compound (826 mg, 3.65 mmol, 82.8%) was obtained as

pale gray powder.
1H-NMR Spectrum (CDCI3) 5 (ppm) : 4.96 (2H, brs) , 6.06
(1H, d, J=5.6 Hz) , 6.5 6 (1H, m) , 6.97 (1H, dd, J=2.4, 8.8 Hz), 7.26-7.28 (1H, m) , 7.38-7.42 (2H, m) , 8.08 (1H, d, J=8.8 Hz), 8.29 (1H, brs).
[0170] Production example 1-3
Nl-Ethyl-5-(2-amino-4-pyrimidyl)oxy-lH-1-indolecarboxamide
Sodium hydride (157 mg, 3.93 mmol) was suspended in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, and 4-(lH-5-indolyloxy)-2-pyrimidinamine
(82 6 mg, 3.65 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice-water bath, phenyl N-ethylcarbamate (633 mg, 3.83 mmol) was added, the reaction mixture was heated to room temperature, and the solution was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography
(eluent; ethyl acetate: hexane =3: 1 to 4: 1) to yield the title compound (691 mg, 2.32 mmol, 63.7%) as white powder.

1H-NMR Spectrum (CDCI3) δ (ppm) : 1.32 (3H, t, 3=1.2 Hz), 3.54 (2H, in), 4.94 (2H, brs), 5.50 (1H, brs) , 6.11 (1H, dd, J=2.4, 5.6 Hz), 6.62 (1H, d, J=3.6 Hz), 7.09 (1H, dd, J=2.4, 8.8 Hz), 7,34 (1H, d, J=2.4 Hz), 7.46 (1H, d, J=3.6 Hz), 8.11 (1H, d, J=5.6 Hz), 8.15 (1H, d, J=8.8 Hz) .
[0171] Example 2
5- (6- (3- (3-Diethylaminopropylamino) ureido) pyrimidin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Phenyl (6-(l-methylcarbamoyl-lH-indol-5-
yloxy)pyrimidin-4-yl)carbamate (161 mg, 0.400 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and 3-(diethylamino)propylamine (130 mg, 1.00 mmol) was added while the reaction mixture was stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate- The solvent was distilled off, and the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate: methanol = 50: 1) . The crystals were precipitated from ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (123 mg, 0.280 mmol, 70%) as white crystals.

1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.93 (6H, t, J=7.0 Hz), 1.52 (2H, m), 2.32-2.46 (6H, m) , 2.84 (3H, d, J=3.6 Hz), 3.12 (2H, m) , 6.69 (1H, d, J=3.6 Hz), 6.98 (1H, s) r 7.06 (1H, dd, J=2.2, 8.8 Hz), 7.37-7.46 (2H, m) , 7.88 (1H, d, J==3, 6 Hz), 8.18 (1H, m) , 8.27 (1H, d, J=8.8 Hz), 8.37 (1H, s), 9.49 (1H, brs).
[0172]
The starting materials were synthesized by the following methods. Production example 2-1 Phenyl N-methylcarbamate
Methylamine hydrochloride (16.9 g, 250 mmol) was dissolved in N,N-dimethylformamide (250 ml) , pyridine (44 ml, 275 mmol) was added thereto, and the reaction mixture was stirred. The reaction mixture was cooled with ice, phenyl chloroformate (35 ml, 275 mmol) was added dropwise thereto, and the reaction mixture was then stirred at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were suspended in diethylether, diluted with hexane, filtered off, washed with the diethylether: hexane =1: 1, and dried by evacuation, to yield the title compound (22.3 g, 147 mmol, 59.1%) as colorless

crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.64 (3H, d, J=3. 6 Hz), 7.07 (2H, d, J=8.0 Hz), 7.17 (1H, t, J=8.4 Hz), 7.35 (2H, dd, J=8.0 Hz, 8.4 Hz), 7.58 (1H, d, J=3.6 Hz).
[0173] Production example 2-2 6-(lH-lndol-5-yloxy)pyrimidin-4-ylamine
Sodium hydride (400 mg, 10.0 mmol) was suspended in dimethyl sulfoxide (20 ml) under nitrogen atmosphere, and 5-hydroxyindole (1.33 g, 10.0 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 20 minutes, 6-chloropyrimidin-4-ylamine (1.04 g, 8.00 mmol) was added thereto, the
reaction mixture was heated at 100 °C and stirred for 1 hour. After the reaction mixture was naturally cooled
to room temperature, the reaction mixture was
partitioned between ethyl acetate and water. The
organic layer was washed with water and brine, and was
dried over anhydrous magnesium sulfate. The solvent
was distilled off, and the residue was purified by
silica gel column chromatography (eluent; ethyl
acetate: hexane =3: 1) to yield the title compound
(1.07 g, 4.73 mmol, 59%) as a brown oil.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 5.54 (1H, s), 6,43
(1H, m) , 6.71 (2H, brs), 6.85 (1H, dd, J-2. 4, 8.8 Hz), 7.29 (1H, d, J=2.4 Hz), 7.40-7.45 (2H, m), 8.06 (1H, s),

11.20 (1H, brs).
[0174] Production example 2-3
5- (6-Aminopyrimidin-4-yloxy.) -1H-indol-l-carboxylic acid methylamide
Sodium hydride (199 mg;. 4.97 mmol) was suspended in N,N-dimethylformamide {10 ml) under nitrogen atmosphere, 6- {lH-indol-5-yloxy)pyrimidin-4-ylamine (1.07 g, 4.73 mmol) synthesized in Production example 2-2 was gradually added while the reaction mixture was stirred at room temperature. After 30 minutes, the reaction mixture was cooled with an ice water bath, then phenyl N-methylcarbamate (751 mg, 4.97 mmol) synthesized in Production example 2-1 was added. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent; ethyl acetate) to yield the title compound (847 mg, 2.99 mmol, 63%) as white crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.85 (3H, d, J=4.0 Hz) , 5.62 (1H, s) , 6.68 (1H, d, J-3.6 Hz) , 6.77 (2H, brs), 7.04 (1H, dd, J=2.4, 9.2 Hz), 7.36 (1H, d, J-2.4

Hz), 7.87 (1H, d, J=3.6Hz), 8,07 (1H, s), 8.15 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=9.2 Hz).
[0175] Production example 2-4
Phenyl (6- (l-iaethylcarbamoyl-lH-indol-5-
yloxy)pyrimidin-4-yl)carbamate
5-(6-Aminopyridin-4-yloxy)-lH-indole-1-cabxylic acid methylamide (847 mg, 2.99 mmol) synthesized in Production example 2-3 was dissolved in N,N-dimethylformamide (10 ml) under nitrogen atmosphere. Pyridine (0.290 ml, 11.5 mmol) and phenyl chlorocarbonate (0.394 ml, 3.15 mmol) were sequentially added dropwise thereto while cooling with an ice water bath- After the reaction mixture was stirred for 30 minutes, triethylamine (0.417 ml, 2.99 mmol) was added, and the reaction mixture was heated to room temperature while stirred. After 30 minutes, the reaction mixture was partitioned between ethyl acetate and water. the organic layer was washed with water and brine, and was dried over anhydrous magnesiiom sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 3: 1) . The crystals were precipitated from ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (504 mg, 1.25 mmol, 42%) as white crystals.

1H-NMR Spectrum (CDCI3) δ (ppm) : 3.05 (3H, d, J=4.8 Hz), 5.53 (1H, q, J=4.8 Hz), 6.58 (1H, d, J=4 .0 Hz), 7,08 (1H, dd, J=2.4, 8.8 Hz), 7.13-7.19 (2H, m) , 7.23-7.29 (1H, m), 7.34 (1H, d, J=2.4 Hz), 7.36-7.44 (3H, in), 7.52 (1H, s), 8.14 (1H, d, J=8.8 Hz), 8.59 (1H, s), 9.99 (1H, brs).
[0176] Example 3
5-(6-(((4-Hydroxypiperidin-l-
yl)carbonyl)amino)pyrimidin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 2, the title compound (100
mg, 0.231 mmol, 5 8%) was obtained as white powder from
phenyl (6-(l-methylcarbamoyl-lH-indol-5-
yloxy)pyrimidin-4-yl)carbamate (161 mg, 0.4 00 mmol) and 4-hydroxypiperidine.
1H-NMR Spectr\am (DMSO-d6) δ (ppm) : 1.24-1.34 (2H, m) , 1.64-1.73 (2H, m) , 2.85 (3H, d, J=4.0 Hz), 3.02-3.12 (2H, m), 3.64 (1H, m) , 3.72-3.80 (2H, m), 4.69 (1H, d, J=4.0 Hz), 6.68 (1H, d, J=3.6 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.20 (1H, s), 7.40 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.17 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.40 (1H, s), 9.72 (1H, brs).
[0177] Example 4 5-(6-((4-(Pyrrolidin-l-yl)piperidin-l-

yl) carbonylamino)pyrimidin-4-yloxy) -lH-indole-1-carboxylic acid methylamide
Similarly to Example 2, the title compound (141 mg, 0.304 mmol, 76%) was obtained as white crystals from phenyl (6-(l-methylcarbamoyl-lH-indol-S-yloxy)pyrimidin-4-yl)carbamate (161 mg, 0.400 mmol) and 4-(l-pyrrolidynyl)piperidine.
1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.23-1.36 (2H, m) , 1.63-1.70 (4H, m) , 1.74-1.84 (2H, m) , 2.08-2.18 (1H, m) , 2.42-2.50 (4H, m), 2.82-2.95 (5H, m), 3.90-3.98 (2H, m) , 6.68 (1H, d, J=3,6 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.2 0 (1H, s) , 7.4 0 (1H, d, J=2,4 Hz) , 7.8 8 (1H, d, J=3.6 Hz), 8.17 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.40 (1H, s), 9.71 (1H, brs).
[0178] Example 5
5-(2-(3-((IR)-l-Carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0,200 mmol) and triethylamine (1 ml) were dissolved in N,N-dimethylformamide (3 ml), and (2R)-2-amino-3-phenylpropionamide hydrochloride (201 mg, 1.00 mmol) was added, and the reaction mixture was stirred for 18 hours. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous

solution of ammonium chloride. The organic layer was washed with water and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 50: 1) . The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (77,2 mg, 0.152 mmol, 76%) as white crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.81 (1H, dd, J=8.0, 13.2 Hz), 2.84 (3H, d, J=4.4 Hz), 3.01 (1H, dd, J-4.8, 13.2 Hz), 4.38 (1H, m) , 6.52 (1H, dd, J=2 .4, 5.0 Hz), 6.69 (1H, d, J=3.2 Hz), 6,86 (1H, s), 7.01-7.07 (2H, m) , 7.15-7.30 (5H, m), 7.37 (1H, d, J=2.4 Hz), 7.50 (1H, s), 7.88 (1H, d, J=3.2 Hz), 8.02 (1H, d, J=6.0 Hz), 8.18 (1H, q, J=4.4 Hz), 8.22-8.34 (2H, m), 9.11 (1H, s).
[0179]
The starting material, Phenyl N-(4-(l-(methylamino)carbonyl-lH-indol-5-yloxy)pyridin-2-yl)-N-(phenoxycarbonyl) carbamate, was synthesized as follows. Production example 5-1
Nl--Methyl-5- (2-amino-4-pyridyl) oxy-lH-1-indolecarboxamide
Sodium hydride (430 mg, 10.75mmol) was suspended in N,N-dimethylformamide (25 ml) under ' nitrogen atmosphere, and 4- (lH-5-indolyloxy)-2-pyridinamine

(2.253 g, 10.00 mmol, CAS No. 417722-11-3) described in WO 02/32 872 was gradually added while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and then phenyl N-methylcarbamate (1.587 g, 10.50 mmol) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was removed by distilled off. The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (2.163 g, 7.66 mmol, 76.6%) as pale brown crystals. 1H-NMR Spectrum (CDCI3) 5 (ppm) : 3.09 (3H, d, J=4. 8 Hz), 4-36 (2H, m) , 5.4 9 (1H, m) , 5.92 (1H, d, J=2.0 Hz) , 6.30 (1H, dd, J=2.0, 6.0 Hz), 6.61 (1H, d, J=3. 6 Hz), 7.07 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2. 4 Hz), 7.45 (1H, d, J=3.6 Hz), 7.92 (1H, d, J=6.0 Hz), 8.17
(1H, d, J=8.8 Hz).
[0180] Production example 5-2
phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate
Nl-Methyl-5-(2-amino-pyridyl)oxy-lH-1-indolecarboxamide (2.0 g, 7.1 mmol) was suspended in

tetrahydrofuran (14 0 ml) and N,N-dimethylformamide (1.4 ml) at room temperature, and triethylamine (2.2 ml, 16 mmol) was added while stirred. The reaction mixture was cooled with an ice, and phenyl chloroformate (1-8 ml, 15 mmol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. Phenyl chloroformate (0.5 ml) was further added, and the reaction mixture was stirred at room temperature for 0.5 hours. Brine was added to the reaction mixture; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, then the precipitated crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (3.3 g, 6.3 mmol, 89%) as pale brown crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 3.30 (3H, d, J=4.4 Hz) , 6.66 (1H, d, J=3.6 Hz) , 6.95 (1H, dd, J-2.4, 6.0 Hz) , 7.10 (1H, dd, J=2.4, 8,8 Hz) , 7.15-7. 18 (4H, m) , 7.27-7.31 (2H, m) , 7.4 0-7.4 5 (5H, m) , 7.52 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.17 (1H, q, J=4.4 Hz), 8.31 (1H, d, J=8.8 Hz), 8.41 (1H, d, J=6.0 Hz).
[0181]
Nl-methyl-5-(2-amino'4-pyridyl)oxy—IH-l-indolecarboxamide described in Production example 5-1,

can be also synthesized as follows. Nl-Methyl-5-(2-amino-4-pyridyl)oxy—lH-1-indolecarboxamide
5- (2-Aminopyridin-4-yloxy) -2, 3-dihydro-lH-indole-1-carboxylic acid methylamide (40 mg, 0.14 mmol) was dissolved in acetic acid (0.9 ml), manganese (III) acetate (29 mg, 0.17 mmol) was added thereto and the ^
reaction mixture was stirred at 70 °C for 3.5 hours. Manganese (III) acetate (29 mg, 0.17 mmol) was further added, and the reaction mixture was further stirred at 70 °C for 0.5 hours. After naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in diethyl ether: acetone = 3: 1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (24 mg, 0.085 mmol, 61%) as colorless crystals.
[0182]
The starting material, 5-(2-Aminopyridin-4-
yloxy)-2,3-dihydro-lH-indole-l-carboxylic acid
methylamide was synthesized as follows. Production example 5-3 5-Benzyloxy-lH-indole-l-carboxylic acid methylamide

Sodium hydride (2.212 g, 55.30 xnmol, 60% in oil) was suspended in N,N-diiciethylforinaiaide (100 lal)^ 5-benzyloxyindole (10.29 g, 46.09 mmol) was added thereto while stirred at room temperature, and the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was cooled with an ice water bath;, and phenyl N-methylcarbamate (8.360 g, 55.30 mmol) was added- After the reaction mixture was stirred for 30 minutes, the solution was stirred at room temperature for 2.5 hours. After water was added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 hour, the obtained crystals were filtered off, then these crystals were sequentially washed with water and diethyl ether, and dried under aeration to yield the title compound (12.07 g, 43.06 mmol, 93.41%) as pale yellow crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.80 (3H, d, J==4.4 Hz), 5.10 (2H, s), 6.56 (1H, d, J=3.8 Hz), 6.93 (1H, dd, J=2.4, 9.0 Hz), 7,16 (1H, d, J=2. 4 Hz), 7.30 (1H, t, J=7.2 Hz), 7.37 (2H, t, J=7.2 Hz), 7.45 (2H, d, J=7.2 Hz), 7.74 (1H, d, J=3.8 Hz), 8.00 (1H, m) , 8.11 (1H, d, J-9.0 Hz).
[0183] Production example 5-4
5"Hydroxy-2, 3-dihydro-lH-indole-l-carboxylic acid
methylamide

