Benzoxazepin oxazolidinone compounds and methods of use

Patent metadata

Field	Value
Publication number	US-9643980-B2
Application number	US-201615200307-A
Country	US
Kind code	B2
Filing date	Jul 1, 2016
Priority date	Jul 2, 2015
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Described herein are benzoxazepin oxazolidinone compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.

First claim

We claim:

1. A compound selected from Formula I:

and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:
R 1 is selected from —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CHF 2 , —CH 2 F, and —CF 3 ;
X is selected from:

where the wavy line indicates the site of attachment; and
R 2 is selected from H, C 1 -C 6 alkyl, cyclopropyl, and cyclobutyl, optionally substituted with F, —OCH 3 , or —OH.

2. The compound of claim 1 from Formula Ia:

3. The compound of claim 1 from Formula Ib:

4. The compound of claim 2 wherein R 1 is selected from —CHF 2 and —CH 2 F.

5. The compound of claim 3 wherein R 1 is selected from —CHF 2 and —CH 2 F.

6. The compound of claim 1 wherein R 2 is —CH 3 .

7. The compound of claim 2 wherein R 2 is —CH 3 .

8. The compound of claim 1 selected from:
(S)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide;
(S)-1-(2-((R)-4-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;
(S)-1-(2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;
(S)-2-((2-((R)-4-ethyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide;
(S)-2-((2-((S)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide;
(S)-1-(2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide;
(S)-2-((2-((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide;
(S)-1-(2-((S)-4-(fluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; and
(S)-2-((2-((S)-4-(fluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)oxy)propanamide.

9. A pharmaceutical composition comprised of a compound of claim 1 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

10. The pharmaceutical composition of claim 9 wherein the pharmaceutically acceptable carrier, glidant, diluent, or excipient is selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, metallic stearates, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.

11. A process for making a pharmaceutical composition comprising combining a compound of claim 1 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

12. A method of treating cancer in a patient having cancer comprising administering to said patient a therapeutically effective amount of a compound of claim 1 wherein the cancer is selected from breast cancer and non-small cell lung cancer.

13. The method of claim 12 further comprising administering to the patient an additional therapeutic agent selected from 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole.

14. The method of claim 12 wherein the cancer is breast cancer.

15. The method of claim 14 wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

16. The method of claim 14 wherein the breast cancer subtype is Basal or Luminal.

17. The method of claim 14 wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R.

18. The method of claim 14 wherein the cancer expresses a PTEN mutant.

19. The method of claim 14 wherein the cancer is HER2 positive.

20. The method of claim 14 wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative.

21. A kit for the therapeutic treatment of breast cancer, comprising:
a) the pharmaceutical composition of claim 9 ; and
b) instructions for use in the therapeutic treatment of breast cancer.

Assignees

• Genentech Inc

Inventors

• Braun Marie-Gabrielle
• Hanan Emily
• Staben Steven T
• Heald Robert Andrew
• Macleod Calum
• Elliott Richard

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title