Nitrogen-containing aromatic derivatives
Compounds represented by the following general formula: [wherein A g is an optionally substituted 5- to 14-membered heterocyclic group, etc.; X g is —O—, —S—, etc.; Y g is an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, etc.; and T g1 is a group represented by the following general formula: (wherein E g is a single bond or —N(R g2 )—, R g1 and R g2 each independently represent a hydrogen atom, an optionally substituted C 1-6 alkyl group, etc. and Z g represents a C 1-8 alkyl group, a C 3-8 alicyclic hydrocarbon group, a C 6-14 aryl group, etc.)], salts thereof or hydrates of the foregoing.
1. A compound represented by the following general formula:
wherein:
R 1 and R 2 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 2-7 acyl group or an optionally substituted C 2-7 alkoxycarbonyl group;
Z 12 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group, an optionally substituted 5- to 14-membered aromatic heterocyclic group or a group represented by the formula:
wherein Z 31 , Z 33 and Z 34 are each independently a methylene group, —CO—, —NH— or —O—, and Z 32 is a single bond, a methylene group, —CO—, —NH— or —O—; and
wherein Z 12 is not pyrazolyl;
Y a1 is a group represented by the formula:
wherein W 31 and W 32 are each independently an optionally substituted carbon atom or a nitrogen atom;
R 300 and R 301 are each independently a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amino group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 2-7 alkoxycarbonyl group, a formyl group, a group represented by the formula
wherein V 300 and V 301 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group, or an optionally substituted C 2-7 acyl group;
R a11 is a group represented by the formula —V a21 —V a22 —V a23 , wherein:
V a21 is an optionally substituted C 1-6 alkylene group, a single bond or a group represented by the formula:
V a22 is a single bond, an oxygen atom, a sulfur atom, —CO—, —SO—, —SO 2 —, —CONR a14 —, —SO 2 NR a14 —, —NR a14 SO 2 —, —NR a14 CO— or —NR a14 —;
wherein R a14 is a hydrogen atom, an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 alicyclic hydrocarbon group; and
V a23 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and
R a12 is a cyano group or a group represented by the formula:
wherein:
V a11 is —CO— or —SO 2 —; and
V a12 , V a13 and V a14 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
with the exception of the following compounds (1) and (2):
(1) a compound wherein R a12 is a group represented by the formula:
wherein:
V a12 and V a13 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R 1 and R 2 are hydrogen atoms; and
Z 12 is a C 6-14 aryl group, a 6- to 14-membered heterocyclic group or a 6- to 14-membered aromatic heterocyclic group;
(2) a compound wherein R a12 is a group selected from the group consisting of the formulae:
wherein:
V a11 is —CO— or —SO 2 —;
V a12 , V a13 and V a14 are each independently a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 3-8 alicyclic hydrocarbon group, an optionally substituted C 6-14 aryl group, an optionally substituted 5- to 14-membered heterocyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group;
R 2 is a hydrogen atom; and
Z 12 is (a) a C 6-14 aryl group, (b) a 5- to 14-membered heterocyclic group, (c) a 5- to 14-membered aromatic heterocyclic group, (d) a C 1.6 alkyl group substituted with a 5- to 10-membered heterocyclic group or a C 5-10 alicyclic hydrocarbon group, (e) a C 2-6 alkenyl group substituted with a 5- to 10-membered heterocyclic group or a C 5-10 alicyclic hydrocarbon group, (f) a C 2-6 alkynyl group substituted with a 5- to 10-membered heterocyclic group or a C 5-10 alicyclic hydrocarbon group, or (g) a C 3-8 alicyclic hydrocarbon group substituted with a 5- to 10-membered heterocyclic group or a C 5-10 alicyclic hydrocarbon group,
or a pharmacologically acceptable salt or hydrate thereof.
2. The compound according to claim 1 , a pharmacologically acceptable salt or hydrate thereof, wherein R a11 is a methyl group, a 2-methoxyethyl group or a group represented by the formula:
wherein:
R a53 is a methyl group, a cyclopropylmethyl group or a cyanomethyl group;
R a51 is a hydrogen atom, a fluorine atom or a hydroxyl group; and
R a52 is a 1-pyrrolidinyl group, a 1-piperidinyl group, a 4-morpholinyl group, a dimethylamino group or a diethylamino group.
3. The compound according to either of claims 1 or 2 , a pharmacologically acceptable salt or hydrate thereof, wherein Z 12 is a methyl group, an ethyl group, a cyclopropyl group, a 2-thiazolyl group or a 4-fluorophenyl group.