5-Ben2yloxy-lH-indole-carboxylic acid
methylamide (10,00 g, 35.67 mmol) was dissolved in methanol (200 ml) and tetrahydrofuran (150 ml) , 10% palladium on carbon (0.9 g) was added, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 9 hours. After the catalyst was removed by filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (4 00 ml) , 10% palladium on carbon (0.9 g) was added, then the reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 6 hours. After the catalyst was removed by filtration, the solvent was distilled off under reduced pressure. The obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (6.522 g, 33-93 mmol, 95.12%) as grayish crystals.
-NMR Spectrum (DMSO-de) 5 (ppm) : 2.61 (3H, d, J-4.4 Hz), 2.99 (2H, t, J=8.6 Hz), 3.76 (2H, t, J=8.6 Hz), 6.33 (IH, d, J=4.4 Hz), 6.43 (IH, dd, J=2.4, 8.4 Hz), 6.54 (IH, d, J=2,4 Hz), 7.58 (IH, d, J=8.4 Hz), 8.82 (IH, s).
[0184] Production example 5-5
5- (2-Aminopyridin-4-yloxy) -2, 3-dihydro-lH'-indole-l-carboxylic acid methylamide

Sodium hydride (202 mg, 3.89 mmol, 60% in oil) was suspended in dimethyl sulfoxide (5.0 ml), then 5-hydroxy-2,3-dihydro-lH-indole-l-carboxylic acid methylamide (971 mg, 5,06 mmol) and 2-amino-4-chloropyridine (500 mg, 3.89 mmol) were added at room temperature under nitrogen atmosphere, and the reaction
mixture was heated and stirred at 160 °C for 12 hours under nitrogen atmosphere. After naturally cooled down to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300; eluent: ethyl acetate, ethyl acetate: methanol =85: 10 in this order). The fractions containing the desired compound were concentrated, and the residue was further purified by silica gel column chromatography (Fuji Silysia NH, eluent; from ethyl acetate to ethyl acetate: methanol = 90: 10) . The obtained crystals were suspended in diethyl ether: acetone = 3: 1, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (51 mg, 0.18 mmol, 4.6%) as pale green crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.65 (3H, d, J=4. 4 Hz), 3.09 (2H, t, J=8.6 Hz), 3.86 (2H, t, J=8. 6 Hz),

5.75 (1H, d, J=2.0 Hz), 5.85 (2H, brs), 6.07 (1H, dd, J-2.0, 6.0 Hz), 6.56 (1H, d, J=4.4 Hz), 6.81 (1H, dd, J=2.4, 8.4 Hz) , 6.90 (1H, d, J=2.4 Hz) , 7.73 (1H, d, J=6.0 Hz), 7.83 (1H, d, J=8.4 Hz).
[0185] Example 6
5- (2- (3- ( (IS) -l-Carbajnoyl-2-phenylethyl) ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Nl-Methyl-5-((2-amino-4-pyridyl)oxy-lH-1-indolcarboxamide (100 mg, 0.354 mmol) synthesized in Production example 5-1 and triethylamine (0.3 ml) were dissolved in N,N-dimethylf ormamide (3 ml) . Phenyl chlorocarbonate (0.0888 ml, 0.708 mmol) was added dropwise thereto at room temperature and the reaction mixture was stirred for 30 minutes. (2S)-2-Amino-3-phenylpropionamide (2 90 mg, 1.77 mmol) was added and the reaction mixture was stirred for 3 days. The reaction mixture was partitioned between a solvent mixture of ethyl acetate-tetrahydrofuran and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 20: 1). The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield

the title compound (69.4 mg, 0.147 mmol, 41%) as white crystals.
[0186] Example 7
5- (2- (3- (2-0x0-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
tert-Butoxycarbonylaminoacetic acid (87 6 mg, 5.00 mmol) and N-methylmorpholine (506 mg, 5.00 mmol) were dissolved in tetrahydrofuran (20 ml) . After isobutyl chloroformate (683 mg, 5.00 mmol) was added dropwise at below -15 °C and the reaction mixture was stirred for 30 minutes, pyrrolidine (782 mg, 11.0 mmol) was added at below -15 °C and the reaction mixture was further stirred at 0 °C for 30 minutes. The reaction mixture was partitioned between ethyl acetate and IN aqueous solution of sodium hydroxide. The organic layer was washed with IN hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was dissolved in a solvent mixture of ethyl acetate (10 ml)-tetrahydrofuran (5 ml). 4N hydrochloric acid Ethyl acetate solution (5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. After the solvent was distilled off, ethyl acetate was added to the crude product to precipitate crystals; and

the crystals were filtered off and dried under aeration to yield 2-ainino-l- (pyrrolidin-1-yl) ethanone hydrochloride (573 mg, 4.16 mmol, 84%) as white crystals.
The title compound (74.7 mg, 0.171 mmol, 8 6%) was obtained as white crystals from phenyl N-(4-(l-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200 mmol) synthesized in Production example 5-2 and the previously obtained 2-amino-l-(pyrrolidin-1-yl)ethanone hydrochloride (165 mg, 1.00 mmol) similarly to Example 5.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1,71-1.81 (2H, m) , 1.83-1.93 (2H, m) , 2.85 (3H, d, J=4.0 Hz) , 3.2 6-3.4 0 (4H, m) , 3.90 (2H, d, J=4.4 Hz), 6.55 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.4 Hz), 6.94 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.0, 9.0 Hz), 7.38 (1H, d, J=2.0 Hz), 7.89 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=6.0 Hz), 8.12-8.26 (2H, m), 8.30 (1H, d, J=9.0 Hz), 9.28 (1H, s).
[0187] Example 8
5-(2-(3-(2-(4-Hydroxy-4-methylpiperidin-l-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
4-Hydoxy-4-methylpiperidine hydrochloride (113 mg, 0.745 mmol) was suspended in N,N-dimethylformamide

(3 ml);. then triethylamine (1 ml) was added; benzotriazole-1-isooxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg, 0.454 mmol) and ((4-(l-methyl carbamoyl-lH-indol-5-yloxy)pyridin-2'-yl) aminocarbonylamino) acetic acid (14 5 mg, 0.37 8 mmol) were added thereto; and the reaction mixture was stirred at room temperature for 2 hours. After water was added to the' reaction mixture, extraction was performed with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH silica gel; ethyl acetate, ethyl acetate: methanol = 20: 1, 10: 1 in this order). After concentration under reduced pressure, the product was solidified with diethyl ether, suspended, filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (137 mg, 0.285 mmol, 75.4%) as a colorless amorphous solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.10 (3H, s) , 1.38-1.4 4 (4H, m) , 2.83 (3H, d, J=3.6 Hz) , 3.02 (2H, m) , 3.90 (2H, m) , 3.9 6 (2H, d, J=4.0 Hz) , 4 .37 (1H, s) , 6.52 (1H, d, J=5.6 Hz), 6.67 (1H, d, J=3.2 Hz), 6.91 (1H, s), 7.04 (1H, d, J=9.0 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.2 Hz), 8.03 (1H, d, J=5. 6 Hz) , 8.17 (2H, m) , 8.28 (1H, d, J=9.0 Hz), 9,27 (1H, s).

The starting materials were synthesized as follows.
Production example 8-1
( (4- (1-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)acetic acid
Methyl aminoacetate hydrochloride (300 mg, 2.3 mmol) was dissolved in N,N-dimethylformamide (4 ml), and then triethylamine (1 ml) was added. Phenyl N-(4" (1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl) carbamate (250 mg, 0.48 mmol) synthesized in Production example 5-2 was added thereto. The reaction mixture was stirred at room temperature for 22 hours. After water was added to the reaction mixture, extraction was performed with a solvent mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate). The obtained pale yellow oil was dissolved in a solvent mixture of tetrahydrofuran (2 ml)-methanol (1 ml) , then 4N aqueous solution of lithium hydroxide (0.48 ml) was added, and the reaction mixture was stirred at room temperature for 1 hour. After that, IN hydrochloric acid (2 ml) was added, and this was

subjected to extraction with ethyl acetate-tetrahydrofuran. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield the title compound (145 mg, 0.38 mmol, 79%) as colorless crystals. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.83 (3H, d, J=3. 6 Hz), 3.81 (2H, d, J=5.6 Hz), 6.57 (1H, m) , 6.68 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.05 (1H, dd, J=2.0, 9.2 Hz), 7.38 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=5.6 Hz), 8.16-8.30 (3H, m), 9.33 (1H, brs).
[0189] Production example 8-2 Benzyl (4-hydroxy-4-methylpiperidin-l-yl)carboxylate
Benzyl (4-oxopiperidin-l-yl)carboxylate (4.7 g, 20 mmol) was dissolved in tetrahydrofuran (2 00 ml) ; methyllithium-diethylether solution (9.0 ml (1.02 M) + 11.6 ml (1.14 M) , . total 22 mmol) was added dropwise thereto (internal temperature: -60 °C or below) while stirred at -78 °C under nitrogen atmosphere; and then the reaction mixture was stirred for 1.5 hours as it stands. On the other hand, a similar reaction was performed by using piperidin-4-one-l-carboxylate (1.1 g, 5.0 mmol) in another container. After the saturated aqueous solution of ammonium chloride was added to each reaction mixture, the two reaction mixtures were mixed. Extraction was performed with ethyl acetate, washed

with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the title compound (4.5 g, 18 mmol, 73%) as colorless crystals. 1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.10 (3H, s), 1.32-1.4 4 (4H, m) , 3.17 (2H, m) , 3.61 (2H, dt, J=3.6, 9.2 Hz), 4.34 (1H, s), 5.04 (2H, s), 7.27-7.37 (5H, m) .
[0190] Production example 8-3 4-Hydroxy-4-methylpiperidine monohydrochloride
Benzyl (4-hydroxy-4-methylpiperidin-l-
yl)carboxylate (4.5 g, 18 mmol) was dissolved in methanol (90 ml), 10% palladium on carbon powder (0.60 g) was added, and the reaction mixture was stirred at room temperature under hydrogen atmosphere overnight. The catalyst was removed by filtration and the resultant solution was concentrated under reduced pressure to yield a crude product of 4-hydroxy-4-methylpiperidine as a pale yellow oil (2.1 g) . After the product was dissolved in methanol, IN hydrochloric acid (17.5 ml) was added and the solvent was distilled off under reduced pressure. The obtained crystals were suspended in acetone, the crystals were filtered off, washed with acetone, and dried under aeration to yield the title compound (2.1 g, 14 mmol, 77%) as colorless

crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.14 (3H, s) , 1.55-1.69 (4H, m), 3.00 (4H, m), 4.68 (1H, brs), 8.77 (1H, brs), 8.89 (1H, brs).
[0191] Example 9
5-(2-(3-((IS)-l-Carbamoylethyl)ureido)pyridin-4-yloxy)-IH-indole-l-carboxylic acid methylamide
Nl-Methyl-5-((2-amino-4-pyridyl)oxy-lH-1-indolecarboxamide (100 mg^. 0.354 mmol) synthesized in Production example 5-1 and triethylamine (1 ml) were dissolved in tetrahydrofuran (3 ml) ;. then phenyl chlorocarbonate (0.0888 ml, 0.708 mmol) was added dropwise at room temperature, and the reaction mixture was stirred for 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in N,N-dimethylformamide (3 ml) . (2S)-2-Aminopropionamide hydrochloride (220 mg, 1.77 mmol) and triethylamine (1 ml) were added and the reaction mixture was stirred for 18 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 2 0:

1) . The crystals were precipitated from a solvent mixture of ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (38,5 mg, 0.0971 mmol, 27%) as white crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.21 (3H, d, J=6.8 Hz); 2.85 (3H, d, J=4.0 Hz), 4.17 (1H, m), 6.55 (1H, d, J=5.2 Hz), 6.70 (1H, d, J=3.6 Hz), 6.93 (1H, s), 7.02 (1H, s), 7.06 (1H, dd, J=2.0, 8.8 Hz), 7.39 (1H, d, J=2.0 Hz), 7.46 (1H, s), 7.90 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.2 Hz) 8.11 (1H, brs) , 8.20 (1H, q, J=4.0 Hz), 8.30 (1H, d, J=8.8 Hz), 9.21 (1H, brs).
[0192] Example 10
5-(2-(3-( (IS)-l-Carbamoyl-3-methylbutyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 9, the title compound (59.5
mg, 0.135 mmol, 38%) was obtained as white crystals
from Nl-methyl-5-(2-amino-4-pyridyl)oxy-lH-1-
indolecarboxamide (100 mg, 0.354 mmol) synthesized in Production example 5-1 and (2S)-2-amino-4-methylpentanamide hydrochloride (295 mg, 1.77 mmol). 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 0.83-0.91 (6H, m) , 1.35-1.50 (2H, m), 1.58 (1H, m), 2.85 (3H, d, J=4,4 Hz), 4.17 (1H, m) , 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.8 Hz), 6.92-7.01 (2H,m), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.48 (1H, s), 7.89 (1H, d.

J=3.8 Hz) 7.98-8.12 (2H, m) , 8.19 (1H, q^ J=4 .4 Hz) , 8.30 (1H, d, J=8,8 Hz), 9.09 (1H, s).
[0193] Example 11
5- (2- (3-Carbainoylmethylureido)pyridin-4-yloxy) -IH-indole-1-carboxylic acid methylamide
Similarly to Example 5, the title compound (52.8 mg, 0.138 mmol, 69%) was obtained as white crystals from phenyl N-(4-(1- (methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate
(104 mg, 0.200 mmol) synthesized in Production example 5-2 and glycinamide hydrochloride (111 mg, 1.00 mmol). 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2. 85 (3H, d, J=4.0 Hz) , 3.7 0 (2H, d, J=5.2 Hz) , 6.53 (1H, dd, J=2. 4, 5.8 Hz) , 6.69 (1H, d, J=3.4 Hz) , 6.92 (1H, d^ J=2. 4 Hz) , 7.01 (1H, s) , 7.06 (1H, dd, J=2.4, 9,2 Hz), 7.34-7.42
(2H, m), 7.89 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=5.8 Hz), 8.14-8.26 (2H, m) , 8.30 (1H, d, J=9.2 Hz), 9.21 (1H, s).
[0194] Example 12
5-(2-(3-Cyclopropylcarbamoylmethylureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5, the title compound (50.7 mg, 0.120 mmol, 60%) was obtained as white powder from phenyl N- (4- (1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200

mmol) synthesized in Production example 5-2 and 2-amino-N-cyclopropylacetamide hydrochloride (151 lag, 1,00 mmol) obtained from tert-butoxycarbonylaminoacetic acid and cyclopropylamine by the method similar to Example 7.
1H-NMR Spectrum (DMSO-d6) δ(ppm): 0,36-0.42 (2H, m) , 0.57-0.63 (2H, m), 2.60 (1H, m), 2.85 (3H, d, J=4.4 Hz),
3.68 (2H, d, J=5.2 Hz), 6.53 (1H, dd, J==2,0, 6.0 Hz),
6.68 (1H, d, J=3.6 Hz), 6.91 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.00 (1H, d, J=4.0 Hz), 8.06 (1H, d, J=6.0 Hz) 8.14-8.26 (2H, m) , 8.30 (1H, d, J=9.0 Hz), 9.21 (1H, s).
[0195] Example 13
5- (2- (3- ( (15)-l-Carbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 9, the title compound (52.1
mg, 0.126 mmol, 36%) was obtained as white crystals
from Nl-methyl-5- (2-amino-4-pyridyl)oxy-lH-1-
indolecarboxamide (100 mg, 0.354 mmol) synthesized in Production example 5-1 and (2S)-2-amino-3-hydroxypropionamide hydrochloride (249 mg, 1.77 mmol). 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.85 (3H, d, J=4.4 Hz), 3,52 (1H, dd, J=4.8, 6.4 Hz), 3.62 (1H, dd, J=4.8,

6.4 Hz), 4.13 (1H, m) , 4.94 (1H, brs), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.99 (1H, s), 7.02-7.10 (2H, m), 7.35 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.10-8.26 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.22 (1H, s).
[0196] Example 14
5- (2- (3- ( (IR) -l-'Carbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid inethylamide
Similarly to Example 9, the title compound (56,0 mg, 0.136 mmol, 68%) was obtained as white crystals from phenyl N- (4- (1- (methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate
(104 mg, 0-200 mmol) synthesized in Production example 5-2 and (2R)-2-amino-3-hydroxypropioamide hydrochloride
(167. mg, 1.00 mmol) obtained from (2R)-2-(tert-buto'xycarbonylamino) -3-hydroxypropionic acid and aqueous ammonia by the method similar to Example 7.
[0197] Example 15
(2S)-2- (3- (4-(l-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)ureido)-1,5-pentanedicarboxylic acid diamide
Similarly to Example 6, the title compound (82.5 mg, 0.189 mmol, 51%) was obtained as white powder from

Nl-methyl-5- (2-ainino-4-pyridyl) oxy-lH-1-indolecarboxamide (100 mg;. 0.354 miaol) synthesized in Production example 5-1 and (23)-2-amino-1,5-pentanedicarboxylic acid diamide hydrochloride (321 mg, 1.77 mmol).
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.66-2.28 (4H, m) , 2.85 (3H, d, J=4.4 Hz), 4.17 (1H, m) , 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.72 (1H, s), 6.97 (1H, s), 7.01-7.10 (2H, m), 7.30 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.49 (1H, s), 7.76 (1H, s) 7.89 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=6.0 Hz), 8.18 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=8.8 Hz), 9.13 (1H, s).
[0198] Example 16
(2S)-2-(3-(4-(l-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)ureido)succinamide
Similarly to Example 6, the title compound (65.7
mg, 0.150 mmol, 42%) was obtained as white crystals
from Nl-methyl-5-(2-amino-4-pyridyl)oxy-lH-1-
indolecarboxamide (100 mg, 0.354 mmol) synthesized in Production example 5-1 and (2S)-2-aminosuccinamide hydrochloride (297 mg, 1.77 mmol).
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.45 (2H, d, J=6.8 Hz), 2.85 (3H, d, J=3.6Hz), 4.40 (1H, m), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.88 (1H, s), 6.95 (1H, s) , 7.00 (1H, d, J=2.4 Hz) , 7.06 (1H, dd.

