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

Abstract

To provide compounds useful as agents in the treatment of CLL, SLL, and / or ALL.SOLUTION: The present invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 267,018, filed January 21, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (ABV12563USOl_ST26.xml; size: 4,991 bytes; and creation date: January 18, 2023) are incorporated herein by reference in their entirety.

[0003] The present invention relates to compounds that inhibit the activity of Bcl-2 protein, and compositions containing said compounds. [Background technology]

[0004] Bcl-2 proteins are important anti-apoptotic regulators of the intrinsic apoptosis pathway. Cellular expression of anti-apoptotic Bcl-2 proteins is associated with the inhibition of apoptosis and, when overexpressed, can lead to certain cancers.

[0005] Molecules capable of inhibiting Bcl-2 protein activity can increase apoptosis, leading to improved outcomes associated with the treatment and prevention of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). For example, venetoclax is the first selective Bcl-2 inhibitor approved by the FDA to treat patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy. Summary of the Invention [Problem to be solved by the invention]

[0006] However, there is a need in the therapeutic arts for compounds with improved activity that inhibit the activity of Bcl-2 proteins. [Means for solving the problem]

[0007] (Abstract) In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008] [ka] (In the formula, L is selected from the group consisting of -NH-, -NHCH2-, and -OCH2-; 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; A optionally contains one or two R 2 substituted by a substituent, optionally one R 3 is substituted by a substituent, R 1 is selected from the group consisting of Cl and NO2; R 2 is selected from the group consisting of F, Cl, Br, I, —OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, and C2-C6 alkoxyalkoxy; and R 3 is selected from the group consisting of cyclobutyl, oxetanyl, and morpholinyl. to provide.

[0009] In another embodiment, the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH.

[0010] In another aspect, the present invention provides a method for producing a compound comprising: 1 is NO2, or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is -NHCH2-.

[0012] In another embodiment, the present invention provides a compound wherein A is tetrahydropyranyl and the tetrahydropyranyl is one R 2 or a pharmaceutically acceptable salt thereof, wherein:

[0013] In another embodiment, the present invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is tetrahydropyranyl, and the tetrahydropyranyl is substituted with one -OCH3.

[0014] In another embodiment, the present invention provides a compound wherein W is CH and R 1 is NO2, or a pharmaceutically acceptable salt thereof.

[0015] In another embodiment, the present invention provides a compound wherein W is CH and R 1 is NO2 and L is -NHCH2-, or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, the present invention provides a compound wherein W is CH and R 1 is NO2, and L is -NHCH2-, and A is tetrahydropyranyl, and the tetrahydropyranyl is one R 2 or a pharmaceutically acceptable salt thereof, wherein:

[0017] In another embodiment, the present invention provides a compound wherein W is CH and R 1 is NO2, and L is -NHCH2-, and A is tetrahydropyranyl, wherein the tetrahydropyranyl is substituted by one -OCH3, or a pharmaceutically acceptable salt thereof.

[0018] In another embodiment, the present invention provides a compound wherein W is CH and R 1is NO2, L is -NHCH2-, and A is

[0019] [ka] or a pharmaceutically acceptable salt thereof.

[0020] In another aspect, the present invention provides a compound comprising: 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]oxazepin-1(7H)-yl)-N-((4-((((1s,3s)-3-(fluoromethyl)-3-hydroxycyclobutyl)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-(((3-hydroxyoxetan-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]oxazepin-1(7H)-yl)-N-((4-(((4-hydroxytetrahydro-2H-pyran-4-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-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-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,5R)-5-methyl-1,4-dioxan-2-yl)methoxy)-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,5R)-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((5-chloro-6-((4-fluoro-1-(2-methoxyethyl)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-((((2R,5S)-5-methyltetrahydro-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,3s)-3-methoxycyclobutyl)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-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-(((4-methoxytetrahydro-2H-pyran-4-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-((((2S,5R)-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-((((1r,4r)-4-morpholinocyclohexyl)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)-4-methoxytetrahydrofuran-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-(((1r,3r)-3-methoxycyclobutyl)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-((1-methylpiperidin-4-yl)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-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)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)methoxy)-3-nitrophenyl)sulfonyl)benzamide; N-((3-chloro-4-((((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)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-(2-methoxyethoxy)tetrahydro-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-hydroxy-4-methylcyclohexyl)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-morpholinotetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((3-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)methoxy)phenyl)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-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((3-chloro-4-(((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methoxy)phenyl)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-methoxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((5-chloro-6-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)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-((3-chloro-4-(((1r,4r)-4-hydroxy-4-methylcyclohexyl)methoxy)phenyl)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-hydroxy-4-methylcyclohexyl)methoxy)-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-((3-nitro-4-(((tetrahydro-2H-pyran-2-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-((3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)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-((((1r,3r)-3-fluoro-3-(methoxymethyl)cyclobutyl)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-((((1r,3r)-3-(fluoromethyl)-3-methoxycyclobutyl)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-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamide; 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; and 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-methoxytetrahydro-2H-pyran-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide The present invention provides a compound of formula (I) selected from the group consisting of:

[0021] In another embodiment, the present invention provides a compound of formula (I), wherein the compound is 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-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0022] In another embodiment, the present invention provides a compound of formula (I), wherein the compound is 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-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0023] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

[0024] In another aspect, the present invention provides a method of treating CLL, SLL and / or ALL (acute lymphoblastic leukemia) in a subject suffering from CLL, SLL and / or ALL, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention describes compounds that inhibit the activity of the Bcl-2 protein.

[0026] The compounds disclosed herein may contain one or more variables that appear more than once in any substituent or formula herein. The definition of a variable at each occurrence is independent of its definition at other occurrences. Furthermore, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds that can be isolated from reaction mixtures.

[0027] definition Certain terms used herein are intended to refer to the following definitions, as detailed below.

[0028] It is noted that, as used in this specification and the intended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a single compound as well as one or more of the same or different compounds. Reference to "a pharmaceutically acceptable carrier" includes a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and so forth.

[0029] As used in this specification and the appended claims, unless specifically specified to the contrary, the following terms have the meanings indicated: The term "C1-C6 alkoxy," as used herein, refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbons, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of "C1-C6 alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0030] The term "C1-C6 alkyl," as used herein, unless otherwise specified, refers to a saturated, straight- or branched-chain hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbons. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl.

[0031] The term "C2-C6 alkoxyalkoxy," as used herein, refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of C2-C6 alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.

[0032] The term "C2-C6 alkoxyalkyl," as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of C2-C6 alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl, and the like.

[0033] The term "halo" or "halogen" as used herein means Cl, Br, I and F.

[0034] The term "C1-C6 haloalkyl" as used herein refers to an alkyl group, as defined herein, in which one or more hydrogen atoms are replaced by halogen. Representative examples of C1-C6 haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, fluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

[0035] In some instances, the number of carbon atoms in a moiety is indicated by the prefix "C x ~C y " where x is the minimum number of carbon atoms in the substituent and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing from 1 to 6 carbon atoms, and "C1-C3 alkyl" means an alkyl substituent containing from 1 to 3 carbon atoms.

[0036] When a moiety is described as "optionally substituted," the moiety can be either (1) unsubstituted or (2) substituted. When a moiety is described as optionally substituted with up to a specified number of non-hydrogen groups, the moiety can be either (1) unsubstituted or (2) substituted with non-hydrogen groups up to the specified number or up to the maximum number of substitutable positions on the moiety, whichever is less.

[0037] With regard to the use of the words "comprise" or "comprises" or "comprising" in this patent application (including the claims), applicants note that they are used with the fundamental and clear understanding that, unless the context otherwise requires, those words should be interpreted inclusively rather than exclusively, and that applicants intend each of those words to be so interpreted in interpreting this patent application, including the claims that follow.

[0038] The phrase "pharmaceutical composition" refers to a composition suitable for administration in medical use.

[0039] The phrase "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio.

[0040] The term "stable" refers to a compound that has sufficient stability to allow for manufacture and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein.

[0041] When a moiety is described as "substituted," a non-hydrogen radical is present in place of a hydrogen radical at any substitutable atom of the moiety. Thus, for example, a substituted heterocyclic moiety is a heterocyclic moiety in which at least one non-hydrogen radical is present in place of a hydrogen radical on the heterocyclic ring. It should be recognized that when a moiety has more than one substitution, each of the non-hydrogen radicals can be the same or different (unless otherwise specified).

[0042] The phrase "therapeutically effective amount" means the amount of a compound or a pharmaceutically acceptable salt thereof that, when administered for treatment, is sufficient to prevent, to some extent, the onset of, or alleviate one or more symptoms of, the condition or disorder being treated in a particular subject or population of subjects.

[0043] The terms "treat," "treating," and "treatment," as used herein, refer to a method of alleviating or abrogating a disease and / or its attendant symptoms.

[0044] The term "one or more" refers to one to five. In one embodiment, the term "one or more" refers to one or four. In another embodiment, the term "one or more" refers to one to four. In one embodiment, the term "one or more" refers to one or three. In another embodiment, the term "one or more" refers to one to three. In a further embodiment, the term "one or more" refers to one to two. In yet another embodiment, the term "one or more" refers to two. In yet another further embodiment, the term "one or more" refers to one.

[0045] compound The compounds of the present invention have the general formula (I) as described herein.

[0046] The compounds of the present invention are named by using the Struct=name naming algorithm as part of CHEMDRAW® Professional v.15.0.0.106.

[0047] Exemplary compounds of formula (I) include, but are not limited to, the compounds set forth below in Table 1, and pharmaceutically acceptable salts thereof. In the event of a discrepancy between the name of a compound found herein and the structure found in Table 1, it is understood that the structure in Table 1 shall control.

[0048] [Table 1] TIFF2025160251000004.tif221166TIFF2025160251000005.tif219168TIFF2025160251 000006.tif219168TIFF2025160251000007.tif219164TIFF2025160251000008.tif91168

[0049] The compounds of formula (I) or formula (II) may be used in the form of a pharmaceutically acceptable salt.

[0050] The compounds of formula (I) or formula (II) may contain either or both basic or acidic functional groups and may, if desired, be converted into a pharmaceutically acceptable salt by using a suitable acid or base.

[0051] Methods of Making Exemplary Compounds The compounds of the present invention can be better understood in connection with the following synthetic schemes and methods, which illustrate the means by which the compounds can be prepared. The compounds of the present invention can be prepared by a variety of synthetic procedures. Representative synthetic procedures are shown in Schemes 1-4, including but not limited to the following. The variables A, L, R 1 and W are defined in detail herein, for example in the Summary of the Invention.

[0052] Abbreviations used in the schemes and descriptions have the following meanings: BOC is tert-butyloxycarbonyl protecting group; Tf is trifluoromethanesulfonyl; SEM is trimethylsilylethoxymethyl, and Ts is toluenesulfonyl.

[0053] [ka]

[0054] Compound 1-12 can be prepared from compound 1-1 as shown in Scheme 1. As shown in Scheme 1, 7,7-dimethyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (1-2) can be prepared by reacting a solution of 5,5-dimethylcyclohexane-1,3-dione (1-1) with paraformaldehyde or alternatively 1,3,5 trioxane in the presence of boron trifluoride diethyl etherate in dichloromethane or dichloroethane. 1-Bromo-4-chlorobenzene in tetrahydrofuran is treated with n-butyllithium at low temperature, followed by the addition of 7,7-dimethyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (1-2), and quenching with aqueous hydrochloric acid affords 4'-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (1-3). Tetraethylammonium chloride and triethylamine are added to a cooled solution of 1-3 in dichloromethane, followed by the addition of methanesulfonyl chloride to afford 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (1-4). Addition of a solution of 1-4 to a mixture of (S)-2-methyl-CBS-oxazaborolidine and BH3 tetrahydrofuran at low temperature affords (R)-4'-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol 1-5. Stirring a mixture of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate 1-6, compound 1-5, sodium iodide, and potassium carbonate in acetonitrile at ambient temperature affords (S)-tert-butyl 4-(((R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate 1-7.To a solution of (1-7) in dichloroethane was added propane-1,3-diylbis(trifluoromethanesulfonate) (1-8), followed by N. 1 ,N 1 ,N 8 ,N 8 Addition of -tetramethylnaphthalene-1,8-diamine and heating affords (4aS,10aR)-tert-butyl 14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,7,8,9,10a,11,12,13,15-dodecadecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine-3(4H)-carboxylate (1-9). Addition of trifluoroacetic acid to a solution of (1-9) in dichloromethane can give, after treatment with aqueous hydrochloric acid, (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine (1-10). Solutions of (1-10), ethyl 2-bromo-4-fluorobenzoate (1-11), and dipotassium hydrogen phosphate in anhydrous dimethyl sulfoxide are stirred and heated together to give ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)benzoate (1-12).

[0055] [ka]

[0056] Treatment of a solution of 1-12 in toluene with 7-{[2-(trimethylsilyl)ethoxy]methyl}-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepine (2-1), cesium carbonate, and palladium catalyst afforded ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,1 0a,11,12,13-Decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate (2-2) can be obtained. Addition of tetra-N-butylammonium fluoride in tetrahydrofuran to a solution of (2-2) gives ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate (2-3). Treatment of (2-3) with lithium hydroxide affords 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxaazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid (2-4).

[0057] [ka]

[0058] As shown in Scheme 3, compound 2-1 can be prepared from compound 3-1. Compound 2-1 can be treated with 3-chloroperbenzoic acid in ethyl acetate to give 5-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (3-2). Compound 3-2 can be treated with 2,2,2-trichloroacetyl chloride in tetrahydrofuran at low temperature to give compound 3-3. Compound 3-3 can be N-protected by treatment with sodium hydride in N,N-dimethylformamide followed by the addition of 2-(trimethylsilyl)ethoxymethyl chloride in N,N-dimethylformamide to give compound 3-4. A solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide can be treated with sodium hydride in tetrahydrofuran followed by the addition of compound 3-4 to give compound 3-5. Compound 3-5 can be cyclized by treatment with potassium carbonate, picolinic acid, and copper(I) iodide in dimethyl sulfoxide under microwave conditions to give compound 3-6. Addition of compound 3-6 in tetrahydrofuran to a mixture of sodium and naphthalene in 1,2-dimethoxyethane gives the deprotected compound 2-1.

[0059] [ka]

[0060] As shown in Scheme 4, compound 2-4 can be prepared by cleaving it into a compound of formula (4-1) (wherein A, L, R 1and W are as described herein. ) and a coupling agent. Examples of the coupling agent include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 1,1'-carbonyldiimidazole, and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate. Examples of the first base include triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures thereof.

[0061] Specific procedures are presented in the Synthetic Examples section.

[0062] Pharmaceutical Composition When used as pharmaceuticals, the compounds of the present invention are usually administered in the form of a pharmaceutical composition, which may comprise a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

[0063] In one embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

[0064] How to use The compounds of Formula (I), Formula (II) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the compounds of Formula (I), Formula (II) or pharmaceutically acceptable salts thereof, can be administered to subjects suffering from CLL, SLL, and / or ALL. The term "administering" refers to the method of contacting a compound with a subject. [Example]

[0065] The following examples may be used for illustrative purposes and should not be construed as narrowing the scope of the present invention.

[0066] All reagents were of commercial grade and were used as received without further purification unless otherwise stated. Commercially available anhydrous solvents were used for reactions carried out under an inert atmosphere. In all other cases, reagent grade solvents were used unless otherwise specified. 1 Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e., CHCl3 (δ 7.27), as an internal reference.

[0067] Unless otherwise specified, the following abbreviations have the meanings indicated: NMR is nuclear magnetic resonance; s is singlet; br is broad singlet; d is doublet or doublet; m is multiplet; t is triplet; q is quartet; LC / MS or LCMS is liquid chromatography-mass spectrometry; min is minute; mL is milliliter; μL is microliter; L is liter; g is gram; mg is milligram; mmol is millimole; HPLC is high-performance liquid chromatography; ppm is parts per million; DCI is desorption chemical ionization; DSI is droplet spray ionization; ESI is electrospray ionization; M is molar concentration (moles / liter); N is normality (equivalents / liter); and APCI is atmospheric pressure chemical ionization.

[0068] [Example 1] 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

[0069] Example 1A 7,7-Dimethyl-4,6,7,8-tetrahydro-2H,5H-1,3-benzodioxin-5-one To a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) was added boron trifluoride diethyl etherate (40.7 mL) over 10 minutes, and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3, the organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in heptane / ethyl acetate (5:1), concentrated, treated with heptane (300 mL), and filtered. The residue was chromatographed on silica gel (ISCO GOLD®) eluting with a 0-16% ethyl acetate / heptane gradient to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 5.13 (s, 2H), 4.43 (t, 2H), 2.28 (t, 2H), 2.22 (s, 2H), 1.08 (s, 6H). MS (DCI+) m / z 183.1 (M+H) + .

[0070] Example 1B 4'-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one To a solution of 1-bromo-4-chlorobenzene (30.3 g) in tetrahydrofuran (200 mL) at −78° C., n-butyllithium (2.5 M in hexane, 60.6 mL) was added dropwise, maintaining the temperature below −70° C. After stirring at −78° C. for 30 minutes, a solution of Example 1A (24 g) in tetrahydrofuran (75 mL) was added dropwise, maintaining the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 hour, warmed to ambient temperature, and stirred for 12 hours. The reaction mixture was treated with 3 M aqueous HCl (80 mL) and stirred for 2 hours. Most of the organic solvent was removed, and the resulting aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (750 g, BIOTAGE® SNAP) eluting with a gradient of 5-22% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.43 - 7.32 (m, 2H), 7.28 - 7.21 (m, 2H), 4.20 (d, 2H), 2.85 (t, 1H), 2.57 (s, 2H), 2.42 (s, 2H), 1.14 (s, 6H). MS (ESI+) m / z 247.2 (M+H) + .

[0071] Example 1C 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one To a solution of Example 1B (15 g) in dichloromethane (800 mL) was added tetraethylammonium chloride (14.08 g) followed by triethylamine (11.85 mL). The reaction mixture was cooled to 0° C. using an ice / water bath, and methanesulfonyl chloride (6.62 mL) was added over 10 minutes. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (330 g, ISCO GOLD®) eluting with a gradient of 0-35% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 7.60 - 7.55 (m, 2H), 7.45 - 7.40 (m, 2H), 4.12 (s, 2H), 2.64 (s, 2H), 2.39 (s, 2H), 1.05 (s, 6H). MS (DCI+) m / z 283.1 (M+H) + .

[0072] Example 1D (R)-4'-Chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol To a solution of (S)-2-methyl-CBS-oxazaborolidine (20.96 g) in anhydrous tetrahydrofuran (230 mL) was added BH3-tetrahydrofuran (1.0 M in tetrahydrofuran, 76 mL) over 45 minutes at −50° C., and the solution was stirred for an additional 40 minutes. A solution of Example 1C (21 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise from the addition funnel over approximately 60 minutes. After the addition, the reaction mixture was stirred at −50° C. for 1.5 hours. The reaction mixture was quenched by the dropwise addition of methanol (130 mL) over approximately 20 minutes at −50° C. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl (250 mL), diluted with water, and extracted with ethyl acetate. The organic layer was washed with additional aqueous saturated NH4Cl and brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (Teledyne Isco RediSep® RF GOLD® 330 g) eluting with a gradient of 0% to 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.44 - 7.36 (m, 2H), 7.21 - 7.13 (m, 2H), 4.40 - 4.28 (m, 2H), 3.85 (d, 1H), 2.24 (dt, 1H), 1.82 (d, 1H), 1.74 (ddd, 1H), 1.43 (dd, 1H), 0.94 (s, 3H), 0.89 (s, 3H). MS (DCI+) m / z 284.1 (M+H) + .

[0073] Example 1E tert-Butyl (S)-4-(((R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate A solution of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.71 g), Example 1D (2.15 g), sodium iodide (1.47 g), and potassium carbonate (2.084 g) in acetonitrile (15.08 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (80 g) eluting with a gradient of 0% to 70% ethyl acetate:ethanol (3:1) / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.37 - 7.29 (m, 2H), 7.07 - 6.99 (m, 2H), 4.95 (d, 1H), 4.80 - 4.73 (m, 1H), 4.34 - 4.24 (m, 1H), 3.69 - 3.58 (m, 4H), 3.29 - 3.23 (m, 1H), 2.95 - 2.68 (m, 2H), 2.67 - 2.58 (m, 1H), 2.34 (d, 1H), 2.06 (dt, 1H), 1.91 - 1.80 (m, 2H), 1.70 (dd, 1H), 1.61 (td, 1H), 1.40 - 1.33 (m, 1H), 1.31 (s, 9H), 0.92 (s, 3H), 0.91 (s, 3H). MS (ESI+) m / z 465.4 (M+H) + .

[0074] Example 1F tert-Butyl (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]azacycloundecine-3(4H)-carboxylate To a solution of Example 1E (100 g) in dichloroethane (2150 mL) was added propane-1,3-diylbis(trifluoromethanesulfonate) (95 g), followed by N 1 ,N 1 ,N8 ,N 8 -Tetramethylnaphthalene-1,8-diamine (122 g) (proton sponge) was added, and the reaction mixture was heated to 50°C for 20 hours. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1 N aqueous HCl (1 L x 3), 1 N aqueous NaOH (3 times), dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (3 kg) using a gradient of 2 L of 5% ethyl acetate / heptane, 4 L of 10% ethyl acetate / heptane, and then 6-8 L of 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.38 - 7.30 (m, 2H), 7.09 - 7.01 (m, 2H), 4.03 - 3.93 (m, 1H), 3.83 - 3.57 (m, 7H), 3.46 - 3.36 (m, 2H), 2.66 (d, 2H), 2.19 (d, 1H), 2.06 (d, 1H), 1.92 - 1.72 (m, 4H), 1.65 - 1.55 (m, 2H), 1.49 - 1.33 (m, 2H), 1.32 (s, 9H), 0.94 (s, 3H), 0.94 (s, 3H). MS (ESI+) m / z 505.3 (M+H) + .

[0075] Example 1G (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine To a solution of Example 1F (90 g) in dichloromethane (713 mL) cooled in an ice bath, trifluoroacetic acid (206 mL) was added dropwise over approximately 20 minutes. The ice bath was removed, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The vigorously stirred solution was neutralized by adding saturated aqueous Na2CO3 (350 mL). The organic layer was separated, washed four times with saturated aqueous Na2CO3, dried over sodium sulfate, filtered, and concentrated to provide the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 7.45 7.33 (m, 2H), 7.13 7.02 (m, 2H), 3.87 (q, J = 8.0 Hz, 1H), 3.79 3.62 (m, 4H), 3.48 3.36 (m, 2H), 2.79 2.53 (m, 4H), 2.19 (d, J = 12.1 Hz, 1H), 2.09 (dt, J = 17.1, 3.0 Hz, 1H), 1.95 1.87 (m, 2H), 1.85 (dd, J = 6.5, 1.8 Hz, 1H), 1.78 1.70 (m, 1H), 1.63 (dq, J = 7.5, 3.9 Hz, 2H), 1.47 (td, J = 11.3, 2.8 Hz, 1H), 1.39 (dd, J = 12.5, 9.1 Hz, 1H), 0.98 (s, 4H), 0.97 (s, 3H). MS (DCI+) m / z 405.3 (M+H) + .

[0076] Example 1H Ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)benzoate A 2 L, three-necked round-bottom flask equipped with a stir bar, heating mantle, nitrogen inlet and outlet, and thermocouple was charged with ethyl 2-bromo-4-fluorobenzoate (44.4 g). Anhydrous dimethyl sulfoxide (346 mL) was added to the flask, and the mixture was stirred at ambient temperature. Example 1G (70 g) was added, followed by potassium hydrogen phosphate (90 g). Once the slurry was thoroughly mixed, the temperature was raised to 60°C, and the slurry was heated under nitrogen for 72 hours. The heating mantle was removed, and the reaction was cooled to 8°C using an ice / water bath. The flask was equipped with a 1 L dropping funnel. Water (850 mL) was added dropwise from the dropping funnel to the cold reaction slurry, and the mixture was sonicated for 30 minutes. The mixture was mechanically stirred and vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered using a Buchner funnel with filter paper. The filtered solid was washed with water (2 x 500 mL) and dried on the filter for 16 hours. The solid was dissolved in ethyl acetate (600 mL), and water (300 mL) was added to the solution. The biphasic solution was stirred for 1 hour. The layers were separated in a separatory funnel, and the organic layer was washed with water (300 mL) and brine (200 mL). The organic layer was dried over 100 g of magnesium sulfate, filtered, and concentrated to give the crude residue. The residue was dissolved in dichloromethane (100 mL) and purified by normal phase chromatography using a 750 g BIOTAGE® Snap Ultra silica gel column, eluting with a gradient of 0-30% ethyl acetate in heptane, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.68 (d, J = 8.9 Hz, 1H), 7.46 - 7.33 (m, 2H), 7.11 (d, J = 2.6 Hz, 1H), 7.10 - 7.07 (m, 2H), 6.91 (dd, J = 9.0, 2.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.04 (t, J = 7.7 Hz, 1H), 3.89 - 3.64 (m, 7H), 3.59 (d, J = 12.0 Hz, 1H), 3.48 (q, J = 8.3 Hz, 1H), 2.95 (dd, J = 12.2, 10.8 Hz, 1H), 2.86 - 2.66 (m, 2H), 2.27 (d, J = 12.2 Hz, 1H), 2.15 - 2.06 (m, 1H), 2.01 (d, J = 10.6 Hz, 1H), 1.97 - 1.83 (m, 2H), 1.75 - 1.57 (m, 3H), 1.40 (dd, J = 12.5, 9.1 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 1.9 Hz, 6H). LC / MS (APCI+) m / z 631.46 (M+H) + .

[0077] Example 1I 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g) in ethyl acetate (200 mL) at 25° C. was added 3-chloroperbenzoic acid (21.90 g) and then stirred at 25° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and then quenched by the addition of saturated sodium bicarbonate (1000 mL). The biphasic mixture was filtered, and the filter cake was washed with water (100 mL) and then dried in vacuo to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.32 (s, 1H), 8.41 - 8.22 (m, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 6.50 (d, J=1.8 Hz, 1H).

[0078] Example 1J 5-Bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine To a solution of Example 1I (30 g) and 1,1,1,3,3,3-hexamethyldisilazane (29.5 mL) in tetrahydrofuran (300 mL) was added 2,2,2-trichloroacetyl chloride (47.1 mL) at 0° C. The resulting mixture was stirred for 0.5 hours and warmed to 25° C. for an additional 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was triturated with ethyl acetate and petroleum ether (1:10, 100 mL) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.05 ( s, 1H), 8.41 (s, 1H), 7.63–7.54 (m, 1H), 6.51–6.45 (m, 1H).

[0079] Example 1K 5-Bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine To a solution of Example 1J (15 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (3.11 g) in small portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, and then a solution of 2-(trimethylsilyl)ethoxymethyl chloride (13.79 mL) in N,N-dimethylformamide (50 mL) was added dropwise. The resulting mixture was stirred for an additional 2 hours at 0° C. The reaction mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.1 Hz, 1H), 5.61 (s, 2H), 3.54 (t, J=7.9 Hz, 2H), 0.92 (t, J=7.9 Hz, 2H), 0.01 (s, 9H).

[0080] Example 1L N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide To a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (0.166 g) in small portions at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hours, and then Example 1K (0.5 g) was added. The reaction mixture was heated to 80° C. and stirred under nitrogen for 12 hours. After cooling, the reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=5:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.03 (s, 1H), 7.76 (d, J =8.2 Hz, 2H), 7.23 (d, J =8.1 Hz, 2H), 7.15 (d, J =3.5 Hz, 1H), 6.42 - 6.37 (m, 1H), 5.53 (s, 2H), 4.47 - 4.41 (m, 2H), 3.55 - 3.48 (m, 2H), 3.23 (q, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.01 ( J=5.7 Hz, 2H), 0.90 - 0.87 (m, 2H), ), -0.03 (s, 9H).

[0081] Example 1M 1-Tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane To a solution of Example 1L (500 mg) in dimethyl sulfoxide (6 mL) was added potassium carbonate (374 mg), picolinic acid (89 mg), and copper(I) iodide (206 mg) at 20° C. The reaction mixture was stirred at 160° C. for 2 hours under microwave irradiation. After cooling to ambient temperature, the reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=3:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.31 (d, J=3.5 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 6.52 (d, J=3.5 Hz, 1H), 5.58 (s, 2H), 4.03 - 3.78 (m, 4H), 3.60 - 3.44 (m, 2H), 2.39 (s, 3H), 1.90 (s, 2H), 0.90 (t, J=8.2 Hz, 2H), -0.05 (s, 9H).

[0082] Example 1N 7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane To a solution of sodium (0.291 g) in 1,2-dimethoxyethane (0.5 mL) was added naphthalene (1.624 g) under nitrogen. The mixture was stirred at 20° C. for 1 hour until the formation of sodium / naphthalene was complete. Next, to the above solution was added a solution of Example 1M (1 g) in anhydrous tetrahydrofuran (10 mL) at −78° C. The resulting mixture was brought to 20° C. and stirred for 2 hours. The reaction was quenched by adding water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.80 (s, 3H), 7.37 (d, J=3.5 Hz, 1H), 6.51 (d, J=3.5 Hz, 1H), 5.59 (s, 2H), 4.38 - 4.27 (m, 2H), 3.61 - 3.46 (m, 4H), 2.41 (s, 2H), 0.93 - 0.86 (m, 2H), -0.06 (s, 9H).

[0083] Example 10 Ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate An oven-dried 2 L three-necked round-bottom flask equipped with a mechanical stirrer, a Huber-cooled reflux condenser, a Claisen head adapter, a nitrogen needle inlet via a septum and outlet to a bubbler, and a thermocouple was charged with Example 1H (79 g), (Example 1N) (26.6 g), and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (5.61 g). The solids were placed under a flow of nitrogen, and then cesium carbonate (81 g) was rapidly added to the reaction flask. The solids were slowly mixed using a mechanical stirrer, and the flow of nitrogen to the reaction flask was continued for 60 minutes. Anhydrous toluene (833 mL) was charged to another oven-dried 2 L round-bottom flask equipped with a stir bar and septum. A copious stream of nitrogen was blown beneath the solvent surface with stirring for 60 minutes. The solvent was then transferred via cannula to a three-neck flask, and the reaction was heated to an internal temperature of 110°C under nitrogen for 16 hours. The reaction was cooled to ambient temperature, and the flask was charged with water (600 mL), followed by the palladium scavenger, ammonium pyrrolidinedithiocarbamate (3 g). The mixture was stirred vigorously for 1 hour. The reaction was further diluted with ethyl acetate (400 mL), stirred for 30 minutes, and then filtered through a plug of diatomaceous earth. The filter cake was washed with ethyl acetate (2 x 500 mL). The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water (200 mL), then brine (200 mL). The combined aqueous layers were back-extracted once with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate (200 g), filtered, and concentrated to yield a crude residue that was dissolved in dichloromethane (200 mL) and purified by normal phase chromatography using a BIOTAGE® Snap Ultra 1.5 kg silica gel column eluted with a gradient of 0 to 50% ethyl acetate in heptane to yield the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 7.44 (d, J = 8.8 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.30 (d, J = 3.5 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.03 (s, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.9, 2.3 Hz, 1H), 6.22 (d, J = 3.5 Hz, 1H), 5.43 (s, 2H), 4.47 - 4.37 (m, 2H), 4.03 (t, J = 8.0 Hz, 1H), 3.89 - 3.69 (m, 7H), 3.66 (q, J = 5.7, 4.5 Hz, 3H), 3.59 (t, J = 11.1 Hz, 2H), 3.52 - 3.42 (m, 3H), 2.96 - 2.87 (m, 1H), 2.85 - 2.77 (m, 1H), 2.67 (td, J = 11.9, 3.0 Hz, 1H), 2.27 (d, J = 12.1 Hz, 1H), 2.11 (dt, J = 17.4, 3.0 Hz, 1H), 2.02 (d, J = 10.8 Hz, 1H), 2.00 - 1.85 (m, 4H), 1.71 (td, J = 11.6, 2.9 Hz, 1H), 1.64 (dd, J = 8.7, 4.8 Hz, 2H), 1.40 (dd, J = 12.4, 9.1 Hz, 1H), 0.98 (s, 6H), 0.94 (t, J = 7.1 Hz, 3H), 0.84 - 0.79 (m, 2H), -0.08 (s, 9H).

