INHIBITORS OF EZH2

• US 20160159782A1
• Filed: 12/01/2015
• Published: 06/09/2016
• Est. Priority Date: 12/05/2014
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Yu, Kuo-Long, Guo, Deqi
• Granted Patent: US 9,527,837 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to compounds that inhibit activity of the histone lysine N-methyltransferase, Enhancer of Zeste Homolog 2 (EZH2), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat cancer, such as hematologic and solid tumors.

Claims

1. A compound selected from the group consisting of:

N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-4-methylthiophene-3-carboxamide;

2. The compound according to claim 1 which is N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-4-methylthiophene-3-carboxamide:

3. The compound according to claim 2 which is N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-4-methylthiophene-3-carboxamide:

4. A pharmaceutical composition comprising a compound selected from the group consisting of:

N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-4-methylthiophene-3-carboxamide;

5. A method of treating cancer, wherein the cancer is selected from the group consisting of lymphomas, diffuse large B-cell lymphoma and follicular lymphoma dependent on either activating mutant or wild-type EZH2, malignant and atypical teratoid rhabdoid or other tumors which lack or are defective for SNF5, synovial sarcoma, glioblastoma, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer, comprising administering to a patient in need thereof, an effective amount of a compound selected from the group consisting of:

N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-4-methylthiophene-3-carboxamide;

6. The method according to claim 5, wherein the cancer is diffuse large B-cell lymphoma.

7. The method according to claim 5, wherein the cancer is follicular lymphoma dependent on activating mutant or wild-type EZH2.

8. The method according to claim 5, wherein the cancer is malignant and atypical teratoid rhabdoid tumor.

9. The method according to claim 5, wherein the cancer is solid tumor which lacks or is defective for SNF5.

10. The method according to claim 5, wherein the cancer is multiple myeloma.