Nitrogen-containing aromatic heterocyclic compound
Provided is a compound useful as a prophylactic and/or therapeutic agent for bladder cancer. As a result of studies on compounds having FGFR inhibitory action, the present inventors have found that the nitrogen-containing aromatic heterocyclic compounds of the present invention have inhibitory action on FGFR1, FGFR2, and/or FGFR3, particularly, mutant FGFR3, and thus, the present invention has been accomplished. The nitrogen-containing aromatic heterocyclic compound of the present invention can be used as a therapeutic agent for various cancers related to FGFR1, FGFR2, and/or FGFR3, such as lung cancer and hormone therapy-resistant breast cancer, stomach cancer, triple negative breast cancer, endometrial cancer, bladder cancer, and glioblastoma, particularly as a prophylactic and/or therapeutic agent for mutant FGFR3-positive bladder cancer.
1. A compound of formula (I) or a salt thereof:
wherein
X is N;
Y is CH;
L 1 is ethylene or methylene-O—;
Z is CH;
each R 1 is independently lower alkyl optionally substituted with halogen, —O-(lower alkyl optionally substituted with halogen), halogen, cyano, or —N(lower alkyl) 2 ;
p is an integer of from 2 to 4;
ring W is an optionally substituted aromatic carbocyclic ring, an optionally substituted aromatic heterocyclic ring, or an optionally substituted non-aromatic heterocyclic ring;
Q is -L 2 -R 2 or R 3 ;
L 2 is an optionally substituted aromatic heterocyclic ring or an optionally substituted non-aromatic heterocyclic ring;
R 2 is a non-aromatic heterocyclic group optionally substituted with lower alkyl, optionally substituted cycloalkyl, lower alkyl optionally substituted with at least one selected from the group consisting of —OH and —O-lower alkyl, —C(O)—R 0 , —C(O)-optionally substituted cycloalkyl, —NH—R 0 , —N(lower alkyl)-R 0 , an -L 3 -optionally substituted non-aromatic heterocyclic group, or H;
R 0 is lower alkyl optionally substituted with —OH;
L 3 is a bond, —NH—, —N(lower alkyl)-, or lower alkylene; and
R 3 is:
a lower alkyl optionally substituted with at least one selected from the group consisting of —C(O)OH, —OH, —O—R 0 , amino optionally substituted with one or two R 0 , carbamoyl optionally substituted with one or two R 0 , an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, and a —C(O)— optionally substituted non-aromatic heterocyclic group,
—O-(lower alkyl optionally substituted with at least one selected from the group consisting of —C(O)OH, —OH, —O—R 0 , carbamoyl optionally substituted with one or two R 0 , an optionally substituted non-aromatic heterocyclic group, and a —C(O)-optionally substituted non-aromatic heterocyclic group),
—NH-(lower alkyl optionally substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and carbamoyl optionally substituted with one or two R 0 ),
—N(lower alkyl)-(lower alkyl optionally substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and carbamoyl optionally substituted with one or two R 0 ),
—C(O)OH,
—C(O)-optionally substituted non-aromatic heterocyclic group,
—O-(a non-aromatic heterocyclic group optionally substituted with lower alkyl), or carbamoyl optionally substituted with one or two R 0 .
2. The compound or salt thereof according to claim 1 ,
wherein
each R 1 is independently —O-lower alkyl or halogen;
p is 2 or 4; and
ring W is an optionally substituted aromatic carbocyclic ring or an optionally substituted aromatic heterocyclic ring.
3. The compound or salt thereof according to claim 2 ,
wherein
p is 4; and
ring W is an optionally substituted benzene ring or optionally substituted pyrazole.
4. The compound or salt thereof according to claim 1 ,
wherein Q is -L 2 -R 2 ;
L 2 is an optionally substituted non-aromatic heterocyclic ring; and
R 2 is lower alkyl optionally substituted with at least one selected from the group consisting of —OH and —O-lower alkyl, —NH-(lower alkyl optionally substituted with —OH), an optionally substituted non-aromatic heterocyclic group, -lower alkylene-(an optionally substituted non-aromatic heterocyclic group), or H.
