1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-B][1,4]oxazepine Bcl-2 inhibitors

Abstract

The present invention relates to compounds of formula (I) useful as medicaments in the treatment of CLL, SLL and / or ALL. TIFF2025504382000025.tif76168 (wherein A, L, W and R 1 has any of the values ​​defined herein.) and pharma- ceutically acceptable salts thereof.

Description

Technical Field

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

[0002] Reference to Electronic Sequence Listing The content of the electronic sequence listing (ABV12563US01_ST26.xml; size: 4,991 bytes; and created on Jan. 18, 2023) is incorporated herein by reference in its entirety.

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

Background Art

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

[0005] Molecules capable of inhibiting Bcl-2 protein activity can increase apoptosis, thereby leading to improved outcomes related to the treatment and prevention of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). For example, venetoclax is a selective Bcl-2 inhibitor first approved by the FDA for treating patients with CLL or SLL, with or without 17p deletion, who have had at least one prior treatment.

Summary of the Invention

Problems to be Solved by the Invention

[0006] However, there is a need for therapeutic technologies related to compounds with improved activity that inhibit the activity of Bcl-2 protein.

Means for Solving the Problems

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

[0008]

Chemical formula

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

[0010] In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is NO2.

[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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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]dioxacycloundecin-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, the method 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 Bcl-2 protein.

[0026] The compounds disclosed herein may contain one or more variable groups that appear more than once in any substituent or formula herein. The definition of a variable group is independent of its definition in another occurrence, each time it appears. Further, combinations of substituents are permitted only if such combinations result in a stable compound. A stable compound is a compound that can be isolated from the reaction mixture.

[0027] Definitions As used herein, certain terms are intended to refer to the following definitions as detailed below.

[0028] As used in this specification and the intended claims, it is noted that the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, when referring to "a compound", a single compound, and one or more of the same or different compounds are included. When referring to "a pharmaceutically acceptable carrier", a single pharmaceutically acceptable carrier and one or more pharmaceutically acceptable carriers are meant, and so on.

[0029] As used in this specification and the appended claims, unless otherwise specified to the contrary, the following terms have the indicated meanings: As used herein, the term "C1-C6 alkoxy" refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbons as defined herein and bonded 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, hexyloxy, and the like.

[0030] As used herein, the term "C1-C6 alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbons, unless otherwise specified. 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] As used herein, the term "C2-C6 alkoxyalkoxy" refers to an alkoxy group as defined herein and bonded 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] As used herein, the term "C2-C6 alkoxyalkyl" refers to an alkoxy group as defined herein and bonded 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, methoxymethyl, and the like.

[0033] When the terms "halo" or "halogen" are used herein, they mean Cl, Br, I, and F.

[0034] When the term "C1-C6 haloalkyl" is used herein, it 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 examples, 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 this substituent and y is the maximum number of carbon atoms in this substituent. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C1-C3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms.

[0036] When a moiety is described as being "optionally substituted", this moiety can be either (1) unsubstituted or (2) substituted. When a moiety is described as being optionally substituted by a certain number of non-hydrogen groups, that moiety can be either (1) unsubstituted or (2) substituted by either up to that certain number or up to the lesser of that certain number or the maximum number of substitutable positions on this moiety by non-hydrogen groups.

[0037] Regarding the use of the words "comprise", "comprises", or "comprising" in this patent application (including the claims), the Applicants use them based on the fundamental and clear understanding that, unless the context specifically requires otherwise, these words should be construed inclusively rather than exclusively, and the Applicants note that each of these words is intended to be so construed when understanding this patent application, including the following claims.

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

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

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

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

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

[0043] As used herein, the terms "treat", "treating", and "treatment" refer to methods of reducing or suppressing a disease and / or its attendant symptoms.

[0044] The term "one or more" refers to 1 to 5. In one embodiment, the term "one or more" refers to 1 or 4. In another embodiment, the term "one or more" refers to 1 to 4. In one embodiment, the term "one or more" refers to 1 or 3. In another embodiment, the term "one or more" refers to 1 to 3. In a further embodiment, the term "one or more" refers to 1 to 2. In yet another embodiment, the term "one or more" refers to 2. In yet another further embodiment, the term "one or more" refers to 1.

[0045] Compound The compounds of the present invention have the general formula (I) 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 shown in Table 1 below and their pharmaceutically acceptable salts. It should be understood that if there is a difference between the name of the compound found herein and the structure found in Table 1, the structure in Table 1 shall prevail.

[0048] [Table 1] TIFF0007714811000004.tif221166TIFF0007714811000005.tif219168TIFF0007714811000006.tif219168TIFF0007714811000007.tif219164TIFF0007714811000008.tif91168

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

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

[0051] Method for preparing exemplary compounds The compounds of the present invention can be better understood when associated with the following synthetic schemes and methods, which illustrate the means by which these compounds can be prepared. The compounds of the present invention can be prepared by various synthetic procedures. Representative synthetic procedures are shown in Schemes 1-4, but are not limited to the following. The variable groups A, L, R 1 and W are defined in detail herein, for example, in the summary of the invention.

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

[0053]

Chemical formula

[0054] As shown in Scheme 1, compound 1-12 can be prepared from compound 1-1. 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, then 7,7-dimethyl-7,8-dihydro-4H-benzo[d][1,3]dioxin-5(6H)-one (1-2) is added and quenched with aqueous hydrochloric acid to obtain 4'-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (1-3). When tetraethylammonium chloride and triethylamine are added to a cooled solution of (1-3) in dichloromethane and then methanesulfonyl chloride is added, 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (1-4) can be obtained. When a solution of (1-4) is added to a mixture of (S)-2-methyl-CBS-oxazaborolidine and BH3 tetrahydrofuran in tetrahydrofuran at low temperature, (R)-4'-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol (1-5) can be obtained. When a mixture of (S)-tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1-6), compound 1-5, sodium iodide and potassium carbonate in acetonitrile is stirred together at ambient temperature, (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) can be obtained.To the solution in dichloroethane of (1-7), propane-1,3-diylbis(trifluoromethanesulfonate) (1-8) is added, and then N. 1 ,N 1 ,N 8 ,N 8 -tetramethylnaphthalene-1,8-diamine is added and heated to obtain (4aS,10aR)-tert-butyl 14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,7,8,9,10a,11,12,13,15-dodecahydrobenzo[f]pyrazino[2,1-c][1,8,4]dioxazacycloundecine-3(4H)-carboxylate (1-9). When trifluoroacetic acid is added to the solution of (1-9) in dichloromethane and then treated 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) can be obtained. When the solution of (1-10), ethyl 2-bromo-4-fluorobenzoate (1-11) and dipotassium hydrogen phosphate in anhydrous dimethyl sulfoxide is stirred together and heated, 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) can be obtained.

[0055]

Chemical formula

[0056] A solution in toluene from 1 to 12 is treated 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 a palladium catalyst to obtain 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 (2-2). When tetra-N-butylammonium fluoride in tetrahydrofuran is added to the solution of (2-2), 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 (2-3) can be obtained. When (2-3) is treated with lithium hydroxide, 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 (2-4) is obtained.

[0057]

Chem.

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

[0059]

Chem.

[0060] As shown in Scheme 4, compound 2-4 can be, with or without using a first base, a compound of formula (4-1) (wherein A, L, R 1And W is as described herein. It can be converted to the compound of formula (4-2) by reacting with 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 section of Synthesis Examples.

[0062] Pharmaceutical Composition When the compounds of the present invention are used as pharmaceuticals, they are usually administered in the form of pharmaceutical compositions. Such compositions may contain 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, a pharmaceutical composition is provided that comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier.

[0064] Method of Use The compounds of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions containing the compounds of formula (I), formula (II), or a pharmaceutically acceptable salt thereof can be administered to a subject suffering from CLL, SLL, and / or ALL. The term "administer" refers to a method of contacting a compound with a subject.

Examples

[0065] The following examples can be used for illustrative purposes and should not be regarded as limiting the scope of the present invention.

