Indazole compound and pharmaceutical use thereof
View Patent ↗The present invention can provide a cancer treatment drug containing, as an active ingredient, a substance selected from the group consisting of an indazole compound of the following formula (I), a pharmaceutically acceptable salt, a hydrate, a water adduct and a solvate:
1. An indazole compound represented by formula (I):
wherein
R 1 is a hydrogen atom, an optionally substituted alkyl, an optionally substituted phenyl or an optionally substituted aromatic heterocyclic ring, and
R 2 is a group of formula (II),
wherein
in the formula (II),
is a single bond or a double bond,
in the formula (II),
s is an integer of 1 or 2,
t is an integer of 1 or 2,
sum of s and t is 3,
R 3 is a hydrogen atom, a halogen atom, an optionally substituted alkyl, a hydroxyl, an alkoxy, a carboxy or an alkoxycarbonyl,
ring Ar 1 is an aryl or an aromatic heterocyclic ring,
R 4 , R 4′ , R 4″ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, a hydroxyl, an alkoxy, a carboxy, an alkoxycarbonyl, an acyl, —O(C═O)R 4a (wherein R 4a is an optionally substituted C 1-6 alkyl), —(C═O)NR 4a′ R 4a″ (wherein R 4a′ and R 4a″ are the same or different and each is a hydrogen atom or an optionally substituted C 1-6 alkyl, or R 4a′ and R 4a″ are taken together to form an optionally substituted 5- to 7-membered non-aromatic heterocyclic ring), —NH(C═O)R 4a (wherein R 4a is an optionally substituted C 1-6 alkyl), —SO 2 NR 4a′ R 4a″ (wherein R 4a′ and R 4a″ are the same or different and each is a hydrogen atom or an optionally substituted C 1-6 alkyl, or R 4a′ and R 4a″ are taken together to form an optionally substituted 5- to 7-membered non-aromatic heterocyclic ring), —NHSO 2 R 4a (wherein R 4a is an optionally substituted C 1-6 alkyl), an amino, an alkylamino, —SR 4a (wherein R 4a is an optionally substituted C 1-6 alkyl), —SO 2 R 4a is an optionally substituted C 1-6 alkyl), a cyano, an optionally substituted phenyl or an optionally substituted heterocyclic ring, or
R 4 and R 4′ are taken together to form an C 1-3 alkylenedioxy, and
R 5 is absent, or a hydrogen atom, a halogen atom, an optionally substituted alkyl, a hydroxyl, an alkoxy, an alkoxycarbonyl, an acyl, —(C═O)NR 5a R 5a′ (wherein R 5a and R 5a′ are the same or different and each is a hydrogen atom or an optionally substituted C 1-6 alkyl), —NH(C═O)R 5a″ (wherein R 5a″ is an optionally substituted C 1-6 alkyl), an amino, an alkylamino, —SR 5a (wherein R 5a is a hydrogen atom or an optionally substituted C 1-6 alkyl) or a cyano,
or a pharmaceutically acceptable salt thereof.
2. The indazole compound of claim 1 ,
wherein, in the formula (I),
R 2 is a group of formula (II)
wherein
in the formula (II),
is a single bond or a double bond,
s is an integer of 1 or 2,
t is an integer of 1 or 2,
sum of s and t is 3,
R 3 is a hydrogen atom, a halogen atom, an optionally substituted alkyl, a carboxyl, an alkoxycarbonyl, a hydroxy or an alkoxy,
ring Ar 1 is a phenyl or an aromatic heterocyclic ring,
R 4 , R 4′ and R 4″ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted alkyl, an alkoxycarbonyl, a hydroxy, an alkoxy, a sulfonamide, a mercapto, a sulfinyl, a sulfonyl, an amino or an alkylamino, and
R 5 is absent, or a hydrogen atom, a halogen atom, an optionally substituted alkyl, a hydroxy, an alkoxy, an amino, an alkylamino, a sulfanyl or a cyano,
or a pharmaceutically acceptable salt thereof.
3. The indazole compound of claim 1 ,
wherein,
in the formula (I),
R 1 is a hydrogen atom or an optionally substituted alkyl,
in the formula (II), is a single bond,
s is an integer of 1,
t is an integer of 2,
R 3 is a hydrogen atom,
ring Ar 1 is a phenyl or a thiophene,
R 4 , R 4′ , R 4″ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted alkyl, a hydroxy, an alkoxy, —SR 4a (wherein R 4a is an optionally substituted C 1-6 alkyl) or an cyano, and
R 5 is a hydroxy or a cyano,
or a pharmaceutically acceptable salt thereof.