5. The compound or salt thereof according to claim 4 ,
wherein p is 4;
L 2 is piperazine optionally substituted with one or more methyl, piperidine optionally substituted with one or more methyl, or 3,9-diazaspiro[5.5]undecane; and
R 2 is piperazine optionally substituted with methyl, piperidine optionally substituted with methyl, 2-hydroxyethylamino, or H.
6. The compound or salt thereof according to claim 5 ,
wherein each R 1 is independently —O-methyl or F;
L 1 is -methylene-O—;
ring W is a benzene ring optionally substituted with —O-methyl;
L 2 is piperidine or 4-methylpiperazine; and
R 2 is 4-methylpiperazine, 2-hydroxyethylamino, or H.
7. The compound or salt thereof according to claim 1 ,
wherein ring W is optionally substituted pyrazole;
Q is R 3 ; and
R 3 is lower alkyl substituted with at least one selected from the group consisting of —C(O)OH, carbamoyl optionally substituted with one or two R 0 , —OH, an optionally substituted non-aromatic heterocyclic group, and —C(O)-(an optionally substituted non-aromatic heterocyclic group).
8. The compound or salt thereof according to claim 7 ,
wherein p is 4; and
R 3 is lower alkyl substituted with at least one selected from the group consisting of —OH, a non-aromatic heterocyclic group optionally substituted with lower alkyl, and —C(O)-(a non-aromatic heterocyclic group optionally substituted with —OH).
9. The compound or salt thereof according to claim 8 ,
wherein each R 1 is independently —O-methyl or F;
L 1 is -methylene-O—;
ring W is pyrazole optionally substituted with methyl; and
R 3 is 2-hydroxyethyl, 2,3-dihydroxypropyl, or 4-methylpiperazin-1-ylmethyl.
10. The compound or salt thereof according to claim 1 , wherein the compound is selected from the group consisting of:
5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine,
(2S)-3-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]propane-1,2-diol,
5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,
5-[2-(2,6-difluoro-3,5-dimethoxyphenyl)ethyl]-N-{3-fluoro-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine,
5-[(2,6-dichloro-3,5-dimethoxybenzyl)oxy]-N-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine,
5-[(2,6-dichloro-3,5-dimethoxybenzyl)oxy]-N-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyrimidin-2-amine,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methoxy-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}pyrimidin-2-amine,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-3-methoxyphenyl}pyrimidin-2-amine,
N-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methoxyphenyl]-5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-amine,
2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]ethanol,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{1-[2-(4-methylpiperazin-1-yl)ethyl]-1 H-pyrazol-4-yl}pyrimidin-2-amine,
2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]-1-(3-hydroxyazetidin-1-yl)ethanone,
(2R)-3-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]propane-1,2-diol,
2-({1-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)phenyl]piperidin-4-yl}amino)ethanol,
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{1-methyl-5-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazol-3-yl}pyrimidin-2-amine, and
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine.
11. The compound or salt thereof according to claim 10 , wherein the compound is
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine.
12. The compound or salt thereof according to claim 10 , wherein the compound is
2-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]ethanol.
13. The compound or salt thereof according to claim 10 , wherein the compound is
(2R)-3-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)-1H-pyrazol-1-yl]propane-1,2-diol.
14. The compound or salt thereof according to claim 10 , wherein the compound is
2-({1-[4-({5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]pyrimidin-2-yl}amino)phenyl]piperidin-4-yl}amino)ethanol.
15. The compound or salt thereof according to claim 10 , wherein the compound is
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-{1-methyl-5-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazol-3-yl}pyrimidin-2-amine.
16. The compound or salt thereof according to claim 10 , wherein the compound is
5-[(2,6-difluoro-3,5-dimethoxybenzyl)oxy]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrimidin-2-amine.
17. A pharmaceutical composition, comprising:
a compound or salt thereof according to claim 10 and
a pharmaceutically acceptable excipient.
18. The pharmaceutical composition according to claim 17 , wherein the compound is suitable for treatment of mutant FGFR3-positive cancer.
19. A method of manufacturing a pharmaceutical composition, the method comprising:
manufacturing the pharmaceutical composition with the compound or salt thereof according to claim 10 ,
wherein the pharmaceutical composition is suitable for treatment of mutant FGFR3-positive cancer.
20. A method of treating mutant FGFR3-positive cancer, the method comprising:
administering an effective amount of the compound or salt thereof according to claim 10 to a subject in need thereof.