Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor, and medicinal composition containing the same
An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X═CH or N; Z═O or S; L=O or S; M=CR 10 R 11 , wherein R 10 and R 11 ═H, alkyl, or alkoxy, NR 12 wherein R 12 ═H or alkyl; R 1 , R 2 , and R 3 ═H or optionally substituted alkoxy; R 4 ═H; R 5-8 ═H, halogen, alkoxy or the like; and R 9 =alkyl optionally substituted by —R 14 , -T-R 15 , or —NR 16 R 17 wherein T=O, S, or NH; R 14 =an optionally substituted carbocyclic or heterocyclic ring; and R 15-17 =alkyl or an optionally substituted carbocyclic or heterocyclic ring, or —NR 18 R 19 wherein R 18 and R 19 ═H, optionally substituted alkyl, or an optionally substituted carbocylic or heterocyclic ring, or optionally substituted carbocyclic or heterocyclic ring.
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein
X represents CH or N;
Z represents O or S;
L represents O;
M represents
(1-1) —CR 10 R 11 — wherein R 10 and R 11 may be the same or different, and each represents a hydrogen atom, C 1-4 alkyl, or C 1-4 alkoxy, or
(1-2) —NR 12 —, wherein R 12 represents a hydrogen atom or C 1-4 alkyl;
R 1 , R 2 , and R 3 may be the same or different, and each represents (2-1) a hydrogen atom, (2-2) hydroxyl, (2-3) a halogen atom, (2-4) nitro, (2-5) —NR 20 R 21 , wherein R 20 and R 21 may be the same or different, and each represents a hydrogen atom or C 1-6 alkyl optionally substituted by hydroxyl or C 1-6 alkoxy, (2-6) C 1-6 alkyl, (2-7) C 2-6 alkenyl, (2-8) C 2-6 alkynyl, or (2-9) C 1-6 alkoxy; wherein the (2-6) C 1-6 alkyl, the (2-7) C 2-6 alkenyl, the (2-8) C 2-6 alkynyl, and the (2-9) C 1-6 alkoxy are optionally substituted by (3-1) hydroxyl, (3-2) a halogen atom, (3-3) C 1-6 alkoxy, (3-4) C 1-6 alkylcarbonyl, (3-5) C 1-6 alkoxy carbonyl, (3-6) —NR 22 R 23 wherein R 22 and R 23 may be the same or different, and each represents a hydrogen atom or C 1-6 alkyl optionally substituted by hydroxyl or C 1-6 alkoxy, or (3-7) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by hydroxyl or C 1-6 alkoxy;
R 5 , R 6 , R 7 , and R 8 may be the same or different, and each represents (4-1) a hydrogen atom, (4-2) a halogen atom, (4-3) C 1-4 alkyl, or (4-4) C 1-4 alkoxy; and
R 9 represents (5-1) C 1-6 alkyl wherein one or more hydrogen atoms on the C 1-6 alkyl are optionally substituted by (6-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, (6-2) -T-R 15 , wherein T represents O, S, or NH, and R 15 represents C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (6-3) —NR 16 R 17 wherein R 16 and R 17 may be the same or different, and each represents C 1-6 alkyl or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by
C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; (5-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain; or (5-3) —NR 18 R 19 , wherein R 18 and R 19 may be the same or different, and each represents (7-1) a hydrogen atom, (7-2) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or
(7-3) C 1-6 alkyl optionally substituted by C 1-6 alkoxy, C 1-6 alkylthio, or a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain,
provided that, when X represents CH; Z represents O; L represents O; M represents —NH—; R 1 , R 5 , R 6 , R 7 , and R 8 represent a hydrogen atom; and R 2 and R 3 represent methoxy, R 9 represents neither phenyl, ethoxy, nor pyridin-2-yl.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein Z is O.
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 1 is a hydrogen atom.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is C 1-6 alkoxy.
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is methoxy.
6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 3 is (8-1) hydroxyl, or (8-2) C 1-6 alkoxy wherein the C 1-6 alkoxy is optionally substituted by (9-1) hydroxyl, (9-2) a halogen atom, (9-3) —NR 22 R 23 wherein R 22 and R 23 have the same meanings as defined above, or (9-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted by hydroxyl or C 1-6 alkoxy.
7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 3 is (10-1) hydroxyl, or (10-2) C 1-4 alkoxy, wherein the C 1-4 alkoxy is optionally substituted by (11-1) hydroxyl, (11-2) a halogen atom, (11-3) —NR 22 R 23 wherein R 22 and R 23 have the same meanings as defined above, or (11-4) a saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted by hydroxyl or C 1-6 alkoxy.
8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 3 is methoxy.
9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein M is —NR 12 — wherein R 12 has the same meaning as defined above.
10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein M is —CR 10 R 11 — and wherein R 10 and R 11 have the same meanings as defined above.
11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 ,
wherein R 9 is C 1-6 alkyl wherein one or more hydrogen atoms on the C 1-6 alkyl are optionally substituted by (12-1) a saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, (12-2) -T-R 15 , wherein T and R 15 have the same meanings as defined above, or (12-3) —NR 16 R 17 , wherein R 16 and R 17 have the same meanings as defined above.
12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 9 is —CH 2 —R 24 wherein R 24 represents a saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group wherein the saturated or unsaturated five- or six-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, or a halogen atom.
13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 wherein R 9 is:
(13-1) —NR 25 R 26 , wherein R 25 represents a hydrogen atom or C 1-4 alkyl, and R 26 represents
(14-1) C 1-4 alkyl optionally substituted by a saturated or unsaturated six-membered carbocyclic group, wherein the saturated or unsaturated six-membered carbocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated six-membered carbocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated six-membered carbocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain, or (14-2) a saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group, wherein the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group may be a bicyclic group condensed with another saturated or unsaturated three- to eight-membered carbocyclic or heterocyclic group, and the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group is optionally substituted by C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, nitro, trifluoromethyl, C 1-6 alkoxy carbonyl, cyano, cyano C 1-6 alkyl, C 1-6 alkylthio, phenoxy, acetyl, or a saturated or unsaturated five- or six-membered heterocyclic ring, and when the saturated or unsaturated four- to seven-membered carbocyclic or heterocyclic group is substituted by two C 1-6 alkyl groups, the two alkyl groups may combine together to form an alkylene chain.
14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 .
15. A method for inhibiting met autophosphorylation comprising administering the compound of claim 1 to a subject in need thereof.
16. The method of claim 15 , wherein said subject has a tumor or cancer whose proliferation, invasion or metastasis is mediated by an HGF-met signal.