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1. (WO2017001658) COMPOSÉS DE BENZOXAZÉPINE OXAZOLIDINONE ET LEURS PROCÉDÉS D'UTILISATION
Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

CLAIMS

1. A compound selected from Formula I:


and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein:

R1 is selected from -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CH2F, and -CF3;

X is selected from:


where the wavy line indicates the site of attachment; and

R is selected from H, Ci-C6 alkyl, cyclopropyl, and cyclobutyl, optionally substituted with F, -OCH3, or -OH.

3. The compound of claim 1 from Formula lb:


4. The compound of claim 2 or 3 wherein R1 is selected from -CHF2 and -CH2F.

5. The compound of any in of claims 1-4 wherein R is -CH3.

6. The compound of any one of claims 1-5 selected from:

(5)-2-((2-((R)-4-isopropyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[f]imidazo[l,2-d] [ 1 ,4] oxazepin-9-yl)oxy)propanamide;

(5,)-l-(2-((R)-4-methyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[/]imidazo[l,2-d] [ 1 ,4] oxazepin-9-yl)pyrrolidine-2-carboxamide;

(5,)-l-(2-((lS')-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[ ]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; (5)-2-((2-((R)-4-ethyl-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[/]imidazo[l,2-d] [ 1 ,4] oxazepin-9-yl)oxy)propanamide;

(5,)-2-((2-((lS,)-2-oxo-4-(trifluoromethyl)oxazolidin-3-yl)-5,6-dihydrobenzo[/]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)oxy)propanamide;

(lS')-l-(2-((lS,)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[ ]imidazo[ 1 ,2-d] [ 1 ,4] oxazepin-9-yl)pyrrolidine-2-carboxamide;

('5,)-2-((2-((lS,)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[ ]imidazo[ 1 ,2-d] [ 1 ,4] oxazepin-9-yl)oxy)propanamide;

(5,)-l-(2-((lS,)-4-(fluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[/]imidazo[ 1 ,2-d] [ 1 ,4]oxazepin-9-yl)pyrrolidine-2-carboxamide; and

(5,)-2-((2-((lS,)-4-(fluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo[ ]imidazo[ 1 ,2-d] [ 1 ,4] oxazepin-9-yl)oxy)propanamide.

7. A pharmaceutical composition comprised of a compound of any one claims 1-6 and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

8. The pharmaceutical composition of claim 7 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.

9. A process for making a pharmaceutical composition comprising combining a compound of any one of claims 1-6 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

10. A method of treating cancer in a patient having cancer comprising

administering to said patient a therapeutically effective amount of a compound of any one claims 1-6 wherein the cancer is selected from breast cancer and non- small cell lung cancer.

11. The method of claim 10 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.

12. The method of claim 10 or 11 wherein the cancer is breast cancer.

13. The method of claim 12 wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

14. The method of claim 12 wherein the breast cancer subtype is Basal or Luminal.

15. The method of claim 12 wherein the cancer expresses a PIK3CA mutant selected from E542K, E545K, Q546R, H1047L and H1047R.

16. The method of claim 12 wherein the cancer expresses a PTEN mutant.

17. The method of claim 12 wherein the cancer is HER2 positive.

18. The method of claim 12 wherein the patient is HER2 negative, ER (estrogen receptor) negative, and PR (progesterone receptor) negative.

19. A kit for the therapeutic treatment of breast cancer, comprising:

a) the pharmaceutical composition of claim 7; and

b) instructions for use in the therapeutic treatment of breast cancer.

20. The use of a compound of any one of claims 1-6 for treating cancer in a patient wherein the cancer is selected from breast cancer and non-small cell lung cancer.

21. The use of a compound of any one of claims 1-6 for the manufacture of a medicament for treating cancer in a patient wherein the cancer is selected from breast cancer and non- small cell lung cancer.

22. The compound of any one of claims 1-6 for use for treating cancer in a patient wherein the cancer is selected from breast cancer and non- small cell lung cancer.

23. The invention as hereinabove described.