Cyclopropylamines as LSD1 inhibitors
The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
1. A method of inhibiting LSD1 in a patient in need thereof, comprising administering to the patient a compound selected from:
3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino} piperidin- 1-yl)azetidine-1-sulfonamide;
[1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino}piperidin-1-yl)azetidin-3-yl] acetonitrile;
3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide; and
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-(4-fluorophenyl)cyclopropyl] amino} piperidin- 1-yl)azetidine-1-sulfonamide;
or a pharmaceutically acceptable salt thereof.
2. A method of treating a hematological cancer in a patient in need thereof, comprising administering to the patient a compound selected from:
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl]amino}piperidin- 1-yl)azetidine-1-sulfonamide;
[1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidin-3-yl]acetonitrile;
3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide; and
3-(cyanomethyl)-3-(4-{R1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino piperidin- 1-yl)azetidine-1-sulfonamide;
or a pharmaceutically acceptable salt thereof, wherein the hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, polycythemia vera (PV), essential thrombocytosis (ET), and multiple myeloma.
3. A method of treating a beta-globinopathy in a patient in need thereof, comprising administering to the patient a compound selected from:
3-(cyanomethyl)-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino} piperidin-1-yl)azetidine-1-sulfonamide;
[1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino}piperidin-1-yl)azetidin-3-yl] acetonitrile;
3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide; and
3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-(4-fluorophenyl)cyclopropyl] amino} piperidin-1-yl)azetidine-1-sulfonamide;
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is 3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino} piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound is [14(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino} piperidin-1-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is 3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the compound is 3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-(4-fluorophenyl)cyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
8. The method of claim 2 , wherein the compound is 3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
9. The method of claim 2 , wherein the compound is [1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino I piperidin-1-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.
10. The method of claim 2 , wherein the compound is 3-(cyanomethyl)-N,N-dimethyl-3-(4-{[(1R,2S)-2-phenylcyclopropyl]amino}piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
11. The method of claim 2 , wherein the compound is 3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-(4-fluorophenyl)cyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
12. The method of claim 3 , wherein the compound is 3-(cyanomethyl)-3-(4-{[(1R,2 S)-2-phenylcyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
13. The method of claim 3 , wherein the compound is [1-[(1-methyl-1H-pyrazol-4-yl)carbonyl]-3-(4-[(1R,2 S)-2-phenylcyclopropyl] amino I piperidin-1-yl)azetidin-3-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.
14. The method of claim 3 , wherein the compound is 3-(cyanomethyl)-N,N-dimethyl-3-(4-[(1R,2 S)-2-phenylcyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
15. The method of claim 3 , wherein the compound is 3-(cyanomethyl)-3-(4-[(1R,2 S)-2-(4-fluorophenyl)cyclopropyl] amino I piperidin-1-yl)azetidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.