Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer

Abstract

This invention is directed to methods of preventing, treating or managing cancer, preferably metastatic cancer, in a patient. The methods comprise administering an effective amount of an Axl inhibitor in combination with the administration of an effective amount of one or more chemotherapeutic agents.

1 .- 4 . (canceled) 
     
     
         5 . A method for treating or managing Acute Myeloid Leukemia (AML) in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an Axl inhibitor selected from 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, and a therapeutically effective amount of cytarabine. 
     
     
         6 . The method of  claim 5 , wherein said Axl inhibitor is selected from the group consisting of:
 a. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;   b. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;   c. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; and   d. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(8)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.   
     
     
         7 . The method of  claim 5 , wherein the Axl inhibitor and the therapeutically effective amount of cytarabine are administered concurrently. 
     
     
         8 . The method of  claim 5 , wherein the Axl inhibitor and the therapeutically effective amount of cytarabine are administered sequentially. 
     
     
         9 . The method of  claim 5 , wherein the Axl inhibitor is administered in a dosing regimen between 0.001 mg/kg to 100 mg/kg for the duration of the treatment. 
     
     
         10 . The method of  claim 5 , wherein the Axl inhibitor is administered in a dosing regimen between 1.0 mg/kg to 100 mg/kg for the duration of the treatment. 
     
     
         11 . The method of  claim 5 , wherein the Axl inhibitor is administered orally. 
     
     
         12 . The method of  claim 5 , wherein the therapeutically effective amount of cytarabine is delivered by sub-cutaneous infusion. 
     
     
         13 . A method for treating or managing Acute Myeloid Leukemia (AML) in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of an Axl inhibitor selected from 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine, as an isolated stereoisomer or mixture thereof or as a tautomer or mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof, and a therapeutically effective amount of a chemotherapeutic agent. 
     
     
         14 . The method of  claim 13 , wherein said chemotherapeutic agent is cytarabine. 
     
     
         15 . The method of  claim 13 , wherein the Axl inhibitor is administered in a dosing regimen between 0.001 mg/kg to 100 mg/kg for the duration of the treatment. 
     
     
         16 . The method of  claim 13 , wherein the Axl inhibitor is administered in a dosing regimen between 1.0 mg/kg to 100 mg/kg for the duration of the treatment. 
     
     
         17 . The method of  claim 13 , wherein the Axl inhibitor and the therapeutically effective amount of said chemotherapeutic agent are administered concurrently. 
     
     
         18 . The method of  claim 13 , wherein the Axl inhibitor and the therapeutically effective amount of said chemotherapeutic agent are administered sequentially. 
     
     
         19 . The method of  claim 13 , wherein the Axl inhibitor is administered orally. 
     
     
         20 . The method of  claim 15 , wherein the therapeutically effective amount of cytarabine is delivered by sub-cutaneous infusion. 
     
     
         21 . The method of  claim 15 , wherein said Axl inhibitor is selected from the group consisting of:
 a. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;   b. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;   c. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine; and   d. 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(8)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.