4. The compound according to any one of claims 1 to 3 , a pharmacologically acceptable salt or hydrate thereof, wherein Y a1 is a group represented by the formula:
wherein R a61 is a hydrogen atom, a methyl group, a trifluoromethyl group, a chlorine atom or a fluorine atom.
5. The compound according to any one of claims 1 to 4 , a salt or hydrate thereof, wherein R a12 is a cyano group or a group represented by the formula —CONHR a62 , wherein R a62 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 is alicyclic hydrocarbon group, an optionally substituted C 1-6 alkoxy group or an optionally substituted C 3-8 cycloalkoxy group.
6. The compound according to claim 1 , a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from:
N-(4-(6-cyano-7-(3-(4-pyridyl)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,
N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-(1,2,3-triazol-2-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(2-(1,2,3-triazol-1-yl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(1,3-thiazol-2-yl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-cyanophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylurea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(1,3-thiazol-2-yl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-cyclopropylurea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-cyclopropylmethylurea,
N-(4-(6-cyano-7-(3-(morpholin-4-yl)propoxy)quinolin-4-yloxy)-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(3-(methylsulfonyl)phenyl)urea,
N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(3-(1-(4-ethylpiperazino))propoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,
N-(4-(6-cyano-7-(3-cyanopropoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(2-(methylsulfonyl)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(3-methoxycarbonylpropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,
N-(4-(6-cyano-7-(3-carboxypropoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,
N-(4-(6-cyano-7-(2-(2-hydroxyethoxy)ethoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea,
N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-(3-(methylsulfonyl)phenyl)urea,
N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(3-(methylsulfonyl)phenyl)urea,
N-(4-(6-cyano-7-(3-(diethylamino)propoxy)-4-quinolyloxy)phenyl)-N′-phenylurea,
N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-phenylurea,
N-(4-(6-cyano-7-(3-(4-morpholino)propoxy)-4-quinolyl)oxyphenyl)-N′-(2-oxo -1,2,3,4-tetrahydro-6-quinolyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxyphenyl)-N′-(3-acetamidophenyl)urea,
N-(4-(6-cyano-7-benzyloxy-4-quinolyl)oxy-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea,
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-phenylurea,
4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide,
4-(4-((anilinocarbonyl)amino)-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
4-(4-((4-fluoroanilino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
7-methoxy-4-(4-((1,3-thiazol-2-ylamino)carbonyl)aminophenoxy)-6-quinolinecarboxamide,
4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(4-((cyclopropylamino)carbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(5-((anilinocarbonyl)amino)-2-pyridyloxy)-7-methoxy-6-quinolinecarboxamide,
4-(4-(anilinocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(4-(anilinocarbonyl)aminophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
4-(4-((2,4-difluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-(2-methoxyethoxy)-6-quinolinecarboxamide,
7-(2-methoxyethoxy)-4-(4-((1,3-thiazol-2-ylamino)carbonyl)amino-3-fluorophenoxy)-6-quinolinecarboxamide; and
4-(4-((4-fluoroanilino)carbonyl)amino-3-fluorophenoxy)-7-methoxy-6-quinolinecarboxamide.
7. The compound according to claim 1 , a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from
N-(4-(6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)-N′-(4-fluorophenyl)urea,
N-(2-chloro-4-((6-cyano-7-((1-methyl-4-piperidyl)methoxy)-4-quinolyl)oxy)phenyl)-N′-cyclopropylurea,
N-(4-((6-cyano-7-(((2R)-3-(diethylamino)-2-hydroxypropyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea,
N-(4-((6-cyano-7-(((2R)-2-hydroxy-3-(1-pyrrolidino)propyl)oxy)-4-quinolyl)oxy)phenyl)-N′-(4-fluorophenyl)urea,
N-{4-[6-cyano-7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-2-methylphenyl}-N′-cyclopropyl-urea,
4-(4-(4-fluoroanilino)carbonyl)-4-methylaminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-(2methoxy-6-quinolinecarboxamide,
N6-cyclopropyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino) phenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-(2-methoxyethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy -6-quinolinecarboxamide,
N6-(2-pyridyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-(2-fluoroethyl)-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-methyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, and
N6-ethyl-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.
8. The compound according to claim 1 , a pharmacologically acceptable salt or hydrate thereof, wherein said compound is a compound selected from
4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide,
N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide,
4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, and
N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-mcthoxy-6-quinolinecarboxamide.
9. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising a compound according to claim 1 in an amount effective to inhibit angiogenesis.
11. A compound having the formula 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.
12. A compound having the formula 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.
13. A compound having the formula N6-methoxy-4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.
14. A compound having the formula 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.
15. A compound having the formula N6-methoxy-4-(3-chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt or hydrate thereof.