Benzoxazepin oxazolidinone compounds and methods of use

Patent metadata

Field	Value
Publication number	US-10112932-B2
Application number	US-201715729507-A
Country	US
Kind code	B2
Filing date	Oct 10, 2017
Priority date	Jul 2, 2015
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

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. Also described are methods of making the benzoxazepin oxazolidinone compounds having the Formula I structure.

First claim

We claim:

1. A process for the preparation of compound 8, having the structure:

or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , cyclopropyl, and cyclobutyl;
R 2 is selected from the group consisting of —CH 3 , —CHF 2 , —CH 2 F, and —CF 3 ;
comprising reacting compound 7, having the structure:

with an amino acid of formula H 2 NCH(R 1 )CO 2 H and a copper catalyst, followed by ammonium chloride, and HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to form 8.

2. The process of claim 1 wherein the copper catalyst to form 8 is CuI.

3. The process of claim 1 wherein R 1 is —CH 3 .

4. The process of claim 1 wherein R 2 is —CHF 2 .

5. The process of claim 1 wherein compound 8 has the structure:

or pharmaceutically acceptable salt thereof.

6. The process of claim 1 wherein compound 7 is prepared by a process comprising reacting compound 6, having the structure:

with a 4-substituted oxazolidin-2-one having the structure:

and a copper catalyst to form 7.

7. The process of claim 6 wherein the 4-substituted oxazolidin-2-one is (S)-4-difluoromethyloxazolidin-2-one.

8. The process of claim 6 wherein the copper catalyst to form 7 is selected from the group consisting of CuI and Cu(OAc) 2 .

9. The process of claim 6 further comprising reacting compound 6, the 4-substituted oxazolidin-2-one, and the copper catalyst, with trans-N, N′-dimethyl-1,2-cyclohexane diamine.

Assignees

• Genentech Inc

Inventors

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

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P15/00

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

• C07D498/04 Primary

  Ortho-condensed systems · CPC title