Inhibitors of EZH2

• US 9,718,838 B2
• Filed: 08/22/2016
• Issued: 08/01/2017
• Est. Priority Date: 08/27/2015
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Nguyen, Anh-Quan Hannah, Guo, Deqi, Richett, Michael Enrico
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US15/242,638
• Publication Number:
  US 20170066780A1
• Time in Patent Office: 344 Days
• Field of Search: None
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention relates to compounds that inhibit activity of the histone lysine 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 which is

2. The compound according to claim 1 which is 5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-{(1R)-1-[4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 which is 5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising 5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, carriers, or diluents.

5. A method of treating cancer in a patient, wherein the cancer is selected from the group consisting of lymphomas, rhabdoid tumors, tumors which lack or are defective in one or more components of the SWI/SNF complex, MLL complexes, and constitutively active PI3K pathway, sarcomas, multiple myeloma, melanoma, gastrointestinal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, and prostate cancer comprising administering to the patient, an effective amount of 5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-{(1R)-1-[trans-4-(3-methoxyazetidin-1-yl)cyclohexyl]ethyl}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one or a pharmaceutically acceptable salt thereof.

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

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

8. The method according to claim 5 wherein the cancer is a rhabdoid tumor that lacks SNF5.

9. The method according to claim 5 wherein the cancer is gastric cancer.

10. The method according to claim 5 wherein the cancer is ovarian cancer.

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

12. The method according to claim 10 further comprising administering to the patient carboplatin and paclitaxel.

13. The method according to claim 9 further comprising administering to the patient oxaliplatin and paclitaxel.

14. The method according to claim 5 wherein the cancer is lung cancer and further comprising administering to the patient gemcitabine and cisplatin.

15. The method according to claim 5 wherein the cancer is colorectal cancer and further comprising administering to the patient irinotecan and oxaliplatin.