[0084] Example 1P Ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate A 2 L, three-necked flask equipped with a mechanical stirrer, heating mantle, Claisen head adapter, reflux condenser, nitrogen inlet and outlet to a bubbler, and thermocouple was charged with Example 10 (69 g). The solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution at ambient temperature was added ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL). The reaction was heated to an internal temperature of 66° C. for 24 hours. The heating mantle was removed, and the reaction was cooled to 8° C. in an ice / water bath. The mixture was quenched with water (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and then partitioned in a separatory funnel. The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate (100 g), filtered, and concentrated in vacuo to give the crude product. The residue was suspended in 1:1 methyl tert-butyl ether:heptane (400 mL), sonicated for 30 minutes, and then stirred vigorously for 1 hour. The solid was filtered, and the filter cake was washed with 1:1 methyl tert-butyl ether:heptane (50 mL). The solid was dried on a Buchner funnel to give the title compound. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 11.13 (t, J = 2.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.14 (dd, J = 3.4, 2.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.02 (d, J = 0.7 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.13 (dd, J = 3.4, 1.9 Hz, 1H), 4.44 - 4.33 (m, 2H), 4.03 (tt, J = 7.1, 3.5 Hz, 1H), 3.90 - 3.69 (m, 4H), 3.68 - 3.62 (m, 3H), 3.61 - 3.54 (m, 2H), 3.51 - 3.44 (m, 1H), 2.92 - 2.86 (m, 1H), 2.84 - 2.78 (m, 1H), 2.66 (td, J = 11.9, 3.0 Hz, 1H), 2.32 - 2.28 (m, 1H), 2.26 (d, J = 12.1 Hz, 1H), 2.11 (d, J = 17.1 Hz, 1H), 2.02 (d, J = 10.8 Hz, 1H), 1.98 - 1.86 (m, 4H), 1.70 (td, J = 11.7, 3.0 Hz, 1H), 1.66 - 1.58 (m, 2H), 1.40 (dd, J = 12.5, 9.2 Hz, 1H), 1.36 - 1.30 (m, 1H), 1.29 - 1.22 (m, 1H), 0.98 (s, 6H), 0.95 (t, J = 7.1 Hz, 3H).

[0085] Example 1Q 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid A 5 L, three-neck flask equipped with a mechanical stirrer, heating mantle, reflux condenser, Claisen adapter, nitrogen inlet and outlet to a bubbler, and thermocouple was charged with Example 1P (58.7 g). The residue was dissolved in 1,4-dioxane (991 mL) and methanol (496 mL) and stirred at ambient temperature for 5 minutes. Lithium hydroxide (18.99 g) and then water (496 mL) were added, and the reaction was heated to an internal temperature of 75°C for 16 hours. The heating mantle was removed, and the reaction was cooled to 5°C in an ice / water bath. The reaction was neutralized to pH 7 by careful addition of 3N aqueous hydrochloric acid (100 mL). The pH was further adjusted to pH 6 by addition of saturated aqueous ammonium chloride (100 mL). The mixture was diluted with dichloromethane (300 mL), and the layers were separated in a separatory funnel. The aqueous layer was extracted with dichloromethane (2 x 100 mL), and the combined organic layers were dried over sodium sulfate (50 g). The solids were filtered off and the filtrate was concentrated in vacuo to yield a crude residue. The residue was dissolved in dichloromethane (50 mL) and purified by normal phase chromatography on a silica gel cartridge (Teledyne Isco RediSep® RF GOLD®, 330 g) eluting with 0-10% methanol in dichloromethane to give the title compound. 11H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.28 (s, 1H), 11.20 (t, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.17 (dd, J = 3.4, 2.5 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.01 (d, J = 0.7 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 8.9, 2.4 Hz, 1H), 6.15 (dd, J = 3.3, 1.9 Hz, 1H), 4.34 (t, J = 5.5 Hz, 2H), 4.03 (t, J = 7.7 Hz, 1H), 3.88 - 3.75 (m, 3H), 3.74 - 3.6A (m, 3H), 3.64 - 3.58 (m, 1H), 3.57 (s, 6H), 3.51 - 3.43 (m, 1H), 2.92 (t, J = 11.4 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.68 (td, J = 12.0, 3.0 Hz, 1H), 2.26 (d, J = 12.1 Hz, 1H), 2.11 (d, J = 17.4 Hz, 1H), 2.02 (d, J = 10.9 Hz, 1H), 1.97 (p, J = 5.8 Hz, 1H), 1.95 - 1.85 (m, 2H), 1.70 (td, J = 11.6, 2.9 Hz, 1H), 1.66 - 1.60 (m, 0H), 1.40 (dd, J = 12.5, 9.1 Hz, 1H), 0.98 (s, 6H). LC / MS (APCI+) m / z 712.29 (M+H) + .

[0086] Example 1R It should be noted that there seems to be a small error in the original text where "3.74 - 3.6A (m, 3H)" is likely a typo and should probably be "3.74 - 3.64 (m, 3H)". This has been corrected in the translation.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 Example 1Q (0.080 g), 3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzenesulfonamide (0.039 g), N,N-dimethylpyridin-4-amine (0.041 g), and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.043 g) in dichloromethane (1 mL) was stirred. After stirring for 16 h, the reaction was loaded directly onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted using a gradient of 1% to 4% dichloromethane / methanol over 30 min to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 11.94 (s, 1H), 11.28 (s, 1H), 8.56 (s, 1H), 8.48 (d, 1H), 7.60 (dd, 1H), 7.52 (d, 1H), 7.43 - 7.37 (m, 2H), 7.24 - 7.19 (m, 1H), 7.14 - 7.07 (m, 2H), 6.91 - 6.86 (m, 2H), 6.80 - 6.75 (m, 2H), 6.14 (dd, 1H), 4.23 (s, 2H), 4.05 (t, 1H), 3.90 - 3.71 (m, 6H), 3.58 (d, 4H), 3.49 (q, 1H), 3.32 - 3.24 (m, 6H), 2.97 (t, 1H), 2.82 (d, 1H), 2.75 (t, 1H), 2.28 (d, 1H), 2.13 (d, 1H), 2.04 (d, 4H), 1.98 - 1.81 (m, 2H), 1.75 - 1.67 (m, 1H), 1.66 - 1.59 (m, 4H), 1.42 (dd, 1H), 1.32 - 1.20 (m, 2H), 1.00 (s, 6H). LC / MS (APCI+) m / z 1009.56 (M+H) + .

[0087] [Example 2] 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

[0088] Example 2A: (R)-(3,4-Dihydro-2H-pyran-2-yl)methanol The title compound was prepared according to literature procedures (Angew Chem Int Ed 2015, 54, pp. 13538-13544). Optical rotation (measured value) [α] D 25 =-78.93 (c 1.06 in chloroform); (Reference) [α] D 25 =-74.32 (c 1.07 in chloroform).

[0089] Example 2B (R)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran A suspension of sodium hydride (60% wt. in mineral oil, 0.788 g) in tetrahydrofuran (50 mL) was placed in an ice bath for approximately 5 minutes, and then Example 2A (1.5 g) was added as a solution in tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes, then neat benzyl bromide (2.5 mL) was added, and the ice bath was removed. The reaction was stirred for 4 hours, and then the reaction mixture was replaced in the ice bath and carefully quenched with 1:1 saturated aqueous ammonium chloride and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified using flash chromatography (40 g silica column, 0-5% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.37 - 7.31 (m, 4H), 7.31 - 7.25 (m, 1H), 6.39 (dt, J = 6.4, 1.9 Hz, 1H), 4.67 (dddd, J = 6.2, 4.9, 2.5, 1.3 Hz, 1H), 4.63 - 4.53 (m, 2H), 4.02 (dddd, J = 10.4, 6.4, 4.3, 2.3 Hz, 1H), 3.58 (dd, J = 10.2, 6.3 Hz, 1H), 3.51 (dd, J = 10.1, 4.3 Hz, 1H), 2.08 (dddt, J = 17.2, 10.6, 6.5, 2.4 Hz, 1H), 1.96 (ddddd, J = 17.2, 6.1, 4.6, 2.7, 1.6 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.68 (dtd, J = 13.5, 10.4, 5.9 Hz, 1H).

[0090] Example 2C (3S,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol To a solution of Example 2B (2.00 g) in tetrahydrofuran (24.0 mL) was added 9-borabicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) dropwise at 0° C. for 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath, and 10% aqueous sodium hydroxide (15 mL) and then 30% aqueous hydrogen peroxide (16 mL) were carefully added to the mixture at 0° C. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (20 mL) at 0° C. and concentrated under reduced pressure. The residue was transferred to a separatory funnel and extracted with 3:1 ethyl acetate / heptane (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J = 3.9 Hz, 4H), 7.31 - 7.27 (m, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.05 (ddd, J = 10.8, 4.9, 2.3 Hz, 1H), 3.72 (tt, J = 10.1, 4.9 Hz, 1H), 3.53 - 3.38 (m, 3H), 3.14 (dd, J = 10.7, 10.1 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.76 - 1.65 (m, 1H), 1.51 - 1.41 (m, 3H). LC / MS (APCI+) m / z 223.08 (M+H) + .

[0091] Example 2D (R)-6-((benzyloxy)methyl)dihydro-2H-pyran-3(4H)-one A solution of Example 2C (1.85 g) in dichloromethane (37.0 mL) was treated with sodium bicarbonate (1.850 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (4.24 g). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured onto saturated aqueous sodium bicarbonate (20 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (40 g silica column, 10-60% ethyl acetate / heptane) to provide the title compound. 1H NMR (600 MHz, CDCl3) δ ppm 7.38 - 7.33 (m, 4H), 7.32 - 7.28 (m, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.58 (d, J = 12.2 Hz, 1H), 4.19 (dd, J = 16.5, 1.5 Hz, 1H), 4.00 (dt, J = 16.5, 0.8 Hz, 1H), 3.92 (ddt, J = 10.1, 6.1, 3.9 Hz, 1H), 3.59 (dd, J = 10.2, 6.1 Hz, 1H), 3.54 (dd, J = 10.2, 4.1 Hz, 1H), 2.66 - 2.58 (m, 1H), 2.51 - 2.42 (m, 1H), 2.10 - 2.03 (m, 1H), 1.95 (dddd, J = 13.7, 11.0, 10.2, 6.1 Hz, 1H). LC / MS (APCI+) m / z 221.06 (M+H) + .

[0092] Example 2E (3S,6R)-6-((benzyloxy)methyl)-3-methyltetrahydro-2H-pyran-3-ol A solution of 2,6-di-tert-butyl-4-methylphenol (10.57 g) and anhydrous toluene (40.0 mL) was placed in a water bath. A solution of trimethylaluminum (2 M in toluene, 11.99 mL) was carefully added over 30 minutes. The clear, colorless solution was stirred at ambient temperature for 75 minutes, and then the water bath was replaced with a dry ice / acetone bath. A solution of Example 2D (1.79 g) in anhydrous toluene (3 mL) was added dropwise, followed by toluene washes (2 mL). A solution of methyllithium (1.6 M in diethyl ether, 15.24 mL) was added dropwise, and the reaction was stirred in the dry ice bath for 2 hours. The reaction mixture was carefully quenched with 0.25 M hydrochloric acid (10 mL) and then poured onto 1 M hydrochloric acid (50 mL) and filtered. The filtrate was extracted with 2:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.39 - 7.27 (m, 5H), 4.62 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 3.64 (dd, J = 10.8, 2.5 Hz, 1H), 3.60 - 3.49 (m, 2H), 3.48 - 3.36 (m, 1H), 3.27 (dd, J = 10.8, 1.0 Hz, 1H), 1.89 - 1.76 (m, 1H), 1.71 - 1.54 (m, 3H), 1.54 - 1.37 (m, 1H), 1.33 (s, 3H). LC / MS (ESI+) m / z 219.10 (M+H-HO) + .

[0093] Example 2F ((2R,5S)-5-Hydroxy-5-methyltetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate A solution of Example 2E (1.5 g) in ethanol (13.22 mL) was treated with Pd(OH)2 / C (20 wt% Pd, 50% water, 0.150 g) in a 25 mL Hastelloy C reactor. The reactor was purged with nitrogen. The mixture was stirred under hydrogen (60 psi) at ambient temperature. After 20 minutes, the reactor was evacuated and the reaction mixture was filtered. The filtrate was concentrated and dissolved in dichloromethane (12.00 mL). To this solution was added triethylamine (2.00 mL) and 4-methylbenzene-1-sulfonyl chloride (1.25 g), and the reaction was stirred at ambient temperature. After 30 minutes, the reaction appeared complete and was purified using flash chromatography (40 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.82 - 7.76 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.01 (d, J = 5.2 Hz, 2H), 3.53 (ddq, J = 10.7, 5.4, 2.7 Hz, 2H), 3.17 (dd, J = 10.9, 1.0 Hz, 1H), 2.45 (s, 3H), 1.81 (ddt, J = 12.5, 4.3, 2.8 Hz, 1H), 1.68 - 1.53 (m, 3H), 1.41 (tdd, J = 12.8, 11.0, 4.2 Hz, 1H), 1.26 (q, J = 1.9, 1.4 Hz, 3H). LC / MS (ESI+) m / z 283.32 (M+H-H2O) + .

[0094] Example 2G (3S,6R)-6-(azidomethyl)-3-methyltetrahydro-2H-pyran-3-ol A solution of Example 2F (0.80 g) in N,N-dimethylformamide (7.00 mL) was treated with sodium azide (0.80 g). The reaction was stirred at 85° C. for 16 hours. The reaction was cooled to ambient temperature and then poured into water (40 mL) and extracted with dichloromethane (2×40 mL). The combined organic layers were washed with water (4×40 mL), dried over magnesium sulfate, and concentrated. The residue was purified using flash chromatography (12 g silica column, 0-50% ethyl acetate / heptane) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.62 (dd, J = 10.8, 2.6 Hz, 1H), 3.49 (dddd, J = 10.7, 6.6, 4.3, 2.4 Hz, 1H), 3.39 - 3.20 (m, 3H), 1.90 - 1.80 (m, 1H), 1.69 - 1.48 (m, 4H), 1.34 (s, 3H).

[0095] Example 2H (3S,6R)-6-(aminomethyl)-3-methyltetrahydro-2H-pyran-3-ol In a 20 mL glass-lined reactor, a solution of Example 2G (160 mg) in tetrahydrofuran (3.2 mL) was added to a slurry of Raney-Ni2800 in water (79.3 mg). The reactor was purged with nitrogen. The mixture was stirred under hydrogen (50 psi) at 25° C. After 20 hours, the reactor was vented and the reaction mixture was filtered. The filtrate was concentrated to give the title compound. 1 H NMR (500 MHz, CDCl) δ ppm 3.56 (dd, J = 10.7, 2.6 Hz, 1H), 3.27 - 3.18 (m, 2H), 2.68 (d, J = 5.8 Hz, 2H), 1.85 - 1.71 (m, 2H), 1.62 - 1.53 (m, 2H), 1.43 - 1.34 (m, 2H), 1.28 (t, J = 0.9 Hz, 3H). The absolute stereochemistry was confirmed using X-ray diffraction studies on crystals obtained from the (D)-tartrate salt of the title compound.

[0096] Example 2I 4-((((2R,5S)-5-hydroxy-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide Example 2H (66 mg), 4-fluoro-3-nitrosulfonamide (75 mg), and triethylamine (0.080 mL) were stirred together in dichloromethane (1 mL) at ambient temperature for 16 hours. The reaction was loaded onto a silica gel flash chromatography column (12 g silica) and eluted using a gradient of 20% to 100% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.51 (t, 1H), 8.44 (d, 1H), 7.80 (dd, 1H), 7.29 (s, 2H), 7.23 (d, 1H), 4.55 (s, 1H), 3.58 - 3.46 (m, 2H), 3.45 - 3.33 (m, 2H), 3.16 - 3.07 (m, 1H), 1.69 - 1.58 (m, 2H), 1.57 - 1.33 (m, 2H), 1.14 (s, 3H). LC / MS (APCI+) m / z 346.05 (M+H). + .

[0097] Example 2J 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-N-((4-((((2R,5S)-5-hydroxy-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzamide Example 1Q (0.062 g), Example 2I (0.027 g), N,N-dimethylpyridin-4-amine (0.032 g) and N1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.033 g) in dichloromethane (0.9 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4.5% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 11.91 (s, 1H), 11.23 (s, 1H), 8.54 (s, 1H), 8.47 (d, 1H), 7.64 - 7.59 (m, 1H), 7.49 (d, 1H), 7.41 - 7.36 (m, 2H), 7.19 (dd, 1H), 7.12 - 7.06 (m, 2H), 6.90 - 6.85 (m, 2H), 6.78 - 6.73 (m, 2H), 6.12 (dd, 1H), 4.60 (s, 1H), 4.22 (s, 2H), 4.03 (d, 1H), 3.76 (m, 8H), 3.61 - 3.41 (m, 6H), 3.38 - 3.35 (m, 1H), 3.14 (dd, 1H), 2.95 (t, 1H), 2.85 - 2.77 (m, 1H), 2.73 (s, 1H), 2.26 (d, 1H), 2.11 (d, 1H), 2.02 (d, 2H), 1.96 - 1.86 (m, 2H), 1.75 - 1.60 (m, 6H), 1.55 (td, 1H), 1.49 - 1.36 (m, 2H), 1.18 (s, 3H), 0.98 (s, 6H). LC / MS (APCI+) m / z 1040.77 (M+H) + .

[0098] [Example 3] 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

[0099] Example 3A: (S)-2-((2-chloroethoxy)methyl)oxirane To a solution of 2-chloroethanol (391 g) in toluene (750 mL) was added boron trifluoride etherate (13.8 g) and the temperature was warmed to 38° C. To the reaction mixture was added (R)-2-(chloromethyl)oxirane (150 g) below 49° C. The reaction mixture was stirred at 49° C. to 33° C. for 20 minutes and then cooled to 15° C. To the reaction mixture was added sodium hydroxide in water (20% by weight, 800 mL) below 17° C. The reaction mixture was stirred at 15° C. for 1 hour. The reaction mixture was diluted with water (500 mL) and separated. The water was extracted with tert-butyl methyl ether (200 mL). The combined organic phase was washed with water (300 mL) and brine (300 mL), dried over sodium sulfate, and concentrated to give the title compound.

[0100] Example 3B (S)-(1,4-Dioxan-2-yl)methanol To an aqueous solution of sodium hydroxide (20% by weight, 1000 mL) was added Example 3A (222 g) at 90° C. The reaction was stirred at 90° C. for 16 hours. The reaction was extracted with ethyl acetate, and the organic phase was washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the product. The aqueous layer was concentrated to dryness and triturated with ethyl acetate (1000 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give the crude residue. The crude residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.70 - 4.13 (m, 5H), 3.56 -3.61 (m, 3H), 3.46 (t, J = 10.4 Hz, 1H).

[0101] Example 3C (R)-(1,4-Dioxan-2-yl)methyl methanesulfonate To a solution of Example 3B (35.0 g) in dichloromethane (175 mL) was added triethylamine (39.0 g) at 0° C. Then, methanesulfonyl chloride (44.1 g) was added at 0° C. The reaction was then stirred at 15° C. for 1 hour. The reaction was poured into ice-cold saturated sodium bicarbonate solution (300 mL). The dichloromethane phase was separated and dried over sodium sulfate. The organic phase was filtered and concentrated to give the title compound.

[0102] Example 3D (S)-2-(azidomethyl)-1,4-dioxane To a solution of Example 3C (58.0 g) and sodium bicarbonate (49.7 g) in N,N-dimethylformamide (300 mL) was added sodium azide (24.0 g). The reaction was heated at 80° C. for 3.5 hours and stirred at 15° C. for 12 hours. The reaction was quenched with water (600 mL) and extracted with ethyl acetate (300 mL, 200 mL, 100 mL). The combined organic phase was washed with water (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to half its volume. The residue was further concentrated under a stream of nitrogen. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound. 1 H NMR(400 MHz, CDCl3) δ ppm 3.64 - 3.71 (m, 5H), 3.50 - 3.51 (m, 1H), 3.31 - 3.37 (m, 1H), 3.18 - 3.21 (m, 2H).

[0103] Example 3E (S)-(1,4-Dioxan-2-yl)methanamine hydrochloride To a solution of Example 3D (18.0 g) in tetrahydrofuran (130 mL) and water (15 mL) under nitrogen was added triphenylphosphine (66.0 g). The reaction was stirred at 15° C. for 16 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and water (50 mL). The water was separated and extracted with ethyl acetate (50 mL). The aqueous layer was then dried by lyophilization. The product was dissolved in ethyl acetate (10 mL) and treated with HCl / ethyl acetate (4N, 10 mL). After stirring for 1 hour, the reaction was filtered and dried to give the title compound. 1 H NMR (400 MHz, MeOD) δ ppm 3.72 - 3.76 (m, 5H), 3.57 - 3.61 (m, 1H), 3.32 - 3.34 (m, 1H), 3.03 - 3.09 (m, 1H), 2.82 - 2.96 (m, 1H)

[0104] Example 3F (S)-4-(((1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide A solution of 4-fluoro-3-nitrobenzenesulfonamide (2.6 g) and Example 3E (2.00 g) in tetrahydrofuran (40 mL) was treated with N,N-diisopropylethylamine (6.19 mL). The resulting mixture was stirred at ambient temperature for 3 days. The reaction was diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (40 g, 40-80% ethyl acetate in heptane) to give the title compound. MS (APCI+) m / z 318.0 (M+H) + .

[0105] Example 3G 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 Example 1Q (0.067 g), Example 3F (0.027 g), N,N-dimethylpyridin-4-amine (0.035 g), and N 1 -((ethylimino)methylene)-N 3 ,N 3A solution of N,N-dimethylpropane-1,3-diamine hydrochloride (0.036 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 hours, N,N-dimethylformamide (1 mL) was added and stirring continued for 6 hours. The reaction was concentrated, dissolved in dimethyl sulfoxide / methanol (1:1, 3 mL), quenched with 2,2,2-trifluoroacetic acid (0.073 mL), and purified by HPLC using a gradient of 10% to 85% acetonitrile / water (containing 2,2,2-trifluoroacetic acid). Product-containing fractions were lyophilized and loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 24 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 11.92 (s, 1H), 11.22 (s, 1H), 8.53 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.67 - 7.56 (m, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.24 - 7.16 (m, 1H), 7.12 - 7.06 (m, 2H), 6.93 - 6.85 (m, 2H), 6.82 - 6.70 (m, 2H), 6.12 (dd, J = 3.4, 2.0 Hz, 1H), 4.22 (s, 2H), 4.03 (t, J = 7.9 Hz, 1H), 3.89 - 3.63 (m, 8H), 3.63 - 3.53 (m, 4H), 3.53 - 3.41 (m, 3H), 3.33 (s, 5H), 2.95 (t, J = 11.5 Hz, 1H), 2.81 (d, J = 11.2 Hz, 1H), 2.73 (t, J = 11.8 Hz, 1H), 2.26 (d, J = 12.1 Hz, 1H), 2.11 (d, J = 17.4 Hz, 1H), 2.06 - 1.97 (m, 3H), 1.96 - 1.85 (m, 2H), 1.74 - 1.67 (m, 1H), 1.63 (s, 2H), 1.40 (dd, J = 12.5, 9.2 Hz, 1H), 0.98 (s, 6H).

[0106] [Example 4] 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

[0107] Example 4A: Ethyl 1-(oxetan-3-yl)piperidine-4-carboxylate A solution of ethyl piperidine-4-carboxylate (3.2 kg) in dichloromethane (5 L) was stirred under nitrogen at 20° C., and then sodium triacetoxyborohydride (101 g) was added portionwise to the solution at 20° C. The reaction mixture was stirred at 20° C. for 30 minutes, and then oxetan-3-one (229.2 g) was added dropwise to the mixture, maintaining the temperature below 25° C. The reaction mixture was stirred at 20° C. for 12 hours. The reaction mixture was quenched with saturated sodium carbonate and extracted with dichloromethane (2×2 L). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J = 7.13 Hz, 3H) 1.72 - 1.84 (m, 2H) 1.87 - 1.99 (m, 4H) 2.24 - 2.34 (m, 1H) 2.65 - 2.75 (m, 2H) 3.47 (q, J = 6.63 Hz, 1H) 4.06 - 4.13 (m, 2H) 4.62 (q, J = 6.50 Hz, 4H).

[0108] Example 4B Ethyl 4-fluoro-1-(oxetan-3-yl)piperidine-4-carboxylate Lithium diisopropylamide (2.0 M in tetrahydrofuran, 12 L) was added dropwise to tetrahydrofuran (16 L) at −78° C. A solution of Example 4A (2.6 kg) dissolved in tetrahydrofuran (13 L) was added dropwise to the mixture at −78° C., and the mixture was stirred at −78° C. for 30 minutes. N-fluorobenzenesulfonimide (7.7 kg) was then added to the mixture, and the temperature was maintained at −78° C. After the addition, the reaction mixture was gradually warmed to 25° C. and stirred for 12 hours. The reaction mixture was then cooled to 0° C. and quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 L) and extracted with ethyl acetate (3×5 L). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with 1:1 ethyl acetate:petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J = 7.13 Hz, 3 H) 1.92 - 2.01 (m, 2H) 2.06 - 2.23 (m, 4H) 2.56 - 2.66 (m, 2H) 3.51 (quintet, J = 6.47 Hz, 1H) 4.23 (q, J = 7.13 Hz, 2H) 4.56 - 4.70 (m, 4H).

[0109] Example 4C (4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methanol Under nitrogen, lithium aluminum hydride (241.5 g) was added portionwise to a solution of tetrahydrofuran (7 L) cooled to 0° C. at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, and then a solution of Example 4B (1.4 kg) in tetrahydrofuran (7 L) was added dropwise, maintaining the temperature at 0° C. The reaction mixture was then gradually warmed to 25° C. and stirred for 12 hours. The reaction mixture was cooled to 0° C., and water (241 mL) was added dropwise to the mixture, followed by 15% aqueous sodium hydroxide solution (241 mL). The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.61 - 1.76 (m, 2H) 1.91 - 1.99 (m, 2H) 2.17 (td, J = 11.69, 2.25 Hz, 2H) 2.51 - 2.62 (m, 2H) 3.52 (q, J = 6.47 Hz, 1H) 3.55 - 3.65 (m, 2H) 4.56 - 4.72 (m, 4H).

[0110] Example 4D 5-chloro-6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide Under nitrogen, Example 4C (10 g) and 5,6-dichloropyridine-3-sulfonamide (12.00 g) were stirred together in tetrahydrofuran (200 mL) while cooling to 0° C. Sodium hydride (10.57 g) was added portionwise over 10 minutes, followed by 1 mL portions of tetrahydrofuran until stirring resumed. The ice bath was allowed to melt, and the temperature was allowed to rise to 40° C. with stirring for 16 hours. With stirring, the mixture was slowly poured onto ice. Once the ice had melted, the mixture was extracted with ethyl acetate (2×30 mL), and the combined extracts were washed with brine. The combined aqueous layers were saturated with sodium chloride and then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The concentrate was triturated with tert-butyl methyl ether (100 mL) and acetonitrile (50 mL) to give the title compound. 1 H NMR (300 MHz, dimethyl sulfoxide-d6) δ ppm 8.48 (d, 1H), 8.23 ​​(d, 1H), 7.53 (s, 2H), 4.59 - 4.36 (m, 6H), 3.49 - 3.34 (m, 1H), 2.60 - 2.50 (m, 1H), 2.17 - 1.65 (m, 7H). MS (ESI+) m / z 380.0 (M+H) + .

[0111] Example 4E 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 Example 1Q (0.090 g), Example 4D (0.043 g), N,N-dimethylpyridin-4-amine (0.046 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.048 g) in dichloromethane (1.2 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.15 (s, 1H), 11.25 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.51 (d, 1H), 7.46 - 7.34 (m, 2H), 7.24 - 7.18 (m, 1H), 7.15 - 7.05 (m, 2H), 6.92 (s, 1H), 6.77 - 6.72 (m, 2H), 6.13 (dd, 1H), 4.60 - 4.38 (m, 6H), 4.28 - 4.16 (m, 2H), 4.09 - 4.00 (m, 1H), 3.88 - 3.67 (m, 6H), 3.61 - 3.40 (m, 4H), 3.10 - 2.89 (m, 1H), 2.81 (d, 1H), 2.77 - 2.66 (m, 1H), 2.66 - 2.55 (m, 2H), 2.26 (d, 1H), 2.18 - 1.81 (m, 12H), 1.81 - 1.54 (m, 4H), 1.45 - 1.27 (m, 2H), 0.98 (s, 6H). LC / MS (APCI+) m / z 1075.7 (M+H) + .

[0112] [Example 5] 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

[0113] Example 5A: (1r,4r)-4-Methoxycyclohexyl)methanol To a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 12.2 mL) in tetrahydrofuran (4.8 mL) was added dropwise a solution of (1r,4r)-methyl 4-methoxycyclohexanecarboxylate (3.5 g) in tetrahydrofuran (24 mL) at 0°C, and the reaction was allowed to warm slowly to ambient temperature. After 1 h, the reaction was cooled to 0°C and slowly quenched with water (1 mL), then 10% sodium hydroxide (2 mL), then water (3 mL). The mixture was diluted with water and 10% sodium hydroxide (10 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase on a Teledyne Isco CombiFlash Rf+ (25-65% ethyl acetate in heptane) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 4.42-4.29 (m, 1H), 3.26-3.13 (m, 5H), 3.08-2.93 (m, 1H), 2.06-1.91 (m, 2H), 1.79-1.66 (m, 2H), 1.36-1.19 (m, 1H), 1.13-0.97 (m, 2H), 0.95-0.78 (m, 2H).

[0114] Example 5B (1r,4r)-4-Methoxycyclohexyl)methyl methanesulfonate To a solution of Example 5A (962 mg) in dichloromethane (33.4 mL) at 0° C. was added triethylamine (4.65 mL), followed by methanesulfonyl chloride (0.780 mL), and the reaction was stirred at 0° C. for 15 minutes before warming to ambient temperature. After 1 hour, the reaction was diluted with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound, which was used without further purification.

[0115] Example 5C Di-tert-butyl{[(1r,4r)-4-methoxycyclohexyl]methyl}-2-imidodicarbonate A solution of Example 5B (700 mg) and di-tert-butyl iminodicarboxylate (1026 mg) in N,N-dimethylformamide (15.7 mL) was heated to 85° C. for 16 hours. The reaction was cooled to ambient temperature, diluted with water, and extracted three times with ethyl acetate. The combined organic layers were washed twice with water, then with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by normal phase on a Teledyne Isco CombiFlash Rf+ (0-40% ethyl acetate in heptane) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.39-3.27 (m, 2H), 3.21 (s, 3H), 3.08-2.98 (m, 1H), 2.04-1.91 (m, 2H), 1.68-1.38 (m, 21H), 1.11-0.77 (m, 4H).

[0116] Example 5D (1r,4r)-4-Methoxycyclohexyl)methanamine trifluoroacetic acid To a solution of Example 5C (666 mg) in dichloromethane (9695 μL) at ambient temperature was added trifluoroacetic acid (3.2 mL) and the reaction was allowed to stand for 1 hour. The reaction was concentrated to give the title compound, which was used in the next step without further purification.

[0117] Example 5E 4-((((1r,4r)-4-Methoxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 5D (453 mg) and 4-fluoro-3-nitrobenzenesulfonamide (310 mg) in tetrahydrofuran (7 mL) at ambient temperature was added N,N-diisopropylethylamine (1230 μL) and the reaction was stirred. After 6 hours, the reaction was concentrated under reduced pressure. The residue was purified by normal phase on a Teledyne Isco CombiFlash Rf+ (0-3% methanol in dichloromethane) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.59-8.50 (m, 1H), 8.48 (d, 1H), 7.82 (dd, 1H), 7.32 (br s, 2H), 7.26 (d, 1H), 3.32-3.25 (m, 2H), 3.22 (s, 3H), 3.12-3.00 (m, 1H), 2.06-1.96 (m, 2H), 1.85-1.73 (m, 2H), 1.70-1.54 (m, 1H), 1.17-0.94 (m, 4H).