[0066] All reagents were of commercial grade and were used as received without further purification, unless otherwise specified. Commercial 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) in the 1H NMR spectra were 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 indicated meanings: NMR is nuclear magnetic resonance; s is singlet; br s is broad singlet; d is 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 molarity (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]dioxacycloundecin-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 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. Chromatography of the residue on silica gel (ISCO GOLD (registered trademark)) eluting with a 0-16% gradient of ethyl acetate / heptane gave 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 while maintaining the temperature below -70 °C. After stirring for 30 minutes at -78 °C, a solution of Example 1A (24 g) in tetrahydrofuran (75 mL) was added dropwise while 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 times). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (750 g, BIOTAGE® SNAP) eluted with a 5 - 22% gradient of ethyl acetate / heptane gave 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 A solution of (S)-2-methyl-CBS-oxazaborolidine (20.96 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise with 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 a dropping funnel over about 60 minutes. After the addition, the reaction mixture was stirred at -50 °C for 1.5 hours. The reaction mixture was quenched by adding methanol (130 mL) dropwise over about 20 minutes at -50 °C. The cooling bath was removed and the reaction mixture was warmed to ambient temperature overnight. The reaction mixture was diluted with saturated aqueous NH4Cl solution (250 mL), diluted with water, and extracted with ethyl acetate. The organic layer was washed further with aqueous saturated NH4Cl and brine, dried over sodium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (Teledyne Isco RediSep® RF GOLD® 330 g) eluting with a gradient of 0% - 20% ethyl acetate / heptane gave 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 (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) were stirred at ambient temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel (80 g) eluting with a gradient of 0% - 70% ethyl acetate:ethanol (3:1) / heptane gave 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]dioxacycloundecine-3(4H)-carboxylate To a solution of Example 1E (100 g) in dichloroethane (2150 mL) was added propane-1,3-diylbis(trifluoromethanesulfonate) (95 g), then 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 h. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1 N aqueous HCl (1 L × 3), 1 N aqueous NaOH (3 times), dehydrated with magnesium sulfate, filtered and concentrated. Chromatography of the residue 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 gave 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, a heating mantle, a nitrogen inlet and outlet, and a 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), followed by potassium hydrogen phosphate (90 g) were added. Once the slurry was completely mixed, the temperature was raised to 60 °C and the slurry was heated under nitrogen for 72 h. 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 addition funnel. Water (850 mL) was added dropwise from the addition funnel to the cold reaction slurry and the mixture was sonicated for 30 min. The mixture was mechanically stirred and vigorously stirred at ambient temperature for 1 h. The precipitate was filtered through a Buchner funnel fitted with filter paper. The filtered solid was washed with water (2 × 500 mL) and dried on the filter for 16 h. 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 h. 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 a 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. 11H 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) was added 3-chloroperbenzoic acid (21.90 g) at 25 °C, and then the mixture was stirred at 25 °C for 3 h. 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) portionwise 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 at 0 °C for an additional 2 hours. 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, a solution of Example 1M (1 g) in anhydrous tetrahydrofuran (10 mL) was added to the above solution 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 1O 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 Hoover-cooled reflux condenser, a Claisen head adapter, a needle inlet for nitrogen and an outlet to a bubbler through a septum, 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). These solids were placed under a large stream of nitrogen, and then cesium carbonate (81 g) was quickly added to this reaction flask. The solids were slowly mixed using a mechanical stirrer, and a large stream of nitrogen to the reaction flask was continued for 60 minutes. Anhydrous toluene (833 mL) was charged into another oven-dried 2 L round-bottom flask equipped with a stir bar and a septum. A large stream of nitrogen was blown through the surface of this solvent with stirring for 60 minutes. Next, this solvent was transferred to the three-necked flask via a cannula, and the reaction mixture was heated to an internal temperature of 110 °C under a nitrogen stream for 16 hours. The reaction mixture was cooled to ambient temperature, and water (600 mL) and then ammonium pyrrolidinedithiocarbamate (3 g), a palladium scavenger, were added to the flask. This mixture was stirred vigorously for 1 hour. The reaction mixture 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 × 500 mL). The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water (200 mL) and 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 give a crude residue. The residue was dissolved in dichloromethane (200 mL) and purified by normal-phase chromatography using a BIOTAGE® Snap Ultra 1.5 kg silica gel column eluting with a gradient of 0 - 50% ethyl acetate in heptane to give the title compound. 11H 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 To 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 a thermocouple, Example 1O (69 g) was charged. This solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution, ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL) were added at ambient temperature. 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 a 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). Drying the solid on a Buchner funnel gave the title compound. 11H NMR (600 MHz, dimethyl sulfoxide-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. 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) + .

[0086] 実施例1R 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.043 g) in dichloromethane (1 mL) was stirred. After stirring for 16 hours, the reaction mixture 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 minutes to give the title compound. 11H 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]dioxacycloundecin-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 the literature procedure (Angew Chem Int Ed 2015, 54, 13538 - 13544). Optical rotation (measured value) [α] D 25 = -78.93 (c 1.06, in chloroform); (literature) [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 about 5 minutes, and then Example 2A (1.5 g) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture 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 mixture was stirred for 4 hours, then the reaction mixture was placed back in the ice bath and carefully quenched with a 1:1 aqueous solution of saturated ammonium chloride and water (20 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 concentrated. The crude material was purified using flash chromatography (40 g silica column, 0 - 5% ethyl acetate / heptane). Combining and concentrating the fractions containing the desired product gave the title compound. 11H 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 dropwise 9-borabicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) at 0 °C over 1 hour. Next, the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and 10% aqueous sodium hydroxide solution (15 mL) and then 30% aqueous hydrogen peroxide solution (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 solution (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. 11H 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 h. The reaction mixture was poured onto aqueous saturated 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 give the title compound. 11H 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, then the water bath was replaced by a dry ice / acetone bath. A solution of Example 2D (1.79 g) in anhydrous toluene (3 mL), followed by a toluene wash (2 mL), was added dropwise. A solution of methyllithium (1.6 M in diethyl ether, 15.24 mL) was added dropwise and the reaction was stirred in a dry ice bath for 2 hours. The reaction mixture was carefully quenched with 0.25 M hydrochloric acid (10 mL), then poured onto 1 M hydrochloric acid (50 mL) and filtered. The filtrate was extracted with 2:1 ethyl acetate / heptane (2×50). 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-H2O) + .

