Methods of use for trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors
The present invention provides methods for treating a cancer in a subject and for inhibiting tumor growth, metastasis or a dihydrorotate oxygenase enzyme activity of a tumor or cancer cell. At least one trisubstituted benzotriazole derivative with the formula (I) is administered to the subject or is contacted with the cancer cell. Compounds of formula (I) have substituents R 1 , R 2 and R 3 which have the meanings given in the specification, and pharmaceutically acceptable salts thereof.
1. A method for treating a cancer in a subject wherein the cancer is responsive to inhibition of dihydroorotate oxygenase, comprising the step of administering to the subject one or more times a therapeutically effective amount of at least one compound according to 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 and 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 R 5 ;
R 5 is alkyl and —(CH 2 ) n N(R a )R b ;
R a and R b are independently hydrogen, alkyl and —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 heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N; wherein the optional substituent is alkyl; and ‘n’ is an integer 0 and 1.
2. The method of claim 1 , wherein independently R 1 is methyl; R 2 is
R 3 is hydroxy; R 4 is 2,5-dimethyl-1H-pyrrole or phenyl optionally substituted with methyl, acetylamino, isopropylaminomethyl, methylaminomethyl, dimethylaminomethyl,
3. The method of claim 1 , wherein the compound is a compound of formula (Ia)
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is a compound of formula (Ib)
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound 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]-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; and
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.
6. A method for inhibiting growth and/or metastasis of tumor cells in a subject wherein the tumor cells are responsive to inhibition of dihydroorotate oxygenase, comprising the step of administering to the subject one or more times a therapeutically effective amount of at least one compound according to 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 and 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 R 5 ;
R 5 is alkyl and —(CH 2 ) n N(R a )R b ;
R a and R b are independently hydrogen, alkyl and —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 heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N; wherein the optional substituent is alkyl; and ‘n’ is an integer 0 and 1.
7. The method of claim 6 , wherein independently R 1 is methyl; R 2 is
R 3 is hydroxy; R 4 is 2,5-dimethyl-1H-pyrrole or phenyl optionally substituted with methyl, acetylamino, isopropylaminomethyl, methylaminomethyl, dimethylaminomethyl,
8. The method of claim 6 , wherein the compound is a compound of formula (Ia)
or a pharmaceutically acceptable salt thereof.
9. The method of claim 6 , wherein the compound is a compound of formula (Ib)
or a pharmaceutically acceptable salt thereof.
10. The method of claim 6 , wherein the compound 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]-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; and
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. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 6 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.