[0118] Example 5F 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 Example 1Q (0.107 g), Example 5E (0.046 g), N,N-dimethylpyridin-4-amine (0.055 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of 0.058 g of dimethylpropane-1,3-diamine hydrochloride in 1.5 mL of dichloromethane was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted using a gradient of 1% to 4% dichloromethane / methanol over 30 minutes. The product was dissolved in 1:1 dimethyl sulfoxide / methanol (3 mL), and 0.012 mL of 2,2,2-trifluoroacetic acid was added. The solution was purified by preparative HPLC using a Gilson PLC2020 system (Luna column, 250 x 50, flow rate 75 mL / min) with a gradient of 20% to 95% acetonitrile / water over 30 minutes to give the title compound. 1H NMR (400 MHz, pyridine-d5) δ ppm 12.62 (s, 1H), 9.18 (d, 1H), 8.47 (t, 1H), 8.19 (dd, 1H), 8.09 (dd, 1H), 7.45 - 7.40 (m, 2H), 7.39 (dd, 1H), 7.31 (d, 1H), 7.11 - 7.04 (m, 2H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.65 (d, 1H), 6.04 (dt, 1H), 4.37 (s, 2H), 4.21 (s, 1H), 3.97 (d, 2H), 3.90 - 3.49 (m, 10H), 3.31 (t, 1H), 3.01 - 2.79 (m, 6H), 2.45 (d, 1H), 2.19 - 1.62 (m, 14H), 1.57 (dd, 1H), 1.39 (s, 1H), 1.18 - 1.04 (m, 2H), 1.00 (s, 3H), 0.98 (s, 3H), 0.92 - 0.79 (m, 2H). LC / MS (APCI+) m / z 1037.73 (M+H) + .

[0119] [Example 6] 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

[0120] Example 6A (R)-2-((((R)-1-(benzyloxy)propan-2-yl)oxy)methyl)oxirane To a solution of (R)-1-(benzyloxy)propan-2-ol (100 g) in tetrahydrofuran (500 mL) was added sodium hydride (36.1 g) in small portions at 0 °C. After 30 min, (S)-2-(chloromethyl)oxirane (83.5 g) and NaI (781 mg) were added. The reaction was stirred at 50 °C for 12 h. The reaction was poured into water (1000 mL), and the aqueous phase was extracted with ethyl acetate (900 mL, 600 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.26-7.32 (m, 5H), 4.51-4.58 (m, 2H), 3.70-3.81 (m, 2H), 3.41-3.53 (m, 3H), 3.13 (s, 1H), 2.77 (s, 1H), 2.59-2.61 (m, 1H), 1.18 (d, J = 6.0 Hz, 3H).

[0121] Example 6B (R)-2-((R)-oxiran-2-ylmethoxy)propan-1-ol To a solution of Example 6A (30.0 g) in tetrahydrofuran (90 mL) and water (55 mL) under nitrogen was added Pd(OH) (7.50 g, 20% purity). The reaction was stirred under hydrogen (50 psi) at 25° C. for 1 hour. The reaction was filtered and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.73-3.87 (m, 1H), 3.34-3.67 (m, 5H), 3.12-3.16 (m, 1H), 2.79 (t, J = 4.8 Hz, 1H), 2.68-2.70 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H).

[0122] Example 6C ((2S,5R)-5-methyl-1,4-dioxan-2-yl)methanol To a solution of Example 6B (30.0 g) in dichloromethane (150 mL) was added camphorsulfonic acid (7.38 g), and the reaction was stirred at 25° C. for 12 hours. The reaction was washed with saturated sodium bicarbonate solution (200 mL), and the aqueous phase was extracted with dichloromethane (200 mL, 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.72-3.75 (m, 2H), 3.34-3.61 (m, 5H), 3.27 (t, J = 10.8 Hz, 1H), 2.50 (s, 1H), 1.04 (d, J = 6.0 Hz, 3H).

[0123] Example 6D ((2R,5R)-5-methyl-1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate To a solution of Example 6C (25.0 g) in dichloromethane (120 mL) at 0° C., triethylamine (24.9 g) was added dropwise, followed by 4-toluenesulfonyl chloride (43.3 g). The reaction was stirred at 25° C. for 2.5 hours. The reaction was concentrated, and the resulting residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate=100 / 1 to 0 / 1) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 3.91-4.00 (m, 2H), 3.67-3.76 (m, 3H), 3.51-3.57 (m, 1H), 3.37 (t, J = 11.2 Hz, 1H), 3.21 (t, J = 11.6 Hz, 1H), 2.43 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H).

[0124] Example 6E (2S,5R)-2-(azidomethyl)-5-methyl-1,4-dioxane A solution of Example 6D (5 g) in dimethylformamide (25.7 mL) was treated with sodium azide (2.27 g), and the resulting suspension was stirred at 80° C. for 12 hours. The cooled suspension was poured into water (100 mL) and extracted with tert-butyl methyl ether (2×50 mL). The combined organic layers were washed with brine (2×25 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated to give the title compound.

[0125] Example 6F ((2S,5R)-5-methyl-1,4-dioxan-2-yl)methanamine In a 600 mL 316SS reactor, a solution of Example 6E (22 g) in tetrahydrofuran (390 mL) was added to 5% Pd / C (2.2 g) and stirred under hydrogen. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound.

[0126] Example 6G 4-((((2S,5R)-5-methyl-1,4-dioxan-2-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 6F (10.9 g) in tetrahydrofuran (315 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (16.63 g), followed by N,N-diisopropylethylamine (23.75 mL), and the reaction was heated to 45° C. and stirred for 5 hours. The reaction was cooled to ambient temperature and concentrated. The residue was suspended in methanol (200 mL) and stirred vigorously for 2 hours. The precipitate was collected by filtration and dried to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.52 (t, J = 5.7 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 8.9, 2.3 Hz, 1H), 7.33 (s, 2H), 7.27 (d, J = 9.3 Hz, 1H), 3.82 (dd, J = 11.5, 2.6 Hz, 1H), 3.78 (dd, J = 11.5, 2.6 Hz, 1H), 3.75-3.68 (m, 1H), 3.54 (dddd, J = 10.2, 6.3, 4.8, 2.2 Hz, 2H), 3.44-3.34 (m, 2H), 3.20 (dd, J = 11.5, 10.1 Hz, 1H), 0.99 (d, J = 6.3 Hz, 3H).

[0127] Example 6H 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 Example 1Q (0.080 g), Example 6G (0.039 g), N,N-dimethylpyridin-4-amine (0.041 g) and N 1-((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.043 g) in dichloromethane (1.1 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 11.93 (s, 1H), 11.25 (s, 1H), 8.54 (s, 1H), 8.48 (d, 1H), 7.63 (dd, 1H), 7.50 (d, 1H), 7.43 - 7.36 (m, 2H), 7.22 (dd, 1H), 7.14 - 7.07 (m, 2H), 6.92 - 6.87 (m, 2H), 6.76 (d, 2H), 6.13 (dd, 1H), 4.23 (s, 2H), 4.04 (t, 1H), 3.90 - 3.66 (m, 6H), 3.63 - 3.38 (m, 12H), 3.19 (dd, 1H), 2.96 (t, 1H), 2.82 (d, 1H), 2.74 (t, 1H), 2.28 (d, 1H), 2.16 - 2.07 (m, 1H), 2.06 - 2.01 (m, 3H), 1.97 - 1.87 (m, 2H), 1.75 - 1.58 (m, 3H), 1.41 (dd, 1H), 1.01 (s, 3H), 1.00 (s, 6H). LC / MS (APCI+) m / z 1027.63 (M+H) + .

[0128] [Example 7] 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

[0129] Example 7A 5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide To a solution of (4-fluorotetrahydro-2H-pyran-4-yl)methanol (0.567 g) in tetrahydrofuran (20 mL) was added sodium hydride (60% in mineral oil, 676 mg) and the reaction was stirred for 30 minutes. 5,6-Dichloropyridine-3-sulfonamide (0.800 g) was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate / hexane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.49 (d, 1H), 8.21 (d, 1H), 7.54 (bs, 2H), 4.30 (d, 2H), 3.92–3.84 (m, 2H), 3.35–3.27 (m, 1H), 2.14–1.99 (m, 1H), 1.70–1.61 (m, 2H), 1.44–1.27 (m, 2H).

[0130] Example 7B 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 Example 1Q (0.035 g), Example 7A (0.016 g), N,N-dimethylpyridin-4-amine (0.018 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.019 g) in dichloromethane (0.50 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.16 (s, 1H), 11.22 (s, 1H), 8.38 (d, 1H), 8.01 (d, 1H), 7.48 (d, 1H), 7.38 - 7.33 (m, 2H), 7.18 (t, 1H), 7.14 - 7.02 (m, 2H), 6.87 (s, 1H), 6.80 - 6.69 (m, 2H), 6.10 (dd, 1H), 4.46 (d, 2H), 4.18 (s, 2H), 4.02 - 3.98 (m, 1H), 3.88 - 3.38 (m, 12H), 2.93 (t, 1H), 2.84 - 2.62 (m, 2H), 2.23 (d, 1H), 2.13 - 1.54 (m, 16H), 1.37 (dd, 1H), 0.95 (s, 6H). LC / MS (APCI+) m / z 1020.86 (M+H)+ .

[0131] [Example 8] 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

[0132] Example 8A 1-Oxaspiro[2.3]hexane-5-carbonitrile A solution of 3-chloroperbenzoic acid (2.585 g) in dichloromethane (60 mL) was stirred at -10°C for 30 minutes. The mixture was filtered, and the filtrate was added dropwise to a solution of 3-methylenecyclobutanecarbonitrile (930 mg) in dichloromethane (20.00 mL) at 0°C. The mixture was stirred at 30°C for 1 hour. The mixture was cooled to -15°C and stirred for 30 minutes. The mixture was filtered, and the filtrate was washed successively with a 5% solution of sodium sulfite, a saturated solution of sodium bicarbonate, and water. The organic layer was dried over sodium sulfate and concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 2.75 - 2.81 (m, 1H) 2.86 - 2.94 (m, 3H) 3.12 - 3.21 (m, 1H) 4.84 - 4.88 (m, 2H).

[0133] Example 8B (1r,3r)-3-(Fluoromethyl)-3-hydroxycyclobutanecarbonitrile To a solution of tetrabutylammonium fluoride (9.62 mL) was added 40% aqueous hydrogen fluoride (0.418 mL), and the volatiles were removed under reduced pressure to give a crude mixture. Potassium hydrogen fluoride (0.075 g) was added to the resulting mixture, and water was completely removed at 60° C. The solution was cooled to 25° C., and heptane (15 mL) and Example 8A (0.5 g) were added. The mixture was maintained at 120° C. for 24 hours. The reaction mixture was purified by column chromatography on silica gel (20% ethyl acetate in petroleum ether) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 2.29 - 2.42 (m, 4H), 3.34 - 3.42 (m, 1H), 4.24 (s, 1H), 4.36 (s, 1H), 5.70 (s, 1H).

[0134] Example 8C (1r,3r)-3-(aminomethyl)-1-(fluoromethyl)cyclobutan-1-ol To a solution of Example 8B (0.309) in ethanol (15.44 mL) was added ammonium hydroxide (0.335 g) and nickel (0.843 g) under argon. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 25° C. for 24 hours. The suspension was filtered through a pad of diatomaceous earth, and the pad was washed with ethanol (100 mL). The combined filtrate was concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.85 - 1.91 (m, 2H) 2.11 - 2.19 (m, 2H) 2.42 - 2.57 (m, 1H) 2.71 (d, J=7.46 Hz, 2H) 4.21 (s, 1H) 4.33 (s, 1H).

[0135] Example 8D 4-((((1r,3r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 8C (0.23 g) in N,N-dimethylformamide (3.15 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (0.342 g) and N-ethyl-N-isopropylpropan-2-amine (0.893 g). The reaction mixture was stirred at 60° C. for 12 hours. The solution was cooled to 25° C. and directly purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.72 - 1.83 (m, 2H), 2.15 - 2.26 (m, 3H), 3.49 (br t, J = 5.87 Hz, 2H), 4.22 (s, 1H), 4.34 (s, 1H), 5.37 (s, 1H), 7.24 (d, J = 9.17 Hz, 1H), 7.31 (br s, 2H), 7.83 (dd, J = 9.11, 2.14 Hz, 1H), 8.45 - 8.52 (m, 2H).

[0136] Example 8E 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 A mixture of Example 1Q (25 mg) in dichloromethane (1 mL) with triethylamine (5 mg), Example 8D (18 mg) and N 1 -((ethylimino)methylene)-N 3 ,N 3The resulting mixture was treated with 4-dimethylpropane-1,3-diamine hydrochloride (10 mg) and 4-dimethylaminopyridine (6 mg). The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in 1:2 dimethyl sulfoxide:methanol (3 mL) and loaded onto HPLC (C18 column, 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, 25 min). After washing with saturated aqueous sodium bicarbonate, the title compound was obtained. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 11.05 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.22 (t, J = 5.6 Hz, 1H), 7.65 (dd, J = 9.0, 2.1 Hz, 1H), 7.36 (dd, J = 8.4, 5.5 Hz, 3H), 7.12 (t, J = 2.9 Hz, 1H), 7.09 - 7.02 (m, 3H), 6.83 (d, J = 9.2 Hz, 1H), 6.50 (dd, J = 8.7, 2.3 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 6.08 (dd, J = 3.5, 1.7 Hz, 1H), 5.34 (s, 1H), 4.26 (s, 1H), 4.18 (t, J = 5.5 Hz, 2H), 4.14 (s, 1H), 3.97 (s, 1H), 3.86 - 3.61 (m, 4H), 3.48 (d, J = 11.9 Hz, 1H), 3.16 (s, 1H), 2.81 - 2.65 (m, 3H), 2.43 (t, J = 11.4 Hz, 1H), 2.19 (d, J = 12.1 Hz, 1H), 2.11 - 1.81 (m, 7H), 1.74 - 1.54 (m, 5H), 1.37 (dd, J = 12.6, 9.1 Hz, 1H), 1.23 (s, 1H), 0.96 (s, 3H), 0.94 (s, 3H).

[0137] [Example 9] 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]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide

[0138] Example 9A 3-chloro-4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)benzenesulfonamide To a solution of Example 4C (20 g) and 3-chloro-4-fluorobenzenesulfonamide (18.5 g) in tetrahydrofuran (200 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 264 mL) in small portions. The reaction was heated to 55°C for 18 hours. Additional potassium tert-butoxide (1.0 M in tetrahydrofuran, 60 mL) was added, and the reaction was heated to 55°C for an additional 3 hours. The reaction was cooled to -10°C, and aqueous HCl (3.0 M) was added to adjust the pH to 6-6.5. The reaction was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was suspended in tert-butyl methyl ether (300 mL), stirred overnight, sonicated for 30 minutes, and filtered to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.81 (d, 1H), 7.70 (dd, 1H), 7.35 - 7.27 (m, 3H), 4.51 (t, 2H), 4.40 (t, 2H), 4.24 (d, 2H), 3.46 - 3.35 (m, 1H), 2.59 - 2.50 (m, 2H), 2.10 - 1.99 (m, 2H), 1.98 - 1.66 (m, 4H). LC / MS (ESI+) m / z 379.11 (M+H). + .

[0139] Example 9B 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]benzodioxaazacycloundecin-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1(7H)-yl)benzamide Example 1Q (0.090 g), Example 9A (0.043 g), N,N-dimethylpyridin-4-amine (0.046 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.048 g) in dichloromethane (1.3 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.00 (s, 1H), 11.28 (s, 1H), 7.68 (d, 1H), 7.63 (dd, 1H), 7.48 (d, 1H), 7.39 - 7.28 (m, 2H), 7.20 (dd, 1H), 7.10 - 7.02 (m, 3H), 6.86 (s, 1H), 6.73 (d, 2H), 6.11 (dd, 1H), 4.51 (t, 2H), 4.40 (t, 2H), 4.28 - 4.08 (m, 4H), 4.05 - 3.96 (m, 1H), 3.88 - 3.58 (m, 5H). 3.58 - 3.37 (m, 4H), 2.92 (t, 1H), 2.77 (d, 1H), 2.74 - 2.61 (m, 1H), 2.54 (d, 3H), 2.23 (d, 1H), 2.15 - 1.52 (m, 17H), 1.36 (dd, 1H), 0.95 (s, 6H). LC / MS (APCI+) m / z 1074.81 (M+H) + .

[0140] [Example 10] 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

[0141] Example 10A 5-chloro-6-((8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methoxy)pyridine-3-sulfonamide A solution of (8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)methanol (1.00 g) in tetrahydrofuran (22 mL) was cooled in an ice bath. Solid sodium hydride (60 wt% in mineral oil, 0.881 g) was added and stirring was continued for 30 minutes. To this suspension, 5,6-dichloropyridine-3-sulfonamide (1.01 g) was added and the reaction was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was carefully quenched with water (20 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with dichloromethane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.50 (d, J = 2.2 Hz, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.55 (s, 2H), 4.56 (d, J = 21.5 Hz, 2H), 3.89 (s, 4H), 2.02 (td, J = 9.2, 7.7, 3.9 Hz, 2H), 1.86 - 1.61 (m, 6H). LC / MS (ESI+) m / z 381.15 (M+H) + .

[0142] Example 10B 5-chloro-6-((1-fluoro-4-oxocyclohexyl)methoxy)pyridine-3-sulfonamide A solution of Example 10A (1.50 g) and para-toluenesulfonic acid monohydrate (0.824 g) in 1,4-dioxane (10 mL) and water (10 mL) was heated to 85° C. for 2 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (20 mL), and washed with a saturated solution of sodium bicarbonate (20 mL), water (20 mL), and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.51 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.57 (s, 2H), 4.65 (d, J = 21.9 Hz, 2H), 2.63 - 2.52 (m, 2H), 2.39 - 2.24 (m, 4H), 2.20 - 1.96 (m, 2H). LC / MS (APCI+) m / z 337.21 (M+H) + .

[0143] Example 10C 5-chloro-6-(((1s,4s)-1-fluoro-4-morpholinocyclohexyl)methoxy)pyridine-3-sulfonamide A solution of Example 10B (0.20 g) in dichloromethane (3.00 mL) and methanol (3.00 mL) was treated with morpholine (0.102 mL), sodium cyanoborohydride (0.187 g), and acetic acid (0.07 mL). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified using reverse-phase HPLC (5-50% acetonitrile / water (+0.1% trifluoroacetic acid)). The earlier eluting fraction of the two isolated peaks was lyophilized to afford the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.50 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.58 (s, 2H), 4.54 (d, J = 21.1 Hz, 2H), 4.01 (d, J = 12.7 Hz, 2H), 3.67 (t, J = 12.2 Hz, 2H), 3.49 - 3.43 (m, 2H), 3.31 - 3.25 (m, 1H), 3.18 - 3.10 (m, 2H), 2.17 (tt, J = 8.6, 3.0 Hz, 2H), 2.11 - 2.04 (m, 2H), 1.75 - 1.58 (m, 4H). LC / MS (APCI+) m / z 407.90 (M+H) + .

[0144] Example 10D 5-chloro-6-(((1r,4r)-1-fluoro-4-morpholinocyclohexyl)methoxy)pyridine-3-sulfonamide The title compound was isolated as the second peak from the reverse phase HPLC run in Example 10C. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.52 (d, J = 2.2 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.60 (s, 2H), 4.69 (d, J = 25.4 Hz, 2H), 4.03 - 3.97 (m, 2H), 3.70 - 3.62 (m, 2H), 3.14 - 3.06 (m, 2H), 2.27 - 2.22 (m, 2H), 2.13 - 2.04 (m, 2H), 1.76 (qd, J = 12.6, 3.8 Hz, 2H), 1.72 - 1.61 (m, 2H). LC / MS (APCI+) m / z 407.85 (M+H) + .

[0145] Example 10E 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 A solution of Example 10C (36.6 mg) in dichloromethane (0.80 mL) was added to N-ethyl-N-isopropylpropan-2-amine (0.06 mL), Example 1Q (50.0 mg), N,N-dimethylpyridin-4-amine (21.0 mg), and N 1 -((ethylimino)methylene)-N 3 ,N3 -dimethylpropane-1,3-diamine hydrochloride (25.0 mg) and stirring at ambient temperature was continued for 14 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to provide the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 12.23 (s, 1H), 11.27 (t, J = 2.3 Hz, 1H), 9.99 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.10 - 8.05 (m, 1H), 8.05 - 8.02 (m, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.23 (dd, J = 3.4, 2.5 Hz, 1H), 7.19 - 7.14 (m, 2H), 6.91 (s, 1H), 6.81 (d, J = 2.4 Hz, 1H). 6.77 (dd, J = 9.0, 2.3 Hz, 1H), 6.14 - 6.09 (m, 1H), 4.53 - 4.46 (m, 3H), 4.38 (d, J = 13.1 Hz, 1H), 4.29 - 4.21 (m, 2H), 3.95 - 3.90 (m, 1H), 3.84 (ddd, J = 10.8, 9.3, 3.5 Hz, 1H), 3.77 (d, J = 13.3 Hz, 1H), 3.69 (t, J = 12.1 Hz, 2H), 3.57 (ddt, J = 40.3, 15.1, 7.3 Hz, 7H), 3.45 (t, J = 19.0 Hz, 3H), 3.37 - 3.21 (m, 4H), 3.18 - 3.10 (m, 2H), 2.71 - 2.62 (m, 1H), 2.19 - 2.11 (m, 3H), 2.11 - 2.02 (m, 6H), 2.00 - 1.96 (m, LC / MS (APCI+) m / z 1101.26 (M+H)+ .

[0146] [Example 11] 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 The title compound was prepared according to the procedure reported for the final step of Example 10, substituting Example 10D for Example 10C. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 12.26 (s, 1H), 11.27 (t, J = 2.3 Hz, 1H), 9.82 (s, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 2.2 Hz, 1H), 8.00 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.23 (dd, J = 3.4, 2.5 Hz, 1H), 7.19 - 7.13 (m, 2H), 6.91 (s, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.76 (dd, J = 9.0, 2.3 Hz, 1H), 6.14 - 6.10 (m, 1H), 4.65 (d, J = 25.5 Hz, 2H), 4.53 - 4.43 (m, 1H), 4.37 (d, J = 13.1 Hz, 1H), 4.23 (s, 2H), 4.14 (d, J = 10.3 Hz, 1H), 4.09 - 3.87 (m, 4H), 3.65 - 3.57 (m, 1H), 3.57 - 3.48 (m, 3H), 3.44 -3.33 (m, 6H), 3.23 (dt, J = 30.5, 15.9 Hz, 2H), 3.13 - 3.06 (m, 3H), 2.71 - 2.60 (m, 1H), 2.28 - 1.92 (m, 11H), 1.82 - 1.61 (m, 6H), 1.33 (dd, J = 12.2, 9.2 Hz, 1H), 1.02 (s, J = 15.9 Hz, 6H). LC / MS (APCI+) m / z 1101.25 (M+H) + .

[0147] [Example 12] 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

[0148] Example 12A (R)-(3,4-Dihydro-2H-pyran-2-yl)methanol The title compound was prepared according to literature procedures (Angew Chem Int Ed 2015, 54, pp. 13538-13544). Optical rotation (measured value) [α] D 25 =-78.93 (c 1.06 in chloroform); (Reference) [α] D 25 =-74.32 (c 1.07 in chloroform).

[0149] Example 12B (R)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran A suspension of sodium hydride (60% wt. in mineral oil, 0.788 g) in tetrahydrofuran (50 mL) was placed in an ice bath for 5 minutes, followed by the addition of Example 12A (1.5 g) as a solution in tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes, then neat benzyl bromide (2.5 mL) was added and the ice bath was removed. The reaction was stirred for 4 hours, then the reaction mixture was placed back in the ice bath and carefully quenched with 1:1 saturated aqueous ammonium chloride / water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silica column, 0-5% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.37 - 7.31 (m, 4H), 7.31 - 7.25 (m, 1H), 6.39 (dt, J = 6.4, 1.9 Hz, 1H), 4.67 (m, 1H), 4.63 - 4.53 (m, 2H), 4.02 (m, 1H), 3.58 (dd, J = 10.2, 6.3 Hz, 1H), 3.51 (dd, J = 10.1, 4.3 Hz, 1H), 2.08 (m, 1H), 1.96 (m, 1H), 1.88 - 1.79 (m, 1H), 1.68 (m, 1H).

[0150] Example 12C (3S,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol To a solution of Example 12B (2.00 g) in tetrahydrofuran (24.0 mL) was added 9-borabicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) dropwise at 0° C. over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath, and 10% aqueous sodium hydroxide (15 mL) and then 30% aqueous hydrogen peroxide (16 mL) were carefully added to the mixture at 0° C. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (20 mL) at 0° C. and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with 3:1 ethyl acetate / heptane (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J = 3.9 Hz, 4H), 7.31 - 7.27 (m, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.05 (ddd, J = 10.8, 4.9, 2.3 Hz, 1H), 3.72 (tt, J = 10.1, 4.9 Hz, 1H), 3.53 - 3.38 (m, 3H), 3.14 (dd, J = 10.7, 10.1 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.76 - 1.65 (m, 1H), 1.51 - 1.41 (m, 3H). LC / MS (APCI+) m / z 223.08 (M+H) + .

[0151] Example 12D (((3S,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane A solution of Example 12C (1.00 g) in dichloromethane (15.00 mL) was treated with 1H-imidazole (0.60 g) and tert-butylchlorodimethylsilane (0.678 g). The reaction was stirred at ambient temperature for 64 hours, and then the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (2 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (40 g silica column, 0-20% ethyl acetate / heptane) to provide the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 7.27 (d, J = 4.6 Hz, 4H), 7.23 - 7.19 (m, 1H), 4.53 (d, J = 12.2 Hz, 1H), 4.48 (d, J = 12.2 Hz, 1H), 3.85 (ddd, J = 10.9, 4.9, 2.2 Hz, 1H), 3.60 (tt, J = 10.0, 4.8 Hz, 1H), 3.45 - 3.32 (m, 3H), 3.07 (dd, J = 10.9, 10.0 Hz, 1H), 1.99 - 1.92 (m, 1H), 1.63 - 1.55 (m, 1H), 1.43 - 1.30 (m, 2H), 0.81 (s, 9H), -0.01 (d, J = 5.7 Hz, 6H). LC / MS (APCI+) m / z 337.18 (M+H) + .

[0152] Example 12E ((2R,5S)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate A solution of Example 12D (1.50 g) in tetrahydrofuran (15.00 mL) was sparged with nitrogen for 5 minutes and then added to a flask containing Pd(OH)2 / C (20 wt% Pd, 50% water, 10.0 mg). A hydrogen balloon was connected, and the reaction was stirred at ambient temperature for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated and then dissolved in dichloromethane (10.00 mL). To this solution were added N,N-dimethylpyridin-4-amine (0.750 g), N-ethyl-N-isopropylpropan-2-amine (1.50 mL), and 4-methylbenzene-1-sulfonyl chloride (0.774 g). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and purified using flash chromatography (40 g silica column, 0-20% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.86 - 7.71 (m, 2H), 7.37 - 7.30 (m, 2H), 4.00 - 3.91 (m, 2H), 3.81 (ddd, J = 10.9, 5.0, 2.2 Hz, 1H), 3.59 (tt, J = 10.0, 4.7 Hz, 1H), 3.45 (dtd, J = 10.5, 5.0, 2.1 Hz, 1H), 3.03 (dd, J = 10.9, 10.0 Hz, 1H), 2.44 (s, 3H), 2.00 (dtt, J = 13.0, 4.2, 2.0 Hz, 1H), 1.68 - 1.61 (m, 1H), 1.46 - 1.29 (m, 2H), 0.85 (s, 9H), 0.03 (d, J = 5.1 Hz, 6H). LC / MS (APCI+) m / z 400.96 (M+H) + .

[0153] Example 12F (((3S,6R)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane A solution of Example 12E (1.00 g) in N,N-dimethylformamide (6.00 mL) was treated with sodium azide (0.80 g) and the reaction was heated to 80° C. for 20 hours. The reaction mixture was cooled to ambient temperature, poured into water (30 mL), and then extracted with 5:1 ethyl acetate / heptane (2×20 mL). The combined organic layers were washed with water (2×20 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.91 (ddd, J = 10.9, 4.9, 2.2 Hz, 1H), 3.65 (tt, J = 10.0, 4.8 Hz, 1H), 3.42 (dddd, J = 10.7, 6.4, 4.0, 2.2 Hz, 1H), 3.24 (qd, J = 12.8, 5.3 Hz, 2H), 3.12 (dd, J = 10.9, 10.0 Hz, 1H), 2.03 (ddq, J = 8.6, 4.6, 2.7, 2.1 Hz, 1H), 1.72 - 1.59 (m, 1H), 1.52 - 1.35 (m, 2H), 0.87 (s, 9H), 0.06 (d, J = 3.5 Hz, 6H). LC / MS (APCI+) m / z 243.95 (M-N2+H) + .

[0154] Example 12G ((2R,5S)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanamine In a 20 mL glass-lined reactor, a solution of Example 12F (0.55 g) in tetrahydrofuran (6.00 mL) was added to an aqueous slurry of Raney-Ni2800 (0.55 g). The reactor was purged with nitrogen. The mixture was stirred under hydrogen (60 psi) at 25° C. After 20 hours, the reactor was vented, the reaction mixture was filtered, and the filtrate was concentrated to give the title compound. LC / MS (ESI+) m / z 246.32 (M+H). + .

[0155] Example 12H 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 A solution of Example 12G (20.0 mg) in dichloromethane (0.80 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.06 mL) and 4-fluoro-3-nitrobenzenesulfonamide (18.0 mg). The reaction was stirred at ambient temperature for 2 hours. To this reaction mixture was added Example 1Q (50.0 mg), N,N-dimethylpyridin-4-amine (21.0 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3 1,3-Dimethylpropane-1,3-diamine hydrochloride (25.0 mg) was added sequentially, and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction mixture was purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane). Fractions containing the tert-butyldimethylsilyl-protected product were combined and concentrated. The residue was dissolved in dichloromethane (4 mL) and placed in an ice bath. After 5 minutes, trifluoroacetic acid (0.8 mL) was added, followed by water (0.2 mL), and the reaction was stirred in the ice bath for 45 minutes. The reaction mixture was concentrated and purified using reverse-phase HPLC (10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to provide the title compound. 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 11.93 (s, 1H), 11.25 - 11.16 (m, 1H), 8.55 (t, J = 5.4 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J = 9.2, 2.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 2.9 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.90 (t, J = 4.7 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.37 (d, J = 13.3 Hz, 1H), 4.28 - 4.20 (t, J = 5.6 Hz, 3H), 3.96 - 3.88 (m, 2H), 3.84 (ddt, J = 9.6, 4.4, 2.5 Hz, 2H), 3.74 (d, J = 13.2 Hz, 2H), 3.63 -3.42 (m, 8H), 3.37 - 3.16 (m, 5H), 3.00 (t, J = 10.4 Hz, 1H), 2.26 - 2.04 (m, 2H), 2.05 - 1.94 (m, 6H), 1.80 - 1.72 (m, 1H), 1.72 - 1.65 (m, 1H), 1.44 - 1.27 (m, 3H), 1.02 (d, J = 10.6 Hz, 6H). LC / MS (APCI+) m / z 1025.27 (M+H) + .

[0156] [Example 13] 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

[0157] Example 13A (R)-(3,4-Dihydro-2H-pyran-2-yl)methanol The title compound was prepared according to literature procedures (Angew Chem Int Ed 2015, 54, pp. 13538-13544). Optical rotation (measured value) [α] D 25 =-78.93 (c 1.06 in chloroform); (Reference) [α] D 25 = -74.32 (c 1.07 in chloroform). A small amount of this material was dissolved in 3-(4-(trifluoromethyl)phenyl)propanoic acid, N,N-dimethylpyridin-4-amine and N 1 -((ethylimino)methylene)-N 3 ,N 3 Treatment with -dimethylpropane-1,3-diamine hydrochloride gave (R)-(3,4-dihydro-2H-pyran-2-yl)methyl 3-(4-(trifluoromethyl)phenyl)propanoate. Analytical chiral supercritical fluid chromatography (ChiralPak AD-H, 5-50% CHOH, 3 mL / min, 10 min method, 150 bar CO) determined the ee of this ester to be 99%. The retention time of the major enantiomer was 1.19 min, and the retention time of the minor enantiomer was 1.09 min.

