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 provides a compound of formula (I): wherein A, L, W and R1 have any values ​​as defined in the specification; and a pharmaceutically acceptable salt thereof, which can be used as a medicament for the treatment of CLL, SLL and / or ALL.

Description

1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4]㗁Nitrox Bcl-2 inhibitor The present invention relates to compounds that inhibit the activity of Bcl-2 protein and compositions containing such compounds. Bcl-2 protein is a key anti-apoptotic regulator of the inherent apoptosis pathway. The cellular manifestations of anti-apoptotic Bcl-2 proteins are related to inhibition of apoptosis and can cause certain cancers in the event of excessive manifestations. Molecules that inhibit Bcl-2 protein activity can increase cell apoptosis, thereby improving the treatment and prevention of chronic lymphoglobulin leukemia (CLL) or small lymphoglobulin lymphoma (SLL). For example, venetoclax is a selective Bcl-2 inhibitor, the first FDA-approved drug for the treatment of patients suffering from CLL or SLL, with or without a 17p deletion, who have received at least one previous therapy. However, there is a need for compounds that inhibit the activity of Bcl-2 protein in therapeutic techniques. In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, L is selected from the group consisting of -NH-, -NHCH 2 - and -OCH 2 -; W is selected from the group consisting of N and CH; A is selected from the group consisting of: cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, tetrahydrofuranyl, tetrahydroperyl, dihydroperyl, alkyl and piperidinyl; where A is subject to one or two R 2 Substituent substituted and as appropriate through an R 3 substituent substitution; R 1 Select from the group consisting of: Cl and NO 2 ; R 2 Select from the group consisting of: F, Cl, Br, I, -OH, C 1 -C 6 alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkoxyalkyl and C 2 -C 6 alkoxyalkoxy; and R 3 Selected from the group consisting of cyclobutyl, oxetanyl and lynyl. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 It is NO 2 . In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is -NHCH 2 -. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a tetrahydropiperanyl group; wherein the tetrahydroperanyl group is via an R 2 replace. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein A is a tetrahydropiperanyl group; wherein the tetrahydroperanyl group is via a -OCH 3 replace. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH; and R 1 It is NO 2 . In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 It is NO 2 ; and L is -NHCH 2 -. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 It is NO 2 ;L is -NHCH 2 -; and A is a tetrahydropipanyl group; wherein the tetrahydropipanyl group is passed through an R 2 replace. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 It is NO 2 ;L is -NHCH 2 -; and A is a tetrahydroperanyl group; wherein the tetrahydroperanyl group is passed through a -OCH 3 replace. In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W is CH; R 1 It is NO 2 ;L is -NHCH 2 -; and A is . In another aspect, the present invention provides a compound of formula (I), wherein the compound is selected from the group consisting of: 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1-c][1,8]dioxa[4]azetanycin-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((3-nitro-4-(((tetrahydro-2) H-piperan-4-yl)methyl)amine)phenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-hydroxy-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; N-((4-((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( S)-1,4-2 alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide; N-((5-chloro-6-((4-fluoro-1-(oxetin-3-yl)piperidin-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ;4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-methoxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methyl-1,4-di alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; N-((5-chloro-6-((4-fluorotetrahydro-2 H-piperan-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ;4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 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-pyramid and [2,1-g][1,5,8] benzodiac Azehexycycloundelyne-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide; N-((5-chloro-6-((1 s,4 s)-1-fluoro-4-(N- lynyl)cyclohexyl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ; N-((5-chloro-6-((1 r,4 r)-1-fluoro-4-(N- lynyl)cyclohexyl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-1-hydroxy-[1,1'-bis(cyclobutane)]-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((3-hydroxyoxetan-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-hydroxytetrahydrogen-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 R)-5-methyl-1,4-di alkane-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 R)-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; N-((5-chloro-6-((4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-methyltetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-methoxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-methoxytetrahydro-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-(N- lynyl)cyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S)-4-methoxytetrahydrofuran-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((1) r,3 r)-3-methoxycyclobutyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide; N-((3-chloro-4-(((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(2-methoxyethoxy)tetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(N- lyl)tetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide; N-((3-chloro-4-(((1) r,4 r)-4-(N- lynyl)cyclohexyl)methoxy)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ;4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; N-((3-chloro-4-(((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-methoxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; N-((5-chloro-6-((1 r,4 r)-4-hydroxy-4-methylcyclohexyl)methoxy)pyridin-3-yl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ; N-((3-chloro-4-(((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methoxy)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide ;4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((3-nitro-4-(((tetrahydro-2) H-piperan-2-yl)methyl)amine)phenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((3-nitro-4-((tetrahydro-2) H-piperan-4-yl)methoxy)phenyl)sulfonyl)benzolamide; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-fluoro-3-(methoxymethyl)cyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-(fluoromethyl)-3-methoxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((1) s,4 s)-4-hydroxy-4-methylcyclohexyl)methoxy)-3-nitrophenyl)sulfonyl)benzamid; Chloophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide; and 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamid. In another aspect, the invention provides a compound of formula (I), wherein the compound is 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamide or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a compound of formula (I), wherein the compound is 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid; or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a pharmaceutical composition comprising a combination of a therapeutically effective amount of a compound of formula (I) as in Solution 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the invention provides a method for treating CLL, SLL and / or ALL in a subject suffering from CLL, SLL and / or acute lymphoblastic leukemia (ALL), the method comprising the step of administering to the individual a therapeutically effective amount of a compound of formula (I) as in Technical Solution 1 or a pharmaceutically acceptable salt thereof. Interactive reference for related applications This application claims the rights of U.S. Provisional Application No. 63 / 267,018 filed on January 21, 2022, and the disclosure of which is incorporated herein by reference in its entirety. Reference for electronic sequence list The contents of the electronic sequence list (ABV12563USO1_ST26.xml; size: 4,991-bit tuple; and creation date: January 18, 2023) are incorporated herein by reference in full. The present invention describes compounds that inhibit the activity of Bcl-2 protein. The compounds disclosed herein may contain one or more variables that occur more than once in any substituent or formula herein. The definition of variables at each occurrence has nothing to do with their definition at another occurrence. Further, such combinations are allowed only when combinations of substituents produce stable compounds. The stabilized compound is a compound that can be isolated from the reaction mixture. definition Certain terms used in this specification are intended to refer to the following definitions, as detailed below. It should be noted that, as used in this specification and the intended patent scope, the singular forms "a / an" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "one compound" comprises one or more of a single compound and the same or different compounds. Referring to "pharmaceutically acceptable carriers" means a single pharmaceutically acceptable carrier and one or more pharmaceutically acceptable carriers, and similar carriers. As used in this specification and the scope of the accompanying patent application, unless specified to the contrary, the following terms have the meaning indicated: As used herein, the term "C" 1 -C 6 Alkoxy" refers to an alkyl group having one, two, three, four, five or six carbons attached to the parent molecule via an oxygen atom as defined herein. "C 1 -C 6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tertiary butoxy, pentoxy and hexoxy and the like. Unless otherwise specified, the term "C" as used herein 1 -C 6 alkyl" refers to a saturated linear or branched hydrocarbon chain group having one, two, three, four, five or six carbons. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, isobutyl, tertiary butyl, n-pentyl, iso-pentyl, 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 and the like. As used herein, the term "C" 2 -C 6 Alkoxyalkoxy" refers to an alkoxy group as defined herein attached to the parent molecule via another alkoxy group as defined herein. C 2 -C 6 Representative examples of alkoxyalkoxy include, but are not limited to, tertiary butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy and the like. As used herein, the term "C" 2 -C 6 Alkoxyalkyl" refers to an alkoxy group as defined herein attached to the parent molecule via an alkyl group as defined herein. C 2 -C 6 Representative examples of alkoxyalkyl groups include, but are not limited to, tertiary butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl and the like. As used herein, the term "halogen" or "halogen" means Cl, Br, I and F. As used herein, the term "C" 1 -C 6 Haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms are replaced by halogen. C 1 -C 6 Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl and the like. In some cases, the number of carbon atoms in the portion is prefixed "C". x -C y ” indicates that x is the minimum number of carbon atoms in the substituent and y is the maximum number. Therefore, for example, 1 -C 6 alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C 1 -C 3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms. If a portion is described as "substituted as the case may be", the portion may be (1) unsubstituted or (2) substituted. If a portion is described as being substituted by at most certain number of non-hydrogen groups, the portion may be (1) unsubstituted; or (2) replaced by at most certain number of non-hydrogen groups or by at most the largest number of substitutable positions on the portion, whichever is less. Regarding the use of the word "comprise or comprises or comprises" in this patent application (including the scope of the patent application), the applicant notes that unless otherwise required by the context, the basis and clear understanding of the use of the words is that the words will be interpreted inclusively and not exclusively, and the applicant intends to interpret the words in such a way in interpreting this patent application, including the scope of the patent application. The tablet term "medical composition" refers to a composition suitable for administration in medical use. The term "pharmaceutically acceptable salt" refers to those salts that are suitable for contact with humans and lower animals in the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reactions and similar reactions and have a reasonable benefit / risk ratio. The term "stable" means that the compound has sufficient stability to allow for production and maintains the integrity of the compound for a long enough time to be suitable for the purposes detailed herein. If a portion is described as "substituted", a non-hydrogen group replaces any substitutable atomic hydrogen group of the portion. Thus, for example, the substituted heterocyclic moiety is a heterocyclic moiety in which at least one non-hydrogen group replaces the hydrogen group on the heterocyclic ring. It should be appreciated that if there is more than one substitution in the moiety, the non-hydrogen groups may be the same or different (unless otherwise stated). The term "therapeutically effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt thereof, which, when administered to a particular individual or population, is sufficient to prevent the development of one or more symptoms of the condition or condition being treated or to some extent alleviate one or more symptoms. The term "treat, treatment and treatment" as used herein refers to a method of relieving or eliminating the disease and / or its accompanying symptoms. The term "one or more" refers to one to five. In one embodiment, it refers to one or four. In another embodiment, it refers to one to four. In one embodiment, it refers to one or three. In another embodiment, it refers to one to three. In another embodiment, it refers to one to two. In yet other embodiments, it refers to two. In yet other further embodiments, "one or more" refers to one. Compounds The compounds of the invention have general formula (I) as described herein. Compounds of the present invention are by use as CHEMDRAW ® Professional v. Part of 15.0.0.106 to name the Struct=Name naming algorithm. 