[0093] Example 2F ((2R,5S)-5-Hydroxy-5-methyltetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate In a 25 mL Hastelloy C reactor, a solution of Example 2E (1.5 g) in ethanol (13.22 mL) was treated with Pd(OH)2 / C (20 wt% Pd, 50% moisture, 0.150 g). The reactor was purged with nitrogen. The mixture was stirred under hydrogen (60 psi) at ambient temperature. After 20 minutes, the reactor was vented and the reaction mixture was filtered. The filtrate was concentrated and dissolved in dichloromethane (12.00 mL). Triethylamine (2.00 mL) and 4-methylbenzenesulfonyl chloride (1.25 g) were added to this solution and the reaction was stirred at ambient temperature. After 30 minutes, the reaction appeared to be complete and purification using flash chromatography (40 g silica column, 0 - 100% ethyl acetate / heptane) gave 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 mixture was stirred at 85 °C for 16 h. The reaction mixture 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 afford 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 A solution of Example 2G (160 mg) in tetrahydrofuran (3.2 mL) was added to a slurry of Raney-Ni 2800 (79.3 mg) in water in a 20 mL glass-lined reactor. The reactor was purged with nitrogen. The mixture was stirred at 25 °C under hydrogen (50 psi). After 20 h, the reactor was vented and the reaction mixture was filtered. Concentration of the filtrate afforded the title compound. 1 H NMR (500 MHz, CDCl3) 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 a solution of dichloromethane (1 mL) at ambient temperature for 16 h. The reaction mixture was loaded onto a silica gel flash chromatography column (12 g of silica) and eluted using a gradient of 20% - 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]dioxacycloundecin-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 ether complex (13.8 g), and the temperature was warmed to 38 °C. To this reaction was added (R)-2-(chloromethyl)oxirane (150 g) below 49 °C. The reaction was stirred at 49 °C to 33 °C for 20 minutes and then cooled to 15 °C. To this reaction was added sodium hydroxide (20 wt%, 800 mL) in water below 17 °C. The reaction was stirred at 15 °C for 1 hour. The reaction was diluted with water (500 mL) and separated. The water was extracted with tert-butyl methyl ether (200 mL). The combined organic phases were washed with water (300 mL) and brine (300 mL), dehydrated 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 wt%, 1000 mL), Example 3A (222 g) was added at 90 °C. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture 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 a 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. Next, methanesulfonyl chloride (44.1 g) was added at 0 °C. Then, the reaction mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into an ice-cooled saturated aqueous sodium hydrogen carbonate 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 (3×). 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]dioxacycloundecin-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 1,3-dimethylpropan-1,3-diamine hydrochloride (0.036 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 h, N,N-dimethylformamide (1 mL) was added and stirring was continued for 6 h. The reaction mixture was concentrated and 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%–85% acetonitrile / water (containing 2,2,2-trifluoroacetic acid). The product-containing fractions were lyophilized, loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 24 g), and eluted over 30 min using a gradient of 1%–4% dichloromethane / methanol to give the title compound. 11H 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]dioxepino[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 at 20 °C under nitrogen. Then, sodium triacetoxyborohydride (101 g) was added portionwise to this solution at 20 °C. The reaction mixture was stirred at 20 °C for 30 minutes. Then, oxetan-3-one (229.2 g) was added dropwise to this mixture while 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 -dimethylpropane-1,3-diamine hydrochloride (0.048 g) in dichloromethane (1.2 mL) was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 minutes using a gradient of 1% - 4% dichloromethane / methanol 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]dioxacycloundecin-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 A solution of (1r,4r)-methyl 4-methoxycyclohexanecarboxylate (3.5 g) in tetrahydrofuran (24 mL) was added dropwise to a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 12.2 mL) in tetrahydrofuran (4.8 mL) at 0 °C, and the reaction was slowly warmed to ambient temperature. After 1 hour, the reaction was cooled to 0 °C and quenched slowly 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 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). The reaction was stirred at 0 °C for 15 minutes and then warmed 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 give 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 and then with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase chromatography on 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 trifluoroacetate To a solution of Example 5C (666 mg) in dichloromethane (9695 μL) at ambient temperature, trifluoroacetic acid (3.2 mL) was added and the reaction mixture was allowed to stand for 1 hour. The reaction mixture 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, N,N-diisopropylethylamine (1230 μL) was added and the reaction mixture was stirred. After 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by normal phase chromatography on 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.058 g) in dichloromethane (1.5 mL) 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% - 4% dichloromethane / methanol over 30 minutes. The product was dissolved in dimethyl sulfoxide / methanol 1:1 (3 mL) and 2,2,2-trifluoroacetic acid (0.012 mL) was added. The above solution was purified by preparative HPLC using a Gilson PLC2020 system (Luna column, 250×50, flow rate 75 mL / min) with a gradient of 20% - 95% acetonitrile / water over 30 minutes to give the title compound. 11H 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]dioxacycloundecin-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. 11H 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 h. 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 the mixture was 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). The reaction mixture was heated to 45 °C and stirred for 5 hours. The reaction mixture 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]dioxepino[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 -dimethylpropane-1,3-diamine hydrochloride (0.043 g) in dichloromethane (1.1 mL) was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 minutes using a gradient of 1% - 4% dichloromethane / methanol 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]dioxacycloundecin-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 (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 mixture was stirred for 30 minutes. 5,6-Dichloropyridine-3-sulfonamide (0.800 g) was added, and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated. Chromatography on silica gel eluting with ethyl acetate / hexanes gave 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]dioxacycloundecin-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 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 -dimethylpropane-1,3-diamine hydrochloride (0.019 g) in dichloromethane (0.50 mL) was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 minutes using a gradient of 1% - 4% dichloromethane / methanol 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.+ .

[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]dioxacycloundecin-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 hydrogen carbonate, and water. The organic layer was dehydrated with 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) were 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 h. The solution was cooled to 25 °C and purified directly 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]dioxepino[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) was treated 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]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

[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) portionwise. The reaction was heated to 55 °C for 18 h. 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 h. 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 min, and filtered to afford the title compound. 11H 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]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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.048 g) in dichloromethane (1.3 mL) was stirred. After stirring for 16 h, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 min using a gradient of 1% - 4% dichloromethane / methanol to afford 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 was added 5,6-dichloropyridine-3-sulfonamide (1.01 g) and the reaction was warmed 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 and filtered, and the filtrate was concentrated. Trituration of the residue with dichloromethane gave 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 saturated solution of sodium hydrogen carbonate (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and filtered, and concentration of the filtrate gave the title compound. 11H 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 h. 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)). Lyophilization of the earlier eluting fraction of the two isolated peaks gave the title compound. 1 1H 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 performed 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]dioxacycloundecin-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 treated with 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 It was treated with 1,3-dimethylpropan-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 obtain 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, 2H), 1.78 - 1.55 (m, 5H), 1.34 (dd, J = 12.2, 9.3 Hz, 1H), 1.03 (d, J = 16.6 Hz, 6H). 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]dioxacycloundecin-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, replacing Example 10C with Example 10D. 11H NMR (600 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 the literature procedure (Angew Chem Int Ed 2015, 54, 13538 - 13544). Optical rotation (measured value) [α] D 25 = -78.93 (c 1.06, in chloroform); (literature) [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, and then Example 12A (1.5 g) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture 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 mixture was stirred for 4 hours, then the reaction mixture was placed back in the ice bath and carefully quenched with a 1:1 saturated aqueous ammonium chloride / water (20 mL). The biphasic mixture was extracted with ethyl acetate / heptane 3:1 (2 × 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 purged with nitrogen for 5 minutes and then added to a flask containing Pd(OH)2 / C (20 wt% Pd, 50% moisture, 10.0 mg). A hydrogen balloon was attached and the reaction was stirred at ambient temperature for 24 hours. The reaction mixture was filtered, 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-methylbenzenesulfonyl 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 give 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 mixture was heated to 80 °C for 20 h. The reaction mixture was cooled to ambient temperature, poured into water (30 mL), and then extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were washed with water (2 x 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 afford 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 water slurry of Raney-Ni 2800 (0.55 g) was charged with a solution of Example 12F (0.55 g) in tetrahydrofuran (6.00 mL). The reactor was purged with nitrogen. The mixture was stirred at 25 °C under hydrogen (60 psi). After 20 h, the reactor was vented, the reaction mixture was filtered, and the filtrate was concentrated to afford 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]dioxacycloundecin-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 were sequentially added Example 1Q (50.0 mg), N,N-dimethylpyridin-4-amine (21.0 mg) and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride (25.0 mg) and the reaction, stirred at ambient temperature, was continued for 16 hours. The reaction mixture was purified using flash chromatography (24 g silica column, 0 - 100% ethyl acetate / heptane). The 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 45 minutes. The reaction mixture was concentrated and purified using reverse phase HPLC (10 - 100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 11H NMR (400 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 the literature procedure (Angew Chem Int Ed 2015, 54, 13538 - 13544). Optical rotation (measured value) [α] D 25 = -78.93 (c 1.06, in chloroform); (literature) [α] D 25 = -74.32 (c 1.07, in chloroform). A small amount of this substance was treated with 3-(4-(trifluoromethyl)phenyl)propanoic acid, N,N-dimethylpyridin-4-amine and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride to give (R)-(3,4-dihydro-2H-pyran-2-yl)methyl 3-(4-(trifluoromethyl)phenyl)propanoate. Using chiral supercritical fluid chromatography for analysis (ChiralPak AD-H, 5 - 50% CH3OH, 3 mL / min, 10-minute method, 150 bar CO2), the ee of this ester was determined to be 99%. The retention time of the major enantiomer was 1.19 minutes, and the retention time of the minor enantiomer was 1.09 minutes.