[0158] Example 13B (R)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran A suspension of sodium hydride (60% wt. in mineral oil, 0.788 g) in tetrahydrofuran (50 mL) was placed in an ice bath for 5 minutes, followed by the addition of Example 13A (1.5 g) as a solution in tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes, then neat benzyl bromide (2.5 mL) was added and the ice bath was removed. The reaction was stirred for 4 hours, then the reaction mixture was placed back in the ice bath and carefully quenched with 1:1 saturated aqueous ammonium chloride and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silica column, 0-5% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.37 - 7.31 (m, 4H), 7.31 - 7.25 (m, 1H), 6.39 (dt, J = 6.4, 1.9 Hz, 1H), 4.67 (dddd, J = 6.2, 4.9, 2.5, 1.3 Hz, 1H), 4.63 - 4.53 (m, 2H), 4.02 (dddd, J = 10.4, 6.4, 4.3, 2.3 Hz, 1H), 3.58 (dd, J = 10.2, 6.3 Hz, 1H), 3.51 (dd, J = 10.1, 4.3 Hz, 1H), 2.08 (dddt, J = 17.2, 10.6, 6.5, 2.4 Hz, 1H), 1.96 (ddddd, J = 17.2, 6.1, 4.6, 2.7, 1.6 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.68 (dtd, J = 13.5, 10.4, 5.9 Hz, 1H).

[0159] Example 13C (3S,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol To a solution of Example 13B (2.00 g) in tetrahydrofuran (24.0 mL) was added 9-borabicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) dropwise at 0° C. over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath, and 10% aqueous sodium hydroxide (15 mL) and then 30% aqueous hydrogen peroxide (16 mL) were carefully added to the mixture at 0° C. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (20 mL) at 0° C. and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with 3:1 ethyl acetate / heptane (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J = 3.9 Hz, 4H), 7.31 - 7.27 (m, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.05 (ddd, J = 10.8, 4.9, 2.3 Hz, 1H), 3.72 (tt, J = 10.1, 4.9 Hz, 1H), 3.53 - 3.38 (m, 3H), 3.14 (dd, J = 10.7, 10.1 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.76 - 1.65 (m, 1H), 1.51 - 1.41 (m, 3H). LC / MS (APCI+) m / z 223.08 (M+H) + .

[0160] Example 13D (2R,5S)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran To a solution of Example 13C (1.00 g) in tetrahydrofuran (12.00 mL) was added sodium hydride (60% by weight in mineral oil, 0.216 g). After stirring for 20 minutes at ambient temperature, neat iodomethane (0.600 mL) was added and stirring continued for 16 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (20 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (40 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.24 (m, 5H), 4.59 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.15 (ddd, J = 10.7, 4.6, 2.3 Hz, 1H), 3.53 - 3.39 (m, 3H), 3.36 (s, 3H), 3.33 - 3.21 (m, 1H), 3.13 (t, J = 10.4 Hz, 1H), 2.20 (dddd, J = 11.5, 5.8, 3.8, 2.4 Hz, 1H), 1.76 - 1.67 (m, 1H), 1.49 - 1.27 (m, 2H). LC / MS (APCI+) m / z 237.40 (M+H) + .

[0161] Example 13E ((2R,5S)-5-Methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate To a flask containing Pd(OH)2 / C (20 wt% Pd, 50% water, 50 mg) was added a solution of Example 13D (0.600 g, 2.54 mmol) in tetrahydrofuran (5.00 mL) and the solution was sparged with nitrogen. The flask was connected to a hydrogen balloon and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was diluted with dichloromethane (5.00 mL). To this solution was added N,N-dimethylpyridin-4-amine (0.464 g), N-ethyl-N-isopropylpropan-2-amine (0.883 mL), and 4-methylbenzene-1-sulfonyl chloride (0.483 g). The reaction was stirred at ambient temperature for 3 hours. The reaction mixture was filtered and the solids were discarded. The filtrate was concentrated and purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.83 - 7.76 (m, 2H), 7.38 - 7.30 (m, 2H), 4.04 (ddd, J = 10.8, 4.7, 2.2 Hz, 1H), 3.97 (dd, J = 5.1, 1.0 Hz, 2H), 3.48 (dtd, J = 10.3, 5.0, 2.2 Hz, 1H), 3.34 (d, J = 0.9 Hz, 3H), 3.20 (tt, J = 9.8, 4.7 Hz, 1H), 3.09 - 2.99 (m, 1H), 2.45 (s, 3H), 2.23 - 2.16 (m, 1H), 1.75 - 1.63 (m, 1H), 1.44 - 1.24 (m, 2H). LC / MS (APCI+) m / z 301.33 (M+H) + .

[0162] Example 13F (2R,5S)-2-(azidomethyl)-5-methoxytetrahydro-2H-pyran A mixture of Example 13E (0.750 g), N,N-dimethylformamide (6.00 mL), and sodium azide (0.800 g) was heated at 80° C. for 5 hours. The reaction was cooled to ambient temperature, poured into water (30 mL), and extracted with 5:1 ethyl acetate / heptane (2×20 mL). The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 4.15 (ddd, J = 10.7, 4.7, 2.3 Hz, 1H), 3.45 (dddd, J = 10.9, 6.4, 4.0, 2.1 Hz, 1H), 3.38 (s, 3H), 3.33 - 3.20 LC / MS (APCI+) m / z 144.25 (M-N2+H) + .

[0163] Example 13G ((2R,5S)-5-Methoxytetrahydro-2H-pyran-2-yl)methanamine In a 20 mL glass-lined reactor, a solution of Example 13F (0.300 g) in tetrahydrofuran (8.00 mL) was added to an aqueous slurry of Raney-Ni2800 (0.600 g). The reactor was purged with nitrogen, and the mixture was stirred under hydrogen (60 psi) at 25° C. After 20 hours, the reactor was vented, the reaction mixture was filtered, and the filtrate was concentrated to give the title compound. LC / MS (APCI+) m / z 146.24 (M+H). + .

[0164] Example 13H 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 A solution of Example 13G (12 mg) in dichloromethane (1.00 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.080 mL) and 4-fluoro-3-nitrobenzenesulfonamide (18 mg). The reaction was stirred at ambient temperature for 2 hours. To this reaction mixture was added Example 1Q (50 mg), N,N-dimethylpyridin-4-amine (21 mg) and N 1 -((ethylimino)methylene)-N 3 ,N 3 -Dimethylpropane-1,3-diamine hydrochloride (25 mg) was added portionwise and stirring was continued for 16 h. The reaction mixture was concentrated and purified using reverse phase HPLC (5-85% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 11.94 (s, 1H), 11.23 (t, J = 2.3 Hz, 1H), 8.57 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.94 (s, 1H), 7.60 (dd, J = 9.3, 2.3 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.19 (dd, J = 3.4, 2.5 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.91 (d, J = 9.3 Hz, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.09 (dd, J = 3.4, 2.0 Hz, 1H), 4.47 (s, 1H), 4.37 (d, J = 13.2 Hz, 1H), 4.27 - 4.21 (m, 3H), 4.14 (d, J = 10.2 Hz, 1H), 4.03 (ddd, J = 10.6, 4.6, 2.2 Hz, 1H), 3.93 (d, J = 9.1 Hz, 1H), 3.84 (ddd, J = 11.1, 9.4, 3.6 Hz, 1H), 3.51 (dt, J = 16.8, 6.4 Hz, 6H), 3.34 (tt, J = 14.9, 6.4 Hz, 3H), 3.27 (s, 3H), 3.21 (tt, J = 10.1, 3.1 Hz, 3H), 3.04 (t, J = 10.4 Hz, 1H), 2.65 (d, J = 8.6 Hz, 1H), 2.21 - 2.04 (m, 3H), 1.99 (q, J = 5.5 Hz, 5H), 1.83 - 1.76 (m, 1H), 1.72 - 1.65 (m, 1H), 1.42 - 1.22 (m, 3H), 1.02 (d, J = 13.2 Hz, 6H). LC / MS (APCI+) m / z 1039.31 (M+H) + .

[0165] [Example 14] 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

[0166] Example 14A 1-Oxaspiro[2.5]octane-6-carboxylic acid ethyl ester A mixture of ethyl 4-oxocyclohexanecarboxylate (50 g), (CH3)3SOI (64.6 g), and potassium 2-methylpropan-2-olate (33.0 g) in ethylene glycol dimethyl ether (700 mL) was stirred at 90 °C for 12 hours under nitrogen. After the mixture was cooled to ambient temperature, the reaction mixture was filtered, and the filtrate was concentrated. The residue was partitioned between water (250 mL) and methyl tert-butyl ether (250 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6 / 1 to 3 / 1) to give the title compound.

[0167] Example 14B Ethyl 4-(fluoromethyl)-4-hydroxycyclohexanecarboxylate A solution of tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 163 mL) was treated with hydrofluoric acid (7.08 mL, 40% solution in water). The volatiles of this mixture were concentrated. To the residue was added potassium bifluoride (1.272 g). The resulting mixture was heated at 100° C. under vacuum (0.55 mmHg) for 15 minutes. After cooling to ambient temperature, heptane (60 mL) and Example 14A (10 g) were added. The mixture was stirred at 120° C. for 24 hours, then cooled to ambient temperature and water was added. The mixture was extracted with ethyl acetate (×3), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6 / 1 to 3 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.15 Hz, 3H) 1.31 - 1.43 (m, 1H) 1.44 - 1.54 (m, 1H) 1.63 - 1.77 (m, 2H) 1.78 - 1.86 (m, 2H) 1.87 - 1.98 (m, 1H) 2.06 (s, 1H) 2.16 - 2.31 (m, 1H) 2.41 - 2.51 (m, 1H) 4.10 (quintet, J=6.88 Hz, 3H) 4.18 - 4.39 (m, 1H).

[0168] Example 14C 1-(Fluoromethyl)-4-(hydroxymethyl)cyclohexanol To a solution of Example 14B (24 g) in tetrahydrofuran (430 mL) cooled using an ice-water bath, lithium aluminum hydride (6.69 g) was added portionwise. The mixture was stirred at 20°C for 2 hours, then cooled back to 0°C and quenched by adding water (6.7 mL), then 15% aqueous sodium hydroxide (6.7 mL), and then water (20.1 mL). Anhydrous sodium sulfate was added. The resulting mixture was stirred for an additional 30 minutes at ambient temperature, and the precipitate was removed by filtration. The filter cake was washed with diethyl ether. The filtrate was then concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 3 to 1 / 10) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.25 - 1.34 (m, 3H) 1.54 - 1.66 (m, 3H) 1.67 - 1.92 (m, 7H) 3.39 (br t, J=4.77 Hz, 3H) 3.67 (br t, J=6.30 Hz, 5H) 4.04 (s, 1H) 4.11 - 4.29 (m, 1H) 4.30 - 4.40 (m, 1H).

[0169] Example 14D ((1s,4s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate; and

[0170] Example 14E ((1s,4s)-4-(chloromethyl)-4-hydroxycyclohexyl)methyl 4-methylbenzenesulfonate To a solution of Example 14C (14 g) in dichloromethane (140 mL) was added p-toluenesulfonyl chloride (19.75 g) and pyridine (34.9 mL) at 0° C. The mixture was stirred at ambient temperature for 12 hours and then washed with water, 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate=10 / 1) to give Example 14D and Example 14E. Example 14D: 1 H NMR (400 MHz, CDCl3) δ ppm 1.24 - 1.40 (m, 4H) 1.54 - 1.75 (m, 6H) 2.46 (s, 3H) 3.81 - 3.92 (m, 2H) 4.08 - 4.27 (m, 2H) 7.35 (d, J=7.95 Hz, 2H) 7.76 - 7.84 (m, 2H);;Example 14E: 1 H NMR (400 MHz, CDCl3) δ ppm 1.23 - 1.41 (m, 4H) 1.60 - 1.90 (m, 6H) 2.39 - 2.55 (m, 3H) 2.64 (s, 1H) 3.43 - 3.53 (m, 2H) 3.82 - 3.92 (m, 2H) 7.35 (d, J=7.95 Hz, 2H) 7.79 (d, J=8.31 ​​Hz, 2H).

[0171] Example 14F (1s,4s)-4-(azidomethyl)-1-(fluoromethyl)cyclohexanol To a solution of Example 14D (6.6 g) in N,N-dimethylformamide (50 mL) was added sodium azide (2.71 g) in small portions. The reaction mixture was stirred at 80° C. for 12 hours. After cooling to ambient temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×75 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel eluted with 15% ethyl acetate in petroleum ether to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.19 - 1.42 (m, 4H) 1.77 (br d, J=4.28 Hz, 6H) 3.12 - 3.23 (m, 2H) 4.06 - 4.30 (m, 2H).

[0172] Example 14G (1s,4s)-4-(aminomethyl)-1-(fluoromethyl)cyclohexanol To a solution of Example 14F (2.95 g) in methanol (59.0 mL) under argon was added Raney nickel (1.39 g). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was then stirred under hydrogen at ambient temperature for 18 hours. The suspension was filtered through a pad of diatomaceous earth and rinsed thoroughly with methanol (500 mL). The combined filtrate was concentrated to dryness to give the crude product, which was triturated in methyl tert-butyl ether (20 mL) to give the title compound. MS (ESI+) m / z 162.0 (M+H) + .

[0173] Example 14H 4-((((1s,4s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 14G (5 g) in N,N-dimethylformamide (50 mL) was added N,N-diisopropylethylamine (21.67 mL) and 4-fluoro-3-nitrobenzenesulfonamide (5.46 g). The solution was stirred at ambient temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.25 - 1.45 (m, 4H), 1.48 - 1.66 (m, 5H), 3.31 (br s, 2H), 4.02 (s, 1H), 4.14 (s, 1H), 4.48 (s, 1H), 7.23 - 7.36 (m, 3H), 7.82 (dd, J=9.17, 2.08 Hz, 1H), 8.47 (d, J=2.20 Hz, 1H), 8.58 (s, 1H). MS (ESI+) m / z 362.2 (M+H) + .

[0174] Example 14I 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 Example 1Q (50 mg), Example 14H (25.4 mg), N,N-dimethylpyridin-4-amine (8.58 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3To a mixture of 18.84 mg of dimethylpropane-1,3-diamine hydrochloride was added 29.4 μL of triethylamine. The mixture was stirred at ambient temperature for 16 hours and then concentrated. The residue was purified on a Gilson reverse-phase HPLC (C18 column, 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid) to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 11.94 (s, 1H), 11.28 (t, J = 2.3 Hz, 1H), 8.59 (q, J = 6.0, 4.8 Hz, 1H), 8.49 - 8.43 (m, 1H), 7.59 (dd, J = 9.3, 2.3 Hz, 1H), 7.51 (d, J = 9.4 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.20 (dd, J = 3.4, 2.5 Hz, 1H), 7.18 - 7.14 (m, 2H), 6.92 - 6.84 (m, 2H), 6.75 (dq, J = 4.7, 2.4 Hz, 2H), 6.11 (dd, J = 3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.22 (t, J = 4.9 Hz, 2H), 4.12 (d, J = 4.2 Hz, 5H), 4.03 (s, 4H), 3.92 (s, 2H), 3.84 (ddd, J = 13.2, 9.9, 3.6 Hz, 3H), 3.73 (d, J = 13.7 Hz, 1H), 3.63 - 3.48 (m, 6H), 3.41 (s, 1H), 3.28 - 3.17 (m, 4H), 2.11 (d, J = 22.5 Hz, 1H), 2.00 - 1.97 (m, 2H), 1.71 - 1.64 (m, 1H), 1.57 - 1.51 (m, 5H), 1.44 - 1.26 (m, 5H), 1.02 (d, J = 12.8 Hz, 6H). MS (ESI+) m / z 1055.6 (M+H) + .

[0175] [Example 15] 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

[0176] Example 15A N,N-Dibenzyl-3-oxocyclobutanecarboxamide To a solution of 3-oxocyclobutanecarboxylic acid (5 g) in dichloromethane (50 mL) at 0° C. was added N,N-dimethylformamide (0.299 mL) followed by oxalyl chloride (6.67 g). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and a solution of dibenzylamine (7.2 g) and N,N-diisopropylethylamine (15.94 mL) in tetrahydrofuran (40 mL) was added dropwise at 0° C. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature and then stirred at this temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (eluting with 10:1 ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 3.06 - 3.18 (m, 2H) 3.34 - 3.44 (m, 1H) 3.53 - 3.63 (m, 2H) 4.51 (s, 2H) 4.69 (s, 2H) 7.10 - 7.48 (m, 10H).

[0177] Example 15B 3-((dibenzylamino)methyl)cyclobutanol To a suspension of lithium aluminum hydride (3.88 g) in tetrahydrofuran (100 mL) was added dropwise a solution of Example 15A (10 g) in tetrahydrofuran (50 mL) at 0° C. under nitrogen. After the addition, the mixture was warmed to ambient temperature and then stirred at this temperature for 2 hours. The reaction mixture was cooled to 0° C. and quenched sequentially with water (3.8 mL), 15% sodium hydroxide (3.8 mL), and water (11.4 mL). The mixture was stirred at ambient temperature for 15 minutes, and then anhydrous magnesium sulfate was added. The resulting mixture was stirred at ambient temperature for an additional 15 minutes and then filtered. The filter cake was washed with ethyl acetate (300 mL). The filtrate was concentrated to dryness to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.36 - 1.52 (m, 2H) 1.57 - 1.69 (m, 1H) 1.91 - 2.11 (m, 1H) 2.39 - 2.57 (m, 4H) 3.53 (s, 4H) 3.82 (s, 1H) 7.17 - 7.45 (m, 10H).

[0178] Example 15C 3-((dibenzylamino)methyl)cyclobutanone To a solution of oxalyl chloride (3.64 mL) in dichloromethane (80 mL) was added dimethyl sulfoxide (5.55 mL) in dichloromethane (10 mL) at −78° C. After stirring the mixture at −78° C. for 20 minutes, a solution of Example 15B (10 g) in dichloromethane (40 mL) was added. The reaction mixture was stirred for an additional 60 minutes at −78° C. Triethylamine (25.8 mL) was added. The mixture was then warmed to ambient temperature and stirred at this temperature for 60 minutes. Water (80 mL) was added. The mixture was extracted with dichloromethane (3×60 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (15:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 2.53 - 2.68 (m, 5H) 2.96 - 3.14 (m, 2H) 3.62 (s, 4H) 7.18 - 7.43 (m, 10H).

[0179] Example 15D (1s,3s)-3-((dibenzylamino)methyl)-[1,1'-bi(cyclobutan)]-1-ol To a solution of cyclobutylmagnesium bromide (1 M in tetrahydrofuran, 44.7 mL) at −60° C. was added a solution of Example 15C (5 g) in dichloromethane (50 mL). After the addition was complete, the mixture was warmed to 10° C. and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride (80 mL) and extracted with dichloromethane (3×40 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (15:1 petroleum ether / ethyl acetate) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.53 (br t, J=9.15 Hz, 3H) 1.68 - 1.94 (m, 6H) 1.96 - 2.05 (m, 1H) 2.08 - 2.25 (m, 2H) 2.50 (br d, J=7.06 Hz, 2H) 3.53 (s, 4H) 7.14 - 7.44 (m, 10H).

[0180] Example 15E (1s,3s)-3-(aminomethyl)-[1,1'-bi(cyclobutan)]-1-ol To a suspension of Example 15D (4.8 g) and 10% Pd(OH)2 on carbon (2.0 g) in methanol (150 mL) was added acetic acid (15 mL). The mixture was stirred at 25°C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction mixture was filtered, and the filter cake was washed successively with methanol (500 mL) and water (200 mL). The filtrate was concentrated to remove methanol. Saturated aqueous sodium carbonate (80 mL) was added to the residue, and the pH was adjusted to 8-9. The mixture was extracted with 1:6 isopropanol / chloroform (4 x 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound. MS (ESI-) m / z 156.1 (M−H) - .

[0181] Example 15F 4-((((1s,3s)-1-hydroxy-[1,1'-bi(cyclobutan)]-3-yl)methyl)amino)-3-nitrobenzenesulfonamide A mixture of N,N-diisopropylethylamine (6.75 mL), Example 15E (1.5 g), and 4-chloro-3-nitrobenzenesulfonamide (2.058 g) in acetonitrile (16 mL) was stirred under nitrogen at 80° C. for 14 hours. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC (C18 column, 30-50% acetonitrile (in 10 mM NHHCO in HO)) to give the title compound. 1H NMR (400 MHz, methanol-d4) δ ppm 1.70 - 1.99 (m, 8H), 2.16 - 2.33 (m, 3H), 2.54 - 2.68 (m, 1H), 3.46 - 3.54 (m, 2H), 7.16 (d, J=9.26 Hz, 1H), 7.90 (m, 1H), 8.65 (d, J=2.20 Hz, 1H).

[0182] Example 15G 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 The title compound was prepared using the same procedure for the last step of Example 14, substituting Example 15F for Example 14H. 1H NMR (400 MHz, ジメチルスルホキシド-d6) δ ppm 11.92 (s, 1H), 11.25 (t, J = 2.3 Hz, 1H), 8.48 - 8.41 (m, 2H), 7.60 (dd, J = 9.2, 2.3 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.20 (q, J = 2.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 6.91 (s, 1H), 6.85 (d, J = 9.4 Hz, 1H), 6.74 (dq, J = 4.1, 2.3 Hz, 2H), 6.10 (dd, J = 3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.36 (d, J = 13.0 Hz, 1H), 4.23 (s, 2H), 4.13 (d, J = 10.5 Hz, 1H), 4.01 (d, J = 14.2 Hz, 2H), 3.92 (s, 2H), 3.61 - 3.47 (m, 8H), 3.39 (t, J = 5.6 Hz, 3H), 3.24 (dt, J = 26.2, 12.0 Hz, 3H), 2.66 (s, 1H), 2.46 (d, J = 8.4 MS (ESI+) m / z 1049.5 (M+H) + .

[0183] [Example 16] 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)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0184] Example 16A 1-Oxaspiro[2.3]hexane-5-carbonitrile A solution of 3-chloroperbenzoic acid (8.34 g) in dichloromethane (193 mL) was stirred under nitrogen at −15° C. for 0.5 hours. The mixture was filtered, and the filtrate was added dropwise to a solution of 3-methylenecyclobutanecarbonitrile (3 g) in dichloromethane (64 mL) at 0° C. The mixture was then stirred at 25° C. for an additional 15 hours, then cooled back to 0° C. and stirred for 0.5 hours. The reaction mixture was filtered, and the filtrate was washed successively with a 10% aqueous solution of sodium bisulfite (90 mL) and a saturated aqueous solution of sodium bicarbonate (2×90 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 2.76 - 2.99 (m, 6H) 3.03 - 3.27 (m, 1H).

[0185] Example 16B (1r,3r)-3-(fluoromethyl)-3-hydroxycyclobutanecarbonitrile; and

[0186] Example 16C (1s,3s)-3-(Fluoromethyl)-3-hydroxycyclobutanecarbonitrile To a stirred solution of tetrabutylammonium fluoride (65.4 mL of a 1.0 M solution in tetrahydrofuran) was added hydrogen fluoride (2.85 mL), and the volatiles were evaporated under reduced pressure. Potassium hydrogen fluoride (0.511 g) was added to the residue, and the resulting mixture was dried under vacuum (0.55 mmHg) at 60° C. for 30 minutes. After the mixture was cooled to ambient temperature, heptane (102 mL) and Example 16A (3.4 g) were added. The mixture was stirred at 120° C. for 24 hours, then cooled to ambient temperature and concentrated. The residue was quenched with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (15% ethyl acetate in petroleum ether) to give Examples 16B and 16C. Example 16B: 1 H NMR (400 MHz, dimethylsulfoxide-d6) δ ppm 2.29 - 2.42 (m, 4H) 3.35 - 3.40 (m, 1H) 4.24 (s, 1H) 4.36 (s, 1H) 5.70 (s, 1H). Example 16C: 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 2.22 - 2.31 (m, 2H), 2.44 - 2.50 (m, 2H), 2.99 (quintet, J = 8.93 Hz, 1H), 4.23 (s, 1H), 4.35 (s, 1H), 5.84 (s, 1H).

[0187] Example 16D (1s,3s)-3-(aminomethyl)-1-(fluoromethyl)cyclobutanol To a solution of Example 16C (5.5 g) in ethanol (275 mL) was added ammonium hydroxide (5.97 g) and Raney nickel (15.0 g) under an argon atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen gas (15 psi) at 25° C. for 24 hours. The suspension was filtered through a pad of diatomaceous earth and washed with ethanol (200 mL). The combined filtrate was concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.70 - 1.78 (m, 2H) 1.90 - 2.02 (m, 1H) 2.25 - 2.33 (m, 5H) 2.75 (d, J =6.11 Hz, 2H) 4.29 (s, 1H) 4.41 (s, 1H).

[0188] Example 16E 4-((((1s,3s)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 16D (5.75 g) in N,N-dimethylformamide (79 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (8.56 g) and N-ethyl-N-isopropylpropan-2-amine (22.32 g). The reaction mixture was stirred at 60° C. under nitrogen protection for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse-phase HPLC (C18 column, 0% to 30% acetonitrile in water, 25 minutes) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.72–1.83 (m, 2H), 2.15–2.27 (m, 3H), 3.49 (t, J =5.87 Hz, 2H), 4.23 (s, 1H), 4.35 (s, 1H), 5.37 (s, 1H), 7.24 (d, J =9.29 Hz, 1H), 7.33 (s, 2H), 7.83 (dd, J =9.17, 2.08 Hz, 1H), 8.43–8.54 (m, 2H).

[0189] Example 16F 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)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide The title compound was prepared using the same procedure as in the last step of Example 14, substituting Example 16E for Example 14H. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 11.92 (s, 1H), 11.25 (t, J = 2.2 Hz, 1H), 8.50 (t, J = 5.8 Hz, 1H), 8.47 - 8.43 (m, 1H), 7.59 (dd, J = 9.2, 2.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.20 (dd, J = 3.4, 2.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 6.89 (s, 1H), 6.85 (d, J = 9.4 Hz, 1H), 6.75 (d, J = 8.2 Hz, 2H), 6.10 (dd, J = 3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.36 (d, J = 21.9 Hz, 2H), 4.24 (s, 2H), 4.14 (d, J = 10.0 Hz, 1H), 4.03 (d, J = 13.7 Hz, 1H), 3.92 (s, 1H), 3.88 - 3.80 (m, 3H), 3.75 (s, 2H), 3.56 - 3.48 (m, 6H), 3.42 (t, J = 5.7 Hz, 4H), 3.24 (dt, J = 27.7, 14.1 Hz, 3H), 2.23 - 2.07 (m, 5H), 2.03 - 1.95 (m, 4H), 1.79 - 1.73 (m, 2H), 1.68 (d, J = 15.2 Hz, 1H), 1.33 (dd, J = 12.2, 9.3 Hz, 1H), 1.02 (d, J = 12.9 Hz, 6H). LC / MS (ESI+) m / z 1028.4 (M+H) + .

[0190] [Example 17] 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-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0191] Example 17A 4-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrobenzenesulfonamide A solution of 4-fluoro-3-nitrobenzenesulfonamide (0.5 g), 3-(aminomethyl)oxetan-3-ol (0.234 g), and triethylamine (0.95 mL) in dioxane (15 mL) was stirred at 50° C. for 2 hours. The reaction was cooled, diluted with ethyl acetate, and washed three times with aqueous 1.0 M HCl. The combined aqueous washes were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was triturated with ethyl acetate / dichloromethane / methanol to give the title compound. MS (ESI-) m / z 604.7 (MH). - .

[0192] Example 17B 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-(((3-hydroxyoxetan-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.049 g), Example 17A (0.020 g), N,N-dimethylpyridin-4-amine (0.025 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.027) in dichloromethane (0.7 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 6% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 11.86 (s, 1H), 11.22 (s, 1H), 8.46 - 8.41 (m, 2H), 7.61 (dd, 1H), 7.46 (d, 1H), 7.38 - 7.30 (m, 2H), 7.19 - 7.13 (m, 1H), 7.09 - 7.01 (m, 2H), 6.94 (d, 1H), 6.84 (s, 1H), 6.77 - 6.67 (m, 2H), 6.33 (s, 1H), 4.47 (d, 2H), 4.39 (d, 2H), 4.19 (s, 2H), 4.02 - 3.98 (m, 1H), 3.87 - 3.60 (m, 8H), 3.53 (d, 2H), 3.48 - 3.38 (m, 1H), 2.92 (t, 1H), 2.77 (d, 1H), 2.69 (t, 1H), 2.23 (d, 1H), 2.14 - 1.80 (m, 8H), 1.63 (d, 4H), 1.36 (dd, 1H), 0.95 (s, 6H). LC / MS (ESI+) m / z 997.57 (M+H) + .

[0193] [Example 18] 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-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0194] Example 18A N-((4-chloro-3-nitrophenyl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzamide Example 1Q (0.075 g), 4-chloro-3-nitrobenzenesulfonamide (0.027 g), N,N-dimethylpyridin-4-amine (0.013 g), N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of N-dimethylpropane-1,3-diamine hydrochloride (0.040 g) and N-ethyl-N-isopropylpropan-2-amine (0.055 mL, 0.316 mmol) in dichloromethane (1.0 mL) was stirred. After stirring for 16 h, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted using a gradient of 0.5% to 4% dichloromethane / methanol over 30 min to give the title compound. LC / MS (ESI+) m / z 930.44 (M+H) + .

[0195] Example 18B 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-(((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide A solution of Example 18A (0.091 g), 4-(aminomethyl)tetrahydro-2H-pyran-4-ol (0.019 g), and N-ethyl-N-isopropylpropan-2-amine (0.085 mL) in dioxane (1.0 mL) was sealed in a vial under nitrogen and heated to 95° C. for 16 hours. The reaction was cooled, loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g), and eluted using a gradient of 1% to 5% dichloromethane / methanol over 30 minutes. Product-containing fractions were collected and concentrated. The residue was dissolved in 1:1 dimethyl sulfoxide:methanol (2 mL) and purified by HPLC using a gradient of 20% to 85% acetonitrile / water to give the title compound. 11H NMR (500 MHz, pyridine-d5) δ ppm 12.58 (s, 1H), 9.18 (d, J = 2.4 Hz, 1H), 8.98 (t, J = 5.2 Hz, 1H), 8.24 (dd, J = 9.2, 2.3 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.40 (t, J = 2.9 Hz, 1H), 7.34 (s, 1H), 7.16 - 7.09 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.05 (dd, J = 3.5, 1.9 Hz, 1H), 4.40 (s, 2H), 4.25 (t, J = 7.2 Hz, 1H), 4.03 (ddt, J = 14.3, 9.1, 3.9 Hz, 4H), 3.92 - 3.56 (m, 11H), 3.40 - 3.31 (m, 3H), 2.92 (ddd, J = 26.7, 12.1, 3.0 Hz, 2H), 2.49 (d, J = 12.3 Hz, 1H), 2.19 - 2.05 (m, 4H), 1.96 (dd, J = 13.6, 5.9 Hz, 2H), 1.92 - 1.71 (m, 7H), 1.61 (dd, J = 12.6, 8.8 Hz, 1H), 1.03 (d, J = 8.8 Hz, 6H). LC / MS (APCI+) m / z 1025.67 (M+H) + .

[0196] [Example 19] 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-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide

[0197] Example 19A 6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-5-nitropyridine-3-sulfonamide To a solution of Example 4C (1.10 g) in tetrahydrofuran (15 mL) was added sodium hydride (0.297 g), and the mixture was stirred for 20 minutes. 4-Fluoro-3-nitrobenzenesulfonamide (1.067 g) was added, followed by tetrahydrofuran (10 mL), and the solution was stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The residue was triturated with tert-butyl methyl ether and filtered to give the title compound. LC / MS (APCI+) m / z 390.08 (M+H) + .

[0198] Example 19B 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-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.075 g), Example 19A (0.037 g), N,N-dimethylpyridin-4-amine (0.039 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.07 (s, 1H), 11.25 (s, 1H), 8.29 (d, 1H), 7.94 (dd, 1H), 7.49 (d, 1H), 7.43 - 7.36 (m, 2H), 7.31 (d, 1H), 7.25 - 7.20 (m, 1H), 7.14 - 7.07 (m, 2H), 6.93 (s, 1H), 6.77 - 6.72 (m, 2H), 6.15 (dd, 1H), 4.56 (t, 2H), 4.46 (t, 2H), 4.33 (d, 2H), 4.23 (s, 2H), 4.04 (t, 1H), 3.91 - 3.42 (m, 12H), 2.96 (t, 1H), 2.85 - 2.79 (m, 1H), 2.73 (t, 1H), 2.64 - 2.59 (m, 2H), 2.28 (d, 1H), 2.19 - 1.57 (m, 15H), 1.41 (dd, 1H), 1.00 (s, 6H). LC / MS (ESI+) m / z 1083.57 (M+H) + .