4. The indazole compound of claim 1 ,
wherein,
in the formula (I),
R 1 is a hydrogen atom,
in the formula (II), is a single bond,
s is an integer of 1,
t is an integer of 2,
R 3 is a hydrogen atom,
ring Ar 1 is a phenyl,
R 4 , R 4′ , R 4″ are the same or different and each is a hydrogen atom, a halogen atom or an optionally substituted alkyl, and
R 5 is a hydroxy or a cyano
or a pharmaceutically acceptable salt thereof.
5. The indazole compound of claim 1 ,
wherein,
in the formula (I), is a single bond,
R 1 is a hydrogen atom, and
in the formula (II),
s is an integer of 1,
t is an integer of 2,
R 3 is a hydrogen atom,
ring Ar 1 is a phenyl,
R 4 , R 4′ , R 4″ are the same or different and each is a hydrogen atom, a halogen atom or an optionally substituted alkyl, and
R 5 is a hydroxyl,
or a pharmaceutically acceptable salt thereof.
6. The indazole compound of claim 1 , which is selected from
4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(4-chlorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[3-fluoro-5-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[4-fluoro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-[4-methyl-3-(trifluoromethyl)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3,5-difluorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-4-fluorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-2-fluorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3,4-dichlorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-5-fluorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(4-chloro-3-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chlorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(1,3-benzodioxol-5-yl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-(3-methylphenyl)-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-cyanophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-[3-(methylthio)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-ethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(2,5-dichlorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[3,5-bis(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[2-fluoro-5-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[2-chloro-5-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-cyano-4-(2-methoxyphenyl)-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-cyano-4-[3-(trifluoromethyl)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-cyano-4-(2-fluorophenyl)-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-[4-chloro-3-(trifluoromethyl)phenyl]-4-cyano-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(5-bromo-2-thienyl)-4-cyano-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-cyano-4-(3,5-difluorophenyl)-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(4-bromo-2-chlorophenyl)-4-cyano-1-piperidinecarboxylic acid (1H -indazol-3-yl)amide,
4-phenyl-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(2,3-difluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(5-chloro-2-thienyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(3-methyl-2-thienyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(2-thienyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(3,4-dimethoxyphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-[3-(dimethylamino)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-[3-(trifluoromethyl)phenyl]piperidine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-[4-chloro-3-(trifluoromethyl)phenyl]-4-methoxypiperidine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-[4-chloro-3-(trifluoromethyl)phenyl]-4-fluoropiperidine-1-carboxylic acid (1H-indazol-3-yl)amide,
4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-2-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-chloro-4-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-fluoro-2-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(5-fluoro-2-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(4-fluoro-3-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(2,5-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-[2-methyl-3-(trifluoromethyl)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-hydroxy-4-[2-methyl-5-(trifluoromethyl)phenyl]-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3,4-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
4-(3,5-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide, and
4-(2,3-dimethylphenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide,
or a pharmaceutically acceptable salt thereof.
7. The indazole compound of claim 1 , which is 4-hydroxy-4-(3-methylphenyl)-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide, or a pharmaceutically acceptable salt thereof.
8. The indazole compound of claim 1 , which is 4-(3-chloro-2-fluorophenyl)-4-hydroxy-1-piperidinecarboxylic acid (1H-indazol-3-yl)amide, or a pharmaceutically acceptable salt thereof.
9. The indazole compound of claim 1 , which is 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid (1H-indazol-3-yl)amide, or a pharmaceuticallyacceptable salt thereof.
10. A pharmaceutical composition comprising a therapeutically effective amount of an indazole compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , wherein said composition is in a form suitable for oral administration selected from the group consisting of a tablet, a capsule, a powder, a liquid, and an elixir.
12. The pharmaceutical composition of claim 10 , wherein said indazole compound of claim 1 or a pharmaceutically acceptable salt thereof is contained in an amount ranging from 5-95 wt % relative to the total weight of the pharmaceutical composition.
13. The pharmaceutical composition of claim 10 , wherein said indazole compound of claim 1 or a pharmaceutically acceptable salt thereof is contained in an amount ranging from 5-90 wt % relative to the total weight of the pharmaceutical composition.
14. The pharmaceutical composition of claim 10 , wherein said composition is in a foam suitable for parenteral administration.
15. The pharmaceutical composition of claim 14 , wherein said indazole compound of claim 1 or a pharmaceutically acceptable salt thereof is contained in an amount ranging from 0.5-20% by weight relative to the total weight of the pharmaceutical composition.
16. The pharmaceutical composition of claim 14 , wherein said indazole compound of claim 1 or a pharmaceutically acceptable salt thereof is contained in an amount ranging from 1-10% by weight relative to the total weight of the pharmaceutical composition.