J=2.4, 9,2 Hz), 7.28 (1H, s), 7,35 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3. 6 Hz), 8.04 (1H, d, J=6,0 Hz), 8.18 (1H, q, J=4.0 Hz), 8,26 (1H, brs), 8.30 (1H, d, J=9.2 Hz), 9.19 (1H, s) .
[0199] Exajqple 17
5-(2-(3-((IS)"l-Cyclopropylcarbamoyl-2-hydroxyethyl)ureido)pyridin-4-yloxy)-IH-indole-l-carboxylic acid methylaiaide
Similarly to Example 5, the title compound (72.0 mg, 0.159 mmol, 80%) was obtained as white powder from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0,200 mmol) synthesized in Production example 5-2 and (2S)-2-amino-N-cyclopropyl-3-hydroxypropionamide hydrochloride (181 mg, 1,00 mmol) obtained from (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and cyclopropylamine by the method similar to Example 7. 1H-NMR Spectrum (DMSO-d6) δ(ppm): 0,35-0.44 (2H, m) , 0,54-0.63 (2H, m), 2.62 (1H, m), 2.85 (3H, d, J=4.0 Hz), 3.45-3.58 (2H, m), 4.09 (1H, m), 4.91 (1H, t, J=5.2 Hz), 6.53 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3, 6 Hz), 6.99 (1H, d, J=2.0 Hz), 7.04 (1H, dd, J=2.4, 8,8 Hz), 7.38 (1H, d, J=2.4 Hz), 7,89 (1H, d, J=3. 5 Hz), 7.98 (1H, d, J=4.4 Hz) , 8.05 (1H, d, J=6.0 Hz) , 8.09-8.24 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.18 (1H, s).

Example 18
5- (2- (3- ( (IS) -l-Hydroxyinethyl-2-oxo-2-pyrrolidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylaiuide
Similarly to Example 5, the title compound (67.6 mg, 0.14 5 mmol, 73%) was obtained as white powder from phenyl N-(4- (1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (104 mg, 0.200 mmol) synthesized in Production example 5-2 and (2S)-2-amino-3-hydroxy-l-(pyrrolidin-1-yl)propan-1-one hydrochloride (165 mg, 0.84 8 mmol) obtained from (2S)-2- (tert-butoxycarbonylamino)-3-hydroxypropionic acid and pyrrolidine by the method similar to Example 7. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.72-1.81 (2H, m) , 1.81-1.90 (2H, m) , 2.85 (3H, d, J=4.4 Hz) , 3.22-3.36 (2H, m) , 3.46-3.60 (4H, m) , 4.54 (1H, m) , 4.98 (1H, brs), 6.54 (1H, dd, J=2.0, 5.6 Hz) , 6.69 (1H, d, J=3.6 Hz) , 6.97 (1H, d, J-2.0 Hz) , 7.05 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3. 6 Hz), 8.05 (1H, d, J=5.6Hz), 8.13-8.23 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.18 (1H, s).
[0201] Example 19
5-(2-(3-((lR)-l-Hydroxymethyl-2-oxo-2-pyrrolidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic

acid methylamide
Similarly to Example 5;. the title compound (305 mg, 0.654 mmol, 93%) was obtained as white powder from phenyl N- (4- (1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (366 mg, 0.700 mmol) synthesized in Production example 5-2 and (2R)-2-amino-3-hydroxy-l-(pyrrolidin-1-yl)propan-1-one hydrochloride obtained from (2R)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and pyrrolidine by the method similar to Example 7,
[0202] Example 2 0
5-(2-(3-((IS)-l-Hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5^ the title compound (124 mg, 0.258 mmol, 86%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (157 mg, 0.300 mmol) synthesized in Production example 5-2 and (2S)-2-amino-3-hydroxy-l-(piperidin-1-yl)propan-l-one hydrochloride (312 mg, 1.50 mmol) obtained from (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and piperidine by the method similar to Example 7. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.36-1. 61 (6H, m) ,

2.85 (3H, d, J=4.4 Hz), 3.40-3.53 (6H, m) , 4.76 (1H, m), 4.92 (1H, brs), 6.54 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.97 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 9,0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (IE, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.10-8.26 (2H, m) , 8.30 (1H, d, J=9.0 Hz), 9.21 (1H, s).
[0203] Example 21
5-(2-(3-((IR)-l-Hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid iriethylamide
(2R)-2-Benzyloxycarbonylamino-3-hydroxypropionic acid (1-91 g, 8.00 rnmol) and N-methylmorpholine (809 mg, 8.00 mmol) were dissolved in tetrahydrofuran (20 ml). After isobutyl chloroformate (1.09 g, 8.00 mmol) was
added dropwise at -15 °C or below, the reaction mixture was stirred for 30 minutes. Then, pyrrolidine (1.13 g,
16.0 mmol) was added at -15 °C or below, and the reaction mixture was further stirred at 0 °C for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with IN hydrochloric acid, IN aqueous solution of sodium hydroxide, a saturated aqueous solution of sodium hydrogencarbonate, and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was dissolved in a

solvent mixture of methanol (15 ml)-tetrahydrofuran (15
ml). Then, 10% palladium on carbon (wet) (300 mg) was
added, and the reaction mixture was stirred at room
temperature under the stream of hydrogen for 90 minutes.
After the catalyst was removed by filtration, the
solvent of the filtrate was distilled off under reduced
pressure to yield (2R)-2-amino-3-hydroxy-l-(piperidin-
l-yl)propan-l-one (684 mg, 3.97 mmol, 50%) as a
colorless oil. Similarly to Example 5, the title
compound (107 mg, 0.223 mmol, 74%) was obtained as
white crystals from phenyl N-(4-(l-
(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-
(phenoxycarbonyl)carbamate (157 mg, 0.300 mmol)
synthesized in Production example 5-2 and previously
obtained (2R)-2-amino-3-hydroxy-l-(piperidin-1-
yl)propan-l-one (228 mg, 1.32 mmol).
[0204] Example 22
5- (2-(3- ( (15)-l-Hydroxymethyl-2-(4-hydroxypiperidin-l-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5;. the title compound (118 mg, 0.238 mmol, 59%) was obtained as white powder from phenyl N-(4-(1- (methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (17 9 mg, 0.343 mmol) synthesized in Production example 5-2 and (2S)-2-

amino-3-hydroxy-l-(4-hydroxypiperidin-l-yl)propan-l-one hydrochloride (385 mg, 1.71 ininol) obtained from (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and 4-hydroxypiperidine by the method similar to Example 7. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.16-1.40 (2H, m) , 1.61-1.80 (2H, m) , 2.85 (3H, d, J-4.0 Hz), 2.98-3.50 (5H, m), 3.63-3.95 (3H, m) , 4.76 (1H, m) , 4.92 (1H, brs) , 6.55 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.96 (1H, d, J=2.0 Hz), 7.06 (1H, dd, J-2.4, 8.8 Hz) , 7.38 (1H, d, J=2.4 Hz) , 7.90 (1H, d, J=3. 6 Hz) , 8.05 (1H, d, J=6.0 Hz), 8.08-8.26 (2H, m), 8.30 (1H, d, J=8.8 Hz), 9.26 (1H, s).
[0205] Example 23
5-(2-(3-((15)-l-Hydroxymethyl-2-(morpholin-4-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5, the title compound (121 mg, 0-251 mmol, 84%) was obtained as white crystals from phenyl N- (4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (157 mg, 0.300 mmol) synthesized in Production example 5-2 and (2S)-2-amino-3-hydroxy-l-(morpholin-4-yl)propan-l-one hydrochloride (316 mg, 1.50 mmol) obtained from (2S)-2-(tert-butoxycarbonylamino)-3-hydroxypropionic acid and morpholine by the method

similar to Example 7.
1H-NMR Spectriom (DMSO-d6) δ (ppm) : 2.85 (3H, d, J=4.4 Hz), 3.36-3.62 (lOH, m), 4.74 (1H, m), 4.92 (1H, brs), 6.54 (1H, dd, J=2.4, 6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 6.96 (1H, d, J-2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.05 (1H, d, J=6.0 Hz), 8.14-8.28 (2H, m) , 8.30 (1H, d, J=8.8 Hz), 9.25 (1H, s).
[0206] Example 24
5"(2-(3-(2-Cyclopropylcarbamoylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5, the title compound (117 mg, 0.268 mmol, 8 9%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (157 mg, 0.300 mmol) synthesized in Production example 5-2 and 3-amino-N-cyclopropylpropionamide hydrochloride (247 mg, 1.50 mmol) obtained from 3-(tert-butoxycarbonylamino)propionic acid and cyclopropylamine by the method similar to Example 7.
1H-NMR Spectrum (DMSO-d6) δ(ppm) : 0.32-0.38 (2H, m) , 0.54-0.60 (2H, m), 2.19 (2H, t, J=6.4 Hz), 2.60 (1H, m), 2.85 (3H, d, J=4.4 Hz), 3.25-3.33 (2H, m) , 6.53 (1H, dd, J=2.0, 6.0 Hz), 6.69 (1H, d, J=3. 6 Hz), 6.90 (1H, d, J=2.0 Hz), 7.05 (1H, dd, J=2.4, 9.0 Hz), 7.38 (1H, d.

J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 7.93 (1H, d, J=4.0 Hz) r 7.9 6-8.06 (2H, m) , 8.18 (1H, q, J=4.4 Hz) , 8.30 (1H, d, J=9.0 Hz), 9.08 (1H, s).
[0207] Example 25
5- (2-(3-(3-OXO-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Similarly to Example 5, the title compound (122 mg, 0.270 mmol, 90%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (157 mg, 0.300 iranol) synthesized in Production example 5-2 and 3-amino-l-(pyrrolidin-1-yl)propan-1-one hydrochloride (268 mg, 1.50 mmol) obtained from 3-(tert-butoxycarbonylamino)propionic acid and pyrrolidine by the same method similar to Example 7. 1H-NMR Spectrum (DMSO-dg) 5 (ppm) : 1.70-1.78 (2H, m) , 1.80-1.88 (2H, m) , 2.40 (2H, t, J=6.2 Hz), 2.85 (3H, d, J=4.4 Hz), 3.24-3.38 (6H, m) , 6.52 (1H, dd, J=2.0, 5,6 Hz), 6.69 (1H, d, J=3.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.05 (1H, dd, J=2,4, 9.0 Hz), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 7.98-8.10 (2H, m) , 8.18 (1H, q, J=4.4 Hz), 8.30 (1H, d, J=9.0 Hz), 9.10 (1H, s).
[0208] Example 2 6

ml), and then 5N aqueous solution of sodium hydroxide (0.77 ml, 3.8 rnmol) was added, and the reaction mixture was stirred at room temperature. Phenyl N-(4- (1-(methylamino)carbonyl-lH-5-indolyloxy) -2--pyridyl) -N-(phenoxycarbonyl) carbamate (4 00 mg, 0.77 mmol. Production example 5-2) was added thereto, and the reaction mixture was stirred at room temperature for 0.75 hours. Water was added to the reaction mixture, and this was subjected to extraction with ethyl acetate-tetrahydrofuran, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel colxnrin chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale brown oil. This oil was dissolved in tetrahydrofuran (4.0 ml) and methanol (2.0 ml), 4N aqueous solution of lithium hydroxide (0.77 ml) was added at room temperature, and the reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, IN hydrochloric acid (3.1 ml) was added while stirred at room temperature; and this was subjected to extraction with ethyl acetate-tetrahydrofuran, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A small amount of acetone was added to the obtained amorphous solid, and this solution was diluted with diethyl ether. The crystals were filtered

off, washed with diethyl ether, and dried under aeration to yield the title compound (200 mg, 0.50 mmol, 66%) as colorless crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.39 (2H, t, J=6.2 Hz), 2.84 (3H, d, J=4.0 Hz), 3.30 (2H, m) , 6.51 (1H, d, J=5.8 Hz), 6.68 (1H, d, J=3.2 Hz), 6.87 (1H, s), 7.05 (1H, d, J-9.0 Hz), 7.37 (1H, s), 7.88 (1H, d, J=3.2 Hz), 8.01 (1H,. d, J=5.8 Hz), 8.16 (1H, m) , 8.17 (1H, d, J-4.0 Hz), 8.29 (1H, d, J=9.0 Hz), 9.10 (1H, s), 12.24 (1H, s) .
[0210] Example 27
Nl-Ethyl-5-(2-(((2-ethoxyethyl) amino)carbonyl) amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Phenyl N-(4-(1-(ethylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (100 mg, 0.24 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and 2-ethoxyethylamine (0.063 ml, 0.6 mmol) was added while stirred at room temperature. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, the crystals were precipitated from ethyl acetate-hexane (1: 5), filtered off, and dried under aeration to yield the title compound (100 mg, 0.24 mmol, quantitative) as white

crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.09 (3H, t, J=7.2 Hz), 1.17 (3H, t, J=7.2 Hz), 3.21-3.45 (8H, m) , 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.87 (1H, brs), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.91 (1H, d, J=3.6 Hz), 8.01 (1H, d, J=5.6 Hz), 8.12 (1H, m), 8.22 (1H, t, J=4.8 Hz), 8.28 (1H, d, J=8.8 Hz), 9.08 (1H, s).
[0211]
The starting materials were synthesized by the following methods. Production example 27-1
Nl-Ethyl-5-(2-amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Sodium hydride (573 mg, 14.32 mmol) was suspended in N,N-dimethylfonnamide (30 ml) under nitrogen atmosphere. 4-(lH-5-Indolyloxy)-2-pyridinamine (3.00 g, 13.32 mmol, CAS No. 417722-11-3) described in WO 02/32872 was gradually added thereto while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and phenyl N-ethylcarbamate (2.31 g, 13.98 mmol) was added. The reaction mixture was heated to room temperature and was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and

