1,3,4,7-tetrahydro-2h-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine bcl-2 inhibitors

Patent metadata

Field	Value
Publication number	US-2025066388-A1
Application number	US-202418595898-A
Country	US
Kind code	A1
Filing date	Mar 5, 2024
Priority date	Jan 21, 2022
Publication date	Feb 27, 2025
Grant date	—

Abstract

The present invention provides for compounds of Formula (I)wherein A, L, W, and R1 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of CLL, SLL, and/or ALL.

First claim

We claim:

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein,
L is selected from the group consisting of —NH—, —NHCH 2 —, and —OCH 2 —;
W is selected from the group consisting of N and CH;
A is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, and piperidinyl; wherein A is optionally substituted with one or two R 2 substituents and optionally substituted with one R 3 substituent;
R 1 is selected from the group consisting of Cl and —NO 2 ;
R 2 is selected from the group consisting of F, Cl, Br, I, —OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkoxyalkyl, and C 2 -C 6 alkoxyalkoxy; and
R 3 is selected from the group consisting of cyclobutyl, oxetanyl, and morpholinyl.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NO 2 .

4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is —NHCH 2 —.

5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is tetrahydropyranyl; wherein the tetrahydropyranyl is substituted with one R 2 .

6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is tetrahydropyranyl; wherein the tetrahydropyranyl is substituted with one —OCH 3 .

7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH; and R 1 is NO 2 .

8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 is NO 2 ; and L is —NHCH 2 —.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 is NO 2 ; L is —NHCH 2 —; and A is tetrahydropyranyl; wherein the tetrahydropyranyl is substituted with one R 2 .

10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 is NO 2 ; L is —NHCH 2 —; and A is tetrahydropyranyl; wherein the tetrahydropyranyl is substituted with one —OCH 3 .

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 is NO 2 ; L is —NHCH 2 —; and A is

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2R,5S)-5-hydroxy-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; N-((5-chloro-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,4r)-4-methoxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2S,5R)-5-methyl-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1r,3r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-(3-chloro-4-{[4-fluoro-1-(oxetan-3-yl)piperidin-4-yl]methoxy}benzene-1-sulfonyl)-4-[(4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,11,12,13,15-decahydro-7H,10aH-pyrazino[2,1-g][1,5,8]benzodioxazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; N-((5-chloro-6-(((1s,4s)-1-fluoro-4-morpholinocyclohexyl)methoxy)pyridin-3-yl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; N-((5-chloro-6-(((1r,4r)-1-fluoro-4-morpholinocyclohexyl)methoxy)pyridin-3-yl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2R,5S)-5-hydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1s,4s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)-N-((4-((((1s,3s)-1-hydroxy-[1,1′-bi(cyclobutan)]-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyrazino[2,1-c][1,8]dioxa[4]azacycloundecin-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3′,2′:5,6]pyrido[2,3-b][1,4]oxazep

Assignees

• Abbvie Inc

Inventors

• Doherty George A
• Bhat Vikram
• Judd Andrew S
• Souers Andrew J
• Brady Patrick
• Dai Yujia
• Gong Jianchun
• Yu Yiyun

Classifications

• A61P35/02 Primary

  specific for leukemia · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D498/14 Primary

  Ortho-condensed systems · CPC title