[0199] [Example 20] 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,5R)-5-methyl-1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide

[0200] Example 20A 4-(((2R,5R)-5-methyl-1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide To a solution of Example 6C (0.300 g) in tetrahydrofuran (11.35 mL) was added sodium hydride (60% in mineral oil, 0.209 g), the mixture was stirred for 20 minutes, and then 4-fluoro-3-nitrobenzenesulfonamide (0.500 g) was added. The reaction was stirred for 1 hour, then quenched with saturated aqueous ammonium hydroxide (25 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (40 mL), dried over magnesium sulfate, and concentrated. The resulting residue was triturated with dichloromethane (10 mL), filtered, and dried to give the title compound. LC / MS (ESI+) m / z 333.04 (M+H) + .

[0201] Example 20B 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,5R)-5-methyl-1,4-dioxan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.075 g), Example 20A (0.035 g), N,N-dimethylpyridin-4-amine (0.039 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of 0.040-dimethylpropane-1,3-diamine hydrochloride in 1.0 mL of dichloromethane was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted using a gradient of 1% to 4% dichloromethane / methanol over 30 minutes. This material was dissolved in 2 mL of 1:1 dimethyl sulfoxide / methanol, followed by the addition of 0.024 mL of 2,2,2-trifluoroacetic acid and purification by HPLC (Luna 10 μm C18(2) 250 × 50 mm column) using a gradient of 20% to 85% acetonitrile / water over 30 minutes. The product was collected and lyophilized to give the title compound. 11H NMR (500 MHz, pyridine-d5) δ ppm 12.42 (d, J = 2.3 Hz, 1H), 8.96 (d, J = 2.3 Hz, 1H), 8.38 (dd, J = 8.9, 2.3 Hz, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.42 - 7.37 (m, 1H), 7.31 (s, 1H), 7.16 - 7.08 (m, 2H), 7.08 - 7.01 (m, 2H), 6.84 (dd, J = 9.0, 2.3 Hz, 1H), 6.02 (dd, J = 3.4, 1.9 Hz, 1H), 4.40 (s, 2H), 4.26 (t, J = 6.8 Hz, 1H), 4.16 (dd, J = 10.2, 4.9 Hz, 1H), 4.09 (dd, J = 10.2, 4.6 Hz, 1H), 4.02 (ddt, J = 14.2, 7.3, 3.4 Hz, 3H), 3.93 - 3.58 (m, 13H), 3.53 (ddd, J = 10.2, 6.3, 2.7 Hz, 1H), 3.36 (t, J = 11.4 Hz, 1H), 3.22 (dd, J = 11.4, 10.2 Hz, 1H),​​​​​​​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,5R)-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0203] Example 21A (S)-1-Chloro-3-(dibenzylamino)propan-2-ol A mixture of dibenzylamine (50 g) and (S)-(+)-epichlorohydrin (35.2 g) in dichloromethane (150 mL) was stirred at ambient temperature for 96 hours. The reaction mixture was concentrated, and the residue was purified using flash chromatography (silica, 1-2.5% ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.39 - 7.23 (m, 10H), 3.88 (dq, J = 8.5, 5.1 Hz, 1H), 3.78 (d, J = 13.4 Hz, 2H), 3.52 (d, J = 13.5 Hz, 2H), 3.47 (dd, J = 5.4, 2.4 Hz, 2H), 3.23 (d, J = 5.5 Hz, 1H), 2.62 (qd, J = 12.9, 6.6 Hz, 2H).

[0204] Example 21B (S)-N,N-Dibenzyl-1-(oxiran-2-yl)methanamine To a solution of Example 21A (350 g) in N,N-dimethylformamide (1.8 L) was added sodium hydroxide (97 g) and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water (5 L) and extracted with methyl tert-butyl ether (3 x 1 L). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.48 - 7.18 (m, 10H), 3.81 (d, J = 13.7 Hz, 2H), 3.58 (d, J = 13.7 Hz, 2H), 3.09 (dq, J = 6.6, 3.4 Hz, 1H), 2.78 (dd, J = 13.8, 3.6 Hz, 1H), 2.68 (t, J = 4.6 Hz, 1H), 2.50 - 2.38 (m, 2H).

[0205] Example 21C (R)-1-(Dibenzylamino)pent-4-en-2-ol To a solution of Example 21B (140 g) in tetrahydrofuran (1399 mL) was added copper(I) chloride and the reaction was cooled to -10°C. Vinylmagnesium bromide (1 M in tetrahydrofuran, 829 mL) was added dropwise and the reaction was stirred at 0°C for 1 hour. Methanol (55.9 mL) was added followed by water (200 mL) at 0°C and the mixture was extracted with methyl tert-butyl ether (3 x 200 mL). The combined organic layers were washed with water (5 x 200 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated. This material was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ ppm 7.43 - 7.27 (m, 10H), 5.79 (ddt, J = 17.3, 10.4, 7.0 Hz, 1H), 5.12 - 5.01 (m, 2H), 3.89 - 3.73 (m, 3H), 3.43 (d, J = 13.5 Hz, 2H), 3.28 - 3.17 (m, 1H), 2.54 - 2.41 (m, 2H), 2.23 - 2.06 (m, 2H).

[0206] Example 21D (R)-N,N-Dibenzyl-2-((2-methylallyl)oxy)pent-4-en-1-amine A solution of Example 21C (150 g) in tetrahydrofuran (1.5 L) was cooled to 0° C., and potassium tert-butoxide (90 g) was added. Neat 3-bromo-2-methylprop-1-ene (108 g) was added at 0° C., and the mixture was stirred at ambient temperature for 12 hours. The mixture was poured into water (200 mL) and extracted with methyl tert-butyl ether (3×200 mL). The combined organic layers were washed with water (5×200 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated. This material was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.12 (m, 10H), 5.61 (ddt, J = 17.3, 10.2, 7.1 Hz, 1H), 4.96 - 4.70 (m, 4H), 3.88 - 3.77 (m, 2H), 3.60 - 3.44 (m, 4H), 3.39 (p, J = 5.8 Hz, 1H), 2.54 - 2.41 (m, 2H), 2.36 - 2.25 (m, 1H), 2.12 (dddt, J = 14.5, 7.4, 6.2, 1.3 Hz, 1H), 1.64 (s, 3H).

[0207] Example 21E (R)-N,N-Dibenzyl-1-(5-methyl-3,4-dihydro-2H-pyran-2-yl)methanamine To a solution of Example 21D (50 g) in toluene (1 L) was added (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (5.06 g) and the reaction was heated to 110° C. for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with methyl tert-butyl ether (3×100 mL). The combined organic layers were washed with water (2×100 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (silica, 1-3% ethyl acetate / petroleum ether) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.38 - 7.11 (m, 10H), 5.38 (dp, J = 5.6, 1.8 Hz, 1H), 4.00 - 3.82 (m, 2H), 3.69 (d, J = 13.7 Hz, 2H), 3.60 (dtd, J = 9.7, 5.9, 3.7 Hz, 1H), 3.45 (d, J = 13.7 Hz, 2H), 2.55 (dd, J = 13.3, 6.2 Hz, 1H), 2.45 (dd, J = 13.2, 5.5 Hz, 1H), 1.99 - 1.73 (m, 2H), 1.49 (dq, J = 2.5, 1.3 Hz, 3H). LC / MS (ESI+) m / z 308.20 (M+H) + .

[0208] Example 21F ((2R)-5-Methyltetrahydro-2H-pyran-2-yl)methanamine To a glass-lined reactor containing Pd(OH) / C (10 wt% Pd, wet catalyst, 0.200 g) was added a solution of Example 21E (1.00 g) in tetrahydrofuran (10 mL). The reactor was heated to 60°C under hydrogen (50 psi) for 2 days. The reaction was cooled to ambient temperature and filtered. The residue was used directly in the next step.

[0209] Example 21G 4-((((2R,5R)-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide A solution of Example 21F (0.42 g) in dichloromethane (8.00 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (2.00 mL), followed by the addition of 4-fluoro-3-nitrobenzenesulfonamide (0.716 g), and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was purified using flash chromatography (80 g silica column, 20-100% ethyl acetate / heptane) to isolate the mixture of diastereomers. After reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) and lyophilization of the faster-eluting component, the title compound was obtained from the above mixture. 1 H NMR (600 MHz, CDCl3) δ ppm 8.69 (dd, J = 2.3, 1.1 Hz, 1H), 8.59 (s, 1H), 7.78 (ddd, J = 9.1, 2.3, 1.1 Hz, 1H), 6.79 (dd, J = 9.2, 1.1 Hz, 1H), 4.55 (s, 2H), 3.70 - 3.65 (m, 1H), 3.63 - 3.58 (m, 1H), 3.58 - 3.51 (m, 1H), 3.25 (q, J = 4.1, 3.7 Hz, 2H), 1.76 - 1.69 (m, 2H), 1.67 - 1.59 (m, 2H), 1.44 - 1.38 (m, 1H), 1.08 (d, J = 6.9 Hz 3H). LC / MS (ESI+) m / z 330.02 (M+H) + .

[0210] Example 21H 4-((((2R,5S)-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide The title compound was obtained as the second peak from the reverse phase HPLC separation described in Example 21G. 1H NMR (500 MHz, CDCl3) δ ppm 8.76 (d, J = 2.3 Hz, 1H), 8.62 (s, 1H), 7.87 (dd, J = 9.1, 2.4 Hz, 1H), 6.98 - 6.92 (m, 1H), 4.78 (s, 2H), 3.95 (ddd, J = 11.3, 4.4, 2.2 Hz, 1H), 3.60 - 3.51 (m, 1H), 3.48 - 3.29 (m, 2H), 3.06 (t, J = 11.1 Hz, 1H), 1.91 (dp, J = 13.3, 3.5 Hz, 1H), 1.71 (ddt, J = 13.7, LC / MS (ESI+) m / z 330.06 (M+H) + .

[0211] Example 21I 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,5R)-5-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide A solution of Example 21G (27 mg) in dichloromethane (0.80 mL) was added to N-ethyl-N-isopropylpropan-2-amine (0.05 mL), Example 1Q (50 mg), N,N-dimethylpyridin-4-amine (14 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3-dimethylpropane-1,3-diamine hydrochloride (20 mg) and the mixture was stirred for 23 h. The reaction mixture was concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 11.93 (s, 1H), 11.25 - 11.16 (m, 1H), 8.57 (t, J = 5.4 Hz, 1H), 8.47 (t, J = 2.3 Hz, 1H), 7.97 (s, 1H), 7.62 (dd, J = 9.2, 2.3 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.22 - 7.11 (m, 2H), 6.93 - 6.85 (m, 2H), 6.74 (d, J = 7.4 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H), 4.24 (t, J = 5.5 Hz, 2H), 4.13 (d, J = 10.2 Hz, 2H), 4.01 (d, J = 13.6 Hz, 1H), 3.96 - 3.77 (m, 2H), 3.72 (d, J = 13.3 Hz, 1H), 3.66 - 3.48 (m, 8H), 3.41 (ddt, J = 16.1, 8.3, 3.6 Hz, 2H), 3.33 - 3.16 (m, 2H), 2.65 (d, J = 11.1Hz, 1H), 2.20 - 1.89 LC / MS (ESI+) m / z 1023.74 (M+H) + .

[0212] [Example 22] N-((5-chloro-6-((4-fluoro-1-(2-methoxyethyl)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

[0213] Example 22A Ethyl 1-(2-methoxyethyl)piperidine-4-carboxylate To a solution of ethyl piperidine-4-carboxylate (10 g) in ethanol (100 mL) was added potassium carbonate (26.4 g) and 1-bromo-2-methoxyethane (9.73 g). The resulting mixture was stirred at 70° C. for 12 hours. The reaction was cooled and concentrated, and the residue was diluted with water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.21 (t, J=7.09 Hz, 3H), 1.69-1.92 (m, 4H), 2.02 (td, J=11.35, 2.56 Hz, 2H), 2.16-2.30 (tt, J=11.00, 4.20 Hz, 1H), 2.52 (t, J=5.72 Hz, 2H), 2.88 (br d, J =11.68 Hz, 2H), 3.32 (s, 3H), 3.47 (t, J =5.72 Hz, 2H), 4.09 (q, J =7.15 Hz, 2H).

[0214] Example 22B Ethyl 4-fluoro-1-(2-methoxyethyl)piperidine-4-carboxylate To a solution of lithium N,N-diisopropylamine (46.4 mL) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of Example 22A (10 g) in anhydrous tetrahydrofuran (50 mL) at −78° C. The reaction mixture was stirred at −78° C. for 30 minutes. N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (29.3 g) was added in small portions. The resulting mixture was gradually warmed to 25° C. and stirred for 12 hours. The reaction was quenched by the dropwise addition of saturated aqueous ammonium chloride (200 mL) at 0° C. and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 1:1 to 0:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.28 (br t, J =7.09 Hz, 2H), 1.93 (br t, J =11.55 Hz, 1H), 2.05-2.48 (m, 3H), 2.60 (br t, J =5.50 Hz, 1H), 2.83 (br t, J =5.50 Hz, 1H), d, J =10.76 Hz, 1H), 3.35 (s, 1H), 3.51 (br t, J =5.44 Hz, 1H), 4.22 (br d, J =7.09 Hz, 1H).

[0215] Example 22C (4-Fluoro-1-(2-methoxyethyl)piperidin-4-yl)methanol To a solution of Example 22B (5 g) in anhydrous tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.627 g) at 0° C. The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was cooled to 0° C., diluted with tetrahydrofuran, and quenched by the dropwise addition of water (6.5 mL), 15% aqueous sodium hydroxide solution (6.5 mL), and water (19.5 mL), in that order. The reaction mixture was filtered, and the filtrate was concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.61-1.81 (m, 2H), 1.82-1.95 (m, 2H), 2.25-2.38 (m, 2H), 2.59 (t, J=5.62 Hz, 2H), 2.71-2.81 (m, 2H), 3.33 (s, 3H), 3.44-3.54 (m, 3H), 3.58 (s, 1H).

[0216] Example 22D 5-chloro-6-((4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)methoxy)pyridine-3-sulfonamide To a solution of Example 22C (5 g) in N,N-dimethylformamide (70 mL) was added sodium hydride (4.18 g) at 0° C. The reaction mixture was stirred at 25° C. for 30 minutes, then 5,6-dichloropyridine-3-sulfonamide (4.75 g) was added, and stirring was continued for 12 hours. The reaction mixture was quenched by adding water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with 1:1 petroleum ether and ethyl acetate (50 mL) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.69-1.94 (m, 4H), 2.21-2.31 (m, 2H), 2.48 (br s, 2H), 2.68-2.76 (m, 2H), 3.23 (s, 3H), 3.43 (t, J LC / MS: m / z 380.1 (MH) - .

[0217] Example 22E N-((5-chloro-6-((4-fluoro-1-(2-methoxyethyl)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 Example 1Q (0.075 g), Example 22D (0.036 g), N,N-dimethylpyridin-4-amine (0.039 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 hours, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted with a gradient of 1% to 4% dichloromethane / methanol over 30 minutes to give the title compound. 1H NMR (600 MHz, pyridine-d5) δ ppm 12.71 (s, 1H), 9.01 (d, 1H), 8.58 (d, 1H), 8.15 (d, 1H), 7.50 - 7.44 (m, 2H), 7.42 (dd, 1H), 7.37 (s, 1H), 7.15 - 7.09 (m, 2H), 7.05 (d, 1H), 6.86 (dd, 1H), 6.07 (dd, 1H), 4.42 - 4.29 (m, 4H), 4.29 - 4.20 (m, 1H), 4.06 - 3.98 (m, 2H), 3.93 - 3.71 (m, 5H), 3.70 - 3.55 (m, 4H), 3.47 (t, 2H), 3.36 (t, 1H), 3.24 (s, 3H), 2.98 - 2.85 (m, 2H), 2.78 - 2.67 (m, 2H), 2.57 (t, 2H), 2.49 (d, 1H), 2.42 (t, 2H), 2.20 - 2.06 (m, 4H), 2.02 - 1.71 (m, 9H), 1.61 (dd, 1H), 1.03 (d, 6H). LC / MS (ESI+) m / z 1077.65 (M+H) + .

[0218] [Example 23] 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-methyltetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide The title compound was prepared according to the procedure for the last step of Example 21, substituting Example 21H for Example 21G. The crude product was purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-70% acetonitrile / water (+0.1% trifluoroacetic acid)). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 11.93 (s, 1H), 11.23 (t, J = 2.3 Hz, 1H), 8.57 (t, J = 5.4 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.49 (d, J = 9.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.25 - 7.14 (m, 3H), 6.94 - 6.86 (m, 2H), 6.73 (dd, J = 6.6, 2.6 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.52 - 4.17 (m, 6H), 3.89 - 3.68 (m, 6H), 3.65 - 3.43 (m, 8H), 3.38 - 3.16 (m, 4H), 2.96 (t, J = 11.1 Hz, 1H), 2.65 (d, J = 12.5 Hz, 1H), 2.23 - 1.87 (m, 6H), 1.80 (dt, J = 12.6, 3.1 Hz, 1H), 1.73 - 1.62 (m, 2H), 1.57 (dddd, J = 15.4, 11.6, 8.2, 4.2 Hz, 1H), 1.33 (ddt, J = 13.2, 10.2, 6.5Hz, LC / MS (ESI+) m / z 1023.67 (M+H) + .

[0219] [Example 24] 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)-3-methoxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0220] Example 24A N-benzyl-3-oxocyclobutanecarboxamide To a solution of 3-oxocyclobutanecarboxylic acid (5 g) in tetrahydrofuran (50 mL) was added N,N'-carbonyldiimidazole (8.53 g) at 0°C. The reaction mixture was stirred at 20°C for 1.5 hours, and then phenylmethanamine (5.75 mL) was added at 20°C, and the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with 20:1 ethyl acetate / petroleum ether (1 L) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.39 - 7.19 (m, 5H), 6.34 - 6.15 (m, 1H), 4.50 - 4.42 (m, 2H), 3.53 - 3.40 (m, 2H), 3.22 - 3.09 (m, 2H), 3.07 - 2.95 (m, 1H).

[0221] Example 24B (1s,3s)-N-benzyl-3-hydroxycyclobutanecarboxamide To a solution of Example 24A (5 g) in methanol (50 mL) was added sodium borohydride (1.396 g) at 0° C., and the reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with 15:1 ethyl acetate / petroleum ether (1 L) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.34 - 8.14 (m, 1H), 7.37 - 7.15 (m, 5H), 5.22 - 5.00 (m, 1H), 4.29 - 4.20 (m, 2H), 4.00 - 3.85 (m, 1H), 2.46 - 2.37 (m, 1H), 2.32 - 2.21 (m, 2H), 2.02 - 1.91 (m, 2H).

[0222] Example 24C (1s,3s)-N-benzyl-3-methoxycyclobutanecarboxamide To a solution of Example 24B (8 g) in methyl ethyl ketone (100 mL) was added silver oxide (18.06 g) and methyl iodide (7.31 mL) at 20° C., and the reaction mixture was stirred at 70° C. for 24 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was quenched by adding water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (eluting with 3 / 1 petroleum ether / ethyl acetate to ethyl acetate) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.24 (m, 5H), 5.91 - 5.73 (m, 1H), 4.52 - 4.35 (m, 2H), 3.86 - 3.66 (m, 1H), 3.37 - 3.17 (m, 3H), 2.56 - 2.43 (m, 3H), 2.24 - 2.13 (m, 2H).

[0223] Example 24D N-Benzyl-1-((1s,3s)-3-methoxycyclobutyl)methanamine To a solution of Example 24C (5 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.731 g) at 0° C. The reaction mixture was stirred at 70° C. for 2 hours. To the reaction mixture were added water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL), and water (3×1.8 mL). The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 9.65 - 9.32 (m, 2H), 7.51 - 7.29 (m, 5H), 3.95 - 3.77 (m, 2H), 3.75 - 3.60 (m, 1H), 3.28 - 3.06 (m, 3H), 2.93 - 2.69 (m, 2H), 2.42 - 2.23 (m, 2H), 2.14 - 1.97 (m, 1H), 1.63 - 1.45 (m, 2H).

[0224] Example 24E ((1s,3s)-3-Methoxycyclobutyl)methanamine To a solution of Example 24D (3.7 g) in methanol (40 mL) was added Pd / C (4.79 g) at 20° C. The reaction mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 3.80 - 3.64 (m, 1H), 3.26 - 3.10 (m, 3H), 2.80 - 2.63 (m, 2H), 2.38 - 2.24 (m, 2H), 1.90 - 1.71 (m, 3H), 1.54 - 1.45 (m, 2H).

[0225] Example 24F 4-((((1s,3s)-3-Methoxycyclobutyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 24E (1.50 g) in N,N-dimethylformamide (15 mL) at 20° C. was added N,N-diisopropylethylamine (4.55 mL) and 4-chloro-3-nitrobenzenesulfonamide (2.46 g). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (Welch Xtimate C18 250×50 mm 10 μm, mobile phase: A: 10 mM NH4HCO3 in HO; B: acetonitrile) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.56 - 8.48 (m, 1H), 8.48 - 8.44 (m, 1H), 7.89 - 7.78 (m, 1H), 7.42 - 7.29 (m, 2H), 7.28 - 7.21 (m, 1H), 3.76 - 3.64 (m, 1H), 3.51 - 3.44 (m, 2H), 3.15 - 3.07 (m, 3H), 2.37 - 2.26 (m, 2H), 2.24 - 2.09 (m, 1H), 1.68 - 1.54 (m, 2H).

[0226] Example 24G 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)-3-methoxycyclobutyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.040 g), Example 24F (0.017 g), N,N-dimethylpyridin-4-amine (0.021 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.022 g) in dichloromethane (0.6 mL) was stirred for 3 days. The reaction was loaded onto silica gel (Agila, 40 g) and eluted with a gradient of 0.5% to 4.5% dichloromethane / methanol over 30 minutes to give the title compound. 1H NMR (400 MHz, pyridine-d5) δ ppm 12.60 (s, 1H), 9.17 (d, 1H), 8.34 (t, 1H), 8.20 (dd, 1H), 8.10 (d, 1H), 7.46 - 7.40 (m, 2H), 7.38 (dd, 1H), 7.31 (s, 1H), 7.12 - 7.03 (m, 2H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.61 (d, 1H), 6.04 (dd, 1H), 4.36 (s, 2H), 4.21 (d, 1H), 3.96 (d, 2H), 3.88 - 3.51 (m, 10H), 3.30 (t, 1H), 3.10 (dd, 2H), 3.07 (s, 3H), 2.94 - 2.79 (m, 2H), 2.44 (d, 1H), 2.30 - 2.17 (m, 2H), 2.16 - 2.01 (m, 4H), 1.98 - 1.67 (m, 6H), 1.65 - 1.49 (m, 3H), 0.99 (d, 6H). LC / MS (ESI+) m / z 1009.82 (M+H) + .

[0227] [Example 25] 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-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0228] Example 25A (S)-(3,4-Dihydro-2H-pyran-2-yl)methanol To a flask containing racemic (3,4-dihydro-2H-pyran-2-yl)methanol (25.8g) were added dichloromethane (250mL) and N,N-dimethylpyridin-4-amine (32.0g). The flask was placed in an ice bath. After 15 minutes, neat acetyl chloride (16.1mL) was added, and the reaction was stirred in the ice bath for 1 hour. The reaction mixture was poured into a separatory funnel containing water (200mL), and the two layers were separated. The aqueous layer was extracted once with dichloromethane (80mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified using flash chromatography (330g silica column, 0-60% ethyl acetate / heptane) to afford racemic (3,4-dihydro-2H-pyran-2-yl)methyl acetate. To a flask containing water (1 L), potassium phosphate tribasic (4.48 g) and potassium dihydrogen phosphate (4.28 g) were added, and the mixture was stirred until all solids were dissolved. To this solution, racemic (3,4-dihydro-2H-pyran-2-yl)methyl acetate (10.0 g) in acetone (10 mL) was added at ambient temperature, followed by porcine pancreatic lipase (75 mg). In a separate flask, the same reaction was set up on a double scale. The reactions were stirred at ambient temperature for 18 hours, then both were combined in a separatory funnel and extracted with 1:1 ethyl acetate / heptane (2 x 500 mL). The combined organic layer was discarded, and the aqueous layer was extracted with 9:1 ethyl acetate / heptane (2 x 500 mL). The combined organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified using flash chromatography (80 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 6.39 (dt, J = 6.3, 2.0 Hz, 1H), 4.71 (dddd, J = 6.3, 5.0, 2.5, 1.3 Hz, 1H), 3.96 - 3.88 (m, 1H), 3.76 - 3.62 (m, 2H), 2.12 (dddt, J = 17.3, 10.8, 6.6, 2.4 Hz, 1H), 2.04 - 1.94 (m, 1H), 1.88 (dd, J = 7.3, 5.4 Hz, 1H), 1.82 - 1.76 (m, 1H), 1.74 - 1.66 (m, 1H). A small amount of this material was mixed with 3-(4-(trifluoromethyl)phenyl)propanoic acid, N,N-dimethylpyridin-4-amine, and N 1 -((ethylimino)methylene)-N 3 ,N 3 Treatment with -dimethylpropane-1,3-diamine hydrochloride gave (S)-(3,4-dihydro-2H-pyran-2-yl)methyl 3-(4-(trifluoromethyl)phenyl)propanoate. Analytical chiral supercritical fluid chromatography (ChiralPak AD-H, 5-50% CHOH, 3 mL / min, 10 min method, 150 bar CO) determined the ee of this ester to be 93%. The retention time of the major enantiomer was 1.26 min, and the retention time of the minor enantiomer was 1.34 min.

[0229] Example 25B (S)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran To a flask containing sodium hydride (60% by weight in mineral oil, 1.104 g) was added tetrahydrofuran (60.0 mL). The slurry was cooled in an ice bath, and a solution of Example 25A (2.100 g) in tetrahydrofuran (3 mL) was added dropwise, followed by tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes. Neat (bromomethyl)benzene (3.50 mL) was added, and the ice bath was removed. The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and carefully quenched by the dropwise addition of 1:1 water / saturated aqueous ammonium chloride solution (80 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 × 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (80 g silica column, 0–5% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.40 - 7.27 (m, 5H), 6.40 (dt, J = 6.2, 2.0 Hz, 1H), 4.69 (dddd, J = 6.3, 4.9, 2.5, 1.3 Hz, 1H), 4.62 (d, J = 12.2 Hz, 1H), 4.58 (d, J = 12.2 Hz, 1H), 4.03 (dddd, J = 10.4, 6.4, 4.3, 2.3 Hz, 1H), 3.60 (dd, J = 10.2, 6.3 Hz, 1H), 3.53 (dd, J = 10.2, 4.3 Hz, 1H), 2.10 (dddt, J = 17.2, 10.6, 6.5, 2.4 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.90 - 1.81 (m, 1H), 1.70 (dtd, J = 13.5, 10.4, 5.9 Hz, 1H).

[0230] Example 25C (3R,6S)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol To a solution of Example 25B (3.60 g) in tetrahydrofuran (50.0 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 75.0 mL) dropwise at 0° C. over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath, and 10% aqueous sodium hydroxide (25 mL) and then 30% aqueous hydrogen peroxide (32 mL) were carefully added to the mixture at 0° C. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (40 mL) at 0° C. and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with 3:1 ethyl acetate / heptane (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (120 g silica column, 0-60% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.42 - 7.27 (m, 5H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.05 (ddd, J = 10.8, 4.9, 2.3 Hz, 1H), 3.71 (td, J = 10.2, 5.0 Hz, 1H), 3.53 - 3.38 (m, 3H), 3.14 (dd, J = 10.8, 10.2 Hz, 1H), 2.14 (dtd, J = 8.2, 4.7, 4.0, 2.3 Hz, 1H), 1.76 - 1.66 (m, 1H), 1.51 - 1.35 (m, 3H). LC / MS (APCI+) m / z 223.53 (M+H) + .

[0231] Example 25D (2S,5R)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran A solution of Example 25C (1.000 g) in tetrahydrofuran (20.0 mL) was cooled in an ice bath. Solid sodium hydride (60 wt% in mineral oil, 0.270 g) was added, and the mixture was stirred in the ice bath for 15 minutes. Neat iodomethane (0.400 mL) was added, and the reaction was warmed to ambient temperature and stirred for 16 hours. The reaction was quenched by adding 0.1% aqueous trifluoroacetic acid (4 mL) and water (20 mL) and then extracted with 5:1 ethyl acetate / heptane (2 × 30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (40 g silica column, 0-40% ethyl acetate / heptane) to provide the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 7.40 - 7.26 (m, 5H), 4.59 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 4.15 (ddd, J = 10.8, 4.7, 2.3 Hz, 1H), 3.52 - 3.39 (m, 3H), 3.36 (s, 3H), 3.32 - 3.23 (m, 1H), 3.13 (t, J = 10.4 Hz, 1H), 2.24 - 2.16 (m, 1H), 1.76 - 1.68 (m, 1H), 1.46 - 1.30 (m, 2H). LC / MS (APCI+) m / z 237.46 (M+H) + .

[0232] Example 25E ((2S,5R)-5-Methoxytetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate To a flask containing Pd(OH)2 / C (20 wt% Pd, 50% water, 50 mg) was added a solution of Example 25D (0.97 g) in tetrahydrofuran (10.00 mL). The flask was purged with nitrogen and connected to a hydrogen balloon. The reaction was stirred at ambient temperature for 24 hours, then the mixture was filtered and concentrated. The residue was dissolved in dichloromethane (15 mL), then N,N-dimethylpyridin-4-amine (0.750 g), N-ethyl-N-isopropylpropan-2-amine (1.500 mL), and 4-methylbenzene-1-sulfonyl chloride (0.800 g) were added sequentially. The reaction was stirred at ambient temperature for 3 hours, then the mixture was poured into water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (silica, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.79 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 4.04 (ddd, J = 10.8, 4.7, 2.3 Hz, 1H), 3.97 (d, J = 5.1 Hz, 2H), 3.48 (dtd, J = 10.7, 5.1, 2.5 Hz, 1H), 3.34 (s, 3H), 3.25 - 3.15 (m, 1H), 3.04 (dd, J = 10.8, 10.1 Hz, 1H), 2.45 (s, 3H), 2.23 - 2.15 (m, 1H), 1.74 - 1.65 (m, 1H), 1.41 - 1.23 (m, 2H). LC / MS (APCI+) m / z 301.36 (M+H) + .

[0233] Example 25F (2S,5R)-2-(azidomethyl)-5-methoxytetrahydro-2H-pyran A mixture of Example 25E (1.000 g), N,N-dimethylformamide (6.00 mL), and sodium azide (1.000 g) was heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature, poured into water (30 mL), and extracted with 5:1 ethyl acetate / heptane (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 4.13 (ddd, J = 10.8, 4.7, 2.3 Hz, 1H), 3.44 (dddd, J = 10.9, 6.6, 3.9, 2.2 Hz, 1H), 3.36 (s, 3H), 3.30 - 3.19 (m, 3H), 3.11 (t, J = 10.5 Hz, 1H), 2.25 - 2.17 (m, 1H), 1.73 - 1.66 (m, 1H), 1.47 - 1.30 (m, 2H). LC / MS (APCI+) m / z 144.27 (M-N2+H) + .

[0234] Example 25G 4-((((2S,5R)-5-Methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 25F (0.57 g) in tetrahydrofuran (6.00 mL) was added water (0.076 mL) and triphenylphosphine (1.10 g), and the reaction was stirred at ambient temperature for 16 hours. To this reaction mixture was added N-ethyl-N-isopropylpropan-2-amine (2.32 mL) and 4-fluoro-3-nitrobenzenesulfonamide (0.73 g), and stirring at ambient temperature was continued for 2 hours. The reaction mixture was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to provide the title compound. 1H NMR (600 MHz, CDCl3) δ ppm 8.77 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 7.88 (ddd, J = 9.2, 2.3, 0.7 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.75 (s, 2H), 4.18 (ddd, J = 10.8, 4.7, 2.3 Hz, 1H), 3.63 - 3.55 (m, 1H), 3.47 (ddd, J = 13.2, 5.8, 3.7 Hz, 1H), 3.39 (s, 3H), 3.37 - 3.26 (m, 2H), 3.17 (t, J = 10.5 Hz, 1H), 2.27 (dt, J = 12.6, 3.4 Hz, 1H), 1.82 (dq, J = 13.2, 3.1 Hz, 1H), 1.53 - 1.48 (m, 1H), 1.42 (tdd, J = 13.1, 10.7, 4.1 Hz, 1H). LC / MS (APCI+) m / z 346.39 (M+H) + .