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 when there is a difference between the names of the compounds found in this paper and the structure found in Table 1, the structure in Table 1 shall prevail. Table 1. Exemplary compounds The compounds of formula (I) or formula (II) can be used in the form of a pharmaceutically acceptable salt. The compounds of formula (I) or formula (II) may contain basic or acidic functional groups or both and may be converted to pharmaceutically acceptable salts by using suitable acids or bases, if necessary. Method for preparing exemplary compounds The compounds of the present invention can be better understood in conjunction with the following synthesis procedures and methods, which illustrate the ways in which compounds can be prepared. The compounds of the present invention can be prepared by a variety of synthesis procedures. Representative synthesis procedures are presented, but are not limited to, flows 1 to 4. Variables A, L, R 1 and W are defined as herein, for example, as detailed in the Summary of the Invention. The abbreviation used in the procedure and description has the following meanings: BOC: tri-butoxycarbonyl protecting group; Tf: trifluoromethanesulfonyl; SEM: trimethylsilicate ethoxymethyl; and Ts: toluenesulfonyl. Process 1 As shown in Scheme 1, the compound 1-12 can be made of compounds 1-1 Preparation. As shown in Scheme 1, 7,7-dimethyl-7,8-dihydro-4H-benzo[ d][1,3] 2 Xin-5(6 H)-one ( 1-2) It can be made by using 5,5-dimethylcyclohexane-1,3-dione ( 1-1) and paraformaldehyde may alternatively be 1,3,53 A solution of alkyl in dichloromethane or dichloroethane is prepared by reacting in the presence of boron trifluoride and diethyl ether. 1-bromo-4-chlorobenzene in tetrahydrofuran can be treated with n-butyllithium at low temperature, followed by addition of 7,7-dimethyl-7,8-dihydro-4H-benzo[ d][1,3] 2 Xin-5(6 H)-one ( 1-2), after quenching with aqueous hydrochloric acid solution, 4'-chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one ( 1-3 ). Tetraethylammonium chloride and triethylamine can be added to ( 1-3) In a cooling solution in dichloromethane, followed by addition of methanesulfonyl chloride to obtain 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4 H)-one ( 1-4). Can be used at low temperatures ( 1-4) solution added to ( S)-2-methyl-CBS- Zolboridine and BH 3 · In a mixture of tetrahydrofuran in tetrahydrofuran, obtain ( R)-4'-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol ( 1-5). ( S)-3-(hydroxymethyl)piper -1-Triple butyl formate ( 1-6), compounds 1-5. The mixture of sodium iodide and potassium carbonate in acetonitrile can be stirred together at ambient temperature to obtain ( S)-4-(((( R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piper -1-Triple butyl formate ( 1-7). Propane-1,3-diylbis(trifluoromethanesulfonate) ( 1-8) can be added to ( 1-7) in solution in dichloroethane), then add N 1 , N 1 , N 8 , N 8 -tetramethylnaphthalene-1,8-diamine and heated to give (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,7,8,9,10a,11,12,13,15-dodecahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H)-Tripartic butyl formate ( 1-9). Trifluoroacetic acid can be added to ( 1-9) After treatment with aqueous hydrochloric acid solution in dichloromethane, obtain (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-40hydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazene heterocycloundelyne ( 1-10). ( 1-10), 2-bromo-4-fluorobenzoate ( 1-11) and solution of dipotassium hydrogen phosphate in anhydrous dimethyl methazole can be stirred and heated together to obtain 2-bromo-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-yl)ethyl benzoate ( 1-12). Process 2 1-12 The solution in toluene can be 7-{[2-(trimethylsilicon)ethoxy]methyl}-1,3,4,7-tetrahydro-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen ( 2-1), cesium carbonate and palladium catalyst treatment to obtain 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyramid and [2,1-c][1,8,4] dioxazazene heterocycloundelyne-3(4 H,7 H,15 H)-yl)-2-(7-((2-(trimethylsilicate)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate ( 2-2). Tetra-n-butylammonium fluoride in tetrahydrofuran can be added to ( 2-2) solution, 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate ( 2-3). Treatment with lithium hydroxide ( 2-3) Provide 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrox-1-yl)benzoic acid ( 2-4). Process 3 As shown in Scheme 3, the compound 2-1 can be made of compounds 3-1 Preparation. Compounds 2-1 can be used for 3-chloroperoxybenzoic acid treatment in ethyl acetate to obtain 7-oxidation 5-bromo-1 H-pyrrolo[2,3- b]pyridine ( 3-2). Compounds at low temperatures 3-2 can be used for 2,2,2-trichloroacetyl chloride treatment in tetrahydrofuran to obtain compounds 3-3. Compounds 3-3 can be used via N, Sodium hydride in N-dimethylformamide N-protected, then added to N, 2-(trimethylsilicate)ethoxymethyl chloride in N-dimethylformamide to obtain compound 3-4. The solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide can be used for sodium hydride treatment in tetrahydrofuran followed by addition of compounds 3-4, obtain the compound 3-5. Compounds 3-5 The compound can be cyclized by treatment with potassium carbonate, picolinic acid and copper (I) iodide under microwave in dimethylsolidite to obtain 3-6. Compounds that can be added to a mixture of sodium and naphthalene in 1,2-dimethoxyethane in tetrahydrofuran 3-6, obtain a compound that removes the protection group 2-1. Process 4 As shown in Scheme 4, the compound 2-4 The former can be used to make the formula ( 4-1) Compounds (including A, L, R 1 and as described herein) and coupling agent react in the presence or absence of the first base to convert to formula ( 4-2) Compounds. Examples of the coupling agent include 1-ethyl-3-[3-(dimethylamine)propyl]-carbodiimine hydrochloride, 1,1'-carbonyldiimidazole and benzotriazole hexafluorophosphate-1-yl-oxytripyrrolidinyl phosphate. Examples of the first base include triethylamine, N, N-diisopropylethylamine, 4-(dimethylamine)pyridine and mixtures thereof. Specific programs are provided in the Synthesis Examples section. Medical composition When used as a pharmaceutical, the compounds of the invention are usually administered in the form of pharmaceutical compositions. Such compositions may include a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutical composition is provided, comprising a combination of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. How to use A compound of formula (I), a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition including a compound of formula (I), a compound of formula (II) or a pharmaceutically acceptable salt thereof may be administered to an individual suffering from CLL, SLL and / or ALL. The term "administered" refers to a method of contacting an individual with a compound. Example The following examples are for illustrative purposes and should not be considered limiting the scope of the invention. Unless otherwise stated, all reagents are commercial grade and are used as is without further purification. Anhydrous solvents commercially available under an inert atmosphere are used for the reaction. Reagent grade solvents are used in all other cases unless otherwise specified. 1 The chemical shift (δ) of the H NMR spectrum is relative to the tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl 3 (δ 7.27) part-millionth ratio (ppm) reported. Unless otherwise indicated, the following abbreviations have indicated meanings: NMR represents nuclear magnetic resonance; s represents single peak; br s represents wide single peak; d represents double peak or double peak; m represents multiple peak; t represents triplet peak; q represents quadrupole; LC / MS or LCMS represents liquid chromatography-mass spectrometry; min represents minute; mL represents milliliter; μL represents microliter; L represents liter; g represents gram; mg represents milligram; mmol represents millimeters; HPLC represents high-pressure liquid chromatography; ppm represents part millions; DCI represents desorption chemical ionization; DSI represents droplet spray ionization; ESI represents electrospray ionization; M represents mol concentration (mol / liter); N represents equivalent concentration (equivalent / liter); and APCI represents atmospheric pressure chemical ionization. Example 1 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((3-nitro-4-(((tetrahydro-2) H-piperan-4-yl)methyl)amine)phenyl)sulfonyl)benzolamide Example 1A 7,7-dimethyl-4,6,7,8-tetrahydro-2 H,5 H-1,3-benzodime cin-5-ketone To a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) over 10 minutes, boron trifluoride and diethyl ether (40.7 mL) were added to a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture is by adding saturated aqueous NaHCO 3 The solution was quenched, the organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in heptane / ethyl acetate (5:1), concentrated, treated with heptane (300 mL) and filtered. The residue is made of silicone (ISCO Gold) ® ) Chromatography and dissolved with a gradient of 0 to 16% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 5.13 (s, 2H), 4.43 (t, 2H), 2.28 (t, 2H), 2.22 (s, 2H), 1.08 (s, 6H). MS (DCI+) m / z183.1 (M+H) + . Example 1B 4'-Chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4 H)-Ke 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 to a solution of 1-bromo-4-chlorobenzene (30.3 g) in tetrahydrofuran (200 mL) at -78°C, keeping the temperature below -70°C. After stirring at -78°C for 30 minutes, a solution of Example 1A (24 g) in tetrahydrofuran (75 mL) was added dropwise, keeping the temperature below -60°C. The reaction mixture was stirred at -78°C for one hour, warmed to ambient temperature and stirred for 12 hours. The reaction mixture was treated with 3 M aqueous HCl solution (80 mL) and stirred for 2 hours. Most of the organic solvent was removed and the resulting aqueous layer was extracted with ethyl acetate (three times). