Uracil derivatives as AXL and c-MET kinase inhibitors
The present application provides compounds of Formula I or salt forms thereof, wherein R a , R b , R c , R d , D, W, R 1a , R 1b , R 1c , Y, R 3 , X, E and G are as defined herein, compositions, methods of treatment and uses thereof.
1. A method of treating an AXL or c-met-mediated disorder or condition in a subject, wherein said disorder or condition is a cancer selected from chronic myelogenous leukemia, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, ovarion cancer, pancreatic cancer, gastric cancer, liver cancer, tyroid cancer, renal cell carcinoma, glioblastoma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine cancer, malignant glioma, melanoma, uveal melanoma, osteosarcoma, and soft tissue sarcoma, the method comprising administering to said subject a therapeutically effective amount of a compound which is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3fluorophenyl]-amide having the structure
or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1 , wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.001 mg/kg to about 100 mg/kg.
3. A method according to claim 1 , wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.1 mg/kg to about 10 mg/kg.
4. A method according to claim 1 , wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 0.5 mg/kg to about 5 mg/kg.
5. A method according to claim 1 , wherein said therapeutically effective amount of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is from about 1 mg/kg to about 2 mg/kg.
6. A method according to claim 1 , wherein said 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide, or a pharmaceutically acceptable salt thereof, is administered to said subject daily.
7. A method according to claim 1 , wherein said cancer is resistant to at least one cancer therapy.
8. A method according to claim 1 , wherein said cancer is selected from non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, melanoma, and glioblastoma.
9. A method according to claim 8 , wherein said cancer is non-small cell lung cancer.
10. A method according to claim 8 , wherein said cancer is breast cancer.
11. A method according to claim 8 , wherein said cancer is pancreatic cancer.
12. A method according to claim 8 , wherein said cancer is colorectal cancer.
13. A method according to claim 8 , wherein said cancer is melanoma.
14. A method according to claim 8 , wherein said cancer is glioblastoma.
15. A pharmaceutical composition, comprising a therapeutically effective amount of a compound which is 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]-amide having the structure
or a pharmaceutically acceptable salt thereof, and another therapeutic agent.