[0235] Example 25H 7,7-Dimethyl-4,6,7,8-tetrahydro-2H,5H-1,3-benzodioxin-5-one To a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) was added boron trifluoride diethyl etherate (40.7 mL) over 10 minutes, and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3, the organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in heptane / ethyl acetate (5:1), concentrated, treated with heptane (300 mL), and filtered. The residue was chromatographed on silica gel (ISCO GOLD®) eluting with a 0-16% ethyl acetate / heptane gradient to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 5.13 (s, 2H), 4.43 (t, 2H), 2.28 (t, 2H), 2.22 (s, 2H), 1.08 (s, 6H). MS (DCI+) m / z 183.1 (M+H) + .

[0236] Example 25I 4'-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one To a solution of 1-bromo-4-chlorobenzene (30.3 g) in tetrahydrofuran (200 mL) at −78° C., n-butyllithium (2.5 M in hexanes, 60.6 mL) was added dropwise, maintaining the temperature below −70° C. After stirring at −78° C. for 30 minutes, a solution of Example 25H (24 g) in tetrahydrofuran (75 mL) was added dropwise, maintaining the temperature below −60° C. The reaction mixture was stirred at −78° C. for 1 hour, warmed to ambient temperature, and stirred for 12 hours. The reaction mixture was treated with 3 M aqueous HCl (80 mL) and stirred for 2 hours. Most of the organic solvent was removed, and the resulting aqueous layer was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (750 g, BIOTAGE® SNAP) eluting with a gradient of 5-22% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.43 - 7.32 (m, 2H), 7.28 - 7.21 (m, 2H), 4.20 (d, 2H), 2.85 (t, 1H), 2.57 (s, 2H), 2.42 (s, 2H), 1.14 (s, 6H). MS (ESI+) m / z 247.2 (M+H) + .

[0237] Example 25J 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one To a solution of Example 25I (15 g) in dichloromethane (800 mL) was added tetraethylammonium chloride (14.08 g) followed by triethylamine (11.85 mL). The reaction mixture was cooled to 0° C. using an ice / water bath, and methanesulfonyl chloride (6.62 mL) was added over 10 minutes. The reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was washed with saturated aqueous ammonium chloride and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (330 g, ISCO GOLD®) eluting with a gradient of 0-35% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 7.60 - 7.55 (m, 2H), 7.45 - 7.40 (m, 2H), 4.12 (s, 2H), 2.64 (s, 2H), 2.39 (s, 2H), 1.05 (s, 6H). MS (DCI+) m / z 283.1 (M+H) + .

[0238] Example 25K (R)-4'-Chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol To a solution of (S)-2-methyl-CBS-oxazaborolidine (20.96 g) in anhydrous tetrahydrofuran (230 mL) was added BH3-tetrahydrofuran (1.0 M in tetrahydrofuran, 76 mL) over 45 minutes at −50° C., and the solution was stirred for an additional 40 minutes. A solution of Example 25J (21 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise via addition funnel over approximately 60 minutes. After the addition, the reaction mixture was stirred at −50° C. for 1.5 hours. The reaction mixture was quenched by the dropwise addition of methanol (130 mL) over approximately 20 minutes at −50° C. The cooling bath was removed, and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl (250 mL), diluted with water, and extracted with ethyl acetate. The organic layer was washed with additional aqueous saturated NH4Cl and brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (Teledyne Isco RediSep® Rf GOLD® 330 g) eluting with a gradient of 0% to 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.44 - 7.36 (m, 2H), 7.21 - 7.13 (m, 2H), 4.40 - 4.28 (m, 2H), 3.85 (d, 1H), 2.24 (dt, 1H), 1.82 (d, 1H), 1.74 (ddd, 1H), 1.43 (dd, 1H), 0.94 (s, 3H), 0.89 (s, 3H). MS (DCI+) m / z 284.1 (M+H) + .

[0239] Example 25L tert-Butyl (S)-4-(((R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate A solution of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.71 g), Example 25K (2.15 g), sodium iodide (1.47 g), and potassium carbonate (2.084 g) in acetonitrile (15.08 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (80 g) eluting with a gradient of 0% to 70% 3:1 ethyl acetate:ethanol / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.37 - 7.29 (m, 2H), 7.07 - 6.99 (m, 2H), 4.95 (d, 1H), 4.80 - 4.73 (m, 1H), 4.34 - 4.24 (m, 1H), 3.69 - 3.58 (m, 4H), 3.29 - 3.23 (m, 1H), 2.95 - 2.68 (m, 2H), 2.67 - 2.58 (m, 1H), 2.34 (d, 1H), 2.06 (dt, 1H), 1.91 - 1.80 (m, 2H), 1.70 (dd, 1H), 1.61 (td, 1H), 1.40 - 1.33 (m, 1H), 1.31 (s, 9H), 0.92 (s, 3H), 0.91 (s, 3H). MS (ESI+) m / z 465.4 (M+H) + .

[0240] Example 25M tert-Butyl (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]azacycloundecine-3(4H)-carboxylate Example 2 To a solution of 5 L (100 g) in dichloroethane (2150 mL) was added propane-1,3-diylbis(trifluoromethanesulfonate) (95 g), followed by N 1 ,N 1 ,N8 ,N 8 -Tetramethylnaphthalene-1,8-diamine (122 g) (proton sponge) was added, and the reaction mixture was heated to 50°C for 20 hours. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1 N aqueous HCl (1 L x 3), 1 N aqueous NaOH (3 times), dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (3 kg) using a gradient of 2 L of 5% ethyl acetate / heptane, 4 L of 10% ethyl acetate / heptane, and then 6-8 L of 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.38 - 7.30 (m, 2H), 7.09 - 7.01 (m, 2H), 4.03 - 3.93 (m, 1H), 3.83 - 3.57 (m, 7H), 3.46 - 3.36 (m, 2H), 2.66 (d, 2H), 2.19 (d, 1H), 2.06 (d, 1H), 1.92 - 1.72 (m, 4H), 1.65 - 1.55 (m, 2H), 1.49 - 1.33 (m, 2H), 1.32 (s, 9H), 0.94 (s, 3H), 0.94 (s, 3H). MS (ESI+) m / z 505.3 (M+H) + .

[0241] Example 25N (4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-tetradecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine To a solution of Example 25M (90 g) in dichloromethane (713 mL) cooled in an ice bath, trifluoroacetic acid (206 mL) was added dropwise over approximately 20 minutes. The ice bath was removed, and the reaction mixture was stirred for 3 minutes. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (300 mL). The vigorously stirred solution was neutralized by adding saturated aqueous Na2CO3 (350 mL). The organic layer was separated, washed four times with saturated aqueous Na2CO3, dried over sodium sulfate, filtered, and concentrated to provide the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ 7.45 7.33 (m, 2H), 7.13 7.02 (m, 2H), 3.87 (q, J = 8.0 Hz, 1H), 3.79 3.62 (m, 4H), 3.48 3.36 (m, 2H), 2.79 2.53 (m, 4H), 2.19 (d, J = 12.1 Hz, 1H), 2.09 (dt, J = 17.1, 3.0 Hz, 1H), 1.95 1.87 (m, 2H), 1.85 (dd, J = 6.5, 1.8 Hz, 1H), 1.78 1.70 (m, 1H), 1.63 (dq, J = 7.5, 3.9 Hz, 2H), 1.47 (td, J = 11.3, 2.8 Hz, 1H), 1.39 (dd, J = 12.5, 9.1 Hz, 1H), 0.98 (s, 4H), 0.97 (s, 3H). MS (DCI+) m / z 405.3 (M+H) + .

[0242] Example 25O Ethyl 2-bromo-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)benzoate A 2 L, three-necked round-bottom flask equipped with a stir bar, heating mantle, nitrogen inlet and outlet, and thermocouple was charged with ethyl 2-bromo-4-fluorobenzoate (44.4 g). Anhydrous dimethyl sulfoxide (346 mL) was added to the flask, and the mixture was stirred at ambient temperature. Example 25N (70 g) was added, followed by potassium hydrogen phosphate (90 g). Once the slurry was thoroughly mixed, the temperature was raised to 60°C, and the slurry was heated under nitrogen for 72 hours. The heating mantle was removed, and the reaction was cooled to 8°C using an ice / water bath. The flask was equipped with a 1 L dropping funnel. Water (850 mL) was added dropwise from the dropping funnel to the cold reaction slurry, and the mixture was sonicated for 30 minutes. The mixture was mechanically stirred and vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered using a Buchner funnel with filter paper. The filtered solid was washed with water (2 x 500 mL) and dried on the filter for 16 hours. The solid was dissolved in ethyl acetate (600 mL), and water (300 mL) was added to the solution. The biphasic solution was stirred for 1 hour. The layers were separated in a separatory funnel, and the organic layer was washed with water (300 mL) and brine (200 mL). The organic layer was dried over 100 g of magnesium sulfate, filtered, and concentrated to give the crude residue. The residue was dissolved in dichloromethane (100 mL) and purified by normal phase chromatography using a 750 g BIOTAGE® Snap Ultra silica gel column, eluting with a gradient of 0-30% ethyl acetate in heptane, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 7.68 (d, J = 8.9 Hz, 1H), 7.46 - 7.33 (m, 2H), 7.11 (d, J = 2.6 Hz, 1H), 7.10 - 7.07 (m, 2H), 6.91 (dd, J = 9.0, 2.5 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.04 (t, J = 7.7 Hz, 1H), 3.89 - 3.64 (m, 7H), 3.59 (d, J = 12.0 Hz, 1H), 3.48 (q, J = 8.3 Hz, 1H), 2.95 (dd, J = 12.2, 10.8 Hz, 1H), 2.86 - 2.66 (m, 2H), 2.27 (d, J = 12.2 Hz, 1H), 2.15 - 2.06 (m, 1H), 2.01 (d, J = 10.6 Hz, 1H), 1.97 - 1.83 (m, 2H), 1.75 - 1.57 (m, 3H), 1.40 (dd, J = 12.5, 9.1 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 1.9 Hz, 6H). LC / MS (APCI+) m / z 631.46 (M+H) + .

[0243] Example 25P 5-Bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g) in ethyl acetate (200 mL) at 25° C. was added 3-chloroperbenzoic acid (21.90 g) and then stirred at 25° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and then quenched by the addition of saturated sodium bicarbonate (1000 mL). The biphasic mixture was filtered, and the filter cake was washed with water (100 mL) and then dried in vacuo to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.32 (s, 1H), 8.41 - 8.22 (m, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 6.50 (d, J=1.8 Hz, 1H).

[0244] Example 25Q 5-Bromo-6-chloro-1H-pyrrolo[2,3-b]pyridine To a solution of Example 25P (30 g) and 1,1,1,3,3,3-hexamethyldisilazane (29.5 mL) in tetrahydrofuran (300 mL) was added 2,2,2-trichloroacetyl chloride (47.1 mL) at 0° C. The resulting mixture was stirred for 0.5 hours and warmed to 25° C. for an additional 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was triturated with ethyl acetate and petroleum ether (1:10, 100 mL) to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.05 ( s, 1H), 8.41 (s, 1H), 7.63–7.54 (m, 1H), 6.51–6.45 (m, 1H).

[0245] Example 25R 5-Bromo-6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine To a solution of Example 25Q (15 g) in N,N-dimethylformamide (150 mL) was added sodium hydride (3.11 g) in small portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour, and then a solution of 2-(trimethylsilyl)ethoxymethyl chloride (13.79 mL) in N,N-dimethylformamide (50 mL) was added dropwise. The resulting mixture was stirred for an additional 2 hours at 0° C. The reaction mixture was diluted with brine (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate=10:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.48 (d, J=2.1 Hz, 1H), 5.61 (s, 2H), 3.54 (t, J=7.9 Hz, 2H), 0.92 (t, J=7.9 Hz, 2H), 0.01 (s, 9H).

[0246] Example 25S N-(3-((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide To a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL) was added sodium hydride (0.166 g) in small portions at 0° C. The resulting mixture was stirred at 0° C. for 0.5 hours, and then Example 25R (0.5 g) was added. The reaction mixture was heated to 80° C. and stirred under nitrogen for 12 hours. After cooling, the reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=5:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.03 (s, 1H), 7.76 (d, J =8.2 Hz, 2H), 7.23 (d, J =8.1 Hz, 2H), 7.15 (d, J =3.5 Hz, 1H), 6.42 - 6.37 (m, 1H), 5.53 (s, 2H), 4.47 - 4.41 (m, 2H), 3.55 - 3.48 (m, 2H), 3.23 (q, J=6.0 Hz, 2H), 2.37 (s, 3H), 2.01 ( J=5.7 Hz, 2H), 0.90 - 0.87 (m, 2H), ), -0.03 (s, 9H).

[0247] Example 25T 1-Tosyl-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane To a solution of Example 25S (500 mg) in dimethyl sulfoxide (6 mL) was added potassium carbonate (374 mg), picolinic acid (89 mg), and copper(I) iodide (206 mg) at 20° C. The reaction mixture was stirred at 160° C. for 2 hours under microwave irradiation. After cooling to ambient temperature, the reaction mixture was diluted with water (100 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=3:1) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.31 (d, J=3.5 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 6.52 (d, J=3.5 Hz, 1H), 5.58 (s, 2H), 4.03 - 3.78 (m, 4H), 3.60 - 3.44 (m, 2H), 2.39 (s, 3H), 1.90 (s, 2H), 0.90 (t, J=8.2 Hz, 2H), -0.05 (s, 9H).

[0248] Example 25U 7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepane To a solution of sodium (0.291 g) in 1,2-dimethoxyethane (0.5 mL) was added naphthalene (1.624 g) under nitrogen. The mixture was stirred at 20° C. for 1 hour until the formation of sodium / naphthalene was complete. Next, to the above solution was added a solution of Example 25T (1 g) in anhydrous tetrahydrofuran (10 mL) at −78° C. The resulting mixture was brought to 20° C. and stirred for 2 hours. The reaction was quenched by adding water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.80 (s, 3H), 7.37 (d, J=3.5 Hz, 1H), 6.51 (d, J=3.5 Hz, 1H), 5.59 (s, 2H), 4.38 - 4.27 (m, 2H), 3.61 - 3.46 (m, 4H), 2.41 (s, 2H), 0.93 - 0.86 (m, 2H), -0.06 (s, 9H).

[0249] Example 25V Ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate An oven-dried 2 L three-necked round-bottom flask equipped with a mechanical stirrer, a Huber-cooled reflux condenser, a Claisen head adapter, a nitrogen needle inlet via a septum and outlet to a bubbler, and a thermocouple was charged with Example 25U (79 g), (Example 1N) (26.6 g), and methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (5.61 g). The solids were placed under a flow of nitrogen, and then cesium carbonate (81 g) was rapidly added to the reaction flask. The solids were slowly mixed using a mechanical stirrer, and the flow of nitrogen to the reaction flask was continued for 60 minutes. Anhydrous toluene (833 mL) was charged to another oven-dried 2 L round-bottom flask equipped with a stir bar and septum. A copious stream of nitrogen was blown beneath the solvent surface with stirring for 60 minutes. The solvent was then transferred via cannula to a three-neck flask, and the reaction was heated to an internal temperature of 110°C under a nitrogen stream for 16 hours. The reaction was cooled to ambient temperature, and the flask was charged with water (600 mL), followed by the palladium scavenger, ammonium pyrrolidinedithiocarbamate (3 g). The mixture was stirred vigorously for 1 hour. The reaction was further diluted with ethyl acetate (400 mL), stirred for 30 minutes, and then filtered through a plug of diatomaceous earth. The filter cake was washed with ethyl acetate (2 x 500 mL). The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water (200 mL), then brine (200 mL). The combined aqueous layers were back-extracted once with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate (200 g), filtered, and concentrated to yield a crude residue that was dissolved in dichloromethane (200 mL) and purified by normal phase chromatography using a BIOTAGE® Snap Ultra 1.5 kg silica gel column eluted with a gradient of 0 to 50% ethyl acetate in heptane to yield the title compound. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 7.44 (d, J = 8.8 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.30 (d, J = 3.5 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.03 (s, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.9, 2.3 Hz, 1H), 6.22 (d, J = 3.5 Hz, 1H), 5.43 (s, 2H), 4.47 - 4.37 (m, 2H), 4.03 (t, J = 8.0 Hz, 1H), 3.89 - 3.69 (m, 7H), 3.66 (q, J = 5.7, 4.5 Hz, 3H), 3.59 (t, J = 11.1 Hz, 2H), 3.52 - 3.42 (m, 3H), 2.96 - 2.87 (m, 1H), 2.85 - 2.77 (m, 1H), 2.67 (td, J = 11.9, 3.0 Hz, 1H), 2.27 (d, J = 12.1 Hz, 1H), 2.11 (dt, J = 17.4, 3.0 Hz, 1H), 2.02 (d, J = 10.8 Hz, 1H), 2.00 - 1.85 (m, 4H), 1.71 (td, J = 11.6, 2.9 Hz, 1H), 1.64 (dd, J = 8.7, 4.8 Hz, 2H), 1.40 (dd, J = 12.4, 9.1 Hz, 1H), 0.98 (s, 6H), 0.94 (t, J = 7.1 Hz, 3H), 0.84 - 0.79 (m, 2H), -0.08 (s, 9H).

[0250] Example 25W Ethyl 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoate A 2 L, three-necked flask equipped with a mechanical stirrer, heating mantle, Claisen head adapter, reflux condenser, nitrogen inlet and outlet to a bubbler, and thermocouple was charged with Example 25V (69 g). The solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution at ambient temperature was added ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL). The reaction was heated to an internal temperature of 66° C. for 24 hours. The heating mantle was removed, and the reaction was cooled to 8° C. in an ice / water bath. The mixture was quenched with water (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and then partitioned in a separatory funnel. The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate (100 g), filtered, and concentrated in vacuo to give the crude product. The residue was suspended in 1:1 methyl tert-butyl ether:heptane (400 mL), sonicated for 30 minutes, and then stirred vigorously for 1 hour. The solid was filtered, and the filter cake was washed with 1:1 methyl tert-butyl ether:heptane (50 mL). The solid was dried on a Buchner funnel to give the title compound. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 11.13 (t, J = 2.2 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 7.40 - 7.37 (m, 2H), 7.14 (dd, J = 3.4, 2.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.02 (d, J = 0.7 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.55 (dd, J = 8.9, 2.3 Hz, 1H), 6.13 (dd, J = 3.4, 1.9 Hz, 1H), 4.44 - 4.33 (m, 2H), 4.03 (tt, J = 7.1, 3.5 Hz, 1H), 3.90 - 3.69 (m, 4H), 3.68 - 3.62 (m, 3H), 3.61 - 3.54 (m, 2H), 3.51 - 3.44 (m, 1H), 2.92 - 2.86 (m, 1H), 2.84 - 2.78 (m, 1H), 2.66 (td, J = 11.9, 3.0 Hz, 1H), 2.32 - 2.28 (m, 1H), 2.26 (d, J = 12.1 Hz, 1H), 2.11 (d, J = 17.1 Hz, 1H), 2.02 (d, J = 10.8 Hz, 1H), 1.98 - 1.86 (m, 4H), 1.70 (td, J = 11.7, 3.0 Hz, 1H), 1.66 - 1.58 (m, 2H), 1.40 (dd, J = 12.5, 9.2 Hz, 1H), 1.36 - 1.30 (m, 1H), 1.29 - 1.22 (m, 1H), 0.98 (s, 6H), 0.95 (t, J = 7.1 Hz, 3H).

[0251] Example 25X 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecin-3(4H,7H,15H)-yl)-2-(2,3,4,7-tetrahydro-1H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]oxazepin-1-yl)benzoic acid A 5 L, three-neck flask equipped with a mechanical stirrer, heating mantle, reflux condenser, Claisen adapter, nitrogen inlet and outlet to a bubbler, and thermocouple was charged with Example 25W (58.7 g). The residue was dissolved in 1,4-dioxane (991 mL) and methanol (496 mL) and stirred at ambient temperature for 5 minutes. Lithium hydroxide (18.99 g) and then water (496 mL) were added, and the reaction was heated to an internal temperature of 75°C for 16 hours. The heating mantle was removed, and the reaction was cooled to 5°C in an ice / water bath. The reaction was neutralized to pH 7 by careful addition of 3N aqueous hydrochloric acid (100 mL). The pH was further adjusted to pH 6 by addition of saturated aqueous ammonium chloride (100 mL). The mixture was diluted with dichloromethane (300 mL), and the layers were separated in a separatory funnel. The aqueous layer was extracted with dichloromethane (2 x 100 mL), and the combined organic layers were dried over sodium sulfate (50 g). The solids were filtered off, and the filtrate was concentrated in vacuo to yield a crude residue. The residue was dissolved in dichloromethane (50 mL) and purified by normal phase chromatography on a silica gel cartridge (Teledyne Isco RediSep® RF GOLD®, 330 g), eluting with 0-10% methanol in dichloromethane, to give the title compound. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 12.28 (s, 1H), 11.20 (t, J = 2.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.17 (dd, J = 3.4, 2.5 Hz, 1H), 7.12 - 7.06 (m, 2H), 7.01 (d, J = 0.7 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 8.9, 2.4 Hz, 1H), 6.15 (dd, J = 3.3, 1.9 Hz, 1H), 4.34 (t, J = 5.5 Hz, 2H), 4.03 (t, J = 7.7 Hz, 1H), 3.88 - 3.75 (m, 3H), 3.74 - 3.64 (m, 3H), 3.64 - 3.58 (m, 1H), 3.57 (s, 6H), 3.51 - 3.43 (m, 1H), 2.92 (t, J = 11.4 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.68 (td, J = 12.0, 3.0 Hz, 1H), 2.26 (d, J = 12.1 Hz, 1H), 2.11 (d, J = 17.4 Hz, 1H), 2.02 (d, J = 10.9 Hz, 1H), 1.97 (p, J = 5.8 Hz, 1H), 1.95 - 1.85 (m, 2H), 1.70 (td, J = 11.6, 2.9 Hz, 1H), 1.66 - 1.60 (m, 0H), 1.40 (dd, J = 12.5, 9.1 Hz, 1H), 0.98 (s, 6H). LC / MS (APCI+) m / z 712.29 (M+H) + .

[0252] Example 25Y 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-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide A solution of Example 25G (50 mg) in dichloromethane (0.80 mL) was added to N-ethyl-N-isopropylpropan-2-amine (0.10 mL), Example 25X (88 mg), N,N-dimethylpyridin-4-amine (37 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride (44 mg) and the mixture was stirred for 18 h. The reaction mixture was concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 11.93 (s, 1H), 11.22 (t, J = 2.3 Hz, 1H), 8.56 (t, J = 5.6 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J = 9.2, 2.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.19 (dd, J = 3.4, 2.5 Hz, 1H), 7.17 - 7.13 (m, 2H), 6.93 - 6.88 (m, 2H), 6.74 (d, J = 8.0 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.47 (s, 1H), 4.37 (d, J = 13.2 Hz, 1H), 4.24 (t, J = 5.5 Hz, 2H), 4.13 (d, J = 10.4 Hz, 1H), 4.03 (ddt, J = 11.2, 8.7, 5.2 Hz, 2H), 3.92 (t, J = 7.3 Hz, 2H), 3.60 (dt, J = 11.1, 4.3 Hz, 2H), 3.57 - 3.52 (m, 4H), 3.46 - 3.29 (m, 2H), 3.27 (s, 3H), 3.21 (tt, J = 10.2, 4.0 Hz, 2H), 3.04 (t, J = 10.3 Hz, 1H), 2.22 - 2.04 (m, 3H), 2.00 (dq, J = 12.2, 5.7 Hz, 4H), 1.84 - 1.76 (m, 1H), 1.74 - 1.64 (m, 1H), 1.42 - 1.22 (m, 3H), 1.02 (d, J = 12.9 Hz, 6H). LC / MS (APCI+) m / z 1039.65 (M+H) + .

[0253] [Example 26] 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-(((4-methoxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0254] Example 26A 1,6-Dioxaspiro[2.5]octane To a solution of trimethylsulfoxonium iodide (28.6 g) in dimethyl sulfoxide (150 mL) was added sodium hydride (5.19 g) in small portions at 25° C. The resulting mixture was stirred at 25° C. for 1 hour, and then dihydro-2H-pyran-4(3H)-one (10 g) was added dropwise. The resulting mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with methyl tert-butyl ether (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.48 (dt, J=13.45, 4.52 Hz, 2H), 1.81 (ddd, J=13.29, 8.32, 4.63 Hz, 2H), 2.63 (s, 2H), 3.70-3.85 (m, 4H).

[0255] Example 26B (4-Methoxytetrahydro-2H-pyran-4-yl)methanol To a solution of Example 26A (5 g) in methanol (50 mL) was added trifluoroacetic acid (6.75 mL) at 25° C., and the reaction was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 1:1 to 0:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CD3OD-d4) δ ppm 1.51-1.64 (m, 2H), 1.67-1.77 (m, 2H), 3.25 (s, 3H), 3.50 (s, 2H), 3.69 (dd, J=8.05, 2.76 Hz, 4H).

[0256] Example 26C (4-Methoxytetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate To a solution of Example 26B (4 g) in dichloromethane (50 mL) was added triethylamine (7.63 mL), 4-dimethylaminopyridine (0.334 g), and para-toluenesulfonyl chloride (7.82 g) at 0° C. The resulting mixture was stirred at 25° C. for 12 hours. The mixture was quenched by adding water (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 5:1 to 1:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.43-1.57 (m, 2H), 1.59-1.75 (m, 2H), 2.43 (s, 3H), 3.12 (s, 3H), 3.56-3.71 (m, 4H), 3.91(s, 2H), 7.34 (d, J=8.07 Hz, 2H), 7.78 (d, J=8.31 ​​Hz, 2H).

[0257] Example 26D 4-(azidomethyl)-4-methoxytetrahydro-2H-pyran To a solution of Example 26C (6 g) in N,N-dimethylformamide (60 mL) at 25° C. was added sodium azide (2.86 g) and potassium iodide (3.32 g). The resulting mixture was heated to 80° C. and stirred for 12 hours. After cooling to ambient temperature, the reaction mixture was quenched by the addition of water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (3×50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with 10:1 to 3:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.44-1.56 (m, 2H), 1.70 (dd, J=14.33, 2.65 Hz, 2H), 3.18 (s, 3H), 3.20 (s, 2H), 3.58-3.68 (m, 4H).

[0258] Example 26E (4-Methoxytetrahydro-2H-pyran-4-yl)methanamine A mixture of Example 26D (3 g) and palladium on carbon (1.87 g) in methanol (50 mL) was degassed and purged with hydrogen three times. The resulting mixture was stirred under a hydrogen atmosphere at 25° C. for 6 hours. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure to provide the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.38-1.49 (m, 2H), 1.54-1.62 (m, 2H), 2.53 (s, 2H), 3.07 (s, 3H), 3.46-3.59 (m, 4H).

[0259] Example 26F 4-(((4-Methoxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 26E (2 g) in N,N-dimethylformamide (20 mL) was added N,N-diisopropylethylamine (4.81 mL) and 4-chloro-3-nitrobenzenesulfonamide (3.26 g) at 25° C. The resulting mixture was heated to 80° C. and stirred for 12 hours. The reaction was cooled to ambient temperature and quenched by the addition of water (60 mL). The resulting suspension was filtered, and the filter cake was triturated with ethyl acetate to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.55-1.67 (m, 2H), 1.70-1.79 (m, 2H), 3.18 (s, 3H), 3.50-3.61 (m, 4H), 3.61-3.69 (m, 2H), 7.27-7.37 (m, 3H), 7.87 (dd, J=9.15, 2.09 Hz, 1H), 8.38 (br t, J=4.52 Hz, 1H), 8.49 (d, J=2.20 Hz, 1H).

[0260] Example 26G 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-(((4-methoxytetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.075 g), Example 26F (0.035 g), N,N-dimethylpyridin-4-amine (0.039 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) in dichloromethane (1.0 mL) was stirred for 3 days, after which the reaction was loaded onto silica gel (Agila, 40 g) and eluted with a gradient of 0.5% to 4.5% dichloromethane / methane over 30 minutes to give the title compound. 1 H NMR (400 MHz, pyridine-d5) δ ppm 12.65 (s, 1H), 9.23 (d, 1H), 8.55 (t, 1H), 8.29 (dd, 1H), 8.15 (d, 1H), 7.49 - 7.44 (m, 2H), 7.43 (dd, 1H), 7.35 (s, 1H), 7.14 - 7.09 (m, 2H), 7.04 (d, 1H), 6.85 (dd, 1H), 6.72 (d, 1H), 6.08 (dd, 1H), 4.43 - 4.32 (m, 2H), 4.24 (t, 1H), 4.01 (ddt, 2H), 3.93 - 3.55 (m, 12H), 3.40 - 3.30 (m, 1H), 3.20 (d, 2H), 2.98 - 2.82 (m, 2H), 2.48 (d, 1H), 2.18 - 2.05 (m, 4H), 2.01 - 1.70 (m, 10H), 1.65 - 1.51 (m, 4H), 1.03 (s, 3H), 1.02 (s, 3H).

[0261] [Example 27] 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-hydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0262] Example 27A (((3R,6S)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane The title compound was synthesized according to the procedure for Example 12D, substituting Example 25C for Example 12C. 1 H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.16 (m, 5H), 4.52 (d, J = 12.3 Hz, 1H), 4.47 (d, J = 12.2 Hz, 1H), 3.84 (ddd, J = 10.8, 4.9, 2.2 Hz, 1H), 3.59 (tt, J = 9.9, 4.8 Hz, 1H), 3.47 - 3.28 (m, 3H), 3.06 (dd, J = 10.9, 10.0 Hz, 1H), 2.00 - 1.87 (m, 1H), 1.66 - 1.53 (m, 1H), 1.45 - 1.27 (m, 2H), 0.80 (s, 9H), -0.02 (d, J = 3.8 Hz, 6H). LC / MS (APCI+) m / z 337.55 (M+H) + .

[0263] Example 27B ((2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate The title compound was synthesized according to the procedure for Example 12E, substituting Example 27A for Example 12D. 1H NMR (500 MHz, CDCl3) δ ppm 7.82 - 7.76 (m, 2H), 7.36 - 7.30 (m, 2H), 3.96 (d, J = 5.1 Hz, 2H), 3.81 (ddd, J = 10.9, 5.0, 2.2 Hz, 1H), 3.59 (tt, J = 9.9, 4.7 Hz, 1H), 3.45 (dtd, J = 10.7, 5.1, 2.1 Hz, 1H), 3.02 (dd, J = 10.9, 10.0 Hz, 1H), 2.44 (s, 3H), 2.00 (dtt, J = 12.9, 4.1, 2.0 Hz, 1H), 1.68 - 1.61 (m, 1H), 1.46 - 1.29 (m, 2H), 0.86 (s, 9H), 0.03 (d, J = 5.1 Hz, 6H). LC / MS (APCI+) m / z 401.45 (M+H) + .

[0264] Example 27C (((3R,6S)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane The title compound was synthesized according to the procedure for Example 12F, substituting Example 27B for Example 12E. 1 H NMR (600 MHz, CDCl3) δ ppm 3.91 (ddd, J = 10.9, 5.0, 2.2 Hz, 1H), 3.65 (tt, J = 10.0, 4.8 Hz, 1H), 3.43 (dddd, J = 10.7, 6.3, 3.9, 2.2 Hz, 1H), 3.27 (dd, J = 12.8, 6.8 Hz, 1H), 3.21 (dd, J = 12.8, 3.8 Hz, 1H), 3.15 - 3.09 (m, 1H), 2.03 (ddt, J = 9.7, 4.6, 2.6 Hz, 1H), 1.68 - 1.62 (m, 1H), 1.51 - 1.38 (m, 2H), 0.87 (d, J = 0.5 Hz, 10H), 0.06 (d, J = 5.4 Hz, 6H).

[0265] Example 27D ((2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanamine The title compound was synthesized according to the procedure for Example 12G, substituting Example 27C for Example 12F. 1 H NMR (600 MHz, CDCl3) δ ppm 3.88 (ddd, J = 10.8, 4.9, 2.2 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.19 (dddd, J = 11.2, 7.4, 3.8, 2.1 Hz, 1H), 3.11 (dd, J = 10.8, 10.0 Hz, 1H), 2.68 (qd, J = 13.1, 5.6 Hz, 2H), 2.04 - 1.97 (m, 1H), 1.66 - 1.60 (m, 1H), 1.50 - 1.40 (m, 2H), 1.33 (tdd, J = 13.4, 11.1, 3.8 Hz, 2H), 0.87 (s, 9H), 0.05 (d, J = 5.0 Hz, 6H). LC / MS (ESI+) m / z 246.38 (M+H) + .