dried over anhydrous sodium sulfate. The solvent was distilled off^ then the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (3.168 g, 10.69 mmol, 80.3%) as pale brown crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.32 (3H, t, J=7.2 Hz), 2.40-2.50 (2H, m) , 5.74 (1H, d, J=2.4 Hz), 5.83 (2H, brs), 6.12 (1H, dd, J=2.4, 5,6 Hz), 6.66 (1H, d, J=3.6 Hz). 7.01 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.75 (1H, d, J=5.6 Hz), 7.88 (1H, d, J=3.6 Hz), 8.19 (1H, t, J=5.6 Hz), 8.26 (1H, d, J=8.8 Hz).
[0212] Production example 27-2
Phenyl N-(4-(1-(ethylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate
Nl-ethyl-5- (2-airLino-4-pyridyl) oxy-lH-1-indolecarboxamide (3.168 g, 10.69 mmol) synthesized in Production example 27-1 was dissolved in N,N-dimethylformamide (30 ml) under nitrogen atmosphere. Pyridine (1.25 ml, 15.4 0 mmol) and phenyl chlorocarbonate (1.61 ml, 12.83 mmol) were sequentially added dropwise while cooled with an ice water bath. The reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and

dried over anhydrous sodium sulfate. The solvent was distilled off, and the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (1.530 g, 3.67 mmol, 34.4%) as white crystals.
1H-NMR Spectrum (CDCI3) 5 (ppm) : 1.32 {3H, t, J=7.2 Hz), 3,53 (2H, m), 5.48 (1H, m) , 6.58 (1H, d, J=4.0 Hz), 6.62 (1H, dd, J«2.4, 5.6 Hz) , 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.15 (2H, m) , 7.20-7.27 (1H, m) , 7.30 (1H, d, J=2.4 Hz), 7.37 (2H, m) , 7.45 (1H, d, J-4.0 Hz), 7.52 (1H, d, J=2.4 Hz), 8.10-8.15 (3H, m).
[0213] Example 28
Nl-Methyl-5-(2-((4-(2-hydroxy-2-
methylpropionyl)piperazin-1-yl)carbonyl)amino-4-pyridyl)oxy-lH-indolecarboxamide
Nl-Methyl-5-(2-amino-4-pyridyl)oxy-lH-1-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 was dissolved in tetrahydrofuran (3 ml). Triethylamine (0.37 ml, 2.66 mmol) and phenyl chlorocarbonate (0.15 ml, 1.2 mmol) were sequentially added dropwise at room temperature, and the reaction mixture was stirred for 30 minutes. 1-(2-Hydroxy-2-methylpropionyDpiperazine (412 mg, 2.39 mmol) and N,N-dimethylformamide (3 ml) were added and the reaction mixture was stirred for 3 days. The reaction mixture

was partitioned between ethyl acetate and water. The organic layer was washed with water and brine^- and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: methanol = 95: 5). The crystals were precipitated from
diethyl ether-hexane (1 : 2) , filtered off, and dried under aeration to yield the title compound (189.4 mg, 0.39 mmol, 74.2%) as white crystals. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.28 (6H, s), 2.83
(3H, d, J=4.0 Hz) , 3.10-3.50 (8H, m) , 5.43 (1H, s) , 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz), 7.3 6 (1H, d, J=2.4 Hz) , 7.87 (1H, d, J=3. 6 Hz) , 8.08
(1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.21 (1H, s). [0214]
1-(2-Hydroxy-2-methylpropionyl)piperazine was synthesized by the following methods. Production example 28-1
Benzyl 4-(2-hydroxy-2-methylpropionyl)pipera2ine-l-
carboxylate
Benzyl piperazine-1-carbamate (2.203 g, 10,0 mmol) was dissolved in tetrahydrofuran (50 ml) ; 2-hydroxy-2-methylpropionic acid (1.25 g, 12.0 mmol) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide

hydrochloride (2.30 g, 12.0 mmol) , 1-hydroxy-lH-benzotriazole laonohydrate (1.84 g, 12.0 ininol) and triethylamine (3.35 ml, 24.0 mmol) were added; and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between ethyl acetate and IN hydrochloric acid. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and dried under reduced pressure to yield the title compound (2.823 g, 9.21 mmol, 92.1%) as a colorless oil.
1H-NIMR Spectrum (CDCI3) 5 (ppm) : 1.50 (6H, s) , 3.52-3.55 (4H, m) , 3.60-3.70 (4H, m) , 3.93 (1H, s)-, 5.16 (2H, s) , 7.34-7.38 (5H, m) .
[0215] Production example 28-2 1-(2-Hydroxy-2-methylpropionyl)piperazine
Benzyl 4-(2-hydroxy-2-
methylpropionyl)piperazine-l-carbamate (2.82 g, 9.20 mmol) synthesized in Production example 28-1 was dissolved in methanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 1.96 g) was added thereto, the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction

system was purged with nitrogen, the catalyst was filtered out, and washed with methanol, then the solvent, together with the filtrate and the washing solution, was distilled off. The residue was dried under reduced pressure to yield the title compound (1.58 g, 9.20 mmol, quantitative) as a colorless oil. 1H-NMR Spectrum (CDCI3) 5(ppm): 1.49 {6H, s), 2.84-2.94 (4H, m), 3.49 (1H, s), 3.62-3.70 (4H, m).
[0216] Example 29 Nl"Methyl-5-(2-((3-
diethylamino)propylamine)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Similarly to Example 27, the title compound (96.4 mg, 0.22 mmol, 73.3%) was obtained as white crystals from phenyl N- (4- (1- (methylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (121 mg, 0.30 mmol) and 3-(diethylamino)propylamine.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : ' 0. 91 (6H, t, J=7 . 2 Hz) , 1.50 (2H, m) , 2.30-2.4 4 (6H, m) , 2.83 (3H, d, J=4.4 Hz), 3.23 (2H, m), 6.50 (1H, dd, J=2.4, 6.0 Hz), 6.68 (1H, d, J=3-6 Hz) , 6.82 (1H, s) , 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.37 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.01 (1H, d, J=6.0 Hz), 8.10-8.17 (2H, m) , 8.29 (1H, d, J=8.8 Hz), 9.04 (1H, s).
[0217]

The starting material was synthesized as follows. Production example 29-1
Phenyl N- (4-(1-(methylamino)carbonyl-lH-S-indolyl)oxy-2-pyridyl)carbamate
Nl-Methyl-5-(2-amino-4-pyridyl)oxy-lH-1-indolecarboxamide (2.163 g, 7.66 mmol) synthesized in Production example 5-1 was dissolved in N,N-dimethylformamide (5 0 ml) under- nitrogen atmosphere; pyridine (0.93 ml, 11.5 mmol), triethylamine (2.4 ml, 17.24 mmol) and phenyl chlorocarbonate (1.44 ml, 11.5 mmol) were sequentially added dropwise while cooled with an ice water bath; and the reaction mixture was heated to room temperature while stirred. After 1 hour, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and then the residue was purified by silica gel column chromatography (eluent; ethyl acetate), precipitated from ethyl acetate-hexane (1: 10), filtered off, and dried under aeration to yield the title compound (2.731 g, 6.79 mmol, 88.6%) as white crystals.
1H-NMR Spectrum (CDCI3) 5 (ppm) : 3.09 (3H, d, J=4.8 Hz), 5.52 (1H, m), 6.62 (1H, d, J=3.6 Hz), 6.98 (1H, dd, J=2.4, 5.6 Hz), 7.01 (1H, d, J=2.4 Hz), 7.11 (1H, dd, J=2,4, 8.8 Hz), 7.14-7.40 (7H, m) , 7.47 (1H, d, J=3.6

Hz), 8.24 (1H, d, J=8.8 Hz), 8.41 (1H, d, J=5.6 Hz).
[0218] Example 30
Nl-Methyl-5-(2-(((3-4-
hydroxypiperidino)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Similarly to Example 27, the title compound
(51.3 mg, 0.11 mmol, 29.5%) was obtained as white crystals, from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (150 mg, 0.37 mmol. Production example 29-1) and 1-(3-aminopropyl)-4-hydroxypiperidine.
1H-NMR Spectrum (DMSO-ds) 5(ppm) : 1.29-1.38 (2H, m) , 1.50-1.55 (2H, m), 1.64-1.68 (2H, m), 1.88-1.92 (2H, m) , 2.20-2.24 (2H, m) , 2.62-2.66 (2H, m) , 2.83 (3H, d, J=4.4 Hz), 3.06-3.12 (2H, m), 3.39 (1H, m) , 4.49 (1H, d, J=4.0 Hz), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.01 (1H, d, J=5.6 Hz), 8.05 (1H, m), 8.16 (1H, q, J=4.4 Hz), 8.28
(1H, d, J=8.8 Hz), 9.02 (1H, s).
[0219] Example 31
Nl-Methyl-5-(2-(((3-(4-methylpiperazin-l-yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-

similarly to Example 27, the title compound (133.2 mg, 0.29 mmol, 7 6.8%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl) oxy-2-pyridyl) carbamate (150 mg, 0. 37 mmol, Production example 29-1) and 1-(3-aminopropyl)-4-methylpiperazine.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.53 (2H, m) , 2.11 (3H, s) r 2.11-2.40 (lOH, m) , 2.83 (3H, d, J=4.0 Hz), 3.09 (2H, m), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.84 (1H, s), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.3 6 (1H, d, J=2.4 Hz) , 7.87 (1H, d, J=3.6 Hz) , 8.01 (1H, d, J=5.6 Hz), 8.05 (1H, m), 8.16 (1H, q, J=4.0 Hz), 8.28 (1H, d, J=8.8 Hz), 9.01 (1H, s).
[0220] Example 32
5- (2- (3- (4-0x0-4-(pyrrolidin-1-yl)butyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
The title compound (113 mg, 0.24 mmol, 77%) was obtained as colorless crystals by performing the reaction similar to Example 8 using 4-((4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl) aminocarbonylamino)butyric acid (130 mg, 0.31 mmol) and pyrrolidine (0.053 ml, 0.63 mmol).
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.64 (2H, m) , 1.71 (2H, m) , 1.82 (2H, m), 2.20 (2H, t, J=6.8 Hz), 2.83 (3H, d, J=4.0 Hz) , 3.09 (2H, q, J=6.8 Hz) . 3.22 (2H, t.

J=6.8 Hz), 3.33 {2H, m), 6.50 (1H, dd, J=2.4, 5.8 Hz), 6.67 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J-2,4, 9.0 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.00 (1H, m), 8.03 (1H, d, J=5.8 Hz), 8.16 (1H, m) , 8.28 (1H, d, J=9.0 Hz), 9.00 (1H, s) .
[0221]
The starting material was synthesized by the following methods. Production example 32-1
4- ( (4- (l-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyric acid
Ethyl 4-aminobutyrate hydrochloride (1.0 g, 6,0
mmol) was suspended in N,N-dimethylformamide (6.7 ml),
5N aqueous solution of sodium hydroxide (1.2 ml, 6.0
mmol) was added and the reaction mixture was stirred at
room temperature. Phenyl N-(4-(l-
(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (700 mg, 1.3 mmol. Production example 5-2) was added thereto and the reaction mixture was stirred at room temperature for 1.2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale yellow oil. This oil

was dissolved in tetrahydrofuran (6.0 ml) and methanol
(3.0 ml); 4N lithium hydroxide (1-1 ml) was added thereto at room temperature; and the reaction mixture was stirred at room temperature for 3.5 hours. Moreoverr IN hydrochloric acid (4.4 ml) and water (2 ml) were added thereto while stirred at room temperature; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the precipitated crystals were suspended in diethyl ether: hexane =1: 1, the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (411 mg, 1.0 mmol, 75%) as colorless crystals. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.63 (2H, m) , 2.20
{2H, t, J=7.4 Hz), 2.83 (3H, d, J=4.0 Hz), 3.10 (2H, m) , 6.52 (1H, d, J=5.4 Hz), 6.68 (1H, d, J=3.6 Hz), 6.87
(1H, s), 7.04 (1H, dd, J=2.4, 9.0 Hz), 7.37 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=3.6 Hz), 8.03 (2H, m) , 8.17
(1H, d, J=4.0 Hz), 8.29 (1H, d, J=9.0 Hz), 9.03 (1H, s), 12.05 (1H, s).
[0222] Example 33
5-(2-(3-(3-(Cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylaiaide
The title compound (166 mg, 0.37 mmol, 76%) was

obtained as colorless crystals by performing the reaction similar to Example 8 using 4-( (4- (1-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl) aminocarbonylamino) butyric acid (200 mg, 0.49 mmol, Production example 32-1) and cyclopropylamine (0.028 ml, 0.58 mmol).
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.33-0.37 .(2H, m) , 0.54-0.59 (2H, m), 1.62 (2H, m), 2.02 (2H, t, J-7.4 Hz), 2.58 (1H, m), 2.85 (3H, m), 3.08 (2H, m) , 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.70 (1H, d, J=3.6 Hz), 6.88 (1H, d, J=2.4 Hz), 7.06 (1H, dd, J=2.4, 8.8 Hz), 7.39 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=3.6 Hz), 7.90 (1H,'d, J=3.6 Hz), 8.04 (1H, m), 8.05 (1H, d, J=6.0 Hz), 8.19 (1H, d, J=4.2 Hz), 8.31 (1H, d, J=8.8 Hz), 9.04 (1H, s).
[0223] Example 34
5-(2-(3-(4-(4-Hydroxy-4-methylpiperidin-l-yl)-4-oxobutyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
The title compound (195 mg, 0.383 mmol, 78.9%) was obtained as colorless crystals by performing the reaction similar to Example 8 using 4-((4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyric acid (200 mg, 0.486 mmol. Production example 32-1) and 4-hydroxy-4-methylpiperidine monohydrochloride (110 mg, 0.729 mmol).

1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.08 (3H, s), 1.22-1.44 (4H, m), 1.62 (2H, m) , 2.27 (2H, t, J=7.4 Hz), 2.83 (3H, d, J=4.0 Hz), 2.97 (1H, m) , 3.08 (2H, m) , 3.29 (1H, m), 3.47 (1H, m) , 3.89 (1H, m), 4.33 (1H, s), 6.50 (1H, d, J=6.0 Hz), 6.67 (1H, d, J=3.6 Hz), 6.87 (1H, s), 7.04 (1H, d, J=9.2 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.01 (1H, m) , 8.02 (1H, d, J=6.0 Hz), 8.16 (1H, m), 8.28 (1H, d, J=9.2 Hz), 9.00 (1H, m).
[0224] Example 35
5-(2-(3-(3-(Diethylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
The title compound (94 mg, 0.20 mmol, 64%) was obtained as colorless crystals by performing the reaction similar to Example 8 using 4-((4-(l-methylcarbamoyl-IH-indol-5-yloxy)pyridin-2-yl) aminocarbonylamino)butyric acid (130 mg, 0.31 mmol. Production example 32-1) and diethylamine (0.066 ml, 0. 63 mmol) .
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.96 (3H, t, J=7.2 Hz), 1.04 (3H, t, J=7.2 Hz), 1.63 (2H, m), 2.25 (2H, t, J=7.2 Hz), 2.83 (3H, d, J=4.4 Hz), 3.09 (2H, m) , 3.22 (4H, m) , 6.51 (1H, dd, J=2.0, 5.6 Hz), 6.67 (1H, d, J=3.4 Hz), 6.86 (1H, d, J=2.0 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.4 Hz), 8.02 (2H, m), 8.16 (1H, d, J=4.4 Hz), 8.29 (1H, d.

