1H-indazole compound
The present invention provides a novel 1H-indazole compound having an excellent JNK inhibitory action. More specifically, it provides a compound represented by the following formula, a salt thereof or a hydrate of them. Wherein R 1 is a C 6 -C 14 aromatic cyclic hydrocarbon group etc.; R 2 , R 4 and R 5 each independently represent a hydrogen atom, a halogen atom, a cyano group etc.; L is a single bond, or a C 1 -C 6 alkylene group etc.; X is a single bond, or a group represented by —CO—NH— or —NH—CO—, etc.; and Y is a C 3 -C 8 cycloalkyl group, a C 6 -C 14 aromatic cyclic hydrocarbon group or a 5- to 14-membered aromatic heterocyclic group etc.
1. A compound represented by the following formula, a salt thereof or a hydrate thereof:
wherein R 1 is a 2-thienyl, 2-furyl, 2-benzofuryl or benzothienyl group thereof, each of which may be substituted;
R 2 , R 4 and R 5 each independently represent a halogen atom, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, a C 1 -C 6 alkyl group which may be substituted, a C 1 -C 6 alkoxy group which may be substituted, a C 2 -C 7 acyl group which may be substituted, —CO—NR 2a R 2b , —NR 2b CO—R 2a or —NR 2a R 2b , wherein R 2a and R 2b each independently represent a hydrogen atom or a C 1 -C 6 alkyl group which may be substituted;
L is a single bond, a C 1 -C 6 alkylene group which may be substituted, a C 2 -C 6 alkenylene group which may be substituted or a C 2 -C 6 alkynylene group which may be substituted;
X is a group represented by —NH—CO—(CH 2 ) t —, wherein t is 0 or 1; and
Y is a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a cyano group, a carboxyl group, a C 1 -C 6 alkyl group which may be substituted, a C 2 -C 6 alkenyl group which may be substituted, a C 2 -C 6 alkynyl group which may be substituted, a C 1 -C 6 alkoxy group which may be substituted, a C 3 -C 8 cycloalkyl group which may be substituted, a C 3 -C 8 cycloalkenyl group which may be substituted, a C 6 -C 14 aromatic cyclic hydrocarbon group which may be substituted, an amino group or —W—R 15 , wherein W is —CO— or —SO 2 —; and R 15 is a C 1 -C 6 alkyl group which may be substituted, a C 6 -C 14 aromatic cyclic hydrocarbon group which may be substituted.
2. The compound according to claim 1 , a salt thereof or a hydrate thereof, wherein R 2 , R 4 and R 5 each independently represent a halogen atom or a C 1 -C 6 alkoxy group which may be substituted.
3. The compound according to claim 1 or 2 , a salt thereof or a hydrate thereof, wherein L is a single bond or a methylene group.
4. The compound according to claim 1 or 2 , a salt thereof or a hydrate thereof, wherein L is a single bond.
5. The compound according to claim 1 or 2 , a salt thereof or a hydrate thereof, wherein Y is a C 1 -C 6 alkyl group, a C 6 -C 14 aromatic cyclic hydrocarbon group, a C 1 -C 6 alkoxy group, or a C 3 -C 8 cycloalkyl group, and Y is a group which may be substituted by one to three groups selected from the following Substituent Group “a2”:
<Substituent Group “a2”> is selected from the group consisting of (1) (a) C 1 -C 6 alkyl groups, (b) C 2 -C 6 alkenyl groups, (c) C 2 -C 6 alkynyl groups, (d) C 1 -C 6 alkoxy groups, (e) C 2 -C 7 acyl groups, (f) an amide group, (g) an amino group, (h) a C 3 -C 8 cycloalkyl group, (i) C 3 -C 8 cycloalkenyl groups, (j) C 6 -C 14 aromatic cyclic hydrocarbon groups, and (k) C 6 -C 14 aryloxy groups, each of which may be substituted by one to three groups selected from the following Substituent Group “b2”, (2) halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group;
<Substituent Group “b2”> is selected from the group consisting of C 1 -C 6 alkyl groups, halogen atoms, a hydroxyl group, a nitro group, a cyano group, and a carboxyl group.