[0266] Example 27E 4-((((2S,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide A solution of Example 27D (150.0 mg) in dichloromethane (2.00 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (0.300 mL) and 4-fluoro-3-nitrobenzenesulfonamide (180 mg). The reaction was stirred at ambient temperature for 2 hours and then purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (d, J = 2.3 Hz, 1H), 8.59 (s, 1H), 7.92 - 7.84 (m, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.86 (s, 2H), 3.95 (ddd, J = 10.9, 4.9, 2.2 Hz, 1H), 3.68 (tt, J = 10.0, 4.9 Hz, 1H), 3.56 (ddt, J = 7.7, 5.8, 3.7 Hz, 1H), 3.46 (ddd, J = 13.2, 5.8, 3.6 Hz, 1H), 3.32 (ddd, J = 12.9, 7.8, 4.6 Hz, 1H), 3.16 (dd, J = 10.9, 10.0 Hz, 1H), 2.11 - 2.04 (m, 1H), 1.82 - 1.71 (m, 1H), 1.51 (ddt, J = 9.7, 7.3, 1.9 Hz, 1H), 0.88 (s, 9H), 0.07 (d, J = 3.1 Hz, 6H). LC / MS (APCI+) m / z 446.41 (M+H) + .

[0267] Example 27F 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-hydroxytetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 27E (60 mg), Example 1Q (80 mg), N,N-dimethylpyridin-4-amine (20 mg), N-ethyl-N-isopropylpropan-2-amine (0.080 mL), and N 1 -((ethylimino)methylene)-N 3 ,N 3A mixture of 1,3-dimethylpropane-1,3-diamine hydrochloride (33 mg) and 1,3-dimethylpropane-1,3-diamine hydrochloride (33 mg) was stirred at ambient temperature for 16 hours. The reaction mixture was purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane). Fractions containing the tert-butyldimethylsilyl-protected product were combined and concentrated. The residue was dissolved in dichloromethane (4 mL) and placed in an ice bath. After 5 minutes, trifluoroacetic acid (0.8 mL) and then water (0.2 mL) were added, and the reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction mixture was concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm, 5-75% acetonitrile / water (+0.1% trifluoroacetic acid)) to provide the title compound. 11H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 11.92 (s, 1H), 11.22 (t, J = 2.3 Hz, 1H), 8.55 (t, J = 5.4 Hz, 1H), 8.46 (d, J = 2.3 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J = 9.2, 2.3 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.45 - 7.42 (m, 2H), 7.19 (dd, J = 3.4, 2.5 Hz, 1H), 7.17 - 7.13 (m, 2H), 6.89 (t, J = 4.7 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.36 (d, J = 13.2 Hz, 2H), 4.24 (d, J = 5.6 Hz, 2H), 4.13 (d, J = 10.3 Hz, 2H), 4.01 (d, J = 13.6 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.83 (ddt, J = 9.3, 4. \alpha Hz, 2H), 3.73 (d, J = 13.6 Hz, 1H), 3.60 (dt, J = 10.9, 4.2 Hz, 1H), 3.56 - 3.40 (m, 5H), 3.36 - 3.18 (m, 4H), 2.99 (t, J = 10.4 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.18 - 2.04 (m, 2H), 2.03 - 1.94 (m, 6H), 1.74 (dt, J = 8.7, 2.0 Hz, 1H), 1.71 - 1.65 (m, 1H), 1.40 - 1.28 (m, 3H), 1.02 (d, J = 13.2 Hz, 6H). LC / MS (APCI+) m / z 1025.68 (M+H) + .

[0268] [Example 28] Note: In the original text, there is an unclear value "4. \alpha Hz" which is maintained as such in the translation. If this is an error in the original, it should be corrected for a more accurate translation.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-morpholinocyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0269] Example 28A tert-Butyl (((1r,4r)-4-morpholinocyclohexyl)methyl)carbamate To a mixture of tert-butyl (((1r,4r)-4-aminocyclohexyl)methyl)carbamate (10 g) in N,N-dimethylformamide (88 mL) was added 1-bromo-2-(2-bromoethoxy)ethane (11.17 g) and triethylamine (13.43 mL), and the mixture was heated to 75° C. for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was concentrated from ethyl ether / heptane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 6.09 (s, 1H), 3.62 3.51 (m, 4H), 2.82 (t, J = 6.3 Hz, 2H), 2.49 2.46 (m, 5H), 2.21 2.08 (m, 1H), 1.90 1.81 (m, 2H), 1.80 1.70 (m, 2H), 1.40 (s, 9H), 1.16 (qd, J = 12.5, 3.4 Hz, 2H), 0.92 (qd, J = 13.0, 3.3 Hz, 2H). MS (DCI+) m / z 299.3 (M+H) + .

[0270] Example 28B ((1r,4r)-4-Morpholinocyclohexyl)methanamine To a mixture of Example 28A (9.04 g) in dioxane (180 mL) was added HCl (4.0 M in dioxane, 37.8 mL) in four portions. The reaction mixture was stirred for 16 hours, then methanol and additional HCl (4.0 M in dioxane, 60 mL) were added. After stirring for an additional 2 hours, the reaction mixture was concentrated, and the resulting residue was concentrated three times with ethyl ether and then dried in vacuo to provide the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 11.50 (s, 1H), 8.16 (s, 3H), 4.00 3.86 (m, 2H), 3.36 (d, J = 8.2 Hz, 5H), 3.12 2.98 (m, 3H), 2.63 (p, J = 6.1 Hz, 2H), 2.26 2.08 (m, 2H), 2.01 1.87 (m, 2H), 1.47 (qd, J = 12.3, 3.2 Hz, 2H), 0.99 (qd, J = 13.2, 3.3 Hz, 2H). MS (DCI+) m / z 199.1 (M+H) + .

[0271] Example 28C 4-(((1r,4r)-4-morpholinocyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide A mixture of Example 28B (5.4 g), N,N-diisopropylethylamine (9.5 mL), and 4-fluoro-3-nitrobenzenesulfonamide (5.7 g) in tetrahydrofuran (300 mL) was stirred at ambient temperature for 16 hours. The reaction was diluted with methyl tert-butyl ether and concentrated. The residue was dissolved in a mixture of dichloromethane and methanol, washed with saturated aqueous ammonium chloride, brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.54 (t, J = 6.0 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 9.2, 2.3 Hz, 1H), 7.31 (s, 2H), 7.25 (d, J = 9.3 Hz, 1H), 3.58 3.48 (m, 4H), 3.28 (d, J = 6.4 Hz, 2H), 2.45 (t, J = 4.6 Hz, 4H), 2.16 (t, J = 11.5 Hz, 1H), 1.92 1.74 (m, 4H), 1.67 1.51 (m, 1H), 1.16 (qd, J = 13.0, 12.5, 3.5 Hz, 2H), 1.08 0.95 (m, 2H). LC / MS (APCI+) m / z 399.17 (M+H) + .

[0272] Example 28D 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-morpholinocyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.100 g), Example 28C (0.053 g), N,N-dimethylpyridin-4-amine (0.051 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of 1,3-dimethylpropane-1,3-diamine hydrochloride (0.054 g) in dichloromethane (1.4 mL) was stirred. After stirring for 3 days, the reaction was 1 ,N 1The mixture was quenched with -dimethylethane-1,2-diamine (0.031 mL), loaded onto silica gel (Agela, 40 g), and eluted using a gradient of 0.5% to 9% dichloromethane / methanol over 30 minutes. Product-containing fractions were concentrated, dissolved in 1:1 dimethyl sulfoxide / methanol (3 mL), and purified by Gilson HPLC (Luna 10 μm C18(2) 250 × 50 mm column, using a gradient of 10% to 85% acetonitrile / water (containing 0.1% trifluoroacetic acid) over 30 minutes) to give the title compound. 1 H NMR (400 MHz, pyridine-d5) δ ppm 12.67 - 12.45 (m, 1H), 9.16 (d, 1H), 8.49 (t, 1H), 8.18 (dd, 1H), 8.08 (d, 1H), 7.45 - 7.39 (m, 3H), 7.30 (s, 1H), 7.12 - 7.04 (m, 2H), 7.00 (d, 1H), 6.81 (dd, 1H), 6.66 (d, 1H), 6.04 (dd, 1H), 4.38 (d, 2H), 4.21 (t, 1H), 4.05 - 3.50 (m, 14H), 3.31 (t, 1H), 3.01 - 2.81 (m, 8H), 2.74 (t, 1H), 2.46 (d, 1H), 2.17 - 1.97 (m, 6H), 1.97 - 1.67 (m, 8H), 1.57 (dd, 1H), 1.39 (tt, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.95 - 0.82 (m, 2H). LC / MS (ESI+) m / z 1092.94 (M+H) + .

[0273] [Example 29] 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)-4-methoxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0274] Example 29A (S)-2-((benzyloxy)methyl)oxirane To a solution of (R)-oxiran-2-ylmethanol (1.792 mL) in tetrahydrofuran (27.0 mL) was added sodium hydride (2.160 g) at 0° C., and the reaction was stirred for 30 minutes. After the bubbling ceased, (bromomethyl)benzene (6.42 mL) and tetrabutylammonium iodide (0.997 g) were added, and the mixture was stirred for 16 hours while warming to ambient temperature. The reaction was carefully quenched with water and partitioned into ethyl acetate. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were concentrated and purified by flash chromatography (80 g silica gel, 0-20% ethyl acetate in hexanes) to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.40 - 7.25 (m, 5H), 4.62 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H), 3.77 (dd, J = 11.4, 3.1 Hz, 1H), 3.45 MS (APCI+) m / z 206.4(M+H+CH3CN) + .

[0275] Example 29B (S)-1-(Benzyloxy)pent-4-yn-2-ol To a solution of Example 29A (3.336 g) in dimethyl sulfoxide (40.6 mL) at 15° C. was added lithium acetylide ethylenediamine complex (2.99 g) in several portions. After 1 h, the reaction was quenched with brine solution and acidified with aqueous 5N HCl. The aqueous layer was extracted with ethyl acetate, and the combined organic fractions were washed with 5% aqueous sodium bicarbonate and brine solutions, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by flash chromatography (0-30% ethyl acetate / heptane) to give the title compound. MS (DCI+) m / z 208.2 (M+NH4). + .

[0276] Example 29C (S)-5-((benzyloxy)methyl)dihydrofuran-3(2H)-one To a solution of Example 29B (1 g) in 1,2-dichloroethane (10.5 mL) at ambient temperature was added 3,5-dichloropyridine 1-oxide (1.724 g), methanesulfonic acid (0.409 mL), and triphenylphosphine gold(i) bis(trifluoromethanesulfonyl)imidate (0.194 g), in that order. The reaction was stirred at ambient temperature for 15 hours. Upon completion, the mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate / heptane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.39 - 7.27 (m, 5H), 4.65 - 4.55 (m, 2H), 4.52 (tdd, J = 7.4, 4.4, 3.2 Hz, 1H), 4.12 (ddt, J = 16.8, 1.1, 0.5 Hz, 1H), 3.91 (dt, J = 16.9, 0.6 Hz, 1H), 3.74 (dd, J = 10.4, 3.3 Hz, 1H), 3.61 (dd, J = 10.4, 4.5 Hz, 1H), 2.53 (ddt, J = 18.0, 7.3, 0.6 Hz, 1H), 2.46 (ddt, J = 18.0, 7.3, 0.8 Hz, 1H).

[0277] Example 29D (5S)-5-((benzyloxy)methyl)tetrahydrofuran-3-ol To a solution of Example 29C (400 mg) in methanol (6.5 mL) at 0° C. was added sodium borohydride (183 mg) in small portions. After the addition was complete, the mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was then carefully quenched with water, and the mixture was concentrated. To the aqueous residue was added ethyl acetate (10 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. MS (APCI+) m / z 209.4 (M+H). + .

[0278] Example 29E (2S)-2-((benzyloxy)methyl)-4-methoxytetrahydrofuran To Example 29D (404 mg) in tetrahydrofuran (5.5 mL) at 0° C. was added sodium hydride (116 mg) and 18-crown-6 (256 mg). The mixture was stirred for 30 minutes, and then iodomethane (182 μL) was slowly added. The mixture was stirred for 16 hours, then quenched with brine solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (0-50% ethyl acetate / heptane) to give the title compound. MS (APCI+) m / z 223.3 (M+H) + .

[0279] Example 29F ((2S)-4-Methoxytetrahydrofuran-2-yl)methanol To a high-pressure vial equipped with a stir bar was added Pd on carbon (56.2 mg), Example 29E (281.2 mg), tetrahydrofuran (3.8 mL), and methanol (1.3 mL). The vial was pressurized with hydrogen (60 psi) and heated at 40° C. for 19 hours. The mixture was filtered through a polypropylene filter funnel equipped with a diatomaceous earth / polyethylene frit disc and washed with methanol. The filtrate was concentrated to give the title compound. MS (APCI+) m / z 133.2 (M+H). + .

[0280] Example 29G ((2S)-4-Methoxytetrahydrofuran-2-yl)methyl methanesulfonate A solution of Example 29F (167 mg) and triethylamine (0.53 mL) in dichloromethane (6.3 mL) was cooled to 0° C. Methanesulfonyl chloride (127 μL) was added dropwise. The mixture was stirred at 0° C. for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated to give the title compound. MS (APCI+) m / z 211.3 (M+H). + .

[0281] Example 29H ((2S)-4-Methoxytetrahydrofuran-2-yl)methanamine Example 29G (266 mg) was dissolved in N,N-dimethylformamide (6.3 mL), to which sodium azide (164 mg) was added in one portion. The mixture was warmed to 40° C. and stirred for 18 hours. The mixture was then cooled, diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (6.3 mL), to which triphenylphosphine resin (844 mg) and water (160 μL) were added. The mixture was stirred at 45° C. for 5 hours, and then filtered. The resin was washed with a large amount of dichloromethane. The filtrate was concentrated to give the title compound. MS (APCI+) m / z 132.2 (M+H) + .

[0282] Example 29I 4-((((2S)-4-Methoxytetrahydrofuran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide Example 29H (166 mg) in tetrahydrofuran (12.7 mL) was treated with N,N-diisopropylethylamine (0.66 mL) at ambient temperature. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (279 mg). The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated, and the residue was purified by flash chromatography (0-10% methanol / dichloromethane) to give the title compound. MS (APCI+) m / z 332.1 (M+H). + .

[0283] Example 29J 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)-4-methoxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide To a mixture of Example 1Q (37 mg) and Example 29I (17.21 mg) in dichloromethane (1.04 mL) was added triethylamine (36.2 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.92 mg), and 4-dimethylaminopyridine (12.69 mg). The mixture was stirred at ambient temperature for 16 hours. The residue after evaporation of the solvent was purified by reverse-phase HPLC (250 × 50 mm C18 LUNA column; 20–75% acetonitrile / water (containing 0.1% trifluoroacetic acid)) to give the title compound. The ratio of cis to trans isomers was 2:1. 1H NMR (600 MHz, ピリジン-d5) δ ppm 12.52 (s, 0.33H), 12.38 (s, 0.66H), 9.25 (d, J = 2.3 Hz, 0.33H), 9.23 (d, J = 2.3 Hz, 0.66H), 8.34 - 8.24 (m, 1H), 8.19 - 8.16 (m, 1H), 7.56 - 7.52 (m, 2H), 7.45 (dd, J = 3.4, 2.5 Hz, 0.33H), 7.42 (dd, J = 3.4, 2.4 Hz, 0.66H), 7.40 (s, 0.33H), 7.39 (s, 0.66H), 7.21 - 7.18 (m, 2H), 7.09 (d, J = 2.5 Hz, 0.33H), 7.08 (d, J = 2.4 Hz, 0.66H), 6.93 - 6.88 (m, 1H), 6.86 (d, J = 9.3 Hz, 0.33H), 6.83 (d, J = 9.3 Hz, 0.66H), 6.11 (dd, J = 3.4, 1.9 Hz, 0.33H), 6.09 (dd, J = 3.4, 1.9 Hz, 0.66H), 4.58 - 4.44 (m, 2H), 4.44 - 4.39 (m, 0.33H), 4.32 (t, J = 7.6 Hz, 1H), 4.30 - 4.22 (m, 0.66H), 4.16 - 4.04 (m, 3H), 4.03 - 3.83 (m, 6H), 3.82 - 3.71 (m, 3H), 3.72 - 3.61 (m, 3H), 3.55 - 3.31 (m, 3H), 3.25 (s, 2H), 3.24 (s, 1H), 3.06 - 2.90 (m, 2H), 2.56 (d, J = 11.8 Hz, 1H), 2.25 - 2.10 (m, 5H), 2.07 - 2.00 (m, 2H), 1.97 - 1.91 (m, 1H), 1.92 - 1.78 (m, 3H), 1.72 - 1.65 (m, 1H), 1.11 (s, 3H), 1.09 (s, 3H). MS (ESI+) m / z 1025.7 (M+H) + .

[0284] [Example 30] 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-methoxycyclobutyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0285] Example 30A 4-(((1r,3r)-3-Methoxycyclobutyl)amino)-3-nitrobenzenesulfonamide (1r,3r)-3-Methoxycyclobutan-1-amine (100 mg) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (518 μL) at ambient temperature. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (218 mg). The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated, and the residue was purified by flash chromatography (0-10% methanol / dichloromethane) to give the title compound. MS (ESI+) m / z 603.2 (2M+H). + .

[0286] Example 30B 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-methoxycyclobutyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 29I and Example 30A were replaced and replaced, and the last step of Example 29 was completed and the title compound was synthesized smoothly. 1 H NMR (600 MHz, ピリジン-d5) δ ppm 12.67 (t, J = 2.1 Hz, 1H), 9.22 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 5.0 Hz, 1H), 8.21 (dd, J = 9.1, 2.2 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.44 (dd, J = 3.4, 2.4 Hz, 1H), 7.35 (s, 1H), 7.18 - 7.12 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 9.0, 2.4 Hz, 1H), 6.47 (d, J = 9.2 Hz, 1H), 6.08 (dd, J = 3.4, 1.9 Hz, 1H), 4.44 (s, 2H), 4.28 (dt, J = 8.3, 4.5 Hz, 1H), 4.05 (tt, J = 10.2, 3.3 Hz, 2H), 4.02 - 3.96 (m, 1H), 3.96 - 3.79 (m, 4H), 3.79 - 3.73 (m, 1H), 3.70 (t, J = 5.6 Hz, 2H), 3.68 - 3.60 (m, 2H), 3.38 (dd, J = 12.1, 10.8 Hz, 1H), 3.17 (s, 3H), 2.98 (dt, J = 11.4, 2.7 Hz, 1H), 2.93 (td, J = 11.9, 3.1 Hz, 1H), 2.52 (d, J = 12.3 Hz, 1H), 2.38 (dddd, J = 10.7, 7.9, 4.6, 1.1 Hz, 2H), 2.20 - 2.05 (m, 6H), 2.03 - 1.95 (m, 2H), 1.91 (td, J = 11.6, 3.1 Hz, 1H), 1.88 - 1.75 (m, 2H), 1.64 (dd, J = 12.7, 8.8 Hz, 1H), 1.07 (s, 3H), 1.05 (s, 3H). MS (ESI+) m / z 995.8 (M+H)+ .

[0287] [Example 31] 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-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0288] Example 31A 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide A suspension of 4-chloro-3-nitrobenzenesulfonamide (26 g) and 1-methylpiperidin-4-amine (28 g) in dioxane (100 mL) was stirred at 90° C. for 16 hours. The reaction mixture was cooled to ambient temperature, and the precipitate was filtered. The precipitate was dissolved in warm 20% methanol / dichloromethane (600 mL), warm-loaded onto silica gel, and eluted with 20% methanol / dichloromethane to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 8.46 (d, 1H), 8.13 (d, 1H), 7.85 (dd, 1H), 7.39 (s, 2H), 7.35 (d, 1H), 4.00 - 3.86 (m, 1H), 3.31 - 3.20 (m, 2H), 2.96 (t, 2H), 2.63 (s, 3H), 2.17 - 2.08 (m, 2H), 1.99 - 1.86 (m, 2H).

[0289] Example 31B 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-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.050 g), Example 31A (0.021), N,N-dimethylpyridin-4-amine (0.026 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3 A solution of 0.027 g of dimethylpropane-1,3-diamine hydrochloride in 0.70 mL of dichloromethane was stirred. After stirring for 3 days, the reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 24 g) and eluted using a gradient of 0.5% to 10% dichloromethane / methanol over 30 minutes. The product-containing fractions were concentrated, dissolved in 2 mL of 1:1 dimethyl sulfoxide / methanol, and purified by Gilson HPLC (Luna 10 μm C18(2) 250 × 50 mm column, using a gradient of 10% to 75% acetonitrile / water (containing 0.1% trifluoroacetic acid) over 30 minutes) to give the title compound. 1H NMR (400 MHz, pyridine-d5) δ ppm 12.56 (s, 1H), 9.13 (d, 1H), 8.31 (d, 1H), 8.18 (dd, 1H), 8.07 (d, 1H), 7.47 - 7.39 (m, 2H), 7.40 - 7.36 (m, 1H), 7.26 (s, 1H), 7.10 - 7.05 (m, 2H), 6.99 (d, 1H), 6.81 (dd, 1H), 6.71 (d, 1H), 6.01 - 5.96 (m, 1H), 4.34 (s, 2H), 4.27 - 4.14 (m, 1H), 3.98 (t, 2H), 3.89 - 3.51 (m, 10H), 3.32 (t, 1H), 3.20 (s, 2H), 2.99 - 2.81 (m, 5H), 2.61 (s, 3H), 2.45 (d, 1H), 2.20 - 1.99 (m, 6H), 2.00 - 1.65 (m, 6H), 1.57 (dd, 1H), 0.99 (d, 6H). LC / MS (ESI+) m / z 108.81 (M+H) + .

[0290] [Example 32] 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-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0291] Example 32A 4-(Hydroxymethyl)cyclohexanone To a mixture of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (10 g) in 1,4-dioxane (60 mL) was added 3 M hydrogen chloride in dioxane (60 mL). After stirring at ambient temperature for 6 hours, the mixture was basified to pH = 8 with aqueous 2 N sodium hydroxide and extracted with dichloromethane (3 times). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.39 - 1.57 (m, 1H) 1.39 - 1.57 (m, 1H) 1.39 - 1.57 (m, 1H) 1.39 - 1.57 (m, 1H) 1.91 - 2.04 (m, 1H) 2.08 - 2.18 (m, 2H) 2.28 - 2.48 (m, 4H) 3.59 (d, J=6.39 Hz, 2H).

[0292] Example 32B 4-(hydroxymethyl)-1-methylcyclohexanol To a mixture of Example 32A (10 g) in tetrahydrofuran (200 mL) was added 3 M methylmagnesium bromide (78 mL) dropwise at 0° C. The mixture was stirred at ambient temperature for 2 hours, then quenched with aqueous ammonium chloride and extracted with ethyl acetate (5 times). The organic phase was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (200:1 to 3:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.05 - 1.26 (m, 3H) 1.30 - 1.84 (m, 8H) 1.98 (br d, J=2.93 Hz, 1H) 2.14 (br dd, J=13.20, 2.81 Hz, 1H) 2.31 - 2.50 (m, 1H) 3.48 - 3.62 (m, 2H).

[0293] Example 32C ((1s,4s)-4-Hydroxy-4-methylcyclohexyl)methyl 4-methylbenzenesulfonate To a mixture of Example 32B (10 g) in pyridine (67.3 mL) was added p-toluenesulfonyl chloride (26.4 g) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours. Ice-cold water was added. The mixture was extracted with dichloromethane (3 times), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.11 (br s, 1H) 1.21 (s, 3H) 1.23 - 1.41 (m, 5H) 1.48 - 1.69 (m, 5H) 2.45 (s, 3H) 3.84 (d, J=6.61 Hz, 2H) 7.34 (br d, J=7.94 Hz, 2H) 7.78 (br d, J=8.16 Hz, 2H).

[0294] Example 32D ((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl 4-methylbenzenesulfonate To a mixture of Example 32B (10 g) in pyridine (67.3 mL) was added p-toluenesulfonyl chloride (26.4 g) at 0° C. The resulting mixture was stirred at ambient temperature for 2 hours. Ice-cold water was added. The mixture was extracted with dichloromethane (3 times), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.03 - 1.16 (m, 2H) 1.19 (s, 3H) 1.32 - 1.47 (m, 3H) 1.61 - 1.76 (m, 5H) 2.46 (s, 3H) 3.87 (br d, J=5.95 Hz, 2H) 7.36 (br d, J=8.16 Hz, 2H) 7.79 (br d, J=8.16 Hz, 2H).

[0295] Example 32E (1r,4r)-4-(azidomethyl)-1-methylcyclohexanol To a mixture of Example 32D (8.75 g) in N,N-dimethylformamide (13 mL) at 25° C. was added sodium azide (4.77 g). The reaction mixture was stirred at 80° C. for 12 hours. After the mixture was cooled to 25° C., it was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (20:1 to 1:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 1.09 - 1.21 (m, 2H) 1.23 - 1.25 (m, 3H) 1.31 - 1.53 (m, 3H) 1.54 - 1.67 (m, 1H) 1.68 - 1.84 (m, 4H) 3.20 (d, J=6.72 Hz, 2H).

[0296] Example 32F (1r,4r)-4-(aminomethyl)-1-methylcyclohexanol To a mixture of Example 32E (4.25 g) in methanol (85 mL) was added Raney nickel (0.147 g). The reaction mixture was stirred at ambient temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.10 - 1.19 (m, 1H) 1.15 (br s, 1H) 1.10 - 1.19 (m, 1H) 1.19 - 1.32 (m, 6H) 1.39 (br t, J=12.29 Hz, 2H) 1.55 - 1.73 (m, 4H) 2.58 (br s, 2H).

[0297] Example 32G 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide A stirred mixture of 4-fluoro-3-nitrobenzenesulfonamide (1 g) and Example 32F (0.781 g) in N,N-dimethylformamide (9 mL) was treated with N,N-diisopropylethylamine (1.586 mL). The mixture was stirred at 40° C. for 2 hours, and then the crude mixture was diluted with water (75 mL). The thick suspension was stirred for several minutes, filtered, and washed with water and ether to give the title compound. MS (ESI+) m / z 344 (M+H). + .

[0298] Example 32H 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-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 1Q (0.050 g), Example 32G (0.024 g), N,N-dimethylpyridin-4-amine (0.026 g) and N 1 -((ethylimino)methylene)-N 3 ,N 3A solution of 1,3-dimethylpropane-1,3-diamine hydrochloride (0.027 g) in dichloromethane (0.70 mL) was stirred. The reaction was stirred for 3 days, then cooled to 200° C. 1 ,N 1 The reaction was quenched with -dimethylethane-1,2-diamine (0.015 mL). The reaction was loaded onto silica gel (Agila, 40 g) and eluted using a gradient of 0.5% to 6% dichloromethane / methanol over 30 minutes to give the title compound. 1 H NMR (400 MHz, pyridine-d5) δ ppm 12.62 (s, 1H), 9.19 (d, 1H), 8.49 (t, 1H), 8.21 (dd, 1H), 8.09 (d, 1H), 7.44 - 7.40 (m, 2H), 7.38 (dd, 1H), 7.32 (s, 1H), 7.11 - 7.03 (m, 2H), 6.98 (d, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.04 (dd, 1H), 4.42 - 4.30 (m, 2H), 4.25 - 4.15 (m, 1H), 4.04 - 3.90 (m, 2H), 3.88 - 3.50 (m, 9H), 3.30 (t, 1H), 3.02 (t, 2H), 2.92 - 2.79 (m, 2H), 2.44 (d, 1H), 2.15 - 2.00 (m, 6H), 1.97 - 1.47 (m, 11H), 1.31 (s, 3H), 1.18 - 1.04 (m, 3H), 0.99 (s, 3H), 0.98 (s, 3H). LC / MS (ESI+) m / z 1037.99 (M+H) + .

[0299] [Example 33] 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)methoxy)-3-nitrophenyl)sulfonyl)benzamide

[0300] Example 33A (R)-(3,4-Dihydro-2H-pyran-2-yl)methanol The title compound was prepared according to literature procedures (Angew Chem Int Ed 2015, 54, pp. 13538-13544). Optical rotation (measured value) [α] D 25 =-78.93 (c 1.06 in chloroform); (Reference) [α] D 25 =-74.32 (c 1.07 in chloroform).

[0301] Example 33B (R)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran A suspension of sodium hydride (60% wt. in mineral oil, 0.788 g) in tetrahydrofuran (50 mL) was placed in an ice bath for 5 minutes, followed by the addition of Example 33A (1.5 g) as a solution in tetrahydrofuran (2 mL). The reaction was stirred in the ice bath for 15 minutes. Neat benzyl bromide (2.5 mL) was added, the ice bath was removed, and the reaction was stirred for 4 hours. The reaction mixture was placed back in the ice bath and carefully quenched with 1:1 saturated aqueous ammonium chloride and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silica column, 0-5% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.37 - 7.31 (m, 4H), 7.31 - 7.25 (m, 1H), 6.39 (dt, J = 6.4, 1.9 Hz, 1H), 4.67 (dddd, J = 6.2, 4.9, 2.5, 1.3 Hz, 1H), 4.63 - 4.53 (m, 2H), 4.02 (dddd, J = 10.4, 6.4, 4.3, 2.3 Hz, 1H), 3.58 (dd, J = 10.2, 6.3 Hz, 1H), 3.51 (dd, J = 10.1, 4.3 Hz, 1H), 2.08 (dddt, J = 17.2, 10.6, 6.5, 2.4 Hz, 1H), 1.96 (m, J = 17.2, 6.1, 4.6, 2.7, 1.6 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.68 (dtd, J = 13.5, 10.4, 5.9 Hz, 1H).

[0302] Example 33C (3S,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol To a solution of Example 33B (2.00 g) in tetrahydrofuran (24.0 mL) was added 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 50.0 mL) dropwise at 0° C. over 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath, and 10% aqueous sodium hydroxide (15 mL) and then 30% aqueous hydrogen peroxide (16 mL) were carefully added to the mixture at 0° C. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite (20 mL) at 0° C. and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with 3:1 ethyl acetate / heptane (2×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatography (40 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J = 3.9 Hz, 4H), 7.31 - 7.27 (m, 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.05 (ddd, J = 10.8, 4.9, 2.3 Hz, 1H), 3.72 (tt, J = 10.1, 4.9 Hz, 1H), 3.53 - 3.38 (m, 3H), 3.14 (dd, J = 10.7, 10.1 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.76 - 1.65 (m, 1H), 1.51 - 1.41 (m, 3H). LC / MS (APCI+) m / z 223.08 (M+H) + .

[0303] Example 33D (2R,5S)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2H-pyran To a solution of Example 33C (1.00 g) in tetrahydrofuran (12.00 mL) was added sodium hydride (60% by weight in mineral oil, 0.216 g). After stirring for 20 minutes at ambient temperature, neat iodomethane (0.600 mL) was added and stirring continued for 16 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (20 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (40 g silica column, 0-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.24 (m, 5H), 4.59 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.15 (ddd, J = 10.7, 4.6, 2.3 Hz, 1H), 3.53 - 3.39 (m, 3H), 3.36 (s, 3H), 3.33 - 3.21 (m, 1H), 3.13 (t, J = 10.4 Hz, 1H), 2.20 (dddd, J = 11.5, 5.8, 3.8, 2.4 Hz, 1H), 1.76 - 1.67 (m, 1H), 1.49 - 1.27 (m, 2H). LC / MS (APCI+) m / z 237.40 (M+H) + .

[0304] Example 33E ((2R,5S)-5-Methoxytetrahydro-2H-pyran-2-yl)methanol To a flask containing Pd(OH) / C (20 wt% Pd, 50% water, 50 mg) was added a solution of Example 33D (0.94 g) in ethyl acetate (8.00 mL). The flask was purged with nitrogen and connected to a hydrogen balloon. The reaction was stirred at ambient temperature for 9 hours. The mixture was filtered, and the filtrate was concentrated to provide the title compound. 1H NMR (600 MHz, CDCl3) δ ppm 4.11 (ddd, J = 10.7, 4.7, 2.3 Hz, 1H), 3.58 (dd, J = 11.5, 3.1 Hz, 1H), 3.48 (dd, J = 11.5, 7.0 Hz, 1H), 3.42 - 3.37 (m, 1H), 3.35 (s, 3H), 3.29 - 3.20 (m, 1H), 3.11 (t, J = 10.4 Hz, 1H), 2.36 - 2.27 (m, 1H), 2.23 - 2.16 (m, 1H), 1.67 - 1.61 (m, 1H), 1.43 - 1.29 (m, 2H).