[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, and then Example 13A (1.5 g) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture 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 mixture was stirred for 4 hours, then the reaction mixture was placed back in the ice bath and carefully quenched with a 1:1 aqueous saturated ammonium chloride solution and water (20 mL). The biphasic mixture was extracted with ethyl acetate / heptane 3:1 (2 × 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). Combining and concentrating the fractions containing the desired product gave 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 dropwise 9-borabicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) over 1 hour at 0 °C. Next, the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and 10% aqueous sodium hydroxide solution (15 mL) and then 30% aqueous hydrogen peroxide solution (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 solution (20 mL) at 0 °C and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with ethyl acetate / heptane (2×50 mL) in a ratio of 3:1. 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 wt% in mineral oil, 0.216 g). After stirring at ambient temperature for 20 minutes, neat iodomethane (0.600 mL) was added and stirring was 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 afford 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% moisture, 50 mg), a solution of Example 13D (0.600 g, 2.54 mmol) in tetrahydrofuran (5.00 mL) was added, and nitrogen was bubbled through this solution. The flask was connected to a hydrogen balloon, and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was filtered, and the filtrate was diluted with dichloromethane (5.00 mL). To this solution were 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 h. The reaction mixture was filtered to discard the solid. The filtrate was concentrated and purified using flash chromatography (24 g silica column, 0 - 100% ethyl acetate / heptane) to afford 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 h. The reaction mixture 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 (m, 3H), 3.13 (dd, J = 10.7, 10.2 Hz, 1H), 2.26 - 2.19 (m, 1H), 1.75 - 1.67 (m, 1H), 1.49 - 1.30 (m, 2H). LC / MS (APCI+) m / z 144.25 (M-N2+H) + .

[0163] Example 13G ((2R,5S)-5-Methoxytetrahydro-2H-pyran-2-yl)methanamine A solution of Example 13F (0.300 g) in tetrahydrofuran (8.00 mL) was added to a water slurry of Raney-Ni 2800 (0.600 g) in a 20 mL glass-lined reactor. The reactor was purged with nitrogen and the mixture was stirred at 25 °C under hydrogen (60 psi). After 20 h, 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]dioxacycloundecin-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 Ethyl 1-oxaspiro[2.5]octane-6-carboxylate A mixture of ethyl 4-oxocyclohexanecarboxylate (50 g), (CH3)3SOI (64.6 g) and potassium 2-methylpropane-2-olate (33.0 g) in ethylene glycol dimethyl ether (700 mL) was stirred at 90 °C for 12 h under nitrogen. After cooling the mixture 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. Concentration of the filtrate gave a crude product which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6 / 1 - 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 volatile portion of this mixture was concentrated. Potassium hydrogen fluoride (1.272 g) was added to this residue. The resulting mixture was heated at 100 °C for 15 minutes under vacuum (0.55 mmHg). 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 a crude product, which was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6 / 1 - 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 solution (6.7 mL), and then water (20.1 mL). Anhydrous sodium sulfate was added. The resulting mixture was further stirred at ambient temperature for 30 minutes, and the precipitate was removed by filtration. The filter cake was washed with diethyl ether. Next, the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 3 - 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(14g) in dichloromethane (140 mL) at 0 °C, p-toluenesulfonyl chloride (19.75 g) and pyridine (34.9 mL) were added. The mixture was stirred at ambient temperature for 12 hours and then washed with water, 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dehydrated over anhydrous sodium sulfate and filtered. Concentration of the filtrate gave a 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) portionwise. The reaction mixture was stirred at 80 °C for 12 h. 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. Concentration of the filtrate under reduced pressure gave a crude product, which was purified by column chromatography on silica gel eluting 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) was added Raney nickel (1.39 g) under argon. The suspension was degassed under vacuum and purged with hydrogen several times. Then, the mixture was stirred at ambient temperature for 18 h under hydrogen. The suspension was filtered through a pad of diatomaceous earth and washed thoroughly with methanol (500 mL). Concentration of the combined filtrates to dryness gave a crude product, which was triturated in methyl tert-butyl ether (20 mL) to give the title compound. MS(ESI+)m / z162.0(M+H) + 。

[0173] Example 14H 4-((((1s,4s)-4-(Fluoromethyl)-4-hydroxycyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide To a solution of Example 14G (5g) in N,N-dimethylformamide (50 mL), N,N-diisopropylethylamine (21.67 mL) and 4-fluoro-3-nitrobenzenesulfonamide (5.46 g) were added. The solution was stirred at ambient temperature for 12 hours. Next, the reaction mixture was concentrated under reduced pressure to obtain a 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]dioxepino[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 in dichloromethane (2 mL) 1 -((ethylimino)methylene)-N 3 ,N 3Triethylamine (29.4 μL) was added to a mixture of -dimethylpropane-1,3-diamine hydrochloride (18.84 mg). The mixture was stirred at ambient temperature for 16 h 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]dioxacycloundecin-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(cyclobutane)]-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 were added N,N-dimethylformamide (0.299 mL) and then oxalyl chloride (6.67 g). The resulting mixture was stirred at ambient temperature for 2 h 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 warmed to ambient temperature and then stirred at this temperature for 3 h. 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. Purification of the residue by column chromatography on silica gel (eluting with 10:1 ethyl acetate / petroleum ether) gave 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 A solution of Example 15A (10 g) in tetrahydrofuran (50 mL) was added dropwise to a suspension of lithium aluminum hydride (3.88 g) in tetrahydrofuran (100 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, then anhydrous magnesium sulfate was added. The resulting mixture was stirred at ambient temperature for a further 15 minutes and then filtered. The filter cake was washed with ethyl acetate (300 mL). The filtrate was concentrated to dryness to give 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) at -78 °C was added dimethyl sulfoxide (5.55 mL) in dichloromethane (10 mL). After stirring this mixture at -78 °C for 20 minutes, a solution of Example 15B (10 g) in dichloromethane (40 mL) was added. The reaction mixture was further stirred at -78 °C for 60 minutes. Triethylamine (25.8 mL) was added. Next, the mixture was warmed to ambient temperature and then 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. Purification of this residue by column chromatography on silica gel (15:1 petroleum ether / ethyl acetate) gave 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(cyclobutane)]-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 solution (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. Purification of this residue by column chromatography on silica gel (15:1 petroleum ether / ethyl acetate) gave the title compound. 11H NMR (400 MHz, CDCl3) δ ppm 1.53 (broad 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 (broad 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(cyclobutane)]-1-ol Acetic acid (15 mL) was added to a suspension of Example 15D (4.8 g) and 10% Pd(OH)2 on carbon (2.0 g) in methanol (150 mL). The mixture was stirred at 25 °C for 12 h under a hydrogen atmosphere (15 psi). The reaction mixture was filtered and the filter cake was successively washed with methanol (500 mL) and water (200 mL). The filtrate was concentrated to remove methanol. Aqueous saturated sodium carbonate solution (80 mL) was added to the residue to adjust the pH to 8 - 9. The mixture was extracted with 1:6 isopropanol / chloroform (4 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. Concentration of the filtrate gave the title compound. MS(ESI-) m / z 156.1 (M - H) - .

[0181] Example 15F 4-((((1s,3s)-1-Hydroxy-[1,1'-bi(cyclobutane)]-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 at 80 °C for 14 h under nitrogen. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC (C18 column, 30 - 50% acetonitrile (in 10 mM NH4HCO3 in H2O)) to give the title compound. 11H 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]dioxacycloundecin-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(cyclobutane)]-3-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide Example 14H was replaced with Example 15F and the title compound was prepared using the same procedure for the last step of Example 14. 11H NMR (400 MHz, dimethyl sulfoxide-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 Hz, 1H), 2.05 (td, J = 28.4, 26.4, 12.6 Hz, 9H), 1.92 - 1.60 (m, 10H), 1.38 - 1.28 (m, 1H), 1.02 (d, J = 9.9 Hz, 6H). 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]dioxacycloundecin-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 at -15 °C for 0.5 h under nitrogen. 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. Next, the mixture was stirred at 25 °C for an additional 15 h, then cooled back to 0 °C and stirred for 0.5 h. 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 hydrogen carbonate (2 × 90 mL), dehydrated over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to give 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 solution of tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 65.4 mL), hydrogen fluoride (2.85 mL) was added with stirring, and the volatile portion was evaporated under reduced pressure. Potassium hydrogen fluoride (0.511 g) was added to this residue, and the resulting mixture was dried at 60 °C for 30 minutes under vacuum (0.55 mmHg). After cooling this mixture 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 a crude product. The crude product was purified by column chromatography on silica gel (15% ethyl acetate in petroleum ether) to give Example 16B and Example 16C. Example 16B: 1 H NMR (400 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 Example 14H was replaced with Example 16E, and the title compound was prepared using the same procedure as the last step of Example 14. 11H NMR (500 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 mixture was cooled, diluted with ethyl acetate, 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. Trituration of the residue with ethyl acetate / dichloromethane / methanol afforded the title compound. MS(ESI-) m / z 604.7 (M-H) - 。

