Tetrahydro-benzodiazepinones

Patent metadata

Field	Value
Publication number	US-10053431-B2
Application number	US-201415037240-A
Country	US
Kind code	B2
Filing date	Nov 14, 2014
Priority date	Nov 18, 2013
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

Disclosed are compounds of Formula I, or pharmaceutically acceptable salts thereof, wherein W, X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as described in this application, and methods of using said compounds in the treatment of cancer.

First claim

The invention claimed is:

1. A compound, selected from the group consisting of: Cyclic-5-[(S)-5-(2-Amino-ethyl)-3-((S)-2-methylamino-propionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl]-6-methoxy-naphthalene-2-carboxylic amide hydrochloride; Cyclic-5-[(S)-5-(3-Amino-propionyl)-3-((S)-2-methylamino-propionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl]-6-methoxy-naphthalene-2-carboxylic amide hydrochloride; Cyclic-5-[(S)-5-(3-amino-propyl)-3-((S)-2-methylamino-propionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl]-6-methoxy-naphthalene-2-carboxylic amide hydrochloride; Cyclic-5-[(S)-5-(4-Amino-butyryl)-3-((S)-2-methylamino-propionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl]-6-methoxy-naphthalene-2-carboxylic amide hydrochloride; and Cyclic-5-[(S)-5-(5-amino-pentanoyl)-3-((S)-2-methylamino-propionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-ylmethyl]-6-methoxy-naphthalene-2-carboxylic amide hydrochloride, or a pharmaceutically acceptable salt thereof.

2. A compound, selected from the group consisting of:
(S)-2-Methylamino-N—((S)-1-naphthalen-1-ylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-propionamide hydrochloride,
(S)—N—((S)-5-Acetyl-1-naphthalen-1-ylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-methylamino-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-5-(3-methyl-butyryl)-1-naphthalen-1-ylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)-2-Methylamino-N—((S)-1-naphthalen-1-ylmethyl-2-oxo-5-phenylacetyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-propionamide hydrochloride,
(S)-2-Methylamino-N—((S)-5-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-5-(3-methyl-butyl)-1-naphthalen-1-ylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)-2-Methylamino-N—((S)-1-naphthalen-1-ylmethyl-2-oxo-5-phenethyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-propionamide trifluoroacetate,
(S)-2-Methylamino-N—[(S)-5-(3-methyl-butyryl)-1-(2-methyl-naphthalen-1-ylmethyl)-2oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-1-(2-methyl-naphthalen-1-naphthalen-1ylmethyl)-2-oxo-5-(pyridine-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)—N—[(S)-5-[2-(2-methoxy-ethoxy)-acetyl]-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—[(S)-5-(2-Carbamoyl-acetyl)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-2-methylamino-N—{(S)-1-(2-methyl-naphthalen-1-ylmethyl)-5-[2-(4-methyl-piperazin-1-yl)-acetyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-propionamide hydrochloride,
(S)—N—[(S)-5-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-acetyl}-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-5-(2-pyridin-4-yl-acetyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide dihydrochloride,
(S)—N—[(S)-5-(4-Methanesulfonyl-benzoyl)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-5-(5-oxo-hexanoyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
methyl 6-((S)-3-((S)-2-(methylamino)propanamido)-5-((2-methylnaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)-6-oxohexanoate hydrochloride,
(S)—N—[(S)-5-(4-Acetyl-benzoyl)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-5-(3,4,5-trimethoxy-benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)—N—((S)-5-(4-acetylbenzoyl)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride,
(S)—N—((S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(2-cyclohexylacetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride,
(S)—N—{(S)-1-(6-Bromo-2-methoxy-naphthalen-1-ylmethyl)-5-[4-(2,2-dimethyl-propionyl)-benzoyl]-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-2-methylamino-propionamide hydrochloride,
(S)—N—{(S)-1-(6-Bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-5-[4-(2,2,2-trifluoro-1,1-dihydroxy-ethyl)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}-2-methylamino-propionamide trifluoroacetate,
(S)—N—[(S)-5-(3-Acetyl-benzoyl)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—[(S)-1-(6-Bromo-2-methoxy-naphthalen-1-ylmethyl)-5-(4-nitro-benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—[(S)-1-(6-Bromo-2-methoxy-naphthalen-1-ylmethyl)-5-(4-nitro-butyryl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—[(S)-5-[2-(4-Acetyl-phenyl)-acetyl]-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—((S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(4-cyanobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride,
(S)—N—[(S)-5-(2-Adamantan-1-yl-acetyl)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
methyl 5-[[(3S)-1-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propanoyl]-3-[[(2S)-2-(methylamino)propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepin-5-yl]methyl]-6-methoxy-naphthalene-2-carboxylate hydrochloride,
(S)—N—[(S)-5-acetyl-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
5-[(S)-3-((S)-2-methylamino-propionylamino)-5-(2-methyl-naphthalen-1-ymethyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1yl]-5-oxo-pentanoic acid hydrochloride,
4-[(S)-3-((S)-2-methylamino-propionylamino)-5-(2-methyl-naphthalen-1-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepine-1-yl]-4-oxo-butyric acid hydrochloride,
(S)-3-((S)-2-methylamino-propionylamino)-5-(2-methyl-naphthalen-1-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-carboxylic acid methylamide hydrochloride,
(S)—N—[(S)-5-methanesulfonylmethanesulfonyl-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide trifluoroacetate,
(S)—N—[(S)-5-methanesulfonyl-1-(2-methyl-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-3-((S)-2-methylamino-propionylamino)-5-(2-methyl-naphthalen-1-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-carboxylic acid methyl ester hydrochloride,
(S)—N—[(S)-1-benzyl-5-(3-methyl-butyryl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)—N—[(S)-1-(2-methoxy-benzyl)-5-(3-methyl-butyryl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b[1,4]diazepin-3-yl]-2-methylamino-propionamide hydrochloride,
(S)-2-Methylamino-N—[(S)-5-(3-methyl-butyryl)-2-oxo-1-phenethyl-2,3,4,5-tetrahydro-1H-benzo[b[1,4]diazepin-3-yl]-propionamide hydrochloride,
(S)—N—[(S)-1-(2-Methoxy-naphthalen-1-ylmethyl)-5-(3-methyl-bu

Assignees

• Hoffmann La Roche

Inventors

• Chen Shaoqing
• Donnell Andrew F
• Kester Robert Francis
• Le Kang
• Lou Yan
• Michoud Christophe
• Remiszewski Stacy
• Rupert Kenneth C
• Weisel Martin

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/06

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

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• C07D243/14 Primary

  1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines · CPC title

• C07D401/06

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