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. Residue through silicone gel (750 g BIOTAGE ® SNAP) chromatography was performed with a gradient of 5 to 22% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z247.2 (M+H) + . Example 1C 4'-Chloro-2-(Chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4 H)-Ke To a solution of Example 1B (15 g) in dichloromethane (800 mL), tetraethylammonium chloride (14.08 g) followed by triethylamine (11.85 mL). The reaction mixture was cooled to 0°C with 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 solution and brine, dried over magnesium sulfate, filtered and concentrated. Residue through silica gel (330 g ISCO Gold ® ) Chromatography and dissolved with a gradient of 0 to 35% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z283.1 (M+H) + . Example 1D ( R)-4'-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol After 45 minutes at -50℃ S)-2-methyl-CBS- BH was added to a solution of zoboridine (20.96 g) in anhydrous tetrahydrofuran (230 mL) 3 -Tetrahydrofuran (1.0 M in tetrahydrofuran, 76 mL), and the solution was stirred for another 40 minutes. A solution of Example 1C (21 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise via an addition funnel over a course of about 60 minutes. After addition, the reaction mixture was stirred at -50°C for 1.5 hours. The reaction mixture was quenched by dropwise addition of methanol (130 mL) at -50°C over about 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. Saturated aqueous NH 4 Cl solution (250 mL) was diluted, diluted with water and extracted with ethyl acetate. The organic layer is made of additional saturated NH 4 The aqueous Cl solution and brine were washed, dried over sodium sulfate, filtered, and concentrated. The residue is made of silicone (Teledyne Isco RediSep ® RF GOLD ® 330 g) chromatography and dissolved with a gradient of 0% to 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z284.1 (M+H) + . Example 1E ( S)-4-(((( R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piper -1-Triple grade butyl ester formate ( S)-3-(hydroxymethyl)piper A solution of -1-Trial Butyl Formate (1.71 g), Example 1D (2.15 g), sodium iodide (1.47 g) and potassium carbonate (2.084 g) in acetonitrile (15.08 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (80 g) and dissolved with a gradient of 0% to 70% ethyl acetate:ethanol / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z465.4 (M+H) + . Example 1F (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-Tripartic Butyl Formate To a solution of Example 1E (100 g) in dichloroethane (2150 mL), propane-1,3-diylbis(trifluoromethanesulfonate) (95 g) was added, followed by N 1 , N 1 , N 8 , N 8-Tetramethylnaphthalene-1,8-diamine (122 g) (proton sponge), and the reaction mixture was heated to 50°C for 20 hours. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1N aqueous HCl solution (1 L×3) and 1N aqueous NaOH solution (three times), dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed with 2 L 5% ethyl acetate / heptane, 4 L 10% ethyl acetate / heptane, followed by 6-8 L 20% ethyl acetate / heptane gradient over silicone gel (3 kg) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z505.3 (M+H) + . Example 1G (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-40hydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazene heterocycloundelyne 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 is by adding saturated Na 2 CO 3 Neutralize aqueous solution (350 mL). Separate the organic layer with saturated Na 2 CO 3 The aqueous solution was washed four times, dried over sodium sulfate, filtered and concentrated to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) 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 / z405.3 (M+H) + . Example 1H 2-Bromo-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-yl)ethyl benzoate Equipped with a stirring rod, heating sleeve, nitrogen inlet and outlet and a 2L three-neck round bottom flask with ethyl 2-bromo-4-fluorobenzoate (44.4 g). Anhydrous dimethylsenozole (346 mL) was added to the flask and the mixture was stirred at ambient temperature. Example 1G (70 g) was added followed by potassium hydrogen phosphate (90 g). Once the slurry is mixed thoroughly, the temperature is raised to 60°C and the slurry is heated under nitrogen for 72 hours. The heating sleeve was removed and the reaction was cooled to 8°C with an ice / water bath. The flask is equipped with a 1 L feed funnel. Water (850 mL) was added dropwise to this cold reaction slurry via an addition funnel and the mixture was sonicated for 30 minutes. The mixture was subjected to mechanical stirring and vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered through a Buchner funnel loaded with filter paper. The filtered solid was washed with water (2 x 500 mL) and allowed to dry on a filter for 16 hours. The solid was dissolved in ethyl acetate (600 mL) and water (300 mL) was added to the solution. Stir the biphasic solution for 1 hour. The layers were separated in a separatory funnel and the organic layers were 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 BIOTAGE was used via normal phase chromatography ® Snap Ultra 750 g silicone tube column, purified with gradient ionization of 0 to 30% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z631.46 (M+H) + . Example 11 7-Oxidation of 5-Bromo-1 H-pyrrolo[2,3- b]pyridine 5-bromo-1 at 25°C To a solution of H-pyrrolo[2,3-b]pyridine (10 g) in ethyl acetate (200 mL), 3-chloroperoxybenzoic acid (21.90 g) was added, followed by stirring 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. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 1J 5-Bromo-6-Chloro-1 H-pyrrolo[2,3- b]pyridine To a solution of Example 11 (30 g) and 1,1,1,3,3,3-hexamethyldisisazane (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 another 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 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 the residue, which was wet-milled with ethyl acetate and petroleum ether (1:10, 100 mL) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 12.05 (s, 1H), 8.41 (s, 1H), 7.63 - 7.54 (m, 1H), 6.51 - 6.45 (m, 1H). Example 1K 5-bromo-6-chloro-1-((2-(trimethylsilicate)ethoxy)methyl)-1 H-pyrrolo[2,3- b]pyridine At 0°C, to Example 1J (15 g) N, Sodium hydride (3.11 g) was added portionwise to the solution in N-dimethylformamide (150 mL). The resulting mixture was stirred at 0°C for 1 hour, followed by dropwise addition of 2-(trimethylsilicon)ethoxymethyl chloride (13.79 mL) to N, Solution in N-dimethylformamide (50 mL). 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 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 10:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 1L N-(3-((5-bromo-1-((2-(trimethylsilicate)ethoxy)methyl)- 1 H-pyrrolo[2,3-b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide At 0°C Sodium hydride (0.166 g) was added portion by portion to a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at 0°C for 0.5 hours, followed by addition of Example 1K (0.5 g). 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 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 5:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 1M 1-Toluenesulfonyl-7-((2-(trimethylsilicon)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Oxyzacycloheptane To a solution of Example 1 L (500 mg) in dimethylol (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 under microwave for 2 hours. After cooling to ambient temperature, the reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 3:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 1N 7-((2-(trimethylsilicon)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Oxyzacycloheptane To a solution of sodium (0.291 g) in 1,2-dimethoxyethane (0.5 mL) under nitrogen (1.624 g). The mixture was stirred at 20°C for 1 hour until the formation of sodium / naphthalene was completed. Subsequently, a solution of Example 1 M (1 g) in anhydrous tetrahydrofuran (10 mL) was added to the above solution at -78°C. The resulting mixture was allowed to reach 20°C and stirred for 2 hours. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3 x 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 the residue which was purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 1O 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-yl)-2-(7-((2-(trimethylsilicate)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate Example 1H (79 g), (Example 1N) (26.6 g) and methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphine)xon](2'-methylamino-1,1'-biphenyl-2-yl)palladium (II) (5.61 g) were fed into a 2L three-neck round bottom flask equipped with a mechanical stirrer, a Huber cooling reflux condenser, a Claisen head adapter, a nitrogen needle inlet and outlet through a separator to a bubbler and an oven-dried thermocouple. This solid was placed under a large stream of nitrogen and cesium carbonate (81 g) was then rapidly added to the reaction flask. The solids were mixed slowly with a mechanical stirrer and a large stream of nitrogen was continued to pass through the reaction flask for 60 minutes. Anhydrous toluene (833 mL) was fed into a 2 L round bottom flask equipped with stirring rods and separators. The solvent was bubbled under the surface of the solvent with a large stream of nitrogen for 60 minutes while stirring. The solvent was then transferred to a three-necked flask via a cannula and the reaction was heated to an internal temperature of 110°C under a stream of nitrogen for 16 hours. The reaction was cooled to ambient temperature and water (600 mL) was fed into the flask followed by pyrrolidine dithiamyl formate palladium scavenger (3 g). The mixture was stirred vigorously for 1 hour. The reaction was further diluted with ethyl acetate (400 mL), stirred for 30 minutes, and then filtered through a plug of diatomaceous earth. The filter cake was washed with ethyl acetate (2 x 500 mL). The filtrate was transferred to a separating funnel and the layers were separated. The organic layer was washed with water (200 mL) and subsequently brine (200 mL). The combined aqueous layers were stripped 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 BIOTAGE was used via normal phase chromatography ® Snap Ultra 1.5 kg silicone tube column, purified by gradient ionization of 0 to 50% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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). Example 1P 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate Example 10 (69 g) was fed into a 2L three-neck flask equipped with a mechanical stirrer, a heating sleeve, a Clayson head adapter, a reflux condenser, a nitrogen inlet and outlet to the bubbler and a thermocouple. The solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution was added ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL). The reaction was heated to an internal temperature of 66°C for 24 hours. The heating sleeve was removed and the reaction was cooled to 8°C in an ice / water bath. The mixture was quenched with water (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and then partitioned in a separatory funnel. The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate (100 g), filtered and concentrated in vacuo to give the crude product. The residue was suspended in 1:1 methyltributyl ether:heptane (400 mL), sonic treatment for 30 minutes, followed by vigorous stirring for 1 hour. The solid was filtered off and the filter cake was washed with 1:1 methyltributyl ether heptane (50 mL). The solid was dried over a Buchner funnel to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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). Example 1Q 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrox-1-yl)benzoic acid Example 1P (58.7 g) was fed into a 5L three-neck flask equipped with a mechanical stirrer, a heating sleeve, a reflux condenser, a Clayson adapter, a nitrogen inlet and outlet to the bubbler and a thermocouple. Dissolve the residue in 1,4-dioxide Stir in alkane (991 mL) and methanol (496 mL) and stir at ambient temperature for 5 minutes. Subsequently, lithium hydroxide (18.99 g) and water (496 mL) were added and the reaction was heated to an internal temperature of 75°C for 16 hours. The heating sleeve 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 adding saturated aqueous ammonium chloride solution (100 mL). The mixture was diluted with dichloromethane (300 mL) and the layers were partitioned in a separatory funnel. The aqueous layer was extracted with dichloromethane (2 x 100 mL) and the organic layer was laminated 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 via a silicone cartridge (Teledyne Isco RediSep ® RF GOLD ® , 330 g) normal phase chromatography, purified with 0 to 10% methanol / dichloromethane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z712.29 (M+H) + . Example 1R 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((3-nitro-4-(((tetrahydro-2) H-piperan-4-yl)methyl)amine)phenyl)sulfonyl)benzolamide Example 1Q (0.080 g), 3-nitro-4-(((tetrahydro-2) H-piperan-4-yl)methyl)amino)benzenesulfonamide (0.039 g), N, N-dimethylpyridine-4-amine (0.041 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.043 g) was stirred in dichloromethane (1 mL). After stirring for 16 hours, the reaction was loaded directly onto a silica gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1009.56 (M+H) + . Example 2 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-hydroxy-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 2A ( R)-(3,4-dihydrogen-2 H-piperan-2-yl)methanol Title compounds follow the literature procedure (International Edition of Applied Chemistry ( Angew Chem Int Ed)》 2015, 54, 13538-13544) Preparation. Optical rotation (observation) [α] D 25 = -78.93 (in chloroform c1.06); (Literature) [α] D 25 = -74.32 (in chloroform c1.07). Example 2B ( R)-2-((benzyloxy)methyl)-3,4-dihydro-2 H-Peram 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, followed by addition of Example 2A (1.5 g) as a solution in tetrahydrofuran (2 mL). The reaction was stirred in an ice bath for 15 minutes, followed by addition of pure bromotoluene (2.5 mL) and the ice bath was removed. The reaction was stirred for 4 hours, then the reaction mixture was again placed in an ice bath and carefully quenched with 1:1 aqueous saturated ammonium chloride solution and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude material was purified using flash chromatography (40 g silicon dioxide column, 0-5% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 2C (3 S,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-ol To a solution of Example 2B (2.00 g) in tetrahydrofuran (24.0 mL) was added dropwise to a solution of 9-boron bicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) at 0°C for 1 hour. The mixture was then stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and 10% aqueous sodium hydroxide solution (15 mL) was carefully added to the mixture at 0°C, followed by 30% aqueous hydrogen peroxide solution (16 mL). 