[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]dioxacycloundecin-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 -dimethylpropane-1,3-diamine hydrochloride (0.027) in dichloromethane (0.7 mL) was stirred. After stirring for 16 h, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 min using a gradient of 1% - 6% dichloromethane / methanol to afford 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]dioxacycloundecin-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-decahydrobenzzo[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 A solution of 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 -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 mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 min using a gradient of 0.5% - 4% dichloromethane / methanol 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]dioxacycloundecin-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 In a vial, under nitrogen, 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 and heated to 95 °C for 16 hours. The reaction mixture was cooled, loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g), and eluted over 30 minutes using a gradient of 1% to 5% dichloromethane / methanol. The product-containing fractions were collected and concentrated. The residue was dissolved in 1:1 dimethyl sulfoxide:methanol (2 mL) and purified by HPLC with 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]dioxacycloundecin-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, then tetrahydrofuran (10 mL) was added, and the solution was stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium hydroxide, extracted with ethyl acetate, dehydrated over sodium sulfate and concentrated. Trituration of the residue with tert-butyl methyl ether followed by filtration gave 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.040 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 h, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 min using a gradient of 1% - 4% dichloromethane / methanol 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]dioxacycloundecin-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), and the mixture was stirred for 20 minutes, 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 × 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.040) in dichloromethane (1.0 mL) was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 minutes using a gradient of 1% - 4% dichloromethane / methanol. This material was dissolved in 1:1 dimethyl sulfoxide / methanol (2 mL), then 2,2,2-trifluoroacetic acid (0.024 mL) was added and purification was carried out by HPLC (Luna 10μm C18(2) 250×50 mm column) using a gradient of 20% - 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), 3.01 - 2.87 (m, 2H), 2.50 (d, J = 12.2 Hz, 1H), 2.20 - 2.04 (m, 4H), 2.01 - 1.93 (m, 2H), 1.88 (td, J = 11.4, 3.0 Hz, 1H), 1.84 - 1.74 (m, 1H), 1.61 (dd, J = 12.6, 8.8 Hz, 1H), 1.03 (d, J = 9.7 Hz, 6H), 0.95 (d, J = 6.2 Hz, 3H). LC / MS (ESI+) m / z 1026.67 (M+H) + .

[0202] [Example 21] 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]dioxacycloundecin-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 h. 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 mixture 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 × 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)penta-4-en-2-ol To a solution of Example 21B (140 g) in tetrahydrofuran (1399 mL) was added copper(I) chloride, and the reaction mixture was cooled to -10 °C. Vinylmagnesium bromide (1 M in tetrahydrofuran, 829 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 1 hour. Methanol (55.9 mL) and then water (200 mL) were added at 0 °C, and the mixture was 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 as such 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)penta-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 as is 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 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 mixture was heated to 110 °C for 12 h. 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 give 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)2 / 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), then 4-fluoro-3-nitrobenzenesulfonamide (0.716 g) was added, and the reaction was stirred at ambient temperature for 16 h. The reaction mixture was purified using flash chromatography (80 g silica column, 20-100% ethyl acetate / heptane) to isolate a 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. 11H 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, 10.6, 3.8 Hz, 2H), 1.54 - 1.40 (m, 1H), 1.30 - 1.09 (m, 2H), 0.83 (d, J = 6.6 Hz, 3H). 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]dioxacycloundecin-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 treated with 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) was used for treatment, and this mixture was stirred for 23 hours. The reaction mixture was concentrated and purified using reverse-phase HPLC (column: Luna 10μm C18(2) 250×50 mm, 10 - 100% acetonitrile / water (+0.1% trifluoroacetic acid)), and the title compound was obtained. 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 = 11.1 Hz, 1H), 2.20 - 1.89 (m, 6H), 1.82 - 1.63 (m, 4H), 1.61 - 1.44 (m, 4H), 1.33 (dd, J = 12.2, 9.2 Hz, 1H), 1.07 - 0.95 (m, 9H). 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]dioxacycloundecin-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) were added potassium carbonate (26.4 g) and 1-bromo-2-methoxyethane (9.73 g). The resulting mixture was stirred at 70 °C for 12 h. 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 phases were washed with brine (30 mL), dried over anhydrous sodium sulfate and 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 A solution of Example 22A (10 g) in anhydrous tetrahydrofuran (50 mL) was added dropwise to a solution of lithium N,N - diisopropylamine (46.4 mL) in anhydrous tetrahydrofuran (100 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 portions. The resulting mixture was gradually warmed to 25 °C and stirred for 12 hours. The reaction was quenched by dropwise addition of a saturated aqueous ammonium chloride solution (200 mL) at 0 °C, 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), and the title compound was obtained. 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 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 was cooled to 0 °C, diluted with tetrahydrofuran, and quenched by 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. 11H 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) at 0 °C was added sodium hydride (4.18 g). 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 and filtered, and the filtrate was concentrated. Trituration of the residue with 1:1 petroleum ether and ethyl acetate (50 mL) gave the title compound. 1 1H 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 = 5.81 Hz, 2H), 4.46 - 4.57 (m, 2H), 7.56 (s, 2H), 8.24 (d, J = 2.08 Hz, 1H), 8.50 (d, J = 2.20 Hz, 1H), LC / MS: m / z 380.1 (M - H) - .

[0217] Example 22E N-((5-Chloro-6-((4-fluoro-!-(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]dioxacycloundecin-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 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 -dimethylpropane-1,3-diamine hydrochloride (0.040 g) in dichloromethane (1.0 mL) was stirred. After stirring for 16 hours, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 40 g) and eluted over 30 minutes using a gradient of 1% - 4% dichloromethane / methanol to give the title compound. 11H 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]dioxacycloundecin-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 Example 21G was replaced with Example 21H, and the title compound was prepared according to the procedure for the last step of Example 21. The crude product was purified by reverse-phase HPLC (column: Luna 10μm C18(2) 250×50 mm, 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, 6.5 Hz, 2H), 1.14 (td, J = 12.5, 3.8 Hz, 1H), 1.02 (d, J = 10.3 Hz, 6H), 0.75 (d, J = 6.6 Hz, 3H). 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]dioxacycloundecin-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-oxocyclobutane carboxylic 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 h, then phenylmethanamine (5.75 mL) was added at 20 °C and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by the addition of 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 and filtered, and the filtrate was concentrated. Trituration of the residue with 20:1 ethyl acetate / petroleum ether (1 L) gave 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 h. 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. Trituration of the residue with ethyl acetate / petroleum ether (1 L) in a ratio of 15:1 gave 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) were 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 h. The reaction mixture was filtered through diatomaceous earth, 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. Purification of the residue by column chromatography (eluting with petroleum ether / ethyl acetate from 3 / 1 to ethyl acetate) gave the title compound. 11H 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 this 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 1H 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 at 50 °C for 2 hours under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give the title compound. 11H 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) was added N,N-diisopropylethylamine (4.55 mL) and 4-chloro-3-nitrobenzenesulfonamide (2.46 g) at 20 °C. The reaction mixture was stirred at 80 °C for 12 h. 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 H2O; B: acetonitrile) to give the title compound. 1 1H 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.022 g) in dichloromethane (0.6 mL) was stirred for 3 days. The reaction mixture was loaded onto silica gel (agela, 40 g) and eluted over 30 minutes using a gradient of 0.5% to 4.5% dichloromethane / methanol to give the title compound. 11H 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]dioxacycloundecin-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 (25.8), dichloromethane (250 mL) and N,N-dimethylpyridin-4-amine (32.0 g) were added. The flask was placed in an ice bath. After 15 minutes, neat acetyl chloride (16.1 mL) was added and the reaction mixture was stirred in the ice bath for 1 hour. The reaction mixture was poured into a separatory funnel containing water (200 mL) and the two layers were separated. The aqueous layer was extracted once with dichloromethane (80 mL). The combined organic layers were dried over magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified using flash chromatography (330 g silica column, 0 - 60% ethyl acetate / heptane) to give 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 the solids had dissolved. To this solution was added racemic (3,4-dihydro-2H-pyran-2-yl)methyl acetate (10.0 g) in acetone (10 mL) at ambient temperature, followed by porcine pancreatic lipase (75 mg). In a separate flask, the same reaction was prepared on a 2-fold scale. The reaction was stirred at ambient temperature for 18 hours and then both were combined in a separatory funnel and extracted with 1:1 ethyl acetate / heptane (2 x 500 mL). The combined organic layers were discarded and the aqueous layer was extracted with 9:1 ethyl acetate / heptane (2 x 500 mL). The combined organic layers were 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 give the title compound. 11H 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 substance was treated with 3-(4-(trifluoromethyl)phenyl)propanoic acid, N,N-dimethylpyridin-4-amine and N 1 -((ethylimino)methylene)-N 3 ,N 3 -dimethylpropane-1,3-diamine hydrochloride to obtain (S)-(3,4-dihydro-2H-pyran-2-yl)methyl 3-(4-(trifluoromethyl)phenyl)propanoate. Using chiral supercritical fluid chromatography for analysis (ChiralPak AD-H, 5 - 50% CH3OH, 3 mL / min, 10-minute method, 150 bar CO2), the ee of this ester was determined to be 93%. The retention time of the major enantiomer was 1.26 minutes, and the retention time of the minor enantiomer was 1.34 minutes.