J=8.8 Hz), 9.00 (1H, s).
[0225] Example 36
5- (2- (3- (3- (Methylcarbainoyl) propyl )ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methyl amide
The title compound (107 mg, 0.25 mmol, 69%) was obtained as colorless crystals by performing the reaction similar to Example 8 using 4-((4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl) aminocarbonylamino) butyric acid (150 mg, 0.36 mmol. Production example 32-1) and methylamine hydrochloride
(49 mg, 0.73 mmol).
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.61 (2H, m) , 2,03
(2H, t, J=7.6 Hz), 2.51 (3H, d, J=4.4 Hz), 2.83 (3H, d, J-4.0 Hz), 3.06 (2H, q, J=6.4 Hz), 6.50 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 6.86 (1H, d, J=2.4 Hz), 7.03 (1H, dd, J=2.4, 9.2 Hz), 7.36 (1H, d, J=2.4 Hz), 7.71 (1H, m), 7.87 (1H, d, J=3. 6 Hz), 8.03 (2H, m) , 8.16 (1H, d, J=4.4 Hz), 8,28 (1H, d, J=9.2 Hz), 9.01
(1H, s) ,
[0226] Example 37 Nl-Methyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-

phenyl N- (4- (1-(methylamino)carbonyl-lH-5-indolyloxy)-
2-pyridyl)-N-(phenoxycarbonyl)carbamate (532 mg, 1. 02
mmol) synthesized in Production example 5-2 and
pyrrolidine (0.42 ml, 5.0 mmol).
MS Spectrum (ESI): 380 (M+1), 759 (2M+1)
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1.78-1.84 (4H, m) ,
2.83 (3H, d, J=4.5 Hz), 3.22-3.36 (4H, m) , 6.54 (1H, dd,
J=2.3, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd,
J=2.3, 8.7 Hz), 7.35 (1H, d, J=2.3 Hz), 7.41 (1H, d,
J=2.3 Hz), 7.87 (1H, d, J=3.6 Hz), 8.04 (1H, d, J=5.6
Hz), 8.16 (1H, m), 8.28 (1H, t, J=8.7 Hz), 8.59 (1H, s).
[0227] Example 38
Nl-Methyl-5-(2-(piperidin-1-ylcarbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Similarly to Example 5, the title compound (2 65 mg, 0.674 mmol, 76%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (4 63 mg, 0.885 mmol) synthesized in Production example 5-2 and piperidine (0.44 ml, 4.4 mmol). MS Spectrum (ESI): 394 (M+1), 787 (2M+1) 1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.37-1.57 (6H, m) , 2.83 (3H, d, J=4.4 Hz), 3.26-3.45 (4H, m) , 6.54 (1H, dd, J=2.4, 5.4 Hz), 6.67 (1H, d, J=3.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.30 (1H, d, J=2.4 Hz), 7.36 (1H, d.

J=2.4 Hz), 7.87 (1H, d, J-3.4 Hz), 8.05 (1H, d, J=5.4 Hz), 8.16 (1H, m) r 8.28 (1H, t, J=8.8 Hz), 9.05 (1H, s).
[0228] Example 39
Nl-Methyl-5-(2-((4-hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-l-indolecarboxamide
Similarly to Example 27, the title compound (86.7 mg, 0.21 mmol, 21.2%) was obtained as white powder from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (4 02 mg, 1.0 mmol) synthesized in Production example 29-1 and 4-hydroxypiperidine.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 1,60-1. 70 (2H, m) , 1.75 (1H, m), 2.83 (3H, d, J=4.4 Hz), 2.95-3.01 (2H, m) , 3.55-3. 65 (2H, m) , 3.71-3.7 6 (2H, m) , 4 . 64 (1H, d, J=4.0 Hz), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.36 (1H, d, J-2.4 Hz), 7.87 (1H, d, J=3.6 Hz) , 8.0 6 (1H, d, J-5.6 Hz) , 8.16 (1H, q, J=4.4 Hz) , 8.28 (1H, d, J=8.8 Hz), 9.10 (1H, s).
[0229] Example 40
Nl-Methyl-5-(2-(4-oxopiperidin-l-ylcarbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide Phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-

mmol) synthesized in Production example 5-2 was dissolved in N^N-dimethylfonaamide (5 ml) ; triethylamine (0.543 ml, 3.90 mmol) and 4-piperidone hydrochloride monohydrate (0.530 g, 3.93 mmol) were added thereto; and the reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was concentrated to yield the title compound (0.202 g, 0.496 mmol, 59%) as a colorless amorphous solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 2.32 (4H, t, J=4.9 Hz), 2.82 (3H, d, J=4.3 Hz), 3.68 (4H, t, J=4. 9 Hz), 6.55 (1H, dd, J=2.3, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.3, 8.6 Hz), 7.37 (2H, s), 7.87 (1H, d, J=3.6 Hz), 8.09 (1H, d, J-5.6 Hz), 8.17 (1H, s), 8.28 (1H, t, J=8.6Hz), 9.37 (1H, s).
[0230] Example 41
5- (2-(( (4-Hydroxy-4-methylpiperidin-l-yl)carbonyl)amino)pyridin-4-yloxy)-lH-l-indole-1-carboxylic acid methylamide
4-Hydroxy-4-methylpiperidine monohydrochloride
(508 mg, 3.83 mmol. Production example 8-3) was
dissolved in N,N-dimethylformamide (8 ml) ;
triethylamine (2 ml) was added; and the reaction
mixture was stirred at room temperature. Phenyl N-(4-
(1- (methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-

(phenoxycarbonyl)carbamate (500 mg, 0.957 mmol, Production example 5-2) was added and the reaction mixture was stirred at room temperature for 8 hours-The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate, ethyl acetate: methanol =20: 1 then 10: 1 ). The obtained amorphous solid was crystallized by adding diethyl ether: acetone =2: 1. Thus obtained crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (385 mg, 0.909 mmol, 95.0%).
1H-NMR Spectrum (DMSO-d6) δ(ppm): 1.08 (3H, s), 1.33-1.40 (4H, m), 2.83 (3H, d, J-4.4 Hz), 3.14 (2H, m) , 3.63 (2H, m), 4.27 (1H, s) , 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.4 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.4 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, m), 8.28 (1H, d, J=8.8 Hz), 9.04 (1H, s).
[0231] Example 42
Nl-Methyl-5-(2-((4-(1-hydroxy-l-
methylethyl)piperidino)carbonyl) amino-4-pyridyl)oxy-lH-1-indolecarboxamide

Similarly to Example 28, the title compound (71.1 mg, 0.16 mmol, 29,7%) was obtained as white crystals from Nl-ethyl-5"( (2'-amino-4-pyridyl) oxy)—IH-l-indolecarboxamide (150 mg, 0.53 mmol) synthesized in Production example 5-1 and 4- (1-hydroxy-l-methylethyDpiperidine (342 mg, 2.39 mmol) . 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.99 (6H, s) , 1. 03-1.09 (2H, m), 1.30 (1H, m) , 1.60-1.64 (2H, m) , 2.54-2.61 (2H, m) , 2.83 (3H, d, J=4.4 Hz) , 4.08 (1H, s) , 4.10-4.15 (2H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.32 (1H, d, J=2,4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.27 (1H, d, J=8.8 Hz), 9.04 (1H, s). [0232]
4-(1-Hydroxy-l-methylethyl)piperidine was synthesized in the following methods. Production example 42-1 Benzyl 4-ethoxycarbonylpiperidine-l-carboxylate
4-Ethoxycarbonylpiperidine (1.572 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 ml); triethylamine (2-79 ml, 20.0 mmol) and benzyl chlorocarbonate (1.71 ml, 12.0 mmol) were added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and the saturated

aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 3) to yield the title compound (2.315 g, 7.95 mmol, 79.5%) as a colorless oil.
1H-NMR Spectrum (CDCI3) 5 (ppm) : 1.26 (3H, t, J=7.2 Hz), 1.60-1.70 (2H, m) , 1.80-2.00 (2H, m) , 2.4 6 (1H, m) , 2.80-3.00 (2H, m) , 4.00-4.20 (2H, m) , 4.15 (2H, q, J=7.2 Hz), 5.13 (2H, s), 7.29-7.38 (5H, m) .
[0233] Production example 42-2
Benzyl 4- (l-hydroxy-l-methylethyl)piperidine-l-
carboxylate
Benzyl 4-ethoxycarbonylpiperidine-l-carboxylate (2.315 g, 7.95 mmol) synthesized in Production example 42-1 was dissolved in tetrahydrofuran (25 ml) under nitrogen atmosphere; methyl magnesium bromide (0.93 M) in tetrahydrofuran (32.5 ml, 30.2 mmol) was added dropwise while cooled with an ice water bath; and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and the saturated aqueous solution of ammonium chloride. The organic layer was washed with brine and dried over anhydrous sodium

sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 1) to yield the title compound (1.786 g, 6.44 mmol, 81%) as a colorless oil.
1H-NMR Spectrum (CDCI3) 5(ppm): 1.18 (6H, s), 1.18-1.27 (2H, m) , 1.40-1.4 8 (1H, m) , 1.74-1.78 (2H, m) , 2.60-2.80 (2H, m) , 4.20-4.40 (2H, m) , 5.13 (2H, s), 7.27-7.37 (5H, m).
[0234] Production example 42-3 4-(1-Hydroxy-l-methylethyl)piperidine
Benzyl 4-(1-hydroxy-l-methylethyl)piperidine-1-carboxylate (1.786 g, 6.44 mmol) synthesized in Production example 42-2 was dissolved in methanol (100 ml) under nitrogen atmosphere; 10% palladium on carbon (50% wet, 1.37 g) was added; the reaction system was purged with hydrogen at atmospheric pressure; and the reaction mixture was stirred overnight. After the reaction system was purged with nitrogen, the catalyst was filtered out, and washed with methanol; the solvent, together with the filtrate and the washing solution, was distilled off; and the residue was dried under reduced pressure to yield the title compound (922 mg, 6.44 mmol, quantitative) as pale gray crystals. 1H-NMR Spectrum (CDCI3) δ(ppm): 1.18 (6H, s), 1.26-1.4 2

{3H, m), 1.74-1.80 (2H, m) , 2.57-2.64 (2H, m) , 3.14-3.22 (2H, m), 3.48 (1H, s).
[0235] Example 43
5- (2- ( ( (4- (3-Methylcarbajaoylpropyl)piperidin"l-yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
4-(1-((4-(l-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)aminocarbonyl)piperidin-4-yl)butyric acid (170 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (7.0 ml); methylamine hydrochloride
(4 8 mg^ 0.71 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (314 mg, 0.71 mmol) and triethylamine (0.35 ml) were added thereto; and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine^ dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH silica gel, hexane-ethyl acetate-methanol system) . After a small amount of acetone and ethyl acetate were added to the obtained amorphous solid; this solution was diluted with diethyl ether; and the solid portion was filtered off, washed with diethyl ether, and dried under

aeration to yield the title compound (30 mg, 0.061 mmolr 17%) as a colorless amorphous solid.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0,87-1.00 (2H, m) , 1.13 (2H, m), 1.33 (1H, m), 1.46 (2H, m), 1.57 (2H, m), 1.99 (2H, t, J=7.4 Hz), 2.52 (3H, d, J=4.4 Hz), 2.65 (2H, m), 2.83 (3H, d, J=4.0 Hz), 4.03 (2H, m), 6.53 (1H, d, J=6.0 Hz) , 6.67 (1H, d, J=3.4 Hz) , 7.03 (1H, d, J=9.0 Hz), 7.31 (1H, s), 7.35 (1H, s), 7.66 (1H, m) , 7.87 (1H, d, J=3.4 Hz), 8.06 (1H, d, J=4.0 Hz), 8.16 (1H, d, J=4.0 Hz), 8.27 (1H, d, J=9.0 Hz), 9.05 (1H, s).
[0236]
The starting materials were synthesized as follows. Production example 43-1
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-
carboxylate
tert-Butyl 4- (2- (toluene-4-
sulfonyloxy)ethyl)piperidine-1-carboxylate (7.55 g, 19.7 mmol, CAS No. 89151-4 5-1) as described in WO 02/32872 was dissolved in ethanol; diethyl malonate (3.3 ml, 21.3 mmol) and sodium ethoxide (1.45 g, 21.3 mmol) were added; and the reaction mixture was heated to reflux under nitrogen atmosphere for 2.5 hours. After naturally cooled to room temperature, the saturated aqueous solution of ammonium chloride was added; this was subjected to extraction with ethyl

acetate, washed with brine, driea over annyarous magnesium sulfate, and concentrated under reduced pressure. After the residue was dissolved in dimethyl sulfoxide (20 ml) ; lithium chloride (1.7 g, 40 mmol) and water (0.36 ml, 20 mmol) were added; and the reaction mixture was stirred at 185 °C for 1.5 hours and further stirred at 195 °C for 2 hours. After naturally cooled to room temperature, the reaction mixture was partitioned between ethyl acetate-brine. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate system) to yield the title compound (2.60 g, 8.7 mmol, 43%) as a pale yellow oil.
1H-NMR Spectrum (CDCI3) 5(ppm) : 1.02-1.13 (2H, m) , 1.23-1.29 (5H, m) , 1.39 (1H, m) , 1.45 (9H, s), 1.62-1.69 (4H, m) , 2.29 (2H, t, J=7.4 Hz), 2.67 (2H, m) , 4.07 (2H, m), 4.13 (2H, q, J=7.2 Hz).
[0237] Production example 43-2 Ethyl 4-(piperidin-4-yl)butyrate
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (1.2 g, 4.0 mmol, Production example 43-1) was dissolved in trifluoroacetic acid (30 ml), and the reaction mixture was stirred at room temperature

for 20 minutes. This was concentrated under reduced pressure, and was further azeotropically distilled with toluene. The obtained residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate. In addition, the aqueous layer was concentrated under reduced pressure to dryness; the obtained solid was suspended in tetrahydrofuran; insoluble portion were filtered off, and this solution was added to the previously obtained organic layer. This was purified by silica gel column chromatography (Fuji Silysia NH, hexane-ethyl acetate-methanol system) to yield the title compound (l-15g, quantitative) as a yellow oil.
1H-NMR Spectrum (CDCI3) 5 (ppm) : 1.26 (3H, m) , 1.28-1.37 (2H, m), 1.40-1.52 (3H, m), 1.64 (2H, m), 1.86 (2H, m) , 2.29 (2H, t, J=7.4 Hz), 2.82 (2H, m) , 3.35 {2H, m) , 4.13 (2H, m) .
[0238] Production example 4 3-3
5-(2-(((4-(3-Ethoxycarbonylpropyl)piperidin-l-yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
Ethyl 4-(piperidin-4-yl)butyrate (650 mg, 2.0 mmol. Production example 43-2) was suspended in N,N-dimethylformamide (3.35 ml) ; phenyl N-(4-(1-

(methylamino)carbonyl-lH-5-indolylcxy)-2-pyridyl)-N-(phenoxycarbonyl) carbamate (350 mg, 0.67 mmol;-Production example 5-2) was added; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300^ hexane-ethyl acetate-methanol system) to yield the title compound (271 mg, 0.54 mmol, 80%) as a pale yellow oil. 1H-NMR Spectrum (CDCI3) 5 (ppm) : 1.05-1.16 (2H, m) , 1.22-1.28 (5H, m), 1.43 (1H, m) , 1.62 (2H, m), 1.71 (2H, m) , 2.27 (2H, t, J-7.4 Hz), 2.80 (2H, m), 2.95 (3H, d, J=4.4 Hz), 3.99 (2H, m), 4.12 (2H, q, J=7.2 Hz), 6.09 (1H,, d, J=4.4 HZ), 6.46 (1H, d, J=3.4 Hz), 6.58 (1H, dd, J=2.0, 5.6 Hz), 7.04 (1H, dd, J=2.0, 8.8 Hz), 7.24 (1H, s) , 7.28 (1H, d, J=2.0 Hz) , 7.32 (1H, d, J=3.4 Hz) , 7.54 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=5.6 Hz), 8.20 (1H, d, J=8.8 Hz).
[0239] Production example, 43-4
4-(1- ( (4-(l-Methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl)aminocarbonyl)piperidin-4-yl)butyric acid
5- (2-( (4- (3-Ethoxycarbonylpropyl)piperidin-1-

carboxylic acid methylamide (271 mg, 0.54 mmol. Production example 4 3-3) was dissolved in tetrahydrofuran (3.0 ml) and methanol (1.5 ml) ; 4N lithium hydroxide (0.54 ml) was added; and the reaction mixture was stirred at room temperature for 3.5 hours. IN hydrochloric acid (2.2 ml) was added thereto while the stirred at room temperature. After the precipitated ■ crystals were filtered off, the crystals were washed with water and diethyl ether sequentially, and dried under aeration to yield the title compound
(170 mg, 0.35 mmol, 66%) as colorless crystals.
1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.93 (2H, m) , 1.16
(2H, m), 1.36 (1H, m) , 1.47 (2H, m), 1.58 (2H, m), 2.15
(2H, t, J=7.4 Hz), 2.66 (2H, m), 2.83 (3H, d, J=4.2 Hz), 4.02 (2H, m) , 6.53 (1H, d, J=6.0 Hz) , 6.67 (1H, d, J=3,4 Hz), 7.03 (1H, d, J=9.2 Hz), 7.31 (1H, s), 7.35
(1H, s), 7.86 (1H, d, J=3.4 Hz), 8.05 (1H, d, J=6.0 Hz), 8.15 (1H, d, J=4.2 Hz), 8.27 (1H, d, J=9.2 Hz), 9.02
(1H, s) .
[0240] Example 4 4
5-(2-(((4-(3-Carbamoylpropyl)piperidin-l-yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide
4- (Piperidin-4-yl) butanamide (547 mg, 1.41 xnmol) was dissolved in N,N-dimethylformamide (3 ml); phenyl

N-(4- (1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl) -N- (phenoxycarbonyl) carbamate (210 mg, 0 . 402 mmol, the product of Production example 5-2) was added thereto; and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The obtained amorphous solid was crystallized by adding diethyl ether. After addition of a small amount of ethanol to make a suspension, this was diluted with hexane. After separation by filtration to obtain crystals, these were rinsed with diethyl ether and dried under aeration. Thus, the title compound was obtained as colorless crystals (157 mg, 0,328 mmol, 81.7%) .
1H-NKR Spectrum (DMSO-d6) δ (ppm) : 0.87-1.00 (2H, m) , 1.10-1.16 (2H, m) , 1.35 (1H, m) , 1.42-1,50 (2H, m) , 1.5 8 (2H, m) , 1.98 (2H, t, J=7.4 Hz) , 2.65 (2H, m) , 2.83 (3H, d, J=4.0 Hz) , 4.03 (2H, m) , 6.53 (1H, dd, J=2.0, 5.6 Hz), 6,67 (2H, m), 7.03 (1H, dd, J=2.0, 9.0 Hz), 7.20 (1H, s), 7.31 (1H, d, J=2.0Hz), 7.35 (1H, d, J=2.0 Hz), 7,87 (1H, d, J=3.2 Hz), 8,06 (1H, d, J=5. 6 Hz), 8.16(1H, m), 8.28 (1H, d, J=9.0 Hz), 9.05 (1H, s).

