Aryl and heteroaryl fused lactams

• US 10,246,433 B2
• Filed: 05/03/2017
• Issued: 04/02/2019
• Est. Priority Date: 12/21/2012
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Edwards, Martin Paul, Kumpf, Robert Arnold, Kung, Pei-Pei, McAlpine, Indrawan James, Ninkovic, Sacha, Rui, Eugene Yuanjin, Sutton, Scott Channing, Tatlock, John Howard, Wythes, Martin James, Zehnder, Luke Raymond
• Primary Examiner(s): Pagonakis, Anna
• Application Number:
  US15/585,880
• Publication Number:
  US 20170233368A1
• Time in Patent Office: 699 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

This invention relates to compounds of general formula (I)

in which R¹, R², U, V, L, M, R⁵, m, X, Y and Z are as defined herein, and the pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.

Claims

1. A compound of formula (II-A):

2. The compound or salt of claim 1, wherein R¹ is chloro.

3. The compound or salt of claim 1, wherein R² is 5-12 membered heteroaryl selected from the group consisting of pyrazolyl, isoxazoyl and triazolyl, where said 5-12 membered heteroaryl is optionally substituted by 1 to 3 R³² groups.

4. The compound or salt of claim 3, wherein each R³² is independently selected from the group consisting of —

CH₃ and —

CH₂CH₃.

5. The compound or salt of claim 1, wherein R⁴ is halo.

6. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

7. A method for the treatment of abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein the abnormal cell growth is cancer.

9. The method of claim 7, wherein the subject is human.

10. A compound that is 5-bromo-8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

12. The compound of claim 10 that is 5-bromo-8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one.

13. A pharmaceutically acceptable salt of the compound of claim 10 that is 5-bromo-8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one.

14. A pharmaceutical composition comprising the compound of claim 12, and a pharmaceutically acceptable carrier or excipient.

15. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 13, and a pharmaceutically acceptable carrier or excipient.

16. A compound of formula (II-A):