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 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.08 (M+H) + . Example 2D ( R)-6-((benzyloxy)methyl)dihydro-2 H-piperan-3(4H)-one Example 2C (1.85 g) in dichloromethane (37.0 mL) was treated with sodium bicarbonate (1.850 g) and 1,1,1-ginseng (acetyloxy)-1,1-dihydro-1,2-benzodioxolene-3-(1H)-one (4.24 g). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured over saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (40 g silicon dioxide column, 10-60% ethyl acetate / heptane) to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z221.06 (M+H) + . Example 2E (3 S,6 R)-6-((benzyloxy)methyl)-3-methyltetrahydro-2 H-piperan-3-ol A solution of 2,6-di-tertiary butyl-4-methylphenol (10.57 g) and anhydrous toluene (40.0 mL) was placed in a water bath. Carefully add the solution of trimethylaluminum (2 M in toluene, 11.99 mL) over 30 minutes. The transparent colorless solution was stirred at ambient temperature for 75 minutes and then the water bath was replaced with a dry ice / acetone bath. A solution of Example 2D (1.79 g) in anhydrous toluene (3 mL) was added dropwise, followed by a toluene washing solution (2 mL). A solution of methyl lithium (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 by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z219.10 (M+H−H 2 O) + . Example 2F 4-methylbenzenesulfonic acid ((2 R,5 S)-5-hydroxy-5-methyltetrahydro-2 H-piperan-2-yl)methyl ester Solution of Example 2E (1.5 g) in ethanol (13.22 mL) in 25 mL Hastelloy C reactor with Pd(OH) 2 / C (20 wt% Pd, 50% moisture, 0.150 g) treatment. Purge the reactor with nitrogen. The mixture was stirred under hydrogen (60 psi) at ambient temperature. After 20 minutes, the reactor was aerated and the reaction mixture was filtered. The filtrate was concentrated and dissolved in dichloromethane (12.00 mL). To the solution were added triethylamine (2.00 mL) and 4-methylbenzene-1-sulfonyl chloride (1.25 g) and the reaction was stirred at ambient temperature. After 30 minutes, the reaction was considered complete and purified using flash chromatography (40 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z283.32 (M+H−H 2 O) + . Example 2G (3 S,6 R)-6-(azidomethyl)-3-methyltetrahydro-2 H-piperan-3-ol Example 2F (0.80 g) in The solution in N,N-dimethylformamide (7.00 mL) was treated with sodium azide (0.80 g). The reaction was stirred at 85°C for 16 hours. The reaction was cooled to ambient temperature, then poured on water (40 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with water (4 x 40 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (12 g silicon dioxide column, 0-50% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 2H (3 S,6 R)-6-(aminomethyl)-3-methyltetrahydro-2 H-piperan-3-ol A solution of Example 2G (160 mg) in tetrahydrofuran (3.2 mL) was added to a Raney-Ni 2800 water slurry (79.3 mg) in a 20 mL glass lined reactor. Purge the reactor with nitrogen. The mixture was stirred under hydrogen (50 psi) at 25°C. After 20 hours, the reactor was aerated and the reaction mixture was filtered. The filtrate was concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Absolute stereochemistry was confirmed using X-ray diffraction studies on crystals obtained from the title compound (D)-tartrate. Example 2I 4-(((((2) R,5 S)-5-hydroxy-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide Examples 2H (66 mg), 4-fluoro-3-nitrosulfamide (75 mg) and triethylamine (0.080 mL) were stirred in dichloromethane (1 mL) at ambient temperature for 16 hours. The reaction was loaded onto a silicone flash chromatography column (12 g silicon dioxide) and dissolved using a gradient of 20% to 100% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z346.05 (M+H) + . Example 2J 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-N-((4-(((((((2) R,5 S)-5-hydroxy-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrox-1-yl)benzolamide Example 1Q (0.062 g), Example 2I (0.027 g), N, N-dimethylpyridine-4-amine (0.032 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.033 g) was stirred in dichloromethane (0.9 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and over 30 minutes, lysed with a gradient of 1% to 4.5% dichloromethane / methanol to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z1040.77 (M+H) + . Example 3 N-((4-((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( S)-1,4-2 alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide Example 3A ( S)-2-((2-chloroethoxy)methyl)ethylene oxide To a solution of 2-chloroethanol (391 g) in toluene (750 mL), boron trifluoride (13.8 g) was added, and the temperature was raised to 38°C. Below 49℃, R)-2-(chloromethyl)ethylene oxide (150 g) was added to the reaction. The reaction was stirred at 49°C to 33°C for 20 minutes and then cooled to 15°C. Aqueous sodium hydroxide solution (20 wt%, 800 mL) was added to the reaction at less than 17°C. The reaction was stirred at 15°C for 1 hour. The reaction was diluted with water (500 mL) and separated. The aqueous substance was extracted with tertiary butyl methyl ether (200 mL). The combined organic phases were washed with water (300 mL) and brine (300 mL), dried over sodium sulfate and concentrated to give the title compound. Example 3B ( S)-(1,4-2 alkane-2-yl)methanol To a solution of sodium hydroxide in water (20 wt%, 1000 mL) at 90°C. Example 3A (222 g) was added. The reaction was stirred at 90°C for 16 hours. The reaction was extracted with ethyl acetate and the organic phase was washed with water (200 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the product. The aqueous layer was concentrated to dryness and wet-milled 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 silicone tube column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm3.70 - 4.13 (m, 5H), 3.56 -3.61 (m, 3H), 3.46 (t, J= 10.4 Hz, 1H). Example 3C ( R)-Medsulfonic acid (1,4-dichloride Alkane-2-yl)methyl ester To a solution of Example 3B (35.0 g) in dichloromethane (175 mL) was added triethylamine (39.0 g) at 0°C. Methanesulfonyl chloride (44.1 g) was then added at 0°C. The reaction was then stirred at 15°C for 1 hour. Pour the reaction into ice-cold saturated sodium bicarbonate solution (300 mL). The dichloromethane phase was separated and dried over sodium sulfate. The organic phase was filtered and concentrated to give the title compound. Example 3D ( S)-2-(azidomethyl)-1,4-bis alkyl Example 3C (58.0 g) and sodium bicarbonate (49.7 g) were N, Sodium azide (24.0 g) was added to the solution in N-dimethylformamide (300 mL). 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 organic phases were combined and washed with water (100 mL) and brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to half volume. The residue was further concentrated under a stream of nitrogen. The residue was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 3.64 - 3.71 (m, 5H), 3.50 - 3.51 (m, 1H), 3.31 - 3.37 (m, 1H), 3.18 - 3.21 (m, 2H). Example 3E ( S)-(1,4-2 Alkane-2-yl)methylamine hydrochloride Triphenylphosphine (66.0 g) was added to a solution of Example 3D (18.0 g) in tetrahydrofuran (130 mL) and water (15 mL) under nitrogen. 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 aqueous substance 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) δppm 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) Example 3F ( S)-4-(((1,4-2 Alkane-2-yl)methyl)amine)-3-nitrobenzenesulfonamide Solutions of 4-fluoro-3-nitrobenzenesulfonamide (2.6 g) and Example 3E (2.00 g) in tetrahydrofuran (40 mL) N, N-diisopropylethylamine (6.19 mL) treatment. 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 by a silicone tube column (40 g, 40-80% ethyl acetate / heptane) to give the title compound. MS (APCI+) m / z318.0 (M+H) + . Example 3G N-((4-((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( S)-1,4-2 alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide Example 1Q (0.067 g), Example 3F (0.027 g), N, N-dimethylpyridine-4-amine (0.035 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.036 g) was stirred in dichloromethane (1.0 mL). After stirring for 16 hours, add N, N-dimethylformamide (1 mL) and stirring continued for 6 hours. The reaction was concentrated, dissolved in dimethylol / methanol (1:1,3 mL) and quenched with 2,2,2-trifluoroacetic acid (0.073 mL) and purified by HPLC using 10% to 85% acetonitrile / water containing 2,2,2-trifluoroacetic acid. The soluble smear containing the product was lyophilized and loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 24 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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). Example 4 N-((5-chloro-6-((4-fluoro-1-(oxetin-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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 4A 1-(oxetin-3-yl)piperidine-4-carboxylate A solution of ethyl piperidine-4-formate (3.2 kg) in dichloromethane (5 L) was stirred under nitrogen at 20°C, and sodium triacetyloxyborohydride (101 g) was added to the solution part by portion at 20°C. The reaction mixture was stirred at 20°C for 30 minutes, and then oxetin-3-one (229.2 g) was added dropwise to the mixture, keeping 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 x 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, CDCl 3 ) δppm 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). Example 4B 4-Fluoro-1-(oxetin-3-yl)piperidine-4-carboxylate Lithium diisopropylamine (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. Then, add to the mixture N-fluorobenzenesulfonimide (7.7 kg), keeping the temperature at -78 °C. After 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 dropwise addition of saturated aqueous ammonium chloride solution (10 L) and extracted with ethyl acetate (3 x 5 L). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the residue which was purified by silicone tube column chromatography (dissolved with 1:1 ethyl acetate: petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 (quin, J= 6.47 Hz, 1H) 4.23 (q, J= 7.13 Hz, 2H) 4.56 - 4.70 (m, 4H). Example 4C (4-Fluoro-1-(oxetin-3-yl)piperidin-4-yl)methanol Lithium aluminum hydride (241.5 g) was added portion by portion to the tetrahydrofuran (7 L) solution under nitrogen cooled to 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, and the temperature was kept 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, water (241 mL) was added dropwise to the mixture, followed by dropwise addition of 15% aqueous sodium hydroxide solution (241 mL). Filter the mixture. The filtrate was concentrated under reduced pressure to give the residue which was purified by silicone tube column chromatography (dissolved with ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 4D 5-Chloro-6-((4-fluoro-1-(oxetin-3-yl)piperidin-4-yl)methoxy)pyridin-3-sulfonamide Example 4C (10 g) and 5,6-dichloropyridin-3-sulfonamide (12.00 g) were stirred under nitrogen in tetrahydrofuran (200 mL) while cooling to 0 °C. Sodium hydride (10.57 g) was added portion by portion over 10 minutes, and then tetrahydrofuran was added in 1 mL until stirring was resumed. The ice bath was melted and the temperature was raised to 40°C while stirring for 16 hours. The mixture was slowly poured on ice with stirring. When the ice melted, the mixture was extracted with ethyl acetate (2 x 30 mL) and the combined extracts were washed with brine. The combined aqueous layers were filled with sodium chloride and then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The concentrate was wet milled with tertiary butyl methyl ether (100 mL) and acetonitrile (50 mL) to give the title compound. 