The starting materials were synthesized as follows. Production example 4 4-1
tert-Butyl 4- (3-carbamoylpropyl)piperidine-l-
carboxylate
tert-Butyl 4- (3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example 43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095 q, 1.4 mmol) was added thereto
while stirred and heated at 100 ^C; the reaction mixture was stirred for 2 hours under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate = 95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70%).
1H-NMR Spectrum (CDCI3) 5 (ppm) : 1.03-1.14 (2H, m) , 1.2 6-1.31 (2H, m), 1.35-1.4 5 (1H, m) , 1.4 6 (9H, s) , 1.63-1.71 (4H, m), 2.22 (2H, t, J-7.6 Hz), 2.67 (2H, m), 4.07 (2H, brs), 5.30 (1H, brs), 5.39 .(1H, brs) .

Production example 44-2
4-(Piperidin-4-yl)butanamide
tert-Butyl 4-(3-carbamoylpropyl)piperidine-l-carboxylate (0.38 g, 1.4 mmol, Production exainple 4 4-1) was dissolved in trifluoroacetic acid (2 ml) and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and then azeotropically distilled with toluene. The residue was partitioned between tetrahydrofuran and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure; and the residue was purified by silica gel chromatography (Fuji Silysia NH, ethyl acetate-methanol system) to yield the title compound (0.55 g, quantitative) as pale yellow oil. 1H-NMR Spectrum (DMSO-d6) δ (ppm) : 0.90-1.01 (2H, m) , 1.09-1.15 (2H, m), 1.26 (1H, m), 1.45 (2H, m), 1.55 (2H, m), 1.98 (2H, t, J=7.4 Hz), 2 43 (2H, m), 2.91 (2H, m) , 6.65 (1H, s)r 7.20 (1H, s).
[0243] Example 45
5-(2-((4-Pyrrolidin-l-yl)carbonyl)piperidin-l-yl)carbonylamino)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide

Similarly to Example 5, the title compound (134 mg, 0,273 mmol, 91%) was obtained as white crystals from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate
(157 mg, 0.300 mmol) synthesized in Production example 5-2 and (piperidin-4-yl)-(pyrrolidin-l-yl)methanone
(328 mg^. 1.50 mmol) obtained from N-benzyloxycarbonylisonipecotic acid and pyrrolidine by the method similar to Example 21.
1H NMR Spectrum (DMSO-ds) 5 (ppm) : 1.35-1.48 (2H, m) , 1.56-1.65 (2H, m) , 1.71-1.80 (2H, m) , 1.82-1.91 (2H, m) , 2.61 (1H, m), 2.73-2.84 (2H, m), 2.85 (3H, d, J=4.4 Hz), 3.22-3.28 (2H, m), 3.44-3.50 (2H, m), 4.04-4.12 (2H, m) , 6.56 (1H, d, J=6.0 Hz), 6.69 (1H, d, J=3.6 Hz), 7.06
(1H, dd, J=2.4, 9.2 Hz), 7.34 (1H, s), 7.38 (1H, d, J=2.4 Hz), 7.89 (1H, d, J=3.6 Hz), 8.09 (1H, d, J=6.0 Hz) 8.18 (1H, q, J=4.4 Hz) , 8.30 (1H, d, J=9.2 Hz) , 9.16 (1H, s) . [0244] Example 4 6
Nl-Methyl-5-(2-(((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-indolecarboxamide
Similarly to Example 27, the title compound
(88.5 mg, 0.19 mmol, 63.8%) was obtained as white crystals from phenyl N- (4-(1-(methylamino)carbonyl-lH-

5-indolyl)oxy-2-pyridyl)carbamate (121 mg, 0.30 mxaol. Production example 29-1) and 4-(l-pyrrolidinyl)piperidine.
Phenyl Nl-methyl-5-(2-(((4- (pyrrolidin-l-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide may be synthesized by the following methods.
Phenyl N-(4-(1-(methylamino)carbonyl-lH-5-* indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate
(12.1 g, 23.2 mmol) synthesized in Production example 5-2 was dissolved in dimethylformam.ide (150 ml); 4-(l-pyrrolidinyl) piperidine (14.4 g, 93.3 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool
at 5 °C for overnight to precipitate crystals. The crystals were filtered off, washed with ethyl acetate to yield the title compound (7,8 g, 16.9 mmol, 73%) as white crystals.
1H NMR Spectrum (DMSO-d6) δ (ppm) : 1.20-1.33 (2H, m) , 1.60-1.70 (4H, m), 1.70-1.80 (2H, m), 2.40-2.60 (5H, m), 2.77-2.84 (5H, m) , 3.90-4 .00 (2H, m) , 6.5 4 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz) 7.03 (1H, dd, J=2.4, 8.8 Hz), 7,31 (1H, s), 7.35 (1H, d, J=2.4 Hz),

7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d. J=5.6 Hz), 8.16 (1H, m), 8.28 (1H, d, J=8.8 Hz), 9.11 (1H, s).
[0245] Example 47
Nl-Methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide
Similarly to Example 27, the title compound (94.6 mg, 0.20 mmol, 66.2%) as white crystals was obtained from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl) oxy-2-pyridyl) carbamate (121 mg, 0.30 mmol, Production example 29-1) and 4-piperidinopiperidine.
Nl-Methyl-5-(2-(((4-(piperidin-1-yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide may be prepared by the following methods.
Phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (15,5 g, 29.7 mmol) synthesized in Production example 5-2 was dissolved in dimethylformamide (180 ml); 4-piperidinopiperidine (20.0 g, 119 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 9 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and concentrated to about 100 ml. The residue was allowed to be kept cool

at 5 °C overnight to precipitate crystals. The crystals were filtered off and washed with ethyl acetate to yield the title compound (4.0 g, 8.4 mitiol, 28%) as white crystals.
1H NMR Spectrum (DMSO-de) 5 (ppm) : 1.20-1.65 (lOH, m) , 2.31-2.40 (5H, m), 2.65 (2H, m), 2.83 (3H, d, J=4.4 Hz), 4.08 (2H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.06 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.4 Hz), 8.28 (1H, d, J=8.8 Hz), 9.09 (1H, s).
[0246] Example 4 8
Nl-Methyl-5-(2-((4-ethylpiperazin-l-yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide
Similarly to Example 27, the title compound (73.2 mg, 0.17 mmol, 57.8%) was obtained as white powder from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (121 mg, 0.30 mmol. Production example 29-1) and 1-ethylpiperazine. 1H NMR Spectrum (DMSO-de) 5 (ppm): 0.97' (3H, t, J=7.2 Hz), 2.25-2.32 (6H, m) , 2.83 (3H, d, J=4. 0 Hz), 3.20-3.40 (4H, m) , 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.04 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.36 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3.6 Hz), 8.07 (1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz),

8.28 (1H, d, J=8.8 Hz), 9.13 (1H, s) .
[0247] Example 49
Nl-Methyl-5-(2-((4-(2-hydroxyethyl)piperazin-l-yl)carbonyl)amino-4-pyridyl)oxy-lH-l-indolecarboxainide
Similarly to Example 27, the title compound (97.6 mg, 0.22 mmol, 59.7%) was obtained as pale pink powder from phenyl N-(4-(1-(methylamino)carbonyl-lH-5-indolyl)oxy-2-pyridyl)carbamate (150 mg, 0.37 mmol. Production example 29-1) and 1"(2-hydroxyethyl)piperazine.
1H NMR Spectrxom (DMSO-de) 5 (ppm) : 2.30-2.40 (6H, m) , 2.83 (3H, d, J=4.0 Hz), 3.20-3.40 (4H, m), 3.46 (2H, m) , 4.39 (1H, t, J=5.6 Hz), 6.55 (1H, dd, J=2.4, 5,6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.31 (1H, d, J=2.4 Hz), 7.35 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=3- 6 Hz), 8.06 (1H, d, J=5.6Hz), 8.16 (1H, q, J=4.0 Hz), 8.27 (1H, d, J-8.8 Hz), 9.12 (1H, s).
[0248] Example 5 0 Nl-Methyl-5-(2-((3-
methylsulfonylpropylamino)carbonyl) amino-4-pyridyl)-oxy-lH-1-indolecarboxamide
Similarly to Example 28, the title compound (166.8 mg, 0.37 mmol, 70.5%) was obtained as white crystals from Nl-methyl-5-(2-amino-4-pyridyl)oxy-lH-1-

indolecarboxamide (150 mg, 0.53 mmol. Production example 5-1) and 3-methylsulfonylpropylamine hydrochloride (410 mg, 2.36 mmol).
1H NMR Spectrum (DMSO-de) 5 (ppm) : 1.70-1.90 (2H, m) , 2.83 (3H, d, J=4.4 Hz), 2.94 (3H, s), 3.04-3.09 (2H, m) , 3.17-3.24 (2H, m) , 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.67
(1H, d, J=3.6 Hz), 6.86 (1H, s) , 7.03 (1H, dd, J=2.4, 8.8 Hz), 7.36 (1H, s), 7.87 (1H, d, J=3.6 Hz), 8.03 (1H, d, J=5.6 Hz), 8.10-8.17 (2H, m), 8.28 (1H, d, J=8.8 Hz), 9.07 (1H, s). [0249] Example 51
Nl-Methyl-5-(2-((4-(2-dimethylaminoacetyl)piperazin-l-yl)carbonyl) amino-4-pyridyl)oxy-lH-1-indolecarboxamide Similarly to Example 28, the title compound
(189.8 mg, 0.40 mmol, 74.5%) was obtained as white powder from Nl-methyl-5-(2-amino-4-pyridyl)oxy-lH-1-indolecarboxamide (150 mg, 0.53 mmol. Production example 5-1) and 1-(2-dimethylaminoacetyl)piperazine
(500 mg, 2.92 mmol).
1H-NMR Spectrum (DMSO-de) 5 (ppm): 2.14 (6H, s), 3.04
(3H, d, J=4.0 Hz), 3.29 (2H, s), 3.20-3.49 (8H, m) , 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.67 (1H, d, J=3.6 Hz), 7.03 (1H, dd, J=2.4, 8.8 Hz) 7.30 (1H, d, J=2. 4 Hz), 7.36 (1H, d, J= 2.4 Hz), 7.87 (1H, d, J=3. 6 Hz), 8.08
(1H, d, J=5.6 Hz), 8.16 (1H, q, J=4.0 Hz), 8.28 (1H, d,



Claims
1. A compound represented by the general
formula:

wherein X1 represents a nitrogen atom or a group represented by the formula -CR10=, X2 represents a nitrogen atom or a group represented by the formula -CR11-, and X1 and X2 do not represent a nitrogen atom at the same time;
y represents an oxygen atom a sulfur atom, a sulfinyl group, a sulfonyl group;- or a group represented by the formula -NRy- (wherein Ry represents a hydrogen atom or a C1-6 alkyl group) ;
R1 represents an optionally substituted 'C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12bf a group represented by the formula:


substituted Cl-6 alkylene; An represents a single bond^ an oxygen atom, a carbonyl group or a sulfonyl group; and A12 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a group represented by the formula -NRA10RA11 a group represented by the formula -0RAI2 (wherein RA10, RA11 and RA12 each independently represent a hydrogen atom, a Cl-6 alkyl group or C3-9 cycloalkyl group) or a group represented by the formula:

(wherein e represents 1 or 2; Z represents an oxygen atom, a group represented by the formula -CRx7Rx8- or a group represented by the formula -NRx9-; Rx7, Rx8 and Rx9 each independently represent a hydrogen atom, a hydroxyl group or a C1-6 alkyl group) ) ; and YA3 represents a hydrogen atom or an optionally substituted Cl-6 alkyl group) or a group represented by the formula:



(wherein T2 represents an optionally substituted 5- to 10- membered aromatic heterocycle or an optionally substituted 3- to 10- membered heterocycle); R12a and R12b each independently represent a hydrogen ■ atom, an optionally substituted C1-6 alkyl group, an optionally substituted C3-6 alkenyl group, an optionally substituted C3-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted 3- to 10- membered heterocyclic group, or an optionally substituted C1-5 alkoxy group; R13 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted

C2-6 alkenyl group, an optionally substituted C2-6 alkynyl groupr an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5- to 10- membered heteroaryl group, an optionally substituted 3- to 10- membered heterocyclic group, an optionally substituted C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12b, or a group represented by the formula:

(wherein T2 represents an optionally substituted 5- to 10- membered aromatic heterocycle or an optionally substituted 3- to 10- membered heterocycle); R2 and R14 each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, or a group represented by the formula -CO-R13;
R15 represents an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, an optionally substituted C2-6 alkynyl group, an optionally substituted C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group, an optionally substituted 5- to 10- membered heteroaryl group, or an optionally

substituted 3- to 10- merriered heterocyclic group; R16a and R16b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group^ an optionally substituted C3-5 alkenyl group, an optionally substituted C3-6 alkynyl group, an optionally substituted C3-B cycloalkyl group, an optionally substituted C5-10 aryl grcup, an optionally substituted 5- to 10- membered heteroaryl group, an optionally substituted 3- to 10- membered heterocyclic group, or an optionally substituted C1-6 alkoxy group; and X represents an oxygen atom, a sulfur atom, a carbonyl group, a sulfonyl group, a group represented by the formula -CRx1Rx2-, or a group represented by the formula -NRx3- (wherein Rx1, Rx2 and Rx3 each independently represent a hydrogen atom or a group represented by the formula -A1-A2-A3 (wherein A1 and A2 each independently represent a single bond, an optionally substituted C1-6 alkylene group or a carbonyl group; and A3 represents a hydrogen atom, a C3-8 cycloalkyl group, a group represented by the formula -NRAiRA2f o^ the formula -0RA3 (wherein, RAI, RA2 and RA3 each independently represent a hydrogen atom or a Ci-s alkyl group), or an optionally substituted group represented by the formula:



4. A compound according to claim 1 or 2, a salt
of the compound, or a hydrate of the foregoing, wherein
Y represents an oxygen atom.
5. A compound according to any of claims 1 to 4,
a salt of the compound, or a hydrate of the foregoing,
wherein one of X1 and X2 represents a group represented
by the formula -CH= and the other represents a nitrogen
atom.
6. A compound according to any of claims 1 ro 4,

a salt of the compound, or a hydrate of the foregoing, wherein both X1 and X2 represent a group represented by the formula -CH=,
7. A compound according to any of claims 1 to 6, a salt of the compound, or a hydrate of the foregoing, wherein R5, R4, R5, R6, and R6, each represent a hydrogen atom, and R7 represents a hydrogen atom, a halogen atom or an optionally substituted C1-6 alkyl group.
8. A compound according to any of claims 1 to 7, a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula -NHR17 [wherein R17 represents an optionally substituted C1-6 alkyl group, a C3-6 alkynyl group, a C3-8 cycloalkyl group, an optionally substituted C6-10 aryl group or an optionally substituted 5- to 10- membered heteroaryl group).
9. A compound according to any of claims 1 to 7, a salt of the compound, or a hydrate of the foregoing, wherein Rg represents a group represented by the formula -NR18aR18b (wherein R18a and R18b each independently represent a C1-6 alkyl group).
10. A compound according to any of claims 1 to 7, a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula:


(wherein b1 represents 1 or 2; X represents the same definition as X in claim 1).
11. A compound according to any of claims 1 to 1, a salt of the compound, or a hydrate of the foregoing, wherein R9 represents a group represented by rhe foirmula -NHRic (wherein R19 represents a Ci_6 alkyl group, a C3-6 alkynyl group, a C3-8 cycloalkyl group or a C6-10 aryl group).
12. A compound according to any of claims 1 to
11, a salt of the compound, or a hydrate of the
foregoing, wherein R3, R4, R5, R6, R7 and R8 each
represent a hydrogen atom.
13. A compound according to any of claims 1 to
12, a salt of the compound, or a hydrate of the
foregoing, wherein R2 represents a hydrogen atom.
14- A compound according to any of claims 1 to
13, a salt of the compound, or a hydrate of the
foregoing, wherein R9 represents a group represented by
the formula -NHR20 (wherein R20 represents a methyl
group, an ethyl group or a cyclopropyl group).
15. A compound according to any of claims 1 to 13, a salt of the com.pound, or a hydrate of the foregoing, wherein R9 represents a group represented by the formula -NH(CH3).

