Oxazolidin-2-one compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9458177-B2
Application number	US-201414478523-A
Country	US
Kind code	B2
Filing date	Sep 5, 2014
Priority date	Feb 24, 2012
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The present invention relates to oxazolidin-2-one substituted pyrimidine compounds that act as PI3K (phosphatidylinositol-3-kinase) inhibitors, as well as pharmaceutical compositions thereof, methods for their manufacture and uses for the treatment of conditions, diseases and disorders dependent on PI3K.

First claim

What is claimed is:

1. An amorphous form of a compound of Formula (I)

wherein,
R 1 is

wherein R 1a is H or —CH 3
or R 1 is

wherein D is deuterium;
R 2 is H;
R 3 is H;
R 4 is H, and R 5 is —CH 3 or —CH 2 OH; or
R 4 is —CH 2 OH, and R 5 is H;
or
R 2 is —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH or —CH 2 OC(O)H;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CH(OH)CH 3 or —CH 2 C(OH)(CH 3 ) 2 and R 5 is H, or
R 4 is H, and R 5 is —CH 3 , —CH 2 OH, —CH 2 CH(OH)CH 3 or —CH 2 C(OH)(CH 3 ) 2 , or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ;
or
R 3 is H;
R 4 is H;
R 2 and R 5 are joined and form —(CH 2 ) 4 —;
or
R 4 is H;
R 5 is H; and
R 2 is —CH 2 OH, and R 3 is —CH 3 ; or
R 2 is H or —CH 3 , and R 3 is —CH 2 OH;
or
R 2 is H;
R 4 is H; and
R 3 and R 5 are joined and form the group

or the group

or
R 3 is H;
R 5 is H; and
R 2 and R 4 are joined and form the group

or a pharmaceutically acceptable salt thereof.

2. An amorphous form of the compound according to claim 1 , wherein,
R 2 is —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH or —CH 2 OC(O)H;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH, and R 5 is H, or
R 4 is H, and R 5 is —CH 3 or —CH 2 OH, or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ;
or
R 3 is H;
R 4 is H;
R 2 and R 5 is —(CH 2 ) 4 —;
or
R 4 is H;
R 5 is H; and
R 2 is —CH 2 OH, and R 3 is —CH 3 ; or
R 2 is H or —CH 3 , and R 3 is —CH 2 OH,
or a pharmaceutically acceptable salt thereof.

3. An amorphous form of the compound according to claim 1 , wherein,
R 2 is —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH or —CH 2 OC(O)H;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH, and R 5 is H, or
R 4 is H, and R 5 is —CH 3 or —CH 2 OH, or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ;
or
R 4 is H;
R 5 is H; and
R 2 is —CH 2 OH, and R 3 is —CH 3 ; or
R 2 is H or —CH 3 , and R 3 is —CH 2 OH,
or a pharmaceutically acceptable salt thereof.

4. An amorphous form of the compound according to claim 1 , wherein,
R 2 is —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH or —CH 2 OC(O)H;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH, and R 5 is H, or
R 4 is H, and R 5 is —CH 3 or —CH 2 OH, or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ,
or a pharmaceutically acceptable salt thereof.

5. An amorphous form of the compound according to claim 1 , of formula (IA′)

wherein R 1a is H or —CH 3
or a pharmaceutically acceptable salt thereof.

6. An amorphous form of the compound according to claim 1 , of formula (IA):

wherein,
R 2 is —CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH or —CH 2 OC(O)H;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH, and R 5 is H, or
R 4 is H, and R 5 is —CH 3 or —CH 2 OH, or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ,
or a pharmaceutically acceptable salt thereof.

7. An amorphous form of the compound according to claim 6 , wherein R 2 is —CH 3 or —CH 2 OH;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH, and R 5 is H, or
R 4 is H, and R 5 is —CH 3 or —CH 2 OH, or
R 4 is H or —CH 3 and R 5 is H or —CH 3 ,
or a pharmaceutically acceptable salt thereof.

8. An amorphous form of the compound according to claim 7 , wherein
R 2 is —CH 3 or —CH 2 OH;
R 3 is H;
R 4 is —CH 3 , —CH 2 OH or —CH 2 CH 2 OH and R 5 is H or
R 4 is H and R 5 is CH 3 or —CH 2 OH,
or a pharmaceutically acceptable salt thereof.

9. An amorphous form of the compound, or a pharmaceutically acceptable salt thereof, according to claim 1 which is selected from
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-methyl-oxazolidin-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-hydroxymethyl-5,5-dimethyl-oxazolidin-2-one,
racemic 3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-4,5′-bipyrimidin-6-yl)-4-(hydroxymethyl)-4-methyloxazolidin-2-one,
(S)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-4,5′-bipyrimidin-6-yl)-4-(hydroxymethyl)-4-methyloxazolidin-2-one (absolute stereochemistry not determined),
(R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-4,5′-bipyrimidin-6-yl)-4-(hydroxymethyl)-4-methyloxazolidin-2-one (absolute stereochemistry not determined),
(3aS,7aS)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-hexahydro-benzooxazol-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-methoxymethyl-oxazolidin-2-one,
(4S,5S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-hydroxymethyl-5-methyl-oxazolidin-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-hydroxymethyl-oxazolidin-2-one,
(4S,5R)-3-(2′-Amino-2-(D8-morpholin-4-yl)-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-hydroxymethyl-5-methyl-oxazolidin-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-(2-hydroxy-ethyl)-oxazolidin-2-one,
(4S,5R)-3-[2′-Amino-2-((S)-3-methyl-morpholin-4-yl)-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl]-4-hydroxymethyl-5-methyl-oxazolidin-2-one,
Formic acid (4S,5R)-3-(2′-amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-methyl-2-oxo-oxazolidin-4-ylmethyl ester,
(S)-3-[2′-Amino-2-((S)-3-methyl-morpholin-4-yl)-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl]-4-methyl-oxazolidin-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-hydroxymethyl-oxazolidin-2-one,
(4S,5R)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-hydroxymethyl-4-methyl-oxazolidin-2-one,
(S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-methyl-oxazolidin-2-one,
(S)-3-(2′-amino-2-D8-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-methyloxazolidin-2-one,
(4S,5R)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-4-hydroxymethyl-5-methyl-oxazolidin-2-one,
(4S,5S)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-hydroxymethyl-4-methyl-oxazolidin-2-one,
(R)-3-(2′-Amino-2-morpholin-4-yl-4′-trifluoromethyl-[4,5′]bipyrimidinyl-6-yl)-5-hydroxymethyl-oxazolidin-2-one,
(3aR,6aR)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-tetrahydrofuro[3,4-d]oxazol-2(3H)-one,
racemic (3aR*,6R*,6aR*)-3-(2′-Amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-6-hydroxyhexahydro-2H-cyclopenta[d]oxazol-2-one,
(3aR,6R,6aR)-(2′-Amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-6-hydroxyhexahydro-2H-cyclopenta[d]oxazol-2-one,
(3aS,6S,6aS)-(2′-Amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-6-hydroxyhexahydro-2H-cyclopenta[d]oxazol-2-o

Assignees

• Caravatti Giorgio
• Fairhurst Robin Alec
• Furet Pascal
• Mccarthy Clive
• Rueeger Heinrich
• Seiler Frank Hans
• Stauffer Frédéric
• Novartis Ag

Inventors

• Caravatti Giorgio
• Fairhurst Robin Alec
• Furet Pascal
• Mccarthy Clive
• Rueeger Heinrich
• Seiler Frank Hans
• Stauffer Frédéric

Classifications

• A61P43/00

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title