[0305] Example 33F 4-(((2R,5S)-5-Methoxytetrahydro-2H-pyran-2-yl)methoxy)-3-nitrobenzenesulfonamide A solution of Example 33E (0.250 g) in tetrahydrofuran (5.00 mL) was treated with sodium hydride (60 wt% in mineral oil, 0.094 g). After stirring for 20 minutes at ambient temperature, 4-fluoro-3-nitrobenzenesulfonamide (0.377 g) was added in one portion. After 1 hour, the reaction was quenched by the addition of 1 M aqueous hydrochloric acid (10 mL), and the mixture was extracted with 5:1 ethyl acetate / heptane (2 × 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (24 g silica column, 20 to 100% ethyl acetate / heptane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.38 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 8.9, 2.4 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 4.97 (s, 2H), 4.21 (dd, J = 9.9, 5.3 Hz, 1H), 4.18 - 4.08 (m, 2H), 3.71 (dddd, J = 11.7, 5.2, 4.3, 2.2 Hz, 1H), 3.39 (s, 3H), 3.30 (tt, J = 10.5, 4.5 Hz, 1H), 3.17 (dd, J = 10.7, 10.1 Hz, 1H), 2.29 (dtd, J = 14.2, 3.8, 2.5 Hz, 1H), 1.94 - 1.85 (m, 1H), 1.60 (tdd, J = 13.4, 11.4, 3.9 Hz, 1H), 1.41 (dddd, J = 13.4, 12.6, 10.8, 4.2 Hz, 1H). LC / MS (APCI+) m / z 347.45 (M+H) + .

[0306] Example 33G 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)methoxy)-3-nitrophenyl)sulfonyl)benzamide To a solution of Example 33F (29 mg) in dichloromethane (0.500 mL) was added Example 1Q (60 mg), N-ethyl-N-isopropylpropan-2-amine (0.05 mL), N,N-dimethylpyridin-4-amine (15 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3-dimethylpropane-1,3-diamine hydrochloride (24 mg) was added sequentially. The reaction was stirred at ambient temperature for 6 hours, then concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to provide the title compound. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 12.08 (s, 1H), 11.20 (s, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 9.0, 2.4 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.39 - 7.36 (m, 2H), 7.28 (d, J = 9.1 Hz, 1H), 7.21 (dd, J = 3.4, 2.5 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.90 (s, 1H), 6.79 - 6.72 (m, 2H), 6.13 (dd, J = 3.4, 1.9 Hz, 1H), 4.23 - 4.16 (m, 5H), 4.06 - 3.97 (m, 2H), 3.88 - 3.65 (m, 5H), 3.65 - 3.57 (m, 1H), 3.56 (s, 1H), 3.48 (q, J = 8.3 Hz, 1H), 3.27 (s, 3H), 3.24 - 3.14 (m, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.96 (t, J = 11.4 Hz, 1H), 2.81 (d, J = 11.3 Hz, 1H), 2.74 (t, J = 11.7 Hz, 1H), 2.27 (d, J = 12.1 Hz, 1H), 2.21 - 2.07 (m, 3H), 2.03 (d, J = 9.7 Hz, 3H), 1.97 - 1.85 (m, 2H), 1.77 (dq, J = 13.2, 3.2 Hz, 1H), 1.73 - 1.66 (m, 1H), 1.64 (s, 2H), 1.49 - 1.36 (m, 3H), 1.36 - 1.21 (m, 2H), 0.98 (s, 6H). LC / MS (APCI+) m / z 1040.69 (M+H)+ .

[0307] [Example 34] N-((3-chloro-4-((((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)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

[0308] Example 34A 3-chloro-4-((((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)benzenesulfonamide A solution of Example 13G (41.6 mg), 3-chloro-4-fluorobenzenesulfonamide (50 mg), and N-ethyl-N-isopropylpropan-2-amine (0.10 mL) in 1,4-dioxane (1.00 mL) was heated to 85° C. for 3 days. The reaction mixture was purified using flash chromatography (12 g silica column, 10-100% ethyl acetate / heptane) to give the title compound. LC / MS (APCI+) m / z 335.36 (M+H). + .

[0309] Example 34B N-((3-chloro-4-((((2R,5S)-5-methoxytetrahydro-2H-pyran-2-yl)methyl)amino)phenyl)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 A solution of Example 34A (7 mg) in dichloromethane (0.50 mL) was added to N-ethyl-N-isopropylpropan-2-amine (10 μL), Example 1Q (12 mg), N,N-dimethylpyridin-4-amine (3 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride (5 mg) and the mixture was stirred for 16 hours. The reaction mixture was purified using flash chromatography (4 g silica column, 0-5% methanol / ethyl acetate) to give the title compound. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 11.93 (s, 1H), 11.37 (s, 1H), 7.91 (s, 1H), 7.57 - 7.51 (m, 2H), 7.48 - 7.33 (m, 3H), 7.26 - 7.22 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 15.1 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 6.62 - 6.55 (m, 1H), 6.18 - 6.13 (m, 1H), 6.07 (d, J = 19.2 Hz, 1H), 4.47 (s, 1H), 4.36 (d, J = 13.5 Hz, 1H), 4.19 (s, 2H), 4.13 (d, J = 8.6 Hz, 1H), 4.03 (d, J = 7.6 Hz, 1H), 3.97 (ddd, J = 10.7, 4.7, 2.2 Hz, 1H), 3.93 - 3.65 (m, 3H), 3.65 - 3.43 (m, 6H), 3.25 (s, 3H), 3.23 - 3.12 (m, 4H), 2.96 (t, J = 10.4 Hz, 1H), 2.85 - 2.62 (m, 1H), 2.27 (d, J = 12.2 Hz, 1H), 2.20 - 1.85 (m, 7H), 1.75 - 1.58 (m, 3H), 1.40 (dd, J = 12.4, 9.2 Hz, 1H), 1.36 - 1.29 (m, 1H), 1.29 - 1.18 (m, 2H), 1.06 - 0.94 (m, 6H). LC / MS (APCI+) m / z 1028.65 (M+H) + .

[0310] [Example 35] 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-(2-methoxyethoxy)tetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0311] Example 35A (2R,5S)-2-((benzyloxy)methyl)-5-(2-methoxyethoxy)tetrahydro-2H-pyran The title compound was prepared following the procedure for Example 13D, substituting 1-bromo-2-methoxyethane for iodomethane. 1 H NMR (500 MHz, CDCl3) δ ppm 7.36 - 7.30 (m, 4H), 7.31 - 7.27 (m, 1H), 4.59 (d, J = 12.3 Hz, 1H), 4.54 (d, J = 12.3 Hz, 1H), 4.14 (ddd, J = 10.8, 4.7, 2.3 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.61 (ddd, J = 10.6, 5.1, 4.2 Hz, 1H), 3.51 (dd, J = 5.0, 4.2 Hz, 2H), 3.48 - 3.38 (m, 4H), 3.37 (s, 3H), 3.19 (dd, J LC / MS (APCI+) m / z 281.03 (M+H) + .

[0312] Example 35B ((2R,5S)-5-(2-methoxyethoxy)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate The title compound was prepared following the procedure for Example 12E, substituting Example 35A for Example 12D. 1 H NMR (500 MHz, CDCl3) δ ppm 7.82 - 7.76 (m, 2H), 7.38 - 7.30 (m, 2H), 4.04 (ddd, J = 10.9, 4.8, 2.2 Hz, 1H), 3.97 (d, J = 5.1 Hz, 2H), 3.68 - 3.61 (m, 1H), 3.61 - 3.54 (m, 1H), 3.54 - 3.42 (m, 3H), 3.36 (s, 3H), 3.34 (s, 1H), 3.09 (dd, J = 10.9, 10.2 Hz, 1H), 2.44 (s, 3H), 2.23 - 2.15 (m, 1H), 1.73 - 1.65 (m, 1H), 1.45 - 1.28 (m, 2H). LC / MS (APCI+) m / z 345.43 (M+H) + .

[0313] Example 35C (2R,5S)-2-(azidomethyl)-5-(2-methoxyethoxy)tetrahydro-2H-pyran The title compound was prepared according to the procedure for Example 12F, substituting Example 35B for Example 12E. LC / MS (APCI+) m / z 216.41 (M+H) + .

[0314] Example 35D 4-((((2R,5S)-5-(2-methoxyethoxy)tetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 35C (75 mg) in tetrahydrofuran (1.50 mL) was added water (0.075 mL) and triphenylphosphine (110 mg), and the reaction was stirred at ambient temperature for 3 hours. To this reaction mixture was added N-ethyl-N-isopropylpropan-2-amine (0.20 mL) and 4-fluoro-3-nitrobenzenesulfonamide (77 mg), and stirring at ambient temperature was continued for an additional hour. The reaction mixture was purified using flash chromatography (24 g silica column, 10-100% ethyl acetate / heptane) to provide the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 8.72 (d, J = 2.3 Hz, 1H), 8.57 (t, J = 5.2 Hz, 1H), 7.87 (ddd, J = 9.1, 2.3, 0.7 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 5.04 (s, 2H), 4.15 (ddd, J = 10.9, 4.7, 2.3 Hz, 1H), 3.69 (dt, J = 10.6, 4.5 Hz, 1H), 3.63 (ddd, J = 10.7, 5.1, 4.1 Hz, 1H), 3.60 - 3.55 (m, 1H), 3.53 - 3.50 (m, 2H), 3.49 - 3.39 (m, 2H), 3.38 (s, 3H), 3.32 (ddd, J = 13.2, 7.6, 4.7 Hz, 1H), 3.21 (dd, J = 10.9, 10.2 Hz, 1H), 2.25 (ddt, LC / MS (ESI+) m / z 390.23 (M+H) + .

[0315] Example 35E 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-(2-methoxyethoxy)tetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide To a solution of Example 35D (44 mg) in dichloromethane (1.00 mL) was added Example 1Q (70 mg), N-ethyl-N-isopropylpropan-2-amine (0.06 mL), N,N-dimethylpyridin-4-amine (18 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride (29 mg) was added sequentially. The reaction was stirred at ambient temperature for 62 hours, then concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to provide the title compound. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 11.93 (s, 1H), 11.22 (t, J = 2.3 Hz, 1H), 8.55 (t, J = 5.5 Hz, 1H), 8.48 - 8.43 (m, 1H), 7.98 (s, 1H), 7.65 - 7.59 (m, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.19 (dd, J = 3.4, 2.5 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.93 - 6.86 (m, 2H), 6.74 (d, J = 8.9 Hz, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.48 (s, 1H), 4.37 (d, J = 12.7 Hz, 1H), 4.24 (s, 1H), 4.12 (d, J = 9.3 Hz, 2H), 4.01 (ddd, J = 10.6, 4.7, 2.1 Hz, 2H), 3.97 - 3.88 (m, 2H), 3.84 (ddd, J = 10.9, 9.3, 3.5 Hz, 1H), 3.73 (d, J = 13.4 Hz, 1H), 3.63 - 3.45 (m, 10H), 3.40 (t, J = 4.8 Hz, 2H), 3.38 - 3.29 (m, 2H), 3.28 - 3.24 (m, 1H), 3.23 (s, 3H), 3.22 - 3.17 (m, 1H), 3.09 - 3.01 (m, 1H), 2.20 - 2.04 (m, 3H), 1.99 (dt, J = 12.5, 6.2 Hz, 4H), 1.82 - 1.75 (m, 1H), 1.72 - 1.65 (m, 1H), 1.39 - 1.28 (m, 3H), 1.02 (d, J = 13.2 Hz, 6H). LC / MS (APCI+) m / z 1083.74 (M+H) + .

[0316] [Example 36] 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-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0317] Example 36A 4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide A solution of (1s,4s)-4-(aminomethyl)-1-methylcyclohexanol (1.1 g) in N,N-dimethylformamide (22.00 mL) was treated with N-ethyl-N-isopropylpropan-2-amine (2.68 mL) and 4-chloro-3-nitrobenzenesulfonamide (1.82 g), and the reaction was heated to 80 °C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (4:1 petroleum ether / ethyl acetate) to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ ppm 8.77 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 7.88 (dd, J = 9.1, 2.3 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.74 (s, 2H), 3.26 (t, J = 5.9 Hz, 2H), 1.76 - 1.66 (m, 5H), 1.53 - 1.41 (m, 4H), 1.26 (s, 3H).

[0318] Example 36B 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-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide The title compound was prepared by following the procedure for Example 35E, substituting Example 36A for Example 35D, with a reaction time of 22 hours. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 11.93 (s, 1H), 11.27 (t, J = 2.3 Hz, 1H), 8.55 (t, J = 5.9 Hz, 1H), 8.47 (d, J = 2.3 Hz, 1H), 7.98 (s, 1H), 7.59 (dd, J = 9.2, 2.3 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.20 (dd, J = 3.4, 2.5 Hz, 1H), 7.18 - 7.11 (m, 2H), 6.91 (s, 1H), 6.90 - 6.82 (m, 1H), 6.74 (dq, J = 3.9, 2.4 Hz, 2H), 6.11 (dd, J = 3.4, 1.9 Hz, 1H), 4.51 - 4.44 (m, 1H), 4.36 (d, J = 13.0 Hz, 1H), 4.22 (t, J = 5.4 Hz, 2H), 4.16 - 4.09 (m, 1H), 4.01 (d, J = 13.5 Hz, 1H), 3.91 (ddd, J = 8.6, 5.6, 2.3 Hz, 1H), 3.83 (ddd, J = 11.0, 9.4, 3.5 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.65 - 3.46 (m, 6H), 3.45 - 3.16 (m, 7H), 2.71 - 2.60 (m, 1H), 2.20 - 2.03 (m, 2H), 2.03 - 1.94 (m, 4H), 1.68 (dd, J = 15.5, 4.7 Hz, 1H), 1.59 - 1.29 (m, 9H), 1.22 (td, J = 13.0, 4.1 Hz, 2H), 1.08 (s, 3H), 1.02 (d, J = 13.3 Hz, 6H). LC / MS (APCI+) m / z 1038.37 (M+H) + .

[0319] [Example 37] 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-morpholinotetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0320] Example 37A (3R,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-ol A solution of Example 12C (1.00 g) in 1,4-dioxane (18.00 mL) was treated with benzo[d][1,3]dioxole-5-carboxylic acid (0.747 g) and 2-(diphenylphosphino)pyridine (1.445 g) at ambient temperature. After 5 minutes, a solution of (£)-diethyldiazene-1,2-dicarboxylate (40 wt% in toluene, 2.500 mL) was added dropwise, and stirring was continued for 16 hours. The reaction mixture was concentrated to remove most of the 1,4-dioxane. The resulting residue was diluted with 3:1 ethyl acetate / heptane (25 mL) and washed with 1 M aqueous hydrochloric acid (2 x 20 mL). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated and then purified using flash chromatography (40 g silica column, 0-20% ethyl acetate / heptane). The purified material thus obtained was dissolved in tetrahydrofuran (2.5 mL) and water (0.5 mL) was added. To this solution was added lithium hydroxide (0.200 g) and the reaction was stirred at ambient temperature for 7 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid (10 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.34 (d, J = 4.4 Hz, 4H), 7.31 - 7.27 (m, 1H), 4.61 (d, J = 12.2 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 3.94 (dt, J = 12.1, 2.4 Hz, 1H), 3.77 (s, 1H), 3.65 - 3.54 (m, 2H), 3.51 (dd, J = 10.1, 6.6 Hz, 1H), 3.42 (dd, J = 10.1, 3.7 Hz, 1H), 2.21 (s, 1H), 1.99 - 1.87 (m, 1H), 1.73 - 1.67 (m, 2H), 1.52 - 1.41 (m, 1H). LC / MS (APCI+) m / z 223.01 (M+H) + .

[0321] Example 37B (((3R,6R)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane To a solution of Example 37A (0.275 g) in dichloromethane (4.00 mL) was added 1H-imidazole (0.180 g) and tert-butylchlorodimethylsilane (0.200 g, 1.324 mmol). The reaction was stirred at ambient temperature for 48 hours. The reaction mixture was poured into water (20 mL) and extracted with 3:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1H NMR (600 MHz, CDCl3) δ ppm 7.38 - 7.31 (m, 4H), 7.30 - 7.26 (m, 1H), 4.65 - 4.60 (m, 1H), 4.53 (d, J = 12.1 Hz, 1H), 3.81 (dt, J = 11.9, 2.4 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.63 - 3.51 (m, 3H), 3.43 - 3.38 (m, 1H), 1.82 - 1.72 (m, 2H), 1.70 - 1.62 (m, 1H), 1.42 - 1.36 (m, 1H), 0.90 (s, 9H), 0.05 (d, J = 5.2 Hz, 6H). LC / MS (APCI+) m / z 337.16 (M+H) + .

[0322] Example 37C ((2R,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate To Pd(OH)2 / C (20 wt% Pd, 50% water, 0.04 g) was added a solution of Example 37B (0.40 g) in tetrahydrofuran (5.00 mL). The reaction vessel was purged with nitrogen, and the mixture was stirred at ambient temperature under a hydrogen balloon. After 17 h, the reaction mixture was filtered, and the filtrate was concentrated and dissolved in tetrahydrofuran (7.00 mL). To this solution were added N-ethyl-N-isopropylpropan-2-amine (0.45 mL), N,N-dimethylpyridin-4-amine (0.225 g), and 4-methylbenzene-1-sulfonyl chloride (0.227 g), and the reaction was stirred at ambient temperature. After 3 h, the reaction mixture was concentrated, and the residue was purified using flash chromatography (40 g silica column, 0-40% ethyl acetate / heptane) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.82 - 7.76 (m, 2H), 7.37 - 7.30 (m, 2H), 4.05 - 3.93 (m, 2H), 3.75 - 3.67 (m, 2H), 3.62 - 3.53 (m, 1H), 3.48 - 3.42 (m, 1H), 2.44 (s, 3H), 1.79 - 1.61 (m, 3H), 1.42 - 1.35 (m, 1H), 0.87 (s, 9H), 0.02 (d, J = 1.6 Hz, 6H). LC / MS (APCI+) m / z 401.03 (M+H) + .

[0323] Example 37D (((3R,6R)-6-(azidomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane To a solution of Example 37C (0.37 g) in N,N-dimethylformamide (2.00 mL) was added sodium azide (0.200 g). The reaction was heated at 80° C. for 21 hours. The reaction was cooled to ambient temperature, poured into water (20 mL), and extracted with 5:1 ethyl acetate / heptane (2×20 mL). The combined organic layers were washed with water (3×10 mL), dried over magnesium sulfate, and concentrated. The residue was purified using flash chromatography (12 g silica column, 0-40% ethyl acetate / heptane) to provide the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 3.81 (dt, J = 11.9, 2.3 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.56 - 3.45 (m, 2H), 3.34 (dd, J = 12.7, 7.3 Hz, 1H), 3.19 (dd, J = 12.7, 3.9 Hz, 1H), 1.88 - 1.76 (m, 2H), 1.71 - 1.61 (m, 1H), 1.41 - 1.33 (m, 1H), 0.90 (s, 9H), 0.06 (d, J = 4.6 Hz, 6H). LC / MS (APCI+) m / z 244.01 (M-N2+H)+ .

[0324] Example 37E tert-Butyl (((2R,5R)-5-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)carbamate In a 20 mL glass-lined reactor, a solution of Example 37D (0.125 g) in tetrahydrofuran (3.07 mL) was added to a slurry of Raney-Ni2800 in water (79.3 mg). The reactor was purged with nitrogen. The mixture was stirred under hydrogen (50 psi) at 25°C. After 20 hours, the reactor was evacuated, and the reaction mixture was filtered and concentrated. The residue was dissolved in tetrahydrofuran (2.00 mL), followed by the addition of water (0.5 mL), di-tert-butyl dicarbonate (0.089 g), and sodium bicarbonate (0.07 g). The reaction was stirred at ambient temperature for 20 hours, then poured into water (10 mL), and extracted with 4:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (24 g silica column, 0-100% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1 H NMR (600 MHz, CDCl3) δ ppm 4.96 (s, 1H), 3.78 - 3.71 (m, 2H), 3.49 (dd, J = 11.5, 1.2 Hz, 1H), 3.39 (t, J = 9.4 Hz, 1H), 3.31 (ddd, J = 13.2, 6.8, 2.8 Hz, 1H), 3.05 (ddd, J = 13.7, 7.7, 4.6 Hz, 1H), 1.81 - 1.72 (m, 2H), 1.70 - 1.60 (m, 1H), 1.43 (s, 9H), 1.38 - 1.31 (m, 1H), 0.90 (s, 9H), 0.05 (d, J = 4.5 Hz, 6H). LC / MS (APCI+) m / z 246.02 (M-CO2-tert-Bu+H) + .

[0325] Example 37F (3R,6R)-6-(((tert-butoxycarbonyl)amino)methyl)tetrahydro-2H-pyran-3-yl 4-methylbenzenesulfonate To a solution of Example 37E (0.133 g) in tetrahydrofuran (1.00 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.8 mL), and the reaction was stirred at ambient temperature for 18 hours. The reaction mixture was poured into water (10 mL) and extracted with 4:1 ethyl acetate / heptane (2 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethane (1.00 mL), and then N,N-dimethylpyridin-4-amine (0.050 g), N-ethyl-N-isopropylpropan-2-amine (0.150 mL), and 4-methylbenzene-1-sulfonyl chloride (0.073 g) were added sequentially. The reaction was stirred at ambient temperature for 2 hours, and then the reaction mixture was purified using flash chromatography (12 g silica column, 0-100% ethyl acetate / heptane). Fractions containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl3) δ ppm 7.83 - 7.77 (m, 2H), 7.37 - 7.31 (m, 2H), 4.89 (s, 1H), 4.54 (dq, J = 3.4, 2.0 Hz, 1H), 3.95 (dt, J = 13.0, 2.3 Hz, 1H), 3.49 (dd, J = 13.1, 1.5 Hz, 1H), 3.35 (ddd, J = 22.6, 9.5, 4.0 Hz, 2H), 3.00 (ddd, J = 14.0, 7.8, 4.5 Hz, 1H), 2.44 (s, 3H), 2.02 (d, J = 16.9 Hz, 1H), 1.76 - 1.59 (m, 2H), 1.43 (s, 9H). LC / MS (APCI+) m / z 286.04 (M-CO2-tert-Bu+H) + .

[0326] Example 37G 4-((((2R,5S)-5-morpholinotetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 37F (80 mg) in 1,4-dioxane (1.00 mL) was added morpholine (0.100 mL) and potassium carbonate (60 mg). The reaction was heated to 100° C. and stirred for 5 days. The reaction was cooled to ambient temperature, poured into water (10 mL), and extracted with 3:1 chloroform / 2-propanol. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was treated with hydrochloric acid (3 M in cyclopentyl methyl ether, 3 mL), and the reaction was stirred at ambient temperature for 60 hours. The reaction was concentrated to dryness and then dissolved in dichloromethane (1.00 mL), and N-ethyl-N-isopropylpropan-2-amine (0.400 mL) was added, followed by 4-fluoro-3-nitrobenzenesulfonamide (500 mg). The reaction was stirred at ambient temperature for 2 hours and then concentrated. The residue was dissolved in dimethyl sulfoxide (3 mL) and then purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10–100% acetonitrile / water (+0.1% trifluoroacetic acid)). Fractions containing the desired product were combined and concentrated to give the title compound. 1H NMR (500 MHz, pyridine-d5) δ ppm 8.79 (t, J = 5.4 Hz, 1H), 8.73 (s, 2H), 8.25 (dd, J = 9.1, 2.3 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 4.26 (ddd, J = 10.9, 4.4, 2.3 Hz, 1H), 3.74 (t, J = 4.7 Hz, 4H), 3.51 (dddd, J = 22.8, 13.3, 6.6, 3.4 Hz, 2H), 3.43 - 3.32 (m, 2H), 2.60 (tq, J = 11.7, 6.4 Hz, 4H), 2.54 - 2.45 (m, 1H), 2.02 (dq, J = 11.4, 3.1 Hz, 1H), 1.76 - 1.69 (m, 1H), 1.54 - 1.36 (m, 2H). LC / MS (APCI+) m / z 401.46 (M+H) + .

[0327] Example 37H 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-morpholinotetrahydro-2H-pyran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide A solution of Example 37G (18 mg) in dichloromethane (1.00 mL) was added to N-ethyl-N-isopropylpropan-2-amine (0.026 mL), Example 1Q (31 mg), N,N-dimethylpyridin-4-amine (8 mg), and N 1 -((ethylimino)methylene)-N 3 ,N 3-dimethylpropane-1,3-diamine hydrochloride (12 mg) and stirred at ambient temperature for 18 hours. The reaction mixture was concentrated and purified using reverse-phase HPLC (Luna 10 μm C18(2) 250 × 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1H NMR (600 MHz, ジメチルスルホキシド-d6) δ ppm 11.94 (s, 1H), 11.21 (t, J = 2.2 Hz, 1H), 10.18 (s, 1H), 8.56 (t, J = 5.7 Hz, 1H), 8.48 - 8.43 (m, 1H), 7.98 (s, 1H), 7.64 - 7.58 (m, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.19 (dd, J = 3.4, 2.5 Hz, 1H), 7.18 - 7.13 (m, 2H), 6.94 (d, J = 9.5 Hz, 1H), 6.90 (d, J = 0.7 Hz, 1H), 6.77 - 6.71 (m, 2H), 6.09 (dd, J = 3.4, 1.9 Hz, 1H), 4.40 - 4.35 (m, 4H), 4.33 - 4.27 (m, 1H), 4.27 - 4.18 (m, 2H), 4.13 (d, J = 10.6 Hz, 1H), 4.04 - 3.95 (d, J = 14.1 Hz, 4H), 3.84 (ddd, J = 11.2, 9.6, 3.6 Hz, 2H), 3.77 - 3.58 (m, 4H), 3.58 - 3.45 (m, 4H), 3.40 (ddd, J = 13.3, 7.5, 5.5 Hz, 2H), 3.32 - 3.10 (m, 4H), 2.68 - 2.60 (m, 1H), 2.26 (dt, J = 12.1, 3.3 Hz, 1H), 2.19 - 2.04 (m, 2H), 2.02 - 1.96 (m, 4H), 1.96 - 1.91 (m, 2H), 1.72 - 1.65 (m, 2H), 1.42 (qd, J = 13.4, 4.0 Hz, 1H), 1.34 (dd, J = 12.3, 9.2 Hz, 1H), 1.02 (d, J = 15.1 Hz, 6H). LC / MS (APCI+) m / z 1095.14 (M+H) + .

[0328] [Example 38] N-((3-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)methoxy)phenyl)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

[0329] Example 38A ((1r,4r)-4-morpholinocyclohexyl)methanol To a solution of tert-butyl ((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate (17.5 g) in 1,4-dioxane (100 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 95 mL) and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the crude material was dissolved in acetonitrile (200 mL). To this solution were added N-ethyl-N-isopropylpropan-2-amine (66.6 mL) and 1-bromo-2-(2-bromoethoxy)ethane (19.47 g) sequentially and the reaction was stirred at 70° C. for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated, and the residue was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (5-100% ethyl acetate / heptane) to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 4.36 (t, J = 5.3 Hz, 1H), 3.57–3.50 (m, 4H), 3.18 (dd, J = 6.3, 5.3 Hz, 2H), 2.48–2.41 (m, 4H), 2.10 (tt, J = 11.6, 3.4 Hz, 1H), 1.87–1.72 (m, 4H), 1.26 (dddt, J = 15.0, 9.0, 6.0, 3.4 Hz, 1H), 1.18–1.06 (m, 2H), 0.86 (qd, J = 12.8, 2.9 Hz, 2H).

[0330] Example 38B 3-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)methoxy)benzenesulfonamide To a solution of Example 38A (0.57 g) in tetrahydrofuran (10 mL) was added sodium hydride (60 wt% in mineral oil, 0.24 g). The reaction was stirred at ambient temperature for 20 minutes, then 3-chloro-4-fluorobenzenesulfonamide (0.50 g) was added, and the reaction was heated to 60° C. for 3 hours. The reaction mixture was cooled and quenched by the dropwise addition of saturated aqueous ammonium chloride (20 mL). The mixture was extracted with 4:1 ethyl acetate / heptane (2×25 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified using flash chromatography (40 g silica column, 20-100% ethyl acetate / heptane) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.93 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.7, 2.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 4.72 (s, 2H), 3.89 (d, J = 6.3 Hz, 2H), 3.77 - 3.70 (m, 4H), 2.59 (t, J = 4.7 Hz, 4H), 2.03 (d, J = 15.1 Hz, 4H), 1.85 (s, 1H), 1.38 - 1.10 (m, 4H). LC / MS (APCI+) m / z 389.14 (M+H) + .

[0331] Example 38C N-((3-chloro-4-(((1r,4r)-4-morpholinocyclohexyl)methoxy)phenyl)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 The title compound was prepared according to the procedure for Example 37H, substituting Example 38B for Example 37G and using 1:1 dichloromethane / N,N-dimethylformamide (1.00 mL) as the solvent. 1H NMR (500 MHz, ジメチルスルホキシド-d6) δ ppm 12.05 (s, 1H), 11.36 (t, J = 2.3 Hz, 1H), 9.77 (s, 1H), 7.98 (s, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.7, 2.3 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.25 (dd, J = 3.4, 2.5 Hz, 1H), 7.19 - 7.13 (m, 2H), 7.06 (d, J = 9.0 Hz, 1H), 6.90 (s, 1H), 6.85 - 6.75 (m, 2H), 6.16 - 6.10 (m, 1H), 4.48 (s, 1H), 4.37 (d, J = 13.1 Hz, 2H), 4.01 (dd, J = 12.3, 3.2 Hz, 3H), 3.93 (d, J = 6.1 Hz, 3H), 3.84 (td, J = 10.7, 10.3, 3.5 Hz, 1H), 3.77 - 3.67 (m, 4H), 3.64 - 3.58 (m, 2H), 3.50 (q, J = 5.8 Hz, 3H), 3.42 (d, J = 12.1 Hz, 3H), 3.33 - 3.05 (m, 4H), 2.65 (d, J = 10.6 Hz, 1H), 2.23 - 2.07 (m, 4H), 2.05 - 2.00 (m, 4H), 2.00 - 1.93 (m, 3H), 1.77 (ddt, J = 8.8, 6.0, 3.1 Hz, 1H), 1.71 - 1.64 (m, 1H), 1.52 - 1.42 (m, 2H), 1.34 (dd, J = 12.2, 9.2 Hz, 1H), 1.17 (dt, J = 13.5, 10.6 Hz, 2H), 1.02 (d, J = 12.7 Hz, 6H). LC / MS (APCI+) m / z 1085.10 (M+H) + .

[0332] [Example 39] 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-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide

[0333] Example 39A tert-Butyl 4-fluoro-4-(((2-nitro-4-sulfamoylphenyl)amino)methyl)piperidine-1-carboxylate A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.284 g), tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate (0.300 g), and triethylamine (0.540 mL) in tetrahydrofuran (5.0 mL) was stirred for 4 hours at 50° C. The reaction was concentrated and chromatographed on silica gel (Teledyne Isco RediSep® RF GOLD®, 80 g) eluting with a gradient of 0.5% to 5% methanol / dichloromethane to give the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 8.57 (t, 1H), 8.48 (d, 1H), 7.83 (ddd, 1H), 7.40 (dd, 1H), 7.33 (s, 2H), 3.89–3.71 (m, 4H), 3.06–2.87 (m, 2H), 1.83 (dd, 2H), 1.74–1.59 (m, 2H), 1.40 (s, 9H).

[0334] Example 39B 4-(((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 39A (0.410 g) in dioxane (5.0 mL) was added HCl (4.0 M in dioxane, 1.185 mL). A minimal amount of methanol was added to maintain the reaction homogeneity. After 1 h, the reaction was concentrated. The residue was suspended in dichloromethane (5 mL) and treated with triethylamine (0.132 mL). After stirring for 5 min, oxetan-3-one (0.061 mL) and sodium triacetoxyborohydride (0.261 g) were added, and the suspension was stirred at ambient temperature for 16 h. The reaction was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 80 g) and eluted using a gradient of 0.5% to 9% dichloromethane / methanol over 30 min to give the title compoun...

Claims

[Claim 1] A compound of formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, L is -NH-, -NHCH ２ - and -OCH ２ - selected from the group consisting of 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, and A optionally contains one or two R ２ substituted by a substituent, optionally one R ３ is substituted by a substituent, R １ is Cl and -NO ２ is selected from the group consisting of R ２ is 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).

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