15. A compound according to any of claims 1 to 15, a salt of the compound, or a hydrate of the foregoing, wherein R1 represents a further optionally substituted group represented by the formula:


represented by the formula -A4-A5-A6 (wherein A4 and A5 each independently represent a single bond, an optionally substituted C1-6 alkylene or a carbonyl group; and A6 represents a hydrogen atom, a C3-8 cycloalkyl group or a group represented by the fonr.ula -NRA4RA5 or the formula -ORA6 (wherein RA4, RA5 AMD RA6 each independently represent a hydrogen atom or a C1-6 alkyl group))).
20. A compound according to claim 17, a salt of the compound, or a hydrate of the foregoing, wherein X in the formula (IV) represents a group represented by the formula:


(wherein C1 represents 0, 1 or 2))).
21. A compound according to claim 20, a salt of the compound, or a hydrate of the foregoing, wherein one of Rx5 and Rx6 in the formula (VI) represents a hydroxyl group and the other represents a hydrogen atom or a Ci-6 alkyl group.
22- A compound according to claim 20, a salt of the compound, or a hydrate of the foregoing, wherein one of Rx5 or Rx6 in the formula (VI) represents a hydrogen atom and the other represents a group represented by the formula:


a hydrogen atom, a C3-8 cycloalkyl group, a group represented by the formula -NRA71RA51, or the formula -0RA91 (wherein RA71, RA81, and RA91 each independently represent a hydrogen atom or a C1-6 alkyl group) , or a group represented by the formula:

(wherein YA1 and YA2 each independently represent a group represented by the formula -A10-A11-A12 (wherein A10 represents a single bond or an optionally substituted C1-6 alkylene group; A11 represents a single bond, an oxygen atom, a carbonyl group, or a sulfonyl group; and A12 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C6-10 aryl group, a 5- to 10-membered heteroaryl group, a group represented by the formula -NRA10RA11, or the formula -0RA12 (wherein, RA10, RAH and RA12 each independently represent a hydrogen atom, a C1-6 alkyl group or a C3-5 cycloalkyl group) , or


(wherein e represents 1 or 2; and Z represents an oxygen atom or a group represented by the formula -CRx7Rx8- or the formula -NRx9- (wherein Rx7, Rx8 and Rx9 each independently represent a hydrogen atom, a hydroxyl group or a C1-6 alkyl group) ) ) ; and YA3 represents a hydrogen atom or an optionally substituted C1-6 alkyl group) .
25. A compound according to claim 24, a salt of the compound, or a hydrate of the foregoing, wherein one of YA1 and YA2 in the formula (VIII) represents a hydrogen atom and the other represents a group represented by the formula - (CH2) 2"A13-A14 (wherein A13 represents a single bond, a carbonyl group or a sulfonyl group; and A14 represents a C1-5 alkyl group, a group represented by the formula -NRAISRAI^ (wherein RAI3 and RA14 each independently represent a hydrogen atom, a C1-6 alkyl group or a C3-8 cycloalkyl group), or a group represented by the formula:

(wherein e and Z represent the same definitions as e and Z in claim 24, respectively) ) ; and YA3 in the
formula (VIII) represents a hydrogen atom.


(each of the foregoing members being optionally substituted with a group selected from Substituent Group Alpha,
wherein Substituent Group Alpha is a group consisting of a halogen atom, a hydroxyl group, a thiol group, a nitro group, a cyano group, a carboxyl group, an amino group, a C1-6 alkyl group, a C3-8 cycloalkyl group, and a group represented by the formulas:



28. A compound according to any of claims 1 to
15, a salt of the compound, or a hydrate of the
foregoing, wherein R1 represents a group represented by
the formulas:



30. A compound according to claim 1 or 2, a salt of the compound, or a hydrate of the foregoing, wherein the compound is represented by the general formula:



(wherein RN1 and RN2 each independently represent a hydrogen atom or a C1-6 alkyl group) ) ; and R9 represents a group represented by the formula -NHR20 (wherein R20 represents a methyl group, an . ethyl group or a cyclopropyl group)).
31. A compound according to claim 1, a salt of the compound, or a hydrate of the foregoing, wherein the compound is a compound selected from a group consisting of
(1) Nl-ethyl-5-(2-( (methoxylamino)carbonyl)amino-4-
pyrimidyl)oxy-lH-indolecarboxamide;
(2) 5-(6-(3-(3_
diethylaminopropylamino) ureido)pyrimidin-4-yloxy) -1H-indole-1-carboxylic acid methylamide;
(3) 5- (6- ( ( (4-hydroxypiperidin-l-yl)carbonyl)amino)-
pyrimidin-4-yloxy)-lH-indole-l-carboxylic acid
methylamide;
(4 ) 5_(6-((4-pyrrolidin-1-yl)piperidin-1-

yl)carbonylamino)pyrimidin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(5) 5-(2-(3-( (lR)-l-carbainoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(6) 5-(2-(3-((lS)-l-carbamoyl-2-phenylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(7) 5-(2- (3-(2-OXO-2-(pyrrolidin-1-
yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(8) 5-(2- (3- (2-(4-hydroxy-4-methylpiperidin-l-yl)-2-oxoethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(9) 5- (2-(3-( (IS)-1-carbainoylethyl) ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(10) 5- (2- (3- ( (IS) -l-carbaiuoyl-3-
methylbutyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(11) 5- (2- (3-carbamoylmethylureido)pyridin-4-yloxy) -IH-
indole-l-carboxylic acid methylamide;
(12) 5-(2-(3-cyclopropylcarbamoylmethylureido)pyridin-
4-yloxy)-lH-indole-1'carboxylic acid methylamide;
(13) 5-(2-(3-((lS)-l-carbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;

(14) 5-(2-(3- ( {lR)-l-carbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methyl amide;
(15) (2S)-2-(3-(4-(l-methylcarbamoyl-lH-indol-5-yloxy) pyridin-2-yl)ureido)-1,5-pentanedicarboxylic acid diamide;
(16) (2S)-2-(3-(4-(l-methylcarbamoyl-lH-indol-5-yloxy)pyridin-2-yl) ureido)succinamide;
(17) 5-(2-(3-((IS)-l-cyclopropylcarbamoyl-2-
hydroxyethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(18) 5- (2- (3-((IS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(19) 5-(2-(3-((1R) -l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid methylamide;

(20) 5- (2- (3-((1S)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl) ureido)pyridin-4-yloxy)-lH-indole-l-carboxylic acid methylamide;
(21) 5-(2-(3-( (lR)-l-hydroxymethyl-2-oxo-2--piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-IH-indole-l-carboxylic acid methylamide;
(22) 5-(2-(3-((IS)-l-hydroxymethyl-2-(4-
hydroxypiperidin-l-yl) -2-oxoethyl)ureido)pyridin-4-
yloxy)-lH-indole-1-carboxylic acid methylamide;

(23) 5- (2- (3- ( (1S) -l-hydroxymethyl-2- (morpholin-'4-yl) -
2-oxoethyl)ureido)pyridin-4-yloxy)-IH-indole-l-
carboxylic acid methylamide;
(24) 5-(2'(3-(2-
cyclopropylcarbamoylethyl)ureido)pyridin-4-yloxy)-IH-
indole-1-carbcxylic acid methylamide;
(25) 5- (2- (3-(3-OXO-3-(pyrrolidin-1-
yl)propyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(26) 5-(2-(3- (3-(4-hydroxy-4-methylpiperidin-l-yl)-3-
oxopropyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(27) Nl-ethyl-5-(2-( ( (2-
ethoxyethyl) airiino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(28) Nl-methyl-5-(2-((4-(2-hydroxy-2-
methylpropionyl)piperazin-1-yi)carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(29) Nl-methyl-5-(2-((3-
. (diethylamino)propylamino) carbonyl) amino-4-pyridyl) oxy-
lH-1-indolecarboxamide;
(30) Nl-methyl-5-(2-(((3-(4-
hydroxypiperidino)propyl)amino)carbonyl) amino-4-
pyridyl)oxy-lK-1-indolecarboxamide;
(31) Nl-methyl-5-(2-(((3-(4-methylpiperazin-l-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-

indolecarboxamide;
(32) 5-(2-(3-(4-oxo-4-(pyrrolidin-1-
yl)butyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(33) 5-(2-(3-(3-
(cyclopropylcarbamoyl)propyl)ureido)pyridin-4-yloxy)-
lH-indole-1-carboxylic acid methylamide;
(34) 5-(2- (3-(4-(4-hydroxy-4-methylpiperidin-l-yl)-4-
oxobutyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(35) 5-(2-(3-(3-
(diethylcarbamoyl)propyl) ureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide;
(36) 5-(2-(3-(3-(methylcarbamoyl)propyl)ureido)pyridin-
4-yloxy)-lH-indole-1-carboxylic acid methylamide;
(37) Nl-methyl-5-(2- (pyrrolidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(38) Nl-methyl-5-(2- (piperidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(39) Nl-methyl-5-(2-((4-
hydroxypiperidino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(40) Nl-methyl-5-(2-(4-oxopiperidin-1-ylcarbonyl)amino-
4-pyridyl)oxy-lH-l-indolecarboxamide;
(41) 5- (2-(( (4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-

carboxylic acid methylamide;
(42) Nl-inethyl-5- (2- ( (4- (1-hydroxy-l-
methylethyl)piperidino)carbonyl) amino-4-pyridyl)oxy-lH-
l-indolecarbo>:amide;
(43) 5-(2-.((4- {3-me thy Icarbaiaoylpropyl) piper idin-1-
yl) carbonyl) ar-ino) pyridin-4-yloxy) -lH-indole-1-
carboxylic acid methylamide;
(44) 5- (2- ( ( (4- (3-carbamoylpropyl)piperidin-l-
yl) carbonyl) amino) pyridin-4-yloxy) -lH-indole-1-
carboxylic acid methylamide;
(45) 5-(2-((4-( (pyrrolidine1-yl)carbonyl)piperidin-1-
yl) carbonylamino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(46) Nl-methyl-5- (2-(((4-(pyrrolidin-1-yl)piperidin-1-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(47) Nl-methyl-5-(2-( ( (4-(piperidin-1-yl)piperidin-1-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(48) Nl-methyl-5-(2-((4-ethylpipera2in-l-
yl)carbonyl)amano-4-pyridyl)oxy-lH-1-indolecarboxamide;
(49) Nl-methyl-5- (2- ( (4-(2-hydroxyethyl)pipera2in-l-
yl) carbonyl) amino-4-pyridyl) oxy-lH-1-indolecarboxamide;
(50) Nl-methyl-5-(2-((3-
methylsulfonylpropylamino) carbonyl) amino-4-pyridyl) oxy-
lH-1-indolecarboxamide;

(51) Nl-methyl-5-(2-((4-(2-
dimethylaiainoacetyllpiperazin-l-yl) carbonyl) ainino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(52) Nl-methyl-5- (2- ( (4-cyclohexylpipera2in-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(53) N4-(4-(l-(methyl amino)carbonyl-lH-5-indolyl)oxy-2-
pyridyl)-4-morpholinecarboxamide;
(54 ) Nl-methyl-5- (2- ( (1;. l-dioxothiomorpholin-4-
ylcarbonyl) amino) pyridin-4-yloxy) -lH-1-indolecarboxamide;
(55) 5-(2- (3-((IR)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide;
(56) 5- (2- (3-((lS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-1-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide;

(57) 5- (2- (3-((IR)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide;
(58) 5-(2- (3-((lS)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid ethylamide;
(59) 5-(2-(3-(2-(4-hydroxy-4-methylpiperidin-l-yl)-2-
oxoethyl) ureido) pyridin-4-yloxy) -lH-indole-1-carboxylic
acid ethylamide;
(60) Nl-ethyl-5-(2-( ( ((l-methyl-4-

piperidyl)methyl) amino) carbonyl) amino-4-pyridyl) oxy-lH-1-indolecarboxamide;
(61) Nl-ethyl-5-(2-((,2-
diethylamino)ethyl)amino)carbonyl) amino-4-pyridyl)oxy-
lH-1-indolecarboxamide;
(62) Nl-ethyl-5-(2-(((2-(morpholin-4-
yl) ethyl) amino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(63) Nl-ethyl-5^(2-(((2-(4-
hydroxypiperidino) ethyl) amino) carbonyl) arriino-4-
pyridyl)oxy-lK-1-indolecarboxamide;
(64) Nl-methyl-5^(2-( ((2- (4-
hydroxypiperidino)ethyl)amino)carbonyl)amino-4-
pyridyl)oxy-lK-1-indolecarboxamide;
(65) Nl-ethyl-5-(2-( (3-
(diethylamino)propylamine)carbonyl) amino-4-pyridyl)oxy-
lH-1-indolecarboxamide;
(66) Nl-ethyl-5-(2-(((3-(morpholin-4-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(67) Nl-ethyl-5- (2- ( ( (3- (4-methylpiperazin-l-
yl)propyl)amino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(68) Nl-cyclopropyl-5-(2-(((4- (pyrrolidin-1-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;

(59) 5-(2-{3-((lR)-l-hydroxymethyl-2-oxo-2-pyrrolidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide;
(70) 5- (2-(3-((IS)-i-hydroxymethyl-2-oxo-2-pyrrolidin-
l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid cyclopropylamide;
(71) 5-(2-(3-(2-OXO-2-(pyrrolidin-1-yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide;
(72) 5-(2-(3-(3-OXO-3-(pyrrolidin-1-yl)propyl)ureido)pyridin-4-yloxy)-IH-indole-1-carboxylic acid cyclopropylamide;