6. The compound according to claim 1 or 2 , a salt thereof or a hydrate thereof, wherein Y is a C 3 -C 8 cycloalkyl group or a phenyl group, and Y is a group which may be substituted by one to three groups selected from the Substituent Group “a2”, which is selected from the group consisting of (1) (a) C 1 -C 6 alkyl groups, (b) C 2 -C 6 alkenyl groups, (c) C 2 -C 6 alkynyl groups, (d) C 1 -C 6 alkoxy groups, (e) C 2 -C 7 acyl groups, (f) an amide group, (g) an amino group, (h) a C 3 -C 8 cycloalkyl group, (i) C 3 -C 8 cycloalkenyl groups, (j) C 6 -C 14 aromatic cyclic hydrocarbon groups, and (k) C 6 -C 14 aryloxy groups, each of which may be substituted by one to three groups selected from the following Substituent Group “b2”, (2) halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group;
<Substituent Group “b2”> is selected from the group consisting of C 1 -C 6 alkyl groups, halogen atoms, a hydroxyl group, a nitro group, a cyano group, and a carboxyl group.
7. The compound according to claim 1 or 2 , a salt thereof or a hydrate thereof, wherein Y is a phenyl group, a C 3 -C 8 cycloalkyl group, a tetrahydrothiophenyl group, or a group represented by the formula:
(wherein Y 2a is a group represented by —CONH 2 or —CH 2 OH; and Y 2b and Y 2c each independently represent a hydrogen atom, a phenyl group which may be substituted or a C 1 -C 6 alkyl group which may be substituted), and wherein Y is a group which may be substituted by one to three groups selected from the Substituent Group “a2”, which is selected from the group consisting of (1) (a) C 1 -C 6 alkyl groups, (b) C 2 -C 6 alkenyl groups, (c) C 2 -C 6 alkynyl groups, (d) C 1 -C 6 alkoxy groups, (e) C 2 -C 7 acyl groups, (f) an amide group, (g) an amino group, (h) a C 3 -C 8 cycloalkyl group, (i) C 3 -C 8 cycloalkenyl groups, (j) C 6 -C 14 aromatic cyclic hydrocarbon groups, and (k) C 6 -C 14 aryloxy groups, each of which may be substituted by one to three groups selected from the following Substituent Group “b2”, (2) halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group;
<Substituent Group “b2”> is selected from the group consisting of C 1 -C 6 alkyl groups, halogen atoms, a hydroxyl group, a nitro group, a cyano group, and a carboxyl group.
8. The compound according to claim 5 , a salt thereof or a hydrate thereof, wherein the Substituent Group “a2” is selected from the group consisting of (1) (a) C 1 -C 6 alkyl groups, (b) C 1 -C 6 alkoxy groups, (c) C 2 -C 7 acyl groups, (d) an amide group, (e) an amino group, and (f) C 3 -C 8 cycloalkyl groups, each of which may be substituted by one to three groups selected from the following Substituent Group “b2”, (2) halogen atoms, (3) a hydroxyl group, (4) a nitro group, (5) a cyano group, and (6) a carboxyl group, and the Substituent Group “b2” is selected from the group consisting of C 1 -C 6 alkyl groups, halogen atoms, a hydroxyl group, a nitro group, a cyano group, and a carboxyl group.
9. The compound according to claim 5 , a salt thereof or a hydrate thereof, wherein the Substituent Group “a2” is selected from the group consisting of (1) C 1 -C 6 alkoxy groups, (2) halogen atoms, and (3) a cyano group.
10. A pharmaceutical composition comprising the compound according to claim 1 , a salt thereof or a hydrate thereof, and a pharmacologically acceptable carrier.
11. A c-Jun amino-terminal kinase (JNK) inhibitor, of the compound of formula (1) according to claim 1 , a salt thereof or a hydrate thereof.
12. c-Jun amino-terminal kinase 1 (JNK 1), c-Jun amino-terminal kinase 2 (JNK 2) and/or c-Jun amino-terminal kinase 3 (JNK 3) inhibitors, of the compound of formula (1) according to claim 1 , a salt thereof or a hydrate thereof.
13. A pharmaceutical composition for treating an immunological disease or inflammatory disease, comprising the compound according to claim 1 , a salt thereof or a hydrate thereof.
14. A pharmaceutical composition for treating neurodegenerative disease, comprising the compound according to claim 1 , a salt thereof or a hydrate thereof.
15. A pharmaceutical composition for treating Alzheimer's disease, Parkinson's disease,. Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration, comprising the compound according to claim 1 , a salt thereof or a hydrate thereof.
16. A method for treating an immunological disease, an inflammatory disease and/or a neurodegenerative disease, which comprises administering a pharmacologically effective amount of the compound according to claim 1 , a salt thereof or a hydrate thereof to a patient.
17. A method for treating a disease selected from the group consisting of an immunological disease, an inflammatory disease and a neurodegenerative disease, which comprises administering a pharmacologically effective amount of the compound according to claim 1 , a salt thereof or a hydrate thereof to a patient.
18. The method according to claim 17 , wherein the disease is Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, multiple sclerosis or spinocerebellar degeneration.