Methods of use for trisubstituted benzotriazole derivatives
The present invention provides methods for treating cancer in a subject with a trisubstituted benzotriazole derivative with the formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables R 1 , R 2 and R 3 are as defined herein.
1. A method of treating a cancer selected from chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, diffuse mixed cell lymphoma, myelodysplastic syndrome, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, triple hit diffuse large B cell lymphoma, biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, cancer of the ovary, and cancer of the upper aerodigestive tract in a subject, comprising administering to the subject a therapeutically effective amount of a compound represented by the following structural formula:
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 selected from hydrogen and alkyl;
R 2 is -A-R 4 ;
A is arylene or tetrasubstituted arylene; wherein the substituent is halogen;
R 3 is selected from hydroxy and amino;
R 4 is selected from an aryl and a heteroaryl that is optionally substituted with one or more R 5 ;
R 5 is selected from alkyl and —(CH 2 ) n N(R a )R b ;
R a and R b are independently selected from 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 a 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N and is optionally substituted with alkyl; and
n is an integer selected from 0 and 1.
2. The method according to claim 1 , wherein the cancer is double hit diffuse large B cell lymphoma characterized by gene alterations at c-MYC and BCL2.
3. The method according to claim 1 , wherein the cancer is double hit diffuse large B cell lymphoma characterized by gene alterations at c-MYC and BCL6.
4. The method according to claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
5. A method of treating a cancer selected from chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, diffuse mixed cell lymphoma, myelodysplastic syndrome, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, triple hit diffuse large B cell lymphoma, biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, cancer of the ovary, and cancer of the upper aerodigestive tract in a subject, comprising administering to the subject a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 , wherein the cancer is chemotherapy-resistant acute myeloid leukemia.
7. The method according to claim 5 , wherein the cancer is cytarabine-resistant acute myeloid leukemia.
8. The method according to claim 5 , wherein the cancer is acute monocytic leukemia.
9. The method according to claim 5 , wherein the cancer is diffuse mixed cell lymphoma.
10. The method according to claim 5 , wherein the cancer is myelodysplastic syndrome.
11. The method according to claim 5 , wherein the cancer is primary effusion lymphoma.
12. The method according to claim 5 , wherein the cancer is erythroleukemia.
13. The method according to claim 5 , wherein the cancer is chronic myeloid leukemia.
14. The method according to claim 5 , wherein the cancer is chronic monocytic leukemia.
15. The method according to claim 5 , wherein the cancer is double hit diffuse large B cell lymphoma characterized by gene alterations at c-MYC and BCL2.
16. The method according to claim 5 , wherein the cancer is double hit diffuse large B cell lymphoma characterized by gene alterations at c-MYC and BCL6.
17. The method according to claim 5 , wherein the cancer is triple hit diffuse large B cell lymphoma.