(73) 5- (2- (3-((IR)-l-hydroxymethyl-2-oxo-2-piperidin-l-ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic acid cyclopropylamide;
(74) 5- (2-(3-((IS)-l-hydroxymethyl-2'OXo-2-piperidin-l-ylethyl) ureido) pyridin-4-yloxy) -lH-indole-1-carboxylic acid cyclopropylamide;
(75) Nl-phenyl-5-(2-(((3-
(diethylamino)propyl) amino) carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(76) Nl-phenyl-5- (2- ( ( (3- (4-'methylpipera2in-l-
yl) propyl) amino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(77) Nl-ethyl-5-(2-(((4-(pyrrolidin-l-yl)piperidin-l-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-

indolecarboxamide;
(78) 5- (2- ( ( (4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)anino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid ethylamide;
(79) Nl-ethyl-5-(2-((4-hydroxypiperidin-l-
yl)carbonyl) amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(80) Nl-ethyl-5- (2- (piperidin-1-ylcarbonyl) ainino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(81) Nl-ethyl-5- ( (2- ( (pyrrolidin-1-ylcarbonyl) amino)-4-
pyridyl)oxy)-lH-1-indolecarboxamide;
(82) N4-(4-((l-(ethylamino)carbonyl-lH-5-indolyl)oxy)-
2-pyridyl)-4-morpholinecarboxamide;
(83) Nl-ethyl-5- (2- ( (1, l-dioxothioinorpholin-4-
ylcarbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(84 ) Nl-ethyl-5-(2-((methoxylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(85) Nl-cyclopropyl-5-(2-( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(86) Nl-cyclopropyl-5-(2-(((4-hydroxy-4-
methylpiperidin-1-yl)carbonyl)amino) pyridin-4-yloxy)-
lH-1-indolecarbox-amide;
(87) N4- (4- (1- (cyclopropylamino) carbonyl-lH-5-
indolyl) oxy-2-pyridyl) -4-morpholinecarboxamide;
(88) Nl-cyclopropyl-5-(2-((pyrrolidin-1-

ylcarbonyl) amino) -4-pyridyl) oxy-lH-1-indolecarboxamide;
(89) Nl-cyclopropyl-5-(2-(piperidin-1-ylcarbonyl)amino-
4-pyridyl)oxy~lH-l-indolecarboxamide;
(90) N4-(4-(l-(cyclopentylamino)carbonyl-lH-5-
indolyl) oxy-2-pyridyl) -4-morpholinecarboxamide;
(91) 5-(2-(((4-hydroxypiperidin-l-
yl) carbonyl)ainino)pyridin-4-yloxy) -lH-indole-1-
carboxylic acid cyclopentylamide;
(92) Nl-cyclopentyl-5-(2-((4-(pyrrolidin-1-
yl) piperidin-1-ylcarbonyl) amino) pyridin-4-yloxy) -lH-1-
indolecarboxamide;
(93) Nl- (3-methylbutyl) -5- (2- ( ( (4- (pyrrolidin-1-
yl) piperidin-1-yl) carbonyl) amino) pyridin-4-yloxy) -lH-1-
indolecarboxamide;
(94) Nl-(3-methylbutyl)-5-(2-( (4-
(hydroxypiperidino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(95) N4-(4-(l-((3-methylbutyl)amino)carbonyl-lH-5-
indolyl) oxy-2-pyridyl) -4-morpholinecarboxamide;
(96) Nl-(1-ethylpropyl)-5-(2-({(4-(pyrrolidin-1-
yl)piperidin-l-yl) carbonyl) amino)pyridin-4-yloxy) -lH-1-
indolecarboxamide;
(97) Nl-(1-ethylpropyl)-5-(2-((4 -
hydroxypiperidino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(98) N4-(4-(l-((1-ethylpropyl)amino)carbonyl-lH-5-

indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide;
(99) N4-(4-(l-{(1-pentyl) amino)carbonyl-lE-5-
indolyl) oxy-2-pyridyl) -4-inorpholinecarboxainide;
(100) Nl-(l-pentyl)-5-(2-{((4-hydroxypiperidin-l-
yl) carbonyl) aiaino) pyridin-4-yloxy) -lH-1-
indolecarboxairdde ;
(101) Nl- (1-pentyl)-5-(2-((4-(pyrrolidin-1-
yl) piperidin-1-ylcarbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(102) Nl-methyl-3-chloro-5-(2-(((3-
(diethylamino)propyl)amino)carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(103) Nl-methyl-3-chloro-5-(2-((4-(pyrrolidin-1-
yl)piperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(104) Nl-methyl-3-chloro-5-(2-({4-
hydroxypiperidino)carbonyl) amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(105) Nl-methyl-3-chloro-5-(2-(((3-(4-
hydroxypiperidino)propyl) amino) carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(106) Nl-methyl-3-chloro-5-(2-((4- (2-
hydroxyethyl)piperazin-l-yl)carbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(107) N4-(4- (3-chloro-l-(methylamino)carbonyl-lH-5-
indolyl)oxy-2-pyridyl)-4-morpholinecarboxamide;

(108) Nl-methyl-3-chloro-5-(2-((4-(ethylpiperazin-l-
yl)carbonyl) amino-4-pyridyl)oxy-lH-1-indolecarboxaiuide;
(109) Nl-ethyl-3-chloro-5-(2-( (4-
hydroxypiperidino) carbonyl) amino-4-pyridyl) oxy-lH-1-
indolecarboxamide;
(110) Nl-ethyl-3-chloro-5-(2-(((3-(4-
hydroxypiperidino) propyl)amino)carbonyl)amino-4-
pyridyl) oxy-lH-1-indolecarboxamide;
(111) Nl-ethyl-3-chloro-5-(2-(((3-
(diethylamino)propyl) amino) carbonyl) amino-4-
pyridyl) oxy-lH-1-indolecarboxamide;
(112) Nl,3-dimethyl-5-(2-((4-
hydroxypiperidino) carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(113) Nl,3-dimethyl-5-(2-((4-(pyrrolidin-1-
yl)piperidino)carbonyl) amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(114) Nl-cylopropyl-5-(2-((4-
hydroxypiperidino) carbonyl) amino-4-pyridyl) oxy-3-
methyl-lH-1-indolecarboxamide;
(115) Nl-cylopropyl-5-(2-((4- (2-hydroxyethyl)piperazin-
1-yl) carbonyl) amino-4-pyridyl )'oxy-3-methyl-lH-l-
indolecarboxamide;
(116) Nl-methyl-5-(2-((methylamino)carbonyl)amino-4-
pyridyl) oxy-lH-1-indolecarboxamide;
(117) Nl-methyl-5-(2-((diethylamino)carbonyl)amino-4-

pyridyl)oxy-lK-1-indolecarboxamide;
(118) Nl-(2-propynyl)-5-(2-((pyrrolidin-1-
yl) carbonyl) amino-4-pyridyl)oxy-lH-l-indolecarboxamide;
(119) Nl-methyl-5- (2- (azetidin-l-ylcarbonyl) ainino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(120) Nl-ethyl-5-(2-(azetidin-l-ylcarbonyl)amino-4-
pyridyl)oxy-lH-l-indolecarboxamide;
(121) Nl-cyclcpropyl-5- (2- (azetidin-l-ylcarbonyl) aiuino-
4-pyridyl)oxy-lH-1-indolecarboxamide;
(122) Nl-methyl-5- (2- ( ( (4- (inorpholin-4-yl)piperidin-l-
yl) carbonyl) amino)pyridin-4-yloxy) -lH-1-
indolecarboxaroide;
(123) Nl-iaethyl-5-(2-( ( (4- (azetidin-1-yl) piperidin-1-
yl) carbonyl) ainino)pyridin-4-yloxy) -lH-1-
indolecarboxamide;
(124) Nl-methyl-5-(2-( ( (4- (diethylamino)piperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(125) Nl-methyl-5-(2-( ( (4-(4-hydroxypiperidin-l-
yl) piperidin-1-yl) carbonyl) amino)pyridin-4-yloxy) -lH-1-
indolecarboxamide; and
(126) Nl-propyl-5- (2- (pyrrolidin-1-ylcarbonyl) amino-4-
pyridyl)oxy-lH-1-indolecarboxamide.
32. A compound according to claim 1, a salt of the compound, or a hydrate of the foregoing, wherein the compound is a compound selected from a group

consisting of
(1) 5-(2-(3-(2-oxo-2-(pyrrolidin-l-
yl)ethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(2) 5- (2- (3-carbamoylmethylureido)pyridin-4-yloxy)-IH-
indole-1-carboxylic acid methylamide;
(3) 5-(2-(3-((lS)-l-hydroxymethyl-2-oxo-2-pyrrolidin-l-
ylethyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(4) Nl-methyl-5-(2-((4-(2-hydroxy-2-
methylpropionyl)piperazin-l-yl)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(5) 5-(2-(3-(4-OXO-4-(pyrrolidin-1-
yl) butyl)ureido)pyridin-4-yloxy)-lH-indole-1-carboxylic
acid methylamide;
(6) 5-(2-(3-(3-
(cyclopropylcarbamoyl)propyl) ureido)pyridin-4-yloxy) -
lH-indole-1-carboxylic acid methylamide;
(7) 5- (2- (3-(4-(4-hydroxy-4-methylpiperidin-l-yl)-4-
oxobutyl) ureido)pyridin-4-yloxy) -lH-indole-1-carboxylic
acid methylamide;
(8) 5- (2- (3- (3- (methylcarbamoyl)propyl)ureido)pyridin-
4-yloxy)-IH-indole-l-carboxylic acid methylamide;
(9) Nl-methyl-5-(2- (pyrrolidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(10) Nl-methyl-5-(2-((4-

hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(11) Nl-merhyl-5- (2-(4-oxopiperidin-1-ylcarbonyl)amino-
4-pyridyl)oxy-lH-l-indolecarboxamide;
(12) 5- (2- ( ( {4-hydroxy-4-inethylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(13) 5-(2-(((4- (3-methyl carbamoylpropyl) piper idin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(14) 5- (2- ( ( (4-(3-carbamoylpropyl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(15) Nl-methyl-5-(2-(((4-(pyrrolidin-1-yl) piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(16) Nl-methyl-5-(2- ( ((4-(piperidin-1-yl)piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(17) Nl-methyl^5-(2-( (3-
methylsulfonylpropylamino) carbonyl) amino-4-pyridyl) oxy-
lH-1-indolecarboxamide;
(18) N4- (4- (1- (methylamino) carbonyl-lH-5-indolyl) oxy-2-
pyridyl)-4-morpholinecarboxamide;
(19) Nl-cyclopropyl-5-(2-(((4-(pyrrolidin-1-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-

indolecarboxamide;
(20) 5- (2- ( ( (4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid ethylamide;
(21) N1-ethyl-5-(2-((4-hydroxypiperidin-l-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(22) Nl-ethyl-5-((2-((pyrrolidin-1-ylcarbonyl)amino)-4-
pyridyl)oxy)-lH-1-indolecarboxamide;
(23) N4-(4-((1-(ethylamino)carbonyl-lH-5-indolyl)oxy)-
2-pyridyl)-4-morpholinecarboxamide;
(24) , Nl-cyclopropyl-5-(2-((pyrrolidin-1-
ylcarbonyl)amino)-4-pyridyl)oxy-lH-1-indolecarboxamide;
(25) Nl-methyl-3-chl6ro-5-(2-((4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(2 6) Nl-methyl-5-(2-((methylamino)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(27) Nl-methyl-5-(2-((diethylamino)carbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(28) Nl-(2-propynyl)-5-(2-((pyrrolidin-1-
yl)carbonyl)amino-4-pyridyl)oxy-lH-1-indolecarboxamide;
(29) Nl-methyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(30) Nl-ethyl-5-(2-(azetidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide;
(31) Nl-cyclopropyl-5-(2-(azetidin-1-ylcarbonyl)amino-

4-pyridyl)oxy-lH-l-indolecarboxamide;
(32) N1-methyl-5- (2- ( ( (4- (morpholin-4-yl) piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxaraide;
(33) Nl-methyl-5-(2-(((4-(azetidin-1-yl)piperidin-1-
yl) carbonyl) amino)pyridin-4-yloxy) -lH-1-
indolecarboxamide;
(34) Nl-methyl-5-(2-(((4-(diethylamino) piperidin-1-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide;
(35) Nl-methyl-5-(2-(((4-(4-hydroxypiperidin-l-
yl)piperidin-1-yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide; and
(36) Nl-propyl-5-(2-(pyrrolidin-1-ylcarbonyl)amino-4-
pyridyl)oxy-lH-1-indolecarboxamide.
33. A compound according to claim 1, a salt of the compound, or a hydrate of the foregoing, wherein the compound is a compound selected from a group consisting of
(1) 5- (2- (((4-hydroxy-4-methylpiperidin-l-
yl)carbonyl)amino)pyridin-4-yloxy)-lH-indole-1-
carboxylic acid methylamide;
(2) Nl-methyl-5-(2-( (4-
hydroxypiperidino)carbonyl)amino-4-pyridyl)oxy-lH-1-
indolecarboxamide;
(3) Nl-methyl-5-(2-(((4-(pyrrolidin-1-yl) piperidin-1-

yl)carbonyl)amino)pyridin-4-yloxy)-lH-1-indolecarboxamide;
(4) Nl-methyl-S-(2-(((4-(piperidin-l-yl)piperidin-l-
yl)carbonyl) amino)pyridin-4-yloxy)-lH-1-
indolecarboxamide; and
(5) N4-(4-(1- (methylamino)carbonyl-lH-5-indolyl)oxy-2-
pyridyl) -4-morpholinecarboxamide.
34- A pharmaceutical composition comprising a compound according to any of claims 1 to 33 and a pharmaceutical adjuvant.
35. A prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective, comprising as an active ingredient;. a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.
36. An angiogenesis inhibitor comprising as an active ingredient, a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.
37." An antitumor' agent comprising as an active ingredient, a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.
38. An antitumor agent according to claim 37, wherein the tumor is a pancreatic cancer, a gastric cancer, a colon cancer, a breast cancer, a prostate cancer, a lung cancer, a renal cancer, a brain tumor, a

blood cancer or an ovarian cancer.
39. A therapeutic agent for hemangicma
comprising as an active ingredient , a compound
according to any of claims 1 to 33, a salt thereof, or
a hydrate of the foregoing.
40. A cancer metastasis inhibitor comprising as
an active ingredient, a compound according to any of
claims 1 to 33, a salt thereof, or a hydrate of uhe
foregoing.
41. A therapeutic agent for retinal
neovascularization or diabetic retinopathy comprising
as an active ingredient, a compound according to any of
claims 1 to 33, a salt thereof, or a hydrate of the
foregoing.
42. A therapeutic agent for an inflammatory disease comprising as an active ingredient, a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.
43. A therapeutic agent for an inflammatory disease according to claim 42, wherein the inflammatory disease is deformant arthritis, rheumatoid arthritis, psoriasis or delayed hypersensitivity reaction.
44. A therapeutic agent for atherosclerosis comprising as an active ingredient, a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.

45. A prophylactic or therapeutic method for a disease for which angiogenesis inhibition is effectives-comprising administering to a patient, a pharmacologically effective dose of a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing.
46. Use of a compound according to any of claims 1 to 33, a salt thereof, or a hydrate of the foregoing for the manufacture of a prophylactic or therapeutic agent for a disease for which angiogenesis inhibition is effective.

Documents:

2961-chenp-2004-abstract.pdf

2961-chenp-2004-claims filed.pdf

2961-chenp-2004-claims granted.pdf

2961-chenp-2004-correspondnece-others.pdf

2961-chenp-2004-correspondnece-po.pdf

2961-chenp-2004-description(complete)filed.pdf

2961-chenp-2004-description(complete)granted.pdf

2961-chenp-2004-form 1.pdf

2961-chenp-2004-form 26.pdf

2961-chenp-2004-form 3.pdf

2961-chenp-2004-form 5.pdf

2961-chenp-2004-other document.pdf

2961-chenp-2004-pct.pdf


Patent Number 209812
Indian Patent Application Number 2961/CHENP/2004
PG Journal Number 50/2007
Publication Date 14-Dec-2007
Grant Date 06-Sep-2007
Date of Filing 28-Dec-2004
Name of Patentee EISAI R & D MANAGEMENT CO. LTD.,
Applicant Address 4-6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo 112-8088
Inventors:
# Inventor's Name Inventor's Address
1 TSURUOKA, Akihiko 2-203, 19-1, Azuma 3-chome, Tsukuba-shi, Ibaraki 305-0031
PCT International Classification Number A61K 31/4439
PCT International Application Number PCT/JP2003/010964
PCT International Filing date 2003-08-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2002-253123 2002-08-30 Japan