[0229] Example 25B (S)-2-((benzyloxy)methyl)-3,4-dihydro-2H-pyran To a flask containing sodium hydride (60 wt% in mineral oil, 1.104 g), tetrahydrofuran (60.0 mL) was added. The slurry was cooled in an ice bath, and a solution of Example 25A (2.100 g) in tetrahydrofuran (3 mL) was then added dropwise, followed by tetrahydrofuran (2 mL). The reaction mixture 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 mixture was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and carefully quenched by 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 afford 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 dropwise 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 75.0 mL) over 1 hour at 0 °C. Next, the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and at 0 °C, 10% aqueous sodium hydroxide solution (25 mL) and then 30% aqueous hydrogen peroxide solution (32 mL) were carefully added to the mixture. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous sodium sulfite solution (40 mL) at 0 °C and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with ethyl acetate / heptane 3:1 (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 give 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 addition of 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 give 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% moisture, 50 mg), a solution of Example 25D (0.97 g) in tetrahydrofuran (10.00 mL) was added. The flask was purged with nitrogen and a hydrogen balloon was connected. The reaction was stirred at ambient temperature for 24 hours and then the mixture was filtered and concentrated. The residue was dissolved in dichloromethane (15 mL) and then N,N-dimethylpyridin-4-amine (0.750 g), N-ethyl-N-isopropylpropan-2-amine (1.500 mL) and 4-methylbenzen-1-sulfonyl chloride (0.800 g) were added sequentially. The reaction was stirred at ambient temperature for 3 hours and then the mixture was poured into water (20 mL) and extracted with dichloromethane (2 × 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 give 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 h. The reaction mixture 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 afford 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) were added water (0.076 mL) and triphenylphosphine (1.10 g), and the reaction mixture was stirred at ambient temperature for 16 h. To this reaction mixture were 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 h. The reaction mixture was purified using flash chromatography (40 g silica column, 10 - 100% ethyl acetate / heptane) to afford the title compound. 11H 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 addition of saturated aqueous NaHCO3, and 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. Chromatography of the residue on silica gel (ISCO GOLD (registered trademark)) eluting with a gradient of 0 - 16% ethyl acetate / heptane gave the title compound. 11H 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) was added dropwise n-butyllithium (2.5 M in hexane, 60.6 mL) at -78 °C, maintaining the temperature below -70 °C. After stirring for 30 minutes at -78 °C, 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 times). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (750 g, BIOTAGE® SNAP) eluting with a gradient of 5 - 22% ethyl acetate / heptane gave the title compound. 1 1H 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) were added tetraethylammonium chloride (14.08 g), and then 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 warmed to ambient temperature overnight. The reaction mixture was washed with saturated aqueous ammonium chloride and brine, dehydrated over magnesium sulfate, filtered, and concentrated. Chromatography of the residue on silica gel (330 g, ISCO GOLD (registered trademark)) eluting with a gradient of 0 - 35% ethyl acetate / heptane gave 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 A solution of (S)-2-methyl-CBS-oxazaborolidine (20.96 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise with 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 from a dropping funnel over about 60 minutes. After the addition, the reaction mixture was stirred at -50 °C for 1.5 hours. The reaction mixture was quenched by adding dropwise methanol (130 mL) over about 20 minutes at -50 °C. The cooling bath was removed and the reaction mixture was warmed 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. Chromatography of the residue on silica gel (Teledyne Isco RediSep® Rf GOLD® 330 g) eluting with a gradient of 0% to 20% ethyl acetate / heptane gave 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 (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) were 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. Chromatography on silica gel (80 g) eluting with a gradient of 0% - 70% ethyl acetate:ethanol / heptane 3:1 gave 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]dioxacycloundecin-3(4H)-carboxylate To a solution of Example 25L (100 g) in dichloroethane (2150 mL) was added propane-1,3-diyl bis(trifluoromethanesulfonate) (95 g), then 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 h. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1 N aqueous HCl (1 L × 3), 1 N aqueous NaOH (3 times), dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue 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 gave 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 25 N (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 about 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 4 times with saturated aqueous Na2CO3, dehydrated over sodium sulfate, filtered, and concentrated to give 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]dioxoazacycloundecin-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. 11H 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) was added 3-chloroperbenzoic acid (21.90 g) at 25 °C, and then the mixture was 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. 11H 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 trichloroacetyl chloride (47.1 mL) at 0 °C. The resulting mixture was stirred for 0.5 h and then warmed to 25 °C for an additional 2 h. 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. Concentration of the filtrate under reduced pressure gave a residue, which was triturated with ethyl acetate and petroleum ether (1:10, 100 mL) to give the title compound. 1 1H 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) portionwise 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 further stirred at 0 °C for 2 hours. 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 A solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL) was added portionwise with sodium hydride (0.166 g) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h and then Example 25R (0.5 g) was added. The reaction mixture was heated to 80 °C and stirred under nitrogen for 12 h. 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. Concentration of the filtrate under reduced pressure gave a residue, which 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 under microwave at 160 °C for 2 h. After cooling the reaction to ambient temperature, it 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, which was purified by column chromatography on silica gel (eluted with petroleum ether:ethyl acetate = 3:1) to afford 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) under nitrogen, naphthalene (1.624 g) was added. The mixture was stirred at 20 °C for 1 hour until the formation of sodium / naphthalene was complete. Next, to the above solution, a solution of Example 25T (1 g) in anhydrous tetrahydrofuran (10 mL) was added 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-neck round-bottom flask equipped with a mechanical stirrer, a Hoover-cooled reflux condenser, a Claisen head adapter, a needle inlet for nitrogen and an outlet to a bubbler via a septum, 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). These solids were placed under a large stream of nitrogen, and then cesium carbonate (81 g) was quickly added to this reaction flask. These solids were slowly mixed using a mechanical stirrer, and a large stream of nitrogen to the reaction flask was continued for 60 minutes. Another oven-dried 2 L round-bottom flask equipped with a stir bar and a septum was charged with anhydrous toluene (833 mL). A large stream of nitrogen was blown through the surface of this solvent with stirring for 60 minutes. Next, this solvent was transferred to the three-neck flask via a cannula, and this reaction mixture was heated to an internal temperature of 110 °C under a nitrogen stream for 16 hours. This reaction mixture was cooled to ambient temperature, and water (600 mL) and then ammonium pyrrolidinedithiocarbamate (3 g), a palladium scavenger, were added to the flask. This mixture was stirred vigorously for 1 hour. The reaction mixture 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 × 500 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The organic layer was washed with water (200 mL) and 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 give a crude residue. The residue was dissolved in dichloromethane (200 mL) and purified by normal-phase chromatography using a BIOTAGE® Snap Ultra 1.5 kg silica gel column eluting with a gradient of 0-50% ethyl acetate in heptane to give the title compound. 11H 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).

