Trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors
The present invention provides trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitor compounds of formula (I), which may be therapeutically useful as DHODH inhibitors. wherein, R 1 , R 2 and R 3 have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting DHODH. The present invention also provides methods for synthesizing trisubstituted benzotriazole derivatives of formula (I). The present invention also provides pharmaceutical formulations comprising at least one of the DHODH inhibitor compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein;
the dotted lines [....] in the ring represent an optional bond which may be present in any stable combination;
R 1 is hydrogen or alkyl;
R 2 is -A-R 4 ;
A is arylene or tetrasubstituted arylene; wherein the substituent is halogen;
R 3 is hydroxy and amino;
R 4 is optionally substituted aryl and optionally substituted heteroaryl; wherein the optional substituents are one or more of R 5 ;
R 5 is alkyl and —(CH 2 ) n N(R a )R b ;
R a and R b are independently hydrogen, alkyl or —C(O)alkyl;
alternatively R a and R b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocycle containing 0-2 additional heteroatoms that are independently O or N; wherein the optional substituent is alkyl; and
‘n’ is an integer 0 or 1.
2. The compound according to claim 1 , wherein R 1 is methyl.
3. The compound according to claim 1 , wherein R 2 is
4. The compound according to claim 1 , wherein R 4 is optionally substituted phenyl.
5. The compound according to claim 4 , wherein the optional substituents are methyl, acetylamino, isopropylaminomethyl, methylaminomethyl, dimethylaminomethyl,
6. The compound according to claim 1 , wherein R 4 is 2,5-dimethyl-1H-pyrrole.
7. The compound according to claim 1 , wherein R 3 is hydroxy.
8. The compound according to claim 1 wherein the compound is a compound of formula (Ia)
9. The compound according to claim 1 wherein the compound is a compound of formula (Ib)
10. The compound according to claim 1 that is
Compd
No.
IUPAC Name
1.
1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic
acid;
2.
1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-
carboxamide;
3.
5-([1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylic acid;
4.
6-([1,1′-biphenyl]-4-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-4-carboxylic acid;
5.
6-([1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid;
6.
6-([1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide;
7.
6-([1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-4-carboxylic acid;
8.
2-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic
acid;
9.
1-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic
acid;
10.
1-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-
carboxamide;
11.
2-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-
carboxamide;
12.
5-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-
carboxylic acid;
13.
6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-methyl-2H-benzo[d][1,2,3]triazole-4-
carboxylic acid;
14.
6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1-methyl-1H-benzo[d][1,2,3]triazole-4-
carboxylic acid;
15.
1-methyl-5-(3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-7-carboxylic acid;
16.
2-methyl-6-(3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
17.
1-methyl-5-(3′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-7-carboxylic acid;
18.
1-methyl-6-(3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
19.
1-methyl-5-(2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-
carboxylic acid;
20.
1-methyl-6-(3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
21.
1-methyl-6-(3′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
22.
1-methyl-5-(3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-
benzo[d][1,2,3]triazole-7-carboxylic acid;
23.
2-methyl-6-(3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
24.
2-methyl-6-(2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-
carboxylic acid;
25.
1-methyl-5-(2′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-7-carboxylic acid;
26.
2-methyl-6-(2′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
27.
1-methyl-5-(2′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-7-carboxylic acid;
28.
2-methyl-6-(2′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]
triazole-4-carboxylic acid;
29.
1-methyl-5-(2′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-3a,7a-
dihydro-1H-benzo[d][1,2,3]triazole-7-carboxylic acid;
30.
2-methyl-6-(2′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-2H
-benzo[d][1,2,3]triazole-4-carboxylic acid;
31.
1-methyl-5-(4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]
triazole-7-carboxylic acid;
32.
5-(3′-acetamido-[1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-
carboxylic acid;
33.
1-methyl-5-(2,3,5,6-tetrafluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-
benzo[d][1,2,3]triazole-7-carboxylic acid;
34.
1-methyl-5-(2,3,5,6-tetrafluoro-3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-
benzo[d][1,2,3]triazole-7-carboxylic acid . 2,2,2-trifluoroacetic acid;
35.
1-methyl-5-(2,3,5,6-tetrafluoro-3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-
1H-benzo[d][1,2,3]triazole-7-carboxylic acid;
36.
1-methyl-5-(2,3,5,6-tetrafluoro-3′-((isopropylamino)methyl)-[1,1′-biphenyl]-4-yl)-
1H-benzo[d][1,2,3]triazole-7-carboxylic acid;
37.
1-methyl-5-(2,3,5,6-tetrafluoro-3′-((methylamino)methyl)-[1,1′-biphenyl]-4-yl)-1H-
benzo[d][1,2,3]triazole-7-carboxylic acid;
38.
2-methyl-6-(2,3,5,6-tetrafluoro-3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]b-4-yl)-2H-
benzo[d][1,2,3]triazole-4-carboxylic acid;
39.
2-methyl-6-(2,3,5,6-tetrafluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-
benzo[d][1,2,3]triazole-4-carboxylic acid;
40.
5-(3′-((dimethylamino)methyl)-2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-1-methyl-
1H-benzo[d][1,2,3]triazole-7-carboxylic acid,
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier or excipient or mixtures thereof in all ratios.
12. The pharmaceutical composition according to claim 11 further comprising at least one active ingredient.
13. A method for the treatment of multiple sclerosis comprising the step of administering to a mammal a therapeutically effective amount of at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof.
14. A method for the treatment of rheumatoid arthritis comprising the step of administering to a mammal a therapeutically effective amount of at least one compound according to claim 1 and/or a pharmaceutically acceptable salt thereof.