1 H NMR (300 MHz, diacetium- d 6 ) δppm 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 / z380.0 (M+H) +. Example 4E N-((5-chloro-6-((4-fluoro-1-(oxetin-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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 1Q (0.090 g), Example 4D (0.043 g), N, N-dimethylpyridine-4-amine (0.046 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.048 g) was stirred in dichloromethane (1.2 mL). After stirring for 16 hours, the reaction was loaded onto a silicone (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1075.7 (M+H) + . Example 5 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-methoxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamide Example 5A (1 r,4 r)-4-methoxycyclohexyl)methanol To a solution of lithium aluminum hydride (2 M in tetrahydrofuran, 12.2 mL) in tetrahydrofuran (4.8 mL) dropwise at 0°C (1 r,4 r) A solution of methyl methyl-4-methoxycyclohexanecarboxylate (3.5 g) in tetrahydrofuran (24 mL) and the reaction was slowly warmed to ambient temperature. After 1 hour, the reaction was cooled to 0°C and slowly quenched with water (1 mL), followed by 10% sodium hydroxide (2 mL), followed by 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 / heptane) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 5B (1 r,4 r)-4-methoxycyclohexyl)methyl ester methanesulfonic acid To a solution of Example 5A (962 mg) in dichloromethane (33.4 mL) was added triethylamine (4.65 mL) at 0°C, followed by methanesulfonyl chloride (0.780 mL) and the reaction was stirred at 0°C for 15 minutes before warming to ambient temperature. After 1 hour, the reaction was diluted with saturated sodium bicarbonate and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound which was used without further purification. Example 5C {[(1 r,4 r)-4-methoxycyclohexyl]methyl}-2-imino dicarbonate di-tertiary butyl ester Example 5B (700 mg) and di-tertiary butyl ester (1026 mg) were used in The solution in N,N-dimethylformamide (15.7 mL) was heated to 85°C for 16 hours. The reaction was cooled to ambient temperature, diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water, then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by normal phase on Teledyne Isco CombiFlash Rf+ (0-40% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 5D (1 r,4 r)-4-methoxycyclohexyl)methylamine trifluoroacetic acid To a solution of Example 5C (666 mg) in dichloromethane (9695 μL) was added trifluoroacetic acid (3.2 mL) at ambient temperature and the reaction was allowed to stand for 1 hour. The reactant was concentrated to give the title compound which was used in the next step without further purification. Example 5E 4-(((((1) r,4 r)-4-methoxycyclohexyl)methyl)amine)-3-nitrobenzenesulfonamide Added 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) and the reaction was stirred. After 6 hours, the reaction was concentrated under reduced pressure. The residue was purified by normal phase on Teledyne Isco CombiFlash Rf+ (0-3% methanol / dichloromethane) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 5F 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-methoxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.107 g), Example 5E (0.046 g), N, N-dimethylpyridine-4-amine (0.055 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.058 g) was stirred in dichloromethane (1.5 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol. The product was dissolved in dimethylol / methanol 1:1 (3 mL) and 2,2,2-trifluoroacetic acid (0.012 mL) was added. The solution was purified by preparative HPLC using a Gilson PLC 2020 system (Luna column, 250 x 50, flow rate 75 mL / min) over 30 minutes using a gradient of 20% to 95% acetonitrile / water to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 / z1037.73 (M+H) + . Example 6 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methyl-1,4-di Alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 6A ( R)-2-(((((((((((((((((((((((((())))))))))))-2-((((( R)-1-(benzyloxy)propan-2-yl)oxy)methyl)ethylene oxide At 0°C, Sodium hydride (36.1 g) was added portion by portion to a solution of R)-1-(benzyloxy)propan-2-ol (100 g) in tetrahydrofuran (500 mL). After 30 minutes, add ( S)-2-(chloromethyl)ethylene oxide (83.5 g) and NaI (781 mg). The reaction was stirred at 50°C for 12 hours. 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 subjected to column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to obtain the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 6B ( R)-2-(( R)-ethylene oxide-2-ylmethoxy)propan-1-ol To a solution of Example 6A (30.0 g) in tetrahydrofuran (90 mL) and water (55 mL) under nitrogen gas, Pd(OH) 2 (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, CDCl 3 ) δppm 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). Example 6C ((2 S,5 R)-5-methyl-1,4-di alkane-2-yl)methanol To a solution of Example 6B (30.0 g) in dichloromethane (150 mL), camphorsulfonic acid (7.38 g) was added 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 (silicon, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 6D 4-methylbenzenesulfonic acid ((2 R,5 R)-5-methyl-1,4-di Alkane-2-yl)methyl ester 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 (silicon, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 6E (2 S,5 R)-2-(azidomethyl)-5-methyl-1,4-bis alkyl Example 6D (5 g) solution in dimethylformamide (25.7 mL) was treated with sodium azide (2.27 g) and the resulting suspension was stirred at 80°C for 12 hours. The cooled suspension was poured into water (100 mL) and extracted with tertiary butyl methyl ether (2 x 50 mL). The combined organic layers were washed with brine (2 x 25 mL), dried over sodium sulfate, filtered and the filtrate concentrated to give the title compound. Example 6F ((2 S,5 R)-5-methyl-1,4-di alkane-2-yl)methylamine A solution of Example 6E (22 g) in tetrahydrofuran (390 mL) was added to 5% Pd / C (2.2 g) in 600 mL 316SS reactor and stirred under hydrogen. The reaction mixture was filtered and the filtrate was concentrated to give the title compound. Example 6G 4-(((((2) S,5 R)-5-methyl-1,4-di Alkane-2-yl)methyl)amine)-3-nitrobenzenesulfonamide To a solution of Example 6F (10.9 g) in tetrahydrofuran (315 mL), 4-fluoro-3-nitrobenzenesulfonamide (16.63 g) was added followed by N, N-diisopropylethylamine (23.75 mL) and the reaction was heated to 45°C and stirred for 5 hours. The reaction was cooled to ambient temperature and concentrated. The residue was suspended in methanol (200 mL) and stirred vigorously for 2 hours. The precipitate was collected by filtration and dried to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 6H 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methyl-1,4-di alkane-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.080 g), Example 6G (0.039 g), N, N-dimethylpyridine-4-amine (0.041 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.043 g) was stirred in dichloromethane (1.1 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1027.63 (M+H) + . Example 7 N-((5-chloro-6-((4-fluorotetrahydro-2H-piperan-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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 7A 5-Chloro-6-((4-fluorotetrahydro-2 H-piperan-4-yl)methoxy)pyridine-3-sulfonamide 4-fluorotetrahydrogen-2 To a solution of H-piperan-4-yl)methanol (0.567 g) in tetrahydrofuran (20 mL) sodium hydride (60% in mineral oil, 676 mg) was added and the reaction was stirred for 30 minutes. 5,6-dichloropyridin-3-sulfonamide (0.800 g) was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was diluted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated. The residue was lyophilized by silica gel chromatography with ethyl acetate / hexane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 7B N-((5-chloro-6-((4-fluorotetrahydro-2H-piperan-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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 1Q (0.035 g), Example 7A (0.016 g), N, N-dimethylpyridine-4-amine (0.018 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.019 g) was stirred in dichloromethane (0.50 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 12.16 (s, 1H), 11.22 (s, 1H), 8.38 (d, 1H), 8.01 (d, 1H), 7.48 (d, 1H), 7.38 - 7.33 (m, 2H), 7.18 (t, 1H), 7.14 - 7.02 (m, 2H), 6.87 (s, 1H), 6.80 - 6.69 (m, 2H), 6.10 (dd, 1H), 4.46 (d, 2H), 4.18 (s, 2H), 4.02 - 3.98 (m, 1H), 3.88 - 3.38 (m, 12H), 2.93 (t, 1H), 2.84 - 2.62 (m, 2H), 2.23 (d, 1H), 2.13 - 1.54 (m, 16H), 1.37 (dd, 1H), 0.95 (s, 6H). LC / MS (APCI+) m / z1020.86 (M+H) + . Example 8 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid Example 8A 1-oxaspiro[2.3]hexane-5-forminnitrile A solution of 3-chloroperoxybenzoic acid (2.585 g) in dichloromethane (60 mL) was stirred for 30 minutes at -10°C. The mixture was filtered off and the filtrate was added dropwise to a solution of 3-methylenecyclobutyronitrile (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 off, and the filtrate was washed successively with 5% sodium sulfite solution, saturated sodium bicarbonate solution and water. The organic layer was dried over sodium sulfate and concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 2.75 - 2.81 (m, 1H) 2.86 - 2.94 (m, 3H) 3.12 - 3.21 (m, 1H) 4.84 - 4.88 (m, 2H). Example 8B (1 r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutynitrile To a solution of tetrabutylammonium fluoride (9.62 mL) was added 40% aqueous hydrogen fluoride solution (0.418 mL) and the volatile portion was removed under reduced pressure to obtain a crude mixture. Potassium fluoride hydrofluoride (0.075 g) was added to the resulting mixture and the 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 kept at 120°C for 24 hours. The reaction mixture was purified by silicone hose column chromatography (20% ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 2.29 - 2.42 (m, 4H) 3.34 - 3.42 (m, 1H) 4.24 (s, 1H) 4.36 (s, 1H) 5.70 (s, 1H). Example 8C (1 r,3 r)-3-(aminomethyl)-1-(fluoromethyl)cyclobutan-1-ol To a solution of Example 8B (0.309) in ethanol (15.44 mL) under argon gas, ammonium hydroxide (0.335 g) and nickel (0.843 g). The suspension was degassed in vacuo and purged several times with hydrogen. 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 filtrates were concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 8D 4-(((((1) r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrobenzenesulfonamide To Example 8C (0.23 g) N, 4-fluoro-3-nitrobenzenesulfonamide (0.342 g) was added to the solution of N-dimethylformamide (3.15 mL) and N-ethyl- N-isopropylprop-2-amine (0.893 g). The reaction mixture was stirred at 60°C for 12 hours. The solution was cooled to 25°C and purified directly by preparative HPLC to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 8E 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (25 mg) in dichloromethane (1 mL) with triethylamine (5 mg), Example 8D (18 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (10 mg) and 4-dimethylamine pyridine (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 dimethylol:methanol (3 mL) and loaded on HPLC (C18 column, 20-80% acetonitrile / water containing 0.1% trifluoroacetic acid, 25 minutes), and the title compound was obtained after washing in saturated aqueous sodium bicarbonate solution. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 9 N-(3-chloro-4-{[4-fluoro-1-(oxetin-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-pyramid and [2,1-g][1,5,8] benzodiac Azehexycycloundelyne-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 9A 3-chloro-4-((4-fluoro-1-(oxetin-3-yl)piperidin-4-yl)methoxy)benzosulfonamide Example 4C (20 g) and 3-chloro-4-fluorobenzenesulfonamide (18.5 g) in tetrahydrofuran (200 mL) were added part by portion to a solution of 3-chloro-4-fluorobenzenesulfonamide (18.5 g) in tetrahydrofuran (200 mL). The reaction was heated to 55°C for 18 hours. Additional tertiary potassium butoxide (1.0 M in tetrahydrofuran, 60 mL) was added and the reaction was heated to 55°C for 3 hours. The reaction was cooled to -10°C and an aqueous HCl solution (3.0 M) was added to adjust the pH to 6 to 6.5. The reaction was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was suspended in tertiary butyl methyl ether (300 mL), stirred overnight, sonicated for 30 minutes and filtered to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z379.11 (M+H) + . Example 9B N-(3-chloro-4-{[4-fluoro-1-(oxetin-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-pyramid and [2,1-g][1,5,8] benzodiac Azehexycycloundelyne-3(4H)-yl]-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 1Q (0.090 g), Example 9A (0.043 g), N, N-dimethylpyridine-4-amine (0.046 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.048 g) was stirred in dichloromethane (1.3 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1074.81 (M+H) + . Example 10 N-((5-chloro-6-((1s,4s)-1-fluoro-4-(N- lynyl)cyclohexyl)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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzamid Example 10A 5-chloro-6-((8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)methoxy)pyridine-3-sulfonamide A solution of (8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)methanol (1.00 g) in tetrahydrofuran (22 mL) was cooled in an ice bath. Solid sodium hydride (60% by weight in mineral oil, 0.881 g) was added and stirring was continued for 30 minutes. To the suspension was added 5,6-dichloropyridin-3-sulfonamide (1.01 g) and the reaction was allowed to warm to ambient temperature. After 16 hours, the reaction mixture was carefully quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was wet-milled with dichloromethane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z381.15 (M+H) + . Example 10B 5-Chloro-6-((1-fluoro-4-pendicular oxycyclohexyl)methoxy)pyridine-3-sulfonamide Example 10A (1.50 g) and monohydrated p-toluenesulfonic acid (0.824 g) in 1,4-dioxide The solution of alkane (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 sodium bicarbonate solution (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z337.21 (M+H) + . Example 10C 5-Chloro-6-(((1 s,4 s)-1-fluoro-4-(N- lynyl)cyclohexyl)methoxy)pyridine-3-sulfonamide Example 10B (0.20 g) in dichloromethane (3.00 mL) and methanol (3.00 mL) Treatment with line (0.102 mL), sodium cyanoborohydride (0.187 g) and acetic acid (0.07 mL). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated and the residue was purified using reverse phase HPLC (5-50% acetonitrile / water (+0.1% trifluoroacetic acid). In the two peaks separated, the lyophilization smears that dissolve faster are obtained to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z407.90 (M+H) + . Example 10D 5-Chloro-6-(((1 r,4 r)-1-fluoro-4-(N- lynyl)cyclohexyl)methoxy)pyridine-3-sulfonamide The title compound was isolated as the second peak from reverse phase HPLC in Example 10C. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z407.85 (M+H) + . Example 10E N-((5-chloro-6-((1s,4s)-1-fluoro-4-(N- lynyl)cyclohexyl)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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 10C (36.6 mg) in dichloromethane (0.80 mL) N-ethyl- N-isopropylprop-2-amine (0.06 mL), Example 1Q (50.0 mg), N, N-dimethylpyridine-4-amine (21.0 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (25.0 mg) was treated and stirring was continued at ambient temperature for 14 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (10-100% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z1101.26 (M+H) + . Example 11 N-((5-chloro-6-((1r,4r)-1-fluoro-4-(N- lynyl)cyclohexyl)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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide The title compound was prepared following the procedure reported for the final step of Example 10, and Example 10C was replaced with Example 10D. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z1101.25 (M+H) + . Example 12 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 12A ( R)-(3,4-dihydrogen-2 H-piperan-2-yl)methanol Title compounds follow the literature procedure (International Edition of Applied Chemistry 2015, 54, 13538-13544) Preparation. Optical rotation (observation) [α] D 25 = -78.93 (in chloroform c1.06); (Literature) [α] D 25 = -74.32 (in chloroform c1.07). Example 12B ( R)-2-((benzyloxy)methyl)-3,4-dihydro-2 H-Peram 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 Example 12A (1.5 g) was then added as a solution in tetrahydrofuran (2 mL). The reaction was stirred in an ice bath for 15 minutes, followed by addition of pure bromotoluene (2.5 mL) and the ice bath was removed. The reaction was stirred for 4 hours, then the reaction mixture was again placed in an ice bath and carefully quenched with 1:1 aqueous saturated ammonium chloride solution / water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silicon dioxide column, 0-5% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 12C (3 S,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-ol To a solution of Example 12B (2.00 g) in tetrahydrofuran (24.0 mL) was added dropwise at 0°C for 1 hour. 9-boron bicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) at 0°C. 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 solution (15 mL) was carefully added to the mixture at 0°C, followed by 30% aqueous hydrogen peroxide solution (16 mL). 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 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.08 (M+H) + . Example 12D (((3 S,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-yl)oxy)(trial butyl)dimethylsilane Example 12C (1.00 g) in dichloromethane (15.00 mL) with 1 H-imidazole (0.60 g) and tertiary butchlorodimethylsilane (0.678 g). The reaction was stirred at ambient temperature for 64 hours and the reaction mixture was then poured over water (50 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (40 g silicon dioxide column, 0-20% ethyl acetate / heptane) to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z337.18 (M+H) + . Example 12E 4-methylbenzenesulfonic acid ((2 R,5 S)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methyl ester Example 12D (1.50 g) in tetrahydrofuran (15.00 mL) bubbled with nitrogen for 5 minutes and then added to containing Pd(OH) 2 In a flask of / C (20 wt% Pd, 50% moisture, 10.0 mg). The hydrogen balloon was attached and the reaction was stirred at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated, then dissolved in dichloromethane (10.00 mL). Add to solution N, N-dimethylpyridine-4-amine (0.750 g), N-ethyl- N-isopropylprop-2-amine (1.50 mL) and 4-methylbenzene-1-sulfonyl chloride (0.774 g). The reaction was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and purified by flash chromatography (40 g silicon dioxide column, 0-20% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z400.96 (M+H) + . Example 12F (((3 S,6 R)-6-(azidomethyl)tetrahydro-2 H-piperan-3-yl)oxy)(trial butyl)dimethylsilane Example 12E (1.00 g) in N, The solution in N-dimethylformamide (6.00 mL) was treated with sodium azide (0.80 g) and the reaction was heated to 80°C for 20 hours. The reaction mixture was allowed to cool to ambient temperature and poured over 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 concentrated. The residue was purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z243.95 (M-N 2 +H) + . Example 12G ((2 R,5 S)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methylamine A solution of Example 12F (0.55 g) in tetrahydrofuran (6.00 mL) was added to a Raney-Ni 2800 water slurry (0.55 g) in a 20 mL glass lined reactor. Purge the reactor with nitrogen. The mixture was stirred under hydrogen (60 psi) at 25°C. After 20 hours, the reactor was aerated and the reaction mixture was filtered and the filtrate was concentrated to give the title compound. LC / MS (ESI+) m / z246.32 (M+H) + . Example 12H 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 12G (20.0 mg) in dichloromethane (0.80 mL) N-ethyl- N-isopropylprop-2-amine (0.06 mL) and 4-fluoro-3-nitrobenzenesulfonamide (18.0 mg). The reaction was stirred at ambient temperature for 2 hours. Example 1Q (50.0 mg) was added to the reaction mixture in sequence. N, N-dimethylpyridine-4-amine (21.0 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (25.0 mg) and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane). The solubilized products containing the tertiary butyldimethylsilicon protected were combined and concentrated. The residue was dissolved in dichloromethane (4 mL) and placed in an ice bath. After 5 minutes, trifluoroacetic acid (0.8 mL) was added, followed by water (0.2 mL) and the reaction was stirred in an 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. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1025.27 (M+H) + . Example 13 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 13A ( R)-(3,4-dihydrogen-2 H-piperan-2-yl)methanol Title compounds follow the literature procedure (International Edition of Applied Chemistry 2015, 54, 13538-13544) Preparation. Optical rotation (observation) [α] D 25 = -78.93 (in chloroform c1.06); (Literature) [α] D 25 = -74.32 (in chloroform c1.07). 3-(4-(trifluoromethyl)phenyl)propionic acid for a small amount of material, N, N-dimethylpyridine-4-amine and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride treatment to obtain ( R)-3-(4-(trifluoromethyl)phenyl)propionic acid (3,4-dihydro-2 H-piperan-2-yl)methyl ester. ChiralPak AD-H, 5-50% CH 3 OH, 3 mL / min, 10 min method, 150 bar CO 2 ) The ee of the ester was determined to be 99%. The residence time of the primary enantiomer was 1.19 minutes and the residence time of the secondary enantiomer was 1.09 minutes. Example 13B ( R)-2-((benzyloxy)methyl)-3,4-dihydro-2 H-Peram 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 Example 13A (1.5 g) was then added as a solution in tetrahydrofuran (2 mL). The reaction was stirred in an ice bath for 15 minutes, and then pure bromotoluene (2.5 mL) was added and the ice bath was removed. The reaction was stirred for 4 hours, then the reaction mixture was again placed in an ice bath and carefully quenched with 1:1 aqueous saturated ammonium chloride solution and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silicon dioxide column, 0-5% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 13C (3 S,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-ol To a solution of Example 13B (2.00 g) in tetrahydrofuran (24.0 mL) was added dropwise at 0°C for 1 hour. 9-boron bicyclo[3.3.1]nonane (50.0 mL, 0.5 M in tetrahydrofuran) at 0°C. 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 solution (15 mL) was carefully added to the mixture at 0°C, followed by 30% aqueous hydrogen peroxide solution (16 mL). 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 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.08 (M+H) + . Example 13D (2 R,5 S)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2 H-Peram 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, pure methyl iodide (0.600 mL) was added and stirring continued for 16 hours. The reaction mixture was poured over aqueous saturated ammonium chloride solution (20 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 25 mL). The organic layers were combined, dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by flash chromatography (40 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z237.40 (M+H) + . Example 13E 4-methylbenzenesulfonic acid ((2 R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl ester A solution of Example 13D (0.600 g, 2.54 mmol) in tetrahydrofuran (5.00 mL) was added to contain Pd(OH) 2 In a flask of / C (20 wt% Pd, 50% moisture, 50 mg) and the solution was bubbled with nitrogen. The flask was connected to a hydrogen balloon and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was diluted with dichloromethane (5.00 mL). For solution N, N-dimethylpyridine-4-amine (0.464 g), N-ethyl- N-isopropylprop-2-amine (0.883 mL) and 4-methylbenzene-1-sulfonyl chloride (0.483 g). The reaction was stirred at ambient temperature for 3 hours. The reaction mixture was filtered and the solid was discarded. The filtrate was concentrated and purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z301.33 (M+H) + . Example 13F (2 R,5 S)-2-(azidomethyl)-5-methoxytetrahydro-2 H-Peram Example 13E (0.750 g), N, A mixture of N-dimethylformamide (6.00 mL) and sodium azide (0.800 g) was heated at 80°C for 5 hours. The reaction was allowed to cool to ambient temperature and poured over water (30 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z144.25 (M-N 2 +H) + . Example 13G ((2 R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methylamine A solution of Example 13F (0.300 g) in tetrahydrofuran (8.00 mL) was added to a Raney-Ni 2800 water slurry (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 hours, the reactor was aerated and the reaction mixture was filtered and the filtrate was concentrated to give the title compound. LC / MS (APCI+) m / z146.24 (M+H) + . Example 13H 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 13G (12 mg) in dichloromethane (1.00 mL) N-ethyl- N-isopropylprop-2-amine (0.080 mL) and 4-fluoro-3-nitrobenzenesulfonamide (18 mg). The reaction was stirred at ambient temperature for 2 hours. Example 1Q (50 mg) was added to the reaction mixture in sequence. N, N-dimethylpyridine-4-amine (21 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (25 mg) and stirring continued for 16 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (5-85% acetonitrile / water (+0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1039.31 (M+H) + . Example 14 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid Example 14A 1-oxaspiro[2.5]octane-6-formate ethyl ester 4-Pendant oxycyclohexanecarboxylate (50 g), (CH 3 ) 3 The mixture of SOI (64.6 g) and potassium 2-methylpropyl-2-ate (33.0 g) in ethylene glycol dimethyl ether (700 mL) was stirred under nitrogen at 90°C for 12 hours. After the mixture was cooled to ambient temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between water (250 mL) and methyltributyl ether (250 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product which was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 6 / 1 - 3 / 1) to give the title compound. Example 14B Ethyl 4-(fluoromethyl)-4-hydroxycyclohexanecarboxylate Tetrabutylammonium fluoride solution (1.0 M tetrahydrofuran solution, 163 mL) was treated with hydrofluoric acid (7.08 mL, 40% aqueous solution). The volatile portion of the mixture was concentrated. To the residue was added potassium fluoride hydrofluorate (1.272 g). The resulting mixture was heated at 100°C under vacuum (0.55 mmHg) for 15 minutes. After cooling to ambient temperature, heptane (60 mL) and Example 14A (10 g) were added. The mixture was stirred at 120°C for 24 hours, then cooled to ambient temperature and water was added. The mixture was extracted with ethyl acetate (3×), washed with brine, dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate under reduced pressure gave the crude product which was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 6 / 1 - 3 / 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 (quin, J=6.88 Hz, 3H) 4.18 - 4.39 (m, 1H). Example 14C 1-(fluoromethyl)-4-(hydroxymethyl)cyclohexanol To a solution of Example 14B (24 g) in tetrahydrofuran (430 mL) cooled with an ice water bath, lithium aluminum hydride (6.69 g) was added portion by portion. The mixture was stirred at 20°C for 2 hours and then cooled back to 0°C, quenched by addition of water (6.7 mL), followed by 15% aqueous sodium hydroxide solution (6.7 mL) and subsequently water (20.1 mL). Add anhydrous sodium sulfate. The resulting mixture was stirred at ambient temperature for an additional 30 minutes, and the precipitate was removed by filtration. The filter cake was washed with diethyl ether. The filtrate was then concentrated. The crude product was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 1 / 3 - 1 / 10) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 14D 4-methylbenzenesulfonic acid ((1 s,4 s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl ester; and Example 14E 4-methylbenzenesulfonic acid ((1) s,4 s)-4-(chloromethyl)-4-hydroxycyclohexyl)methyl ester To a solution of Example 14C (14 g) in dichloromethane (140 mL) was added p-toluenesulfonyl chloride (19.75 g) and pyridine (34.9 mL) at 0°C. The mixture was stirred at ambient temperature for 12 hours, then washed with water, 1N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product which was purified by silicone tube column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain Example 14D and Example 14E. Example 14D: 1 H NMR (400 MHz, CDCl 3 ) δppm 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, CDCl 3 ) δppm 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). Example 14F (1 s,4 s)-4-(azidomethyl)-1-(fluoromethyl)cyclohexanol To Example 14D (6.6 g) N, Sodium azide (2.71 g) was added portionwise to the solution in N-dimethylformamide (50 mL). The reaction mixture was stirred at 80°C for 12 hours. After cooling to ambient temperature, the mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product which was purified by silicone tube column chromatography and lyzed with 15% ethyl acetate / petroleum ether to obtain the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 14G (1s,4s)-4-(aminomethyl)-1-(fluoromethyl)cyclohexanol To a solution of Example 14F (2.95 g) in methanol (59.0 mL) under argon, Raney nickel (1.39 g). The suspension was degassed in vacuo and purged several times with hydrogen. The mixture was then stirred under hydrogen at ambient temperature for 18 hours. The suspension was filtered through a pad of diatomaceous earth and rinsed thoroughly with methanol (500 mL). The combined filtrates were concentrated to dryness to give the crude product which was wet-milled in methyl tributyl ether (20 mL) to give the title compound. MS (ESI+) m / z162.0 (M+H) + . Example 14H 4-(((((1) s,4 s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amine)-3-nitrobenzenesulfonamide To Example 14G (5 g) N, Add to the solution of N-dimethylformamide (50 mL) N, N-diisopropylethylamine (21.67 mL) and 4-fluoro-3-nitrobenzenesulfonamide (5.46 g). The solution was stirred at ambient temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure to give the crude product which was purified by silicone tube column chromatography to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z362.2 (M+H) + . Example 14I 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-(fluoromethyl)-4-hydroxycyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (50 mg), Example 14H (25.4 mg), N, N-dimethylpyridine-4-amine (8.58 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 To a mixture of -dimethylpropane-1,3-diamine hydrochloride (18.84 mg) in dichloromethane (2 mL), triethylamine (29.4 μL). The mixture was stirred at ambient temperature for 16 hours and then concentrated. The residue was purified by Gilson reverse phase HPLC (C18 column, 20-80% acetonitrile / water containing 0.1% trifluoroacetic acid) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1055.6 (M+H) + . Example 15 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-1-hydroxy-[1,1'-bis(cyclobutane)]-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamidine Example 15A N, N-dibenzyl-3-pendioxycyclobutanecarboxylate Add to a solution of 3-pendicular oxycyclobutanecarboxylic acid (5 g) in dichloromethane (50 mL) at 0°C N, N-dimethylformamide (0.299 mL), followed by thyroid dichloride (6.67 g). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and dibenzylamine (7.2 g) was added dropwise at 0°C and N, Solution of N-diisopropylethylamine (15.94 mL) in tetrahydrofuran (40 mL). After the addition was completed, the reaction mixture was warmed to ambient temperature and then stirred at ambient temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silicone tube column chromatography (dissolved with 10:1 ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 15B 3-((dibenzylamine)methyl)cyclobutanol To a suspension of lithium aluminum hydride (3.88 g) in tetrahydrofuran (100 mL) in tetrahydrofuran (100 mL) was added dropwise at 0°C under nitrogen. After addition, the mixture was allowed to warm to ambient temperature and then stirred at ambient temperature for 2 hours. The reaction mixture was allowed to cool to 0°C and quenched with water (3.8 mL), 15% sodium hydroxide (3.8 mL) and water (11.4 mL). After stirring the mixture at ambient temperature for 15 minutes, anhydrous magnesium sulfate was added. The resulting mixture was stirred at ambient temperature for an additional 15 minutes and then filtered. The filter cake was washed with ethyl acetate (300 mL). The filtrate was concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 15C 3-((dibenzylamine)methyl)cyclobutane To a solution of thymethoxychloride (3.64 mL) in dichloromethane (80 mL) was added to a solution of thymethoxychloride (5.55 mL) in dichloromethane (10 mL) at -78°C. After stirring the mixture at -78°C for 20 minutes, a solution of Example 15B (10.g) in dichloromethane (40 mL) was added. The reaction mixture was stirred at -78°C for an additional 60 minutes. Add triethylamine (25.8 mL). The mixture was then warmed to ambient temperature and then stirred at ambient temperature for 60 minutes. Add water (80 mL). The mixture was extracted with dichloromethane (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silicone tube column chromatography (15:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 2.53 - 2.68 (m, 5H) 2.96 - 3.14 (m, 2H) 3.62 (s, 4H) 7.18 - 7.43 (m, 10H). Example 15D (1 s,3 s)-3-((dibenzylamine)methyl)-[1,1'-bis(cyclobutane)]-1-ol To a solution of cyclobutylmagnesium bromide (1 M in tetrahydrofuran, 44.7 mL) was added at -60°C. Example 15C (5 g) in dichloromethane (50 mL). After the addition was completed, 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 x 40 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silicone tube column chromatography (15:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 1.53 (br t, J=9.15 Hz, 3H) 1.68 - 1.94 (m, 6H) 1.96 - 2.05 (m, 1H) 2.08 - 2.25 (m, 2H) 2.50 (br d, J=7.06 Hz, 2H) 3.53 (s, 4H) 7.14 - 7.44 (m, 10H). Example 15E (1 s,3 s)-3-(aminomethyl)-[1,1'-bis(cyclobutane)]-1-ol To Example 15D (4.8 g) and 10% Pd(OH) 2 Acetic acid (15 mL) was added to a suspension of carbon (2.0 g) in methanol (150 mL). The mixture was stirred at 25°C under a hydrogen atmosphere (15 psi) for 12 hours. The reaction mixture was filtered and the filter cake was washed sequentially with methanol (500 mL) and water (200 mL). The filtrate was concentrated to remove methanol. To the residue was added saturated aqueous sodium carbonate solution (80 mL) and the pH was adjusted to 8 to 9. The mixture was extracted with 1:6 isopropanol / chloroform (4 x 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give the title compound. MS (ESI-) m / z156.1 (M-H) - . Example 15F 4-(((((1) s,3 s)-1-hydroxy-[1,1'-bis(cyclobutane)]-3-yl)methyl)amine)-3-nitrobenzenesulfonamide N, A mixture of N-diisopropylethylamine (6.75 mL), Example 15E (1.5 g) and 4-chloro-3-nitrobenzenesulfonamide (2.058 g) in acetonitrile (16 mL) was stirred under nitrogen for 14 hours at 80°C. The reaction mixture was concentrated and the residue was subjected to reverse phase HPLC (C18 column, 30-50% acetonitrile in 10 mM NH 4 HCO 3 / H 2 Purification in O) gave the title compound. 1 H NMR (400 MHz, methanol- d 4 ) δppm 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). Example 15G 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-1-hydroxy-[1,1'-bis(cyclobutane)]-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide The title compound was prepared using the same procedure as in the last step of Example 14, and Example 15F was replaced with Example 14H. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1049.5 (M+H) + . Example 16 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid Example 16A 1-oxaspiro[2.3]hexane-5-forminnitrile A solution of 3-chloroperoxybenzoic acid (8.34 g) in dichloromethane (193 mL) was stirred under nitrogen at -15°C for 0.5 hours. The mixture was filtered and the filtrate was added dropwise to a solution of 3-methylenecyclobutyrib (3 g) in dichloromethane (64 mL) at 0°C. The mixture was then stirred at 25°C for another 15 hours and then cooled back to 0°C for 0.5 hours. The reaction mixture was filtered, and the filtrate was washed successively with 10% aqueous sodium bisulfite solution (90 mL) and saturated aqueous sodium bicarbonate solution (2×90 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 2.76 - 2.99 (m, 6H) 3.03 - 3.27 (m, 1H). Example 16B (1 r,3 r)-3-(fluoromethyl)-3-hydroxycyclobutyrib; and Example 16C (1 s,3 s)-3-(fluoromethyl)-3-hydroxycyclobutynitrile To tetrabutylammonium fluoride solution (1.0 M tetrahydrofuran solution, 65.4 mL) was added hydrogen fluoride (2.85 mL) under stirring and the erectile portion was evaporated under reduced pressure. To the residue was added potassium fluoride hydrofluorate (0.511 g) and the resulting mixture was dried in vacuo (0.55 mmHg) at 60°C for 30 minutes. After the mixture was cooled to ambient temperature, heptane (102 mL) and Example 16A (3.4 g) were added. The mixture was stirred at 120°C for 24 hours and then cooled to ambient temperature and concentrated. The residue was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by silicone tube column chromatography (15% ethyl acetate / petroleum ether) to give Example 16B and Example 16C. Example 16B: 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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, diacetium- d 6 ) δppm 2.22 - 2.31 (m, 2H) 2.44 - 2.50 (m, 2H) 2.99 (quin, J=8.93 Hz, 1H) 4.23 (s, 1H) 4.35 (s, 1H) 5.84 (s, 1H). Example 16D (1 s,3 s)-3-(aminomethyl)-1-(fluoromethyl)cyclobutanol To a solution of Example 16C (5.5 g) in ethanol (275 mL) under an argon atmosphere, ammonium hydroxide (5.97 g) and Reynished nickel (15.0 g). The suspension was degassed in vacuo and purged several times with hydrogen. 