[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]dioxoazacycloundecin-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 To 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 a thermocouple, Example 25V (69 g) was charged. This solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution, at ambient temperature, ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL) were added. The reaction mixture was heated to an internal temperature of 66 °C for 24 hours. The heating mantle was removed and the reaction mixture 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 a 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. 11H NMR (600 MHz, dimethyl sulfoxide-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]dioxoazacycloundecin-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 To a 5 L three-necked flask equipped with a mechanical stirrer, heating mantle, reflux condenser, Claisen adapter, nitrogen inlet and outlet to a bubbler, and a thermocouple, Example 25W (58.7 g) was charged. This residue was dissolved in 1,4-dioxane (991 mL) and methanol (496 mL) and stirred at ambient temperature for 5 minutes. Next, 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 carefully adding 3N aqueous hydrochloric acid (100 mL). The pH was further adjusted to pH 6 by adding saturated aqueous ammonium chloride (100 mL). This mixture was diluted with dichloromethane (300 mL) and the layers were partitioned in a separatory funnel. The aqueous layer was extracted with dichloromethane (2 × 100 mL) and the organic layers were combined and dried over sodium sulfate (50 g). The solid was filtered off and the filtrate was concentrated in vacuo to give 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 - 3.64 (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]dioxacycloundecin-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 treated with 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 by reverse-phase HPLC (Luna 10μm C18(2) 250×50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 11H NMR (500 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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) portionwise 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 phases were 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 mixture was stirred at 25 °C for 12 h. 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 petroleum ether:ethyl acetate 1:1 - 0:1) 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) were 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 h. 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 petroleum ether:ethyl acetate 5:1 - 1:1) 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(6g) in N,N-dimethylformamide (60 mL) at 25 °C were 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 and filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate 10:1 to 3:1) 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 at 25 °C for 6 hours under a hydrogen atmosphere. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure to give 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(2g) in N,N-dimethylformamide (20 mL) at 25 °C, N,N-diisopropylethylamine (4.81 mL) and 4-chloro-3-nitrobenzenesulfonamide (3.26 g) were added. The resulting mixture was heated to 80 °C and stirred for 12 hours. The reaction was cooled to ambient temperature and quenched by adding 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]dioxepino[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. After stirring for 3 days, the reaction mixture was loaded onto silica gel (agela, 40 g) and eluted over 30 minutes using a gradient of 0.5% - 4.5% dichloromethane / methane 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]dioxacycloundecin-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 Example 12C was replaced with Example 25C, and the title compound was synthesized according to the procedure for Example 12D. 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 Example 12D was replaced with Example 27A, and the title compound was synthesized according to the procedure for Example 12E. 11H 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 Example 12E was replaced with Example 27B, and the title compound was synthesized according to the procedure for Example 12F. 1 1H 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 Example 12F was replaced with Example 27C, and the title compound was synthesized according to the procedure for Example 12G. 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 give the title compound. 11H 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]dioxacycloundecin-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 -dimethylpropane-1,3-diamine hydrochloride (33 mg) was stirred at ambient temperature for 16 h. The reaction mixture was purified using flash chromatography (24 g silica column, 0–100% ethyl acetate / heptane). The 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 min, trifluoroacetic acid (0.8 mL) and then water (0.2 mL) were added and the reaction was stirred in the ice bath for 30 min and then at ambient temperature for 1 h. 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 give 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, 4.2, 2.3 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] 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]dioxacycloundecin-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) were 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 h. 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. Concentration of the residue from ethyl ether / heptane gave 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 h, then methanol and additional HCl (4.0 M in dioxane, 60 mL) were added. After stirring for an additional 2 h, the reaction mixture was concentrated and the resulting residue was concentrated three times with ethyl ether and then dried in vacuo to afford 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 h. 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 solution, brine, dried over magnesium sulfate, filtered and the filtrate was concentrated to afford the title compound. 11H 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.054 g) in dichloromethane (1.4 mL) was stirred. After stirring for 3 days, the reaction mixture was filtered through N 1 ,N 1Quenched with 1,2-dimethyl-1,2-ethanediamine (0.031 mL), loaded onto silica gel (agela, 40 g), and eluted over 30 minutes using a gradient of 0.5% - 9% dichloromethane / methanol. The fraction containing the product was concentrated, dissolved in 1:1 dimethyl sulfoxide / methanol (3 mL), and purified by Gilson HPLC (Luna 10 μm C18(2) 250×50 mm column, over 30 minutes, using a gradient of 10% - 85% acetonitrile / water (containing 0.1% trifluoroacetic acid)) 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]dioxacycloundecin-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 mixture was stirred for 30 minutes. Next, after the cessation of bubbling, (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 between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated and purified by flash chromatography (80 g of silica gel, 0 - 20% ethyl acetate in hexane) 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 (dd, J = 11.4, 5.8 Hz, 1H), 3.19 (ddt, J = 5.8, 4.1, 2.9 Hz, 1H), 2.81 (dd, J = 5.1, 4.1 Hz, 1H), 2.62 (dd, J = 5.0, 2.7 Hz, 1H). MS (APCI+) m / z 206.4(M+H+CH3CN) + .

