Azaheterocycles as BIR2 and/or BIR3 inhibitors

Patent metadata

Field	Value
Publication number	US-9422332-B2
Application number	US-201314419288-A
Country	US
Kind code	B2
Filing date	Aug 6, 2013
Priority date	Aug 15, 2012
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

Disclosed are compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , m, n and q are described in this application, and methods of using said compounds in the treatment of cancer.

First claim

The invention claimed is:

1. A compound of Formula I:

wherein:
R 1 is halogen;
R 2 is selected from
aryl that optionally may be substituted with C 1-6 -alkyl, OR 4 , and halogen,
aryl that is fused with C 3-7 -cycloalkyl, and
heteroaryl that optionally may be substituted with C 1-6 -alkyl;

R 3 is selected from
C 1-6 -alkyl that optionally may be substituted with OR 4 and aryl,
C 3-7 -cycloalkyl,
heterocyclyl, and
aryl;

R 4 is selected from H and C 1-6 -alkyl;
n is 1 or 2;
m is 0 or 1; and
q is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R 2 is aryl that optionally may be substituted with OR 4 , halogen and C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 wherein R 2 is phenyl or naphthalenyl, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R 2 is heteroaryl that optionally may be substituted with C 1-6 -alkyl, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 wherein R 2 is selected from selected from quinolinyl, benzo[b]thiophenyl or indolyl.

6. The compound of claim 1 wherein R 3 is C 1-6 -alkyl substituted with phenyl, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 3 is OR 4 and R 4 is H, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein R 3 is C 3-7 -cycloalkyl, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein R 3 is cyclohexyl or cyclopentyl, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 wherein R 3 is aryl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 wherein R 3 is phenyl.

12. The compound according to claim 1 wherein R 3 is heterocyclyl, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 wherein R 3 is tetrahydropyran.

14. The compound according to claim 1 wherein m is o, n is 1, and q is o, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 wherein R 2 is aryl, R 3 is C 1-6 -alkyl, n is 1 and m and q are o.

16. The compound of claim 1 , said compound being selected from the group consisting of:
(S)-2-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-isoindole-1-carboxylic acid (2,6-difluoro-phenyl)-amide hydrochloride;
((S)—N-(2, 6-dichlorophenyl)-2-((S)-3-methyl-2-((S)-2-(ethylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2-chloro-6-fluorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(benzo[b]thiophen-4-yl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((2S,3S)-3-methyl-2-((S)-2-(methylamino) propanamido)pentanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-phenylisoindoline-1-carboxamide hydrochloride;
N-(2-methoxyphenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
N-(2-methoxyphenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
N-benzyl-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)isoindoline-1-carboxamide hydrochloride;
2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-phenethylisoindoline-1-carboxamide hydrochloride;
(S)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-(naphthalen-1-yl)isoindoline-1-carboxamide hydrochloride;
(R)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-(naphthalen-1-yl)isoindoline-1-carboxamide hydrochloride;
(S)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-(naphthalen-2-yl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2-fluorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2-chlorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)isoindoline-1-carboxamide hydrochloride;
(S)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-N-(quinolin-8-yl)isoindoline-1-carboxamide hydrochloride;
N-(isoquinolin-1-yl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(1-methyl-1H-indol-4-yl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((2S,3S)-3-methoxy-2-((S)-2-(methylamino) propanamido)butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((2S,3R)-3-hydroxy-2-((S)-2-(methylamino) propanamido)butanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((S)-4-methyl-2-((S)-2-(methylamino)propanamido)pentanoyl)isoindoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((2S,3S)-2-((S)-2-(methylamino)propanamido)-3-phenylbutanoyl)isoindoline-1-carboxamide hydrochloride; and
(S)—N-(2-fluoro-6-methylphenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)isoindoline-1-carboxamide hydrochloride;
or a pharmaceutically acceptable salt of any of the foregoing compounds.

17. The compound of claim 1 , said compound being selected from the group consisting of:
(S)-2-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide hydrochloride;
6-Chloro-2-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide;
6-Fluoro-2-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-1,2,3,4-tetrahydro-isoquinoline-1-carboxylic acid (2,6-difluoro-phenyl)-amide;
(S)—N-(2, 6-difluorophenyl)-2-((2S,3S)-3-methyl-2-((S)-2-(methylamino) propanamido)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride;
(S)—N-(2, 6-dichlorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino)propanamido) butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((S)-3,3-dimethyl-2-((S)-2-(methylamino)propanamido) butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride;
(S)—N-(2,6-difluorophenyl)-2-((2S,3R)-3-methoxy-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrochloride;
N-(2,6-difluorophenyl)-7-fluoro-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;
N-(2,6-difluorophenyl)-7-fluoro-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;
N-(2,6-difluorophenyl)-6-fluoro-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamide;
7-chloro-N-(2,6-difluorophenyl)-2-((S)-3-methyl-2-((S)-2-(methylamino) propanamido)butanoyl)-1,2,3,4-tetrahydroisoqu

Assignees

• Hoffmann La Roche

Inventors

• Hogg Joan Heather
• Le Kang
• Lou Yan
• Mischke Steven Gregory
• Remiszewski Stacy

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07D209/44 Primary

  Iso-indoles; Hydrogenated iso-indoles · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title