[0275] Example 29B (S)-1-(Benzyloxy)penta-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) portionwise. After 1 hour, 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 aqueous 5% sodium hydrogen carbonate solution and brine solution, dehydrated 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 were 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 this 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 give the title compound. 11H 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 Sodium borohydride (183 mg) was added portionwise to a solution of Example 29C (400 mg) in methanol (6.5 mL) at 0 °C. 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. Ethyl acetate (10 mL) was added to the aqueous residue. The layers were separated, the organic layer was dried over sodium sulfate and 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) were added sodium hydride (116 mg) and 18-crown-6 (256 mg) at 0 °C. The mixture was stirred for 30 minutes, 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 were 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 disk and washed with methanol. Concentration of the filtrate gave 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. Concentration of the organic layer gave 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), and sodium azide (164 mg) was added thereto all at once. The mixture was warmed to 40 °C and stirred for 18 hours. Next, the mixture was cooled and diluted with water, and then extracted with dichloromethane. The combined organic layers were dehydrated over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in tetrahydrofuran (6.3 mL), and triphenylphosphine resin (844 mg) and water (160 μL) were added thereto. The mixture was stirred at 45 °C for 5 hours and then filtered. The resin was washed with a large amount of dichloromethane. Concentration of the filtrate gave 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, 4-fluoro-3-nitrobenzenesulfonamide (279 mg) was added. The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture 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]dioxacycloundecin-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) were 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 h. 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 the cis isomer to the trans isomer was 2:1. 11H NMR (600 MHz, pyridine-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]dioxacycloundecin-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 h. The reaction was concentrated and the residue was purified by flash chromatography (0–10% methanol / dichloromethane) to afford 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]dioxacycloundecin-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 was replaced with Example 30A, and the title compound was synthesized according to the procedure for the last step of Example 29. 1 H NMR (600 MHz, pyridine-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]dioxacycloundecin-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 consisting 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), loaded warm 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]dioxacycloundecin-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 A solution of 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 -dimethylpropane-1,3-diamine hydrochloride (0.027 g) in dichloromethane (0.70 mL) was stirred. After stirring for 3 days, the reaction mixture was loaded onto silica gel (Teledyne Isco RediSep® RF GOLD®, 24 g) and eluted over 30 minutes using a gradient of 0.5% to 10% dichloromethane / methanol. The fractions containing the product were concentrated, dissolved in 1:1 dimethyl sulfoxide / methanol (2 mL) and purified over 30 minutes using Gilson HPLC (Luna 10μm C18(2) 250×50 mm column, gradient of 10% to 75% acetonitrile / water (containing 0.1% trifluoroacetic acid)), affording the title compound. 11H 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]dioxacycloundecin-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 3M hydrogen chloride in dioxane (60 mL). After stirring for 6 h at ambient temperature, the mixture was basified to pH = 8 using aqueous 2N 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 - 10:1 petroleum ether / ethyl acetate) to afford 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 dropwise 3M methylmagnesium bromide (78 mL) at 0 °C. The mixture was stirred for 2 h at ambient temperature, quenched with aqueous ammonium chloride solution, 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 - 3:1 petroleum ether / ethyl acetate) to afford 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), dehydrated over sodium sulfate and 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), dehydrated over sodium sulfate and 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. 11H 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 Sodium azide (4.77 g) was added to a mixture of Example 32D (8.75 g) in N,N-dimethylformamide (13 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 12 h. After cooling the mixture to 25 °C, the mixture was diluted with ethyl acetate, washed with water and brine, dehydrated 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 - 1:1 petroleum ether / ethyl acetate) to give the title compound. 1 1H 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 Raney nickel (0.147 g) was added to a mixture of Example 32E (4.25 g) in methanol (85 mL). The reaction mixture was stirred at ambient temperature for 3 h and filtered. The filtrate was concentrated under reduced pressure to give the title compound. 11H 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 h and then the crude mixture was diluted with water (75 mL). The thick suspension was stirred for a few minutes and filtered, washed with water and ether to afford 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]dioxacycloundecin - 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. After stirring this reaction mixture for 3 days, it was quenched with N 1 ,N 1 -dimethylethane-1,2-diamine (0.015 mL). The reaction mixture was loaded onto silica gel (agela, 40 g) and eluted over 30 minutes using a gradient of 0.5% - 6% dichloromethane / methanol 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]dioxacycloundecin-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 the literature procedure (Angew Chem Int Ed 2015, 54, 13538 - 13544). Optical rotation (measured value) [α] D 25 = -78.93 (c 1.06, in chloroform); (literature) [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, and then Example 33A (1.5 g) was added as a solution in tetrahydrofuran (2 mL). The reaction mixture 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 mixture was stirred for 4 hours. The reaction mixture was placed back in the ice bath and carefully quenched with a 1:1 aqueous saturated ammonium chloride solution and water (20 mL). The biphasic mixture was extracted with ethyl acetate / heptane 3:1 (2 × 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). Combining and concentrating the fractions containing the desired product gave 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 dropwise 9-borabicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 50.0 mL) over 1 hour at 0 °C. Next, the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and 10% aqueous sodium hydroxide solution (15 mL) and then 30% aqueous hydrogen peroxide solution (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 solution (20 mL) at 0 °C and concentrated under reduced pressure to remove most of the organic solvent. The residue was extracted with ethyl acetate / heptane 3:1 (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 wt% in mineral oil, 0.216 g). After stirring at ambient temperature for 20 minutes, neat iodomethane (0.600 mL) was added and stirring was 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 × 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 give 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)2 / C (20 wt% Pd, 50% moisture, 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 a hydrogen balloon was attached. The reaction was stirred at ambient temperature for 9 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. 11H 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 adding 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 - 100% ethyl acetate / heptane) to give the title compound. 11H 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]dioxacycloundecin-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) were 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 mixture was stirred at ambient temperature for 6 h and then concentrated and purified by reverse-phase HPLC (column: Luna 10 μm C18(2) 250×50 mm, 10 - 100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give 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]dioxacycloundecin-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 at 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]dioxacycloundecin-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 treated with 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 h. The reaction mixture was purified using flash chromatography (4 g silica column, 0-5% methanol / ethyl acetate) to afford the title compound. 11H NMR (600 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 according to the procedure for Example 13D, replacing iodomethane with 1-bromo-2-methoxyethane. 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 = 10.8, 10.2 Hz, 1H), 2.25 - 2.14 (m, 1H), 1.70 (dddd, J = 9.4, 7.2, 4.2, 2.8 Hz, 1H), 1.49 - 1.34 (m, 2H). 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 Example 12D was replaced with Example 35A, and the title compound was prepared according to the procedure for Example 12E. 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 Example 12E was replaced with Example 35B, and the title compound was prepared according to the procedure for Example 12F. LC / MS(APCI+)m / z216.41(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) were added water (0.075 mL) and triphenylphosphine (110 mg), and the reaction mixture was stirred at ambient temperature for 3 hours. To this reaction mixture were 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 1 hour. The reaction mixture was purified using flash chromatography (24 g silica column, 10 - 100% ethyl acetate / heptane) to afford 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, J = 7.2, 4.9, 2.1 Hz, 1H), 1.85 - 1.79 (m, 1H), 1.56 - 1.43 (m, 2H). 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]dioxacycloundecin-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) were sequentially 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). The reaction mixture was stirred at ambient temperature for 62 h and then concentrated and purified by reverse phase HPLC (Luna 10 μm C18(2) 250×50 mm, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to afford the title compound. 11H NMR (500 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 h. 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 give 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]dioxacycloundecin-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 replacing Example 35D with Example 36A and following the procedure for Example 35E with a reaction time of 22 hours. 11H NMR (500 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 (E)-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 × 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. Lithium hydroxide (0.200 g) was added to this solution 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 × 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 11H 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) were added 1H-imidazole (0.180 g) and tert-butylchlorodimethylsilane (0.200 g, 1.324 mmol). The reaction was stirred at ambient temperature for 48 h. The reaction mixture was poured into water (20 mL) and extracted with 3:1 ethyl acetate / heptane (2 × 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. 11H 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% moisture, 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 hours, the reaction mixture was filtered, 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 hours, the reaction mixture was concentrated and the residue was purified using flash chromatography (40 g silica column, 0 - 40% ethyl acetate / heptane) to give the title compound. 11H 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 Sodium azide (0.200 g) was added to a solution of Example 37C (0.37 g) in N,N-dimethylformamide (2.00 mL). The reaction mixture was heated at 80 °C for 21 h. The reaction mixture 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 afford the title compound. 1 1H 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 Into a 20 mL glass-lined reactor, a water slurry of Raney-Ni 2800 (79.3 mg) was added to a solution of Example 37D (0.125 g) in tetrahydrofuran (3.07 mL). The reactor was purged with nitrogen. The mixture was stirred at 25 °C under hydrogen (50 psi). After 20 hours, the reactor was vented and the reaction mixture was filtered and concentrated. The residue was dissolved in tetrahydrofuran (2.00 mL), and then water (0.5 mL), di-tert-butyl dicarbonate (0.089 g) and sodium hydrogen carbonate (0.07 g) were added. The reaction was stirred at ambient temperature for 20 hours and then poured into water (10 mL) and extracted with 4:1 ethyl acetate / heptane (2 × 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). Combining and concentrating the fractions containing the desired product gave 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 h. The reaction mixture was poured into water (10 mL) and extracted with 4:1 ethyl acetate / heptane (2 × 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 h, 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) were added morpholine (0.100 mL) and potassium carbonate (60 mg). The reaction mixture was heated to 100 °C and stirred for 5 days. The reaction mixture was cooled to ambient temperature, poured into water (10 mL), and extracted with chloroform / 2-propanol (3:1). 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 mixture was stirred at ambient temperature for 60 h. The reaction mixture was concentrated to dryness, then dissolved in dichloromethane (1.00 mL), and N-ethyl-N-isopropylpropan-2-amine (0.400 mL) and then 4-fluoro-3-nitrobenzenesulfonamide (500 mg) were added. The reaction mixture was stirred at ambient temperature for 2 h 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. 11H 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]dioxacycloundecin-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 treated with 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) was treated and stirred at ambient temperature for 18 h. The reaction mixture was concentrated and purified by reverse-phase HPLC (column: Luna 10 μm C18(2) 250×50 mm, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)), and the title compound was obtained. 11H NMR (600 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 h. The reaction mixture was concentrated, and the crude material was dissolved in acetonitrile (200 mL). To this solution were sequentially added N-ethyl-N-isopropylpropan-2-amine (66.6 mL) and 1-bromo-2-(2-bromoethoxy)ethane (19.47 g), and the reaction was stirred at 70 °C for 16 h. 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 afford the title compound. 11H 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 dropwise addition of a saturated aqueous solution of ammonium chloride (20 mL). The mixture was extracted with 4:1 ethyl acetate / heptane (2 × 25 mL), 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 give the title compound. 11H 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]dioxacycloundecin-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 37G was replaced with Example 38B, and 1:1 dichloromethane / N,N-dimethylformamide (1.00 mL) was used as the solvent, and the title compound was prepared according to the procedure for Example 37H. 11H NMR (500 MHz, dimethyl sulfoxide-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]dioxacycloundecin-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 at 50 °C for 4 hours. The reaction mixture was concentrated and chromatographed on silica gel (Teledyne Isco RediSep® RF GOLD®, 80 g) eluting with a gradient of 0.5% - 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 keep the reaction homogeneous. After 1 hour, the reaction mixture wa...

Claims

**Claim 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]dioxacycloundecin-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. **Claim 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]dioxacycloundecin-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.

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