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 washed with ethanol (200 mL). The combined filtrates were concentrated to dryness to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 16E 4-(((((1) s,3 s)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrobenzenesulfonamide To Example 16D (5.75 g) N, 4-fluoro-3-nitrobenzenesulfonamide (8.56 g) was added to the solution of N-dimethylformamide (79 mL) and N-ethyl- N-isopropylprop-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%-30% acetonitrile / water for 25 minutes) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 16F 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-(fluoromethyl)-3-hydroxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide The title compound was prepared using the same procedure as in the last step of Example 14, and Example 16E was replaced with Example 14H. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1028.4 (M+H) + . Example 17 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((3-hydroxyoxetan-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid Example 17A 4-(((3-hydroxyoxetan-3-yl)methyl)amine)-3-nitrophenylsulfonyl Solutions of 4-fluoro-3-nitrobenzenesulfonamide (0.5 g), 3-(aminemethyl)oxetine-3-ol (0.234 g) and triethylamine (0.95 mL) at 50°C in 2 Stir in oxane (15 mL) for 2 hours. The reaction was cooled, diluted with ethyl acetate and washed three times with 1.0 M aqueous HCl. The combined aqueous washing liquids were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was wet-milled with ethyl acetate / dichloromethane / methanol to give the title compound. MS (ESI-) m / z604.7 (M-H) - . Example 17B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((3-hydroxyoxetan-3-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.049 g), Example 17A (0.020 g), N, N-dimethylpyridine-4-amine (0.025 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.027) was stirred in dichloromethane (0.7 mL). After stirring for 16 hours, the reaction was loaded onto a silicone (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 6% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z997.57 (M+H) + . Example 18 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-hydroxytetrahydrogen-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 18A N-((4-chloro-3-nitrophenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrox-1-yl)benzolamide Example 1Q (0.075 g), 4-chloro-3-nitrobenzenesulfonamide (0.027 g), N, N-dimethylpyridine-4-amine (0.013 g), N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (0.040 g) and N-ethyl- A solution of N-isopropylprop-2-amine (0.055 mL, 0.316 mmol) was stirred in dichloromethane (1.0 mL). 16 hours after stirring, the reaction was loaded onto a silica gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and over 30 minutes, lysed with a gradient of 0.5% to 4% dichloromethane / methanol to give the title compound. LC / MS (ESI+) m / z930.44 (M+H) + . Example 18B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-hydroxytetrahydrogen-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 18A (0.091 g), 4-(aminomethyl)tetrahydro-2 under nitrogen H-piperan-4-ol (0.019 g) and N-ethyl- N-isopropylprop-2-amine (0.085 mL) in 2 The solution in alkane (1.0 mL) was sealed in vial and heated to 95°C for 16 hours. Cool the reactants and load them into silicone (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 5% dichloromethane / methanol. The soluble ionizer containing the product was collected and concentrated. The residue was dissolved in 1:1 dimethylol:methanol (2 mL) and purified by HPLC with a gradient of 20% to 85% acetonitrile / water to give the title compound. 1 H NMR (500 MHz, pyridine- d 5 ) δppm 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 / z1025.67 (M+H) + . Example 19 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzamid Example 19A 6-((4-fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-5-nitropyridin-3-sulfonyl To a solution of Example 4C (1.10 g) in tetrahydrofuran (15 mL) was added sodium hydride (0.297 g) and the mixture was stirred for 20 minutes. 4-fluoro-3-nitrobenzenesulfonamide (1.067 g) was added, followed by tetrahydrofuran (10 mL) and the solution was stirred for 16 hours. The reaction was quenched with saturated aqueous ammonium hydroxide solution, extracted with ethyl acetate, dried over sodium sulfate and concentrated. The residue was wet-milled with tertiary butyl methyl ether and filtered to give the title compound. LC / MS (APCI+) m / z390.08 (M+H) + . Example 19B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-((4-Fluoro-1-(oxetan-3-yl)piperidin-4-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.075 g), Example 19A (0.037 g), N, N-dimethylpyridine-4-amine (0.039 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) was stirred in dichloromethane (1.0 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1083.57 (M+H) + . Example 20 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 R)-5-methyl-1,4-di Alkane-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide Example 20A 4-(((2 R,5 R)-5-methyl-1,4-di Alkane-2-yl)methoxy)-3-nitrobenzenesulfonamide Sodium hydride (60% in mineral oil, 0.209 g) was added to a solution of Example 6C (0.300 g) in tetrahydrofuran (11.35 mL) and the mixture was stirred for 20 minutes, followed by 4-fluoro-3-nitrobenzenesulfonamide (0.500 g). The reaction was stirred for 1 h, then quenched with saturated aqueous ammonium hydroxide solution (25 mL) and extracted with dichloromethane (2 x 40 mL). The combined organic layers were washed with saturated aqueous ammonium chloride solution (40 mL), dried over magnesium sulfate and concentrated. The resulting residue was wet-milled with dichloromethane (10 mL), filtered and dried to give the title compound. LC / MS (ESI+) m / z333.04 (M+H) + . Example 20B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 R)-5-methyl-1,4-di alkane-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.075 g), Example 20A (0.035 g), N, N-dimethylpyridine-4-amine (0.039 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040) was stirred in dichloromethane (1.0 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol. The material was dissolved in 1:1 dimethylolite / methanol (2 mL), followed by addition of 2,2,2-trifluoroacetic acid (0.024 mL) and purified by HPLC, Luna 10 mmC18(2) 250 x 50 mm column using a gradient of 20% to 85% acetonitrile / water over 30 minutes. The product was collected and lyophilized to give the title compound. 1 H NMR (500 MHz, pyridine- d 5 ) δppm 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 / z1026.67 (M+H) + . Example 21 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 R)-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 21A ( S)-1-chloro-3-(dibenzylamine)propan-2-ol Diphenylamine (50 g) and ( The mixture of S)-(+)-epichlorohydrin (35.2 g) in dichloromethane (150 mL) was stirred at ambient temperature for 96 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography (silicon dioxide, 1-2.5% ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 21B ( S)- N, N-dibenzyl-1-(ethylene oxide-2-yl)methylamine To Example 21A (350 g) N, To a solution in N-dimethylformamide (1.8 L), sodium hydroxide (97 g) was added and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was poured over water (5 L) and extracted with methyl tributyl ether (3 x 1 L). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 21C ( R)-1-(dibenzylamine)penta-4-ene-2-ol To a solution of Example 21B (140 g) in tetrahydrofuran (1399 mL) was added copper (I) chloride and the reaction was cooled to -10°C. Magnesium ethylene brominated (1 M in tetrahydrofuran, 829 mL) was added dropwise and the reaction was stirred at 0°C for 1 hour. Methanol (55.9 mL) was added at 0°C, followed by water (200 mL), and the mixture was extracted with methyltributyl ether (3 x 200 mL). The combined organic layers were washed with water (5 x 200 mL), dried over magnesium sulfate, filtered and the filtrate concentrated. The material is used as is for the next step. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 21D ( R)- N, N-dibenzyl-2-((2-methylallyl)oxy)penta-4-ene-1-amine The solution of Example 21C (150 g) in tetrahydrofuran (1.5 L) was cooled to 0°C and tertiary potassium butoxide (90 g) was added. Pure 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 on water (200 mL) and extracted with methyl tributyl ether (3 x 200 mL). The combined organic layers were washed with water (5 x 200 mL), dried over magnesium sulfate, filtered and the filtrate concentrated. The material is used as is for the next step. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 21E ( R)- N, N-dibenzyl-1-(5-methyl-3,4-dihydro-2 H-piperan-2-yl)methylamine To a solution of Example 21D (50 g) in toluene (1 L), (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolinidin)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (5.06 g), and the reaction was heated to 110°C for 12 hours. The reaction mixture was poured over water (100 mL) and extracted with methyl tributyl ether (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL), dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by flash chromatography (silicon dioxide, 1-3% ethyl acetate / petroleum ether) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z308.20 (M+H) + . Example 21F ((2 R)-5-methyltetrahydro-2 H-piperan-2-yl)methylamine A solution of Example 21E (1.00 g) in tetrahydrofuran (10 mL) was added to containing Pd(OH) 2 Glass lined reactor / C (10 wt% Pd, wet catalyst, 0.200 g). 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 as is for the next step. Example 21G 4-(((((2) R,5 R)-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide Example 21 Solution of F (0.42 g) in dichloromethane (8.00 mL) was added N-ethyl- N-isopropylprop-2-amine (2.00 mL), followed by 4-fluoro-3-nitrobenzenesulfonamide (0.716 g), and the reaction was stirred at ambient temperature for 16 hours. The reaction mixture was purified by flash chromatography (80 g silicon dioxide column, 20-100% ethyl acetate / heptane) to separate the diastereomers mixture. The title compound was obtained from the mixture after reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) and lyophilized fast dissolution of the components. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z330.02 (M+H) + . Example 21H 4-(((((2) R,5 S)-5-methyltetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide The title compound as a second peak was obtained from the reverse phase HPLC separation described in Example 21G. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z330.06 (M+H) + . Example 21I 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 R)-5-methyltetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 21G (27 mg) in dichloromethane (0.80 mL) N-ethyl- N-isopropylprop-2-amine (0.05 mL), Example 1Q (50 mg), N, N-dimethylpyridine-4-amine (14 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (20 mg) was treated and the mixture was stirred for 23 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1023.74 (M+H) + . 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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 22A 1-(2-methoxyethyl)piperidine-4-carboxylate To a solution of piperidin-4-formate (10 g) in ethanol (100 mL), potassium carbonate (26.4 g) and 1-bromo-2-methoxyethane (9.73 g) were added. The resulting mixture was stirred at 70°C for 12 hours. The reaction was cooled and concentrated, the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 22B 4-fluoro-1-(2-methoxyethyl)piperidine-4-carboxylate At -78°C N, A solution of Example 22A (10 g) in anhydrous tetrahydrofuran (50 mL) was added dropwise to a solution of Example 22A (10 g) in anhydrous tetrahydrofuran (50 mL). The reaction mixture was stirred at -78°C for 30 minutes. Added one by one N-fluorine- N-(phenylsulfonyl)benzenesulfonamide (29.3 g). The resulting mixture was gradually warmed to 25°C and stirred for 12 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (200 mL) dropwise at 0°C and extracted with ethyl acetate (3 x 50 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 1:1 to 0:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ ppm1.28 (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). Example 22C (4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)methanol Lithium aluminum hydride (1.627 g) was added to a solution of Example 22B (5 g) in anhydrous tetrahydrofuran (50 mL) at 0°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction was allowed to cool 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). The reaction mixture was filtered and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δ ppm1.61-1.81 (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). Example 22D 5-Chloro-6-((4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)methoxy)pyridin-3-sulfonamide At 0°C, to Example 22C (5 g) N, Sodium hydride (4.18 g) was added to the solution in N-dimethylformamide (70 mL). The reaction mixture was stirred at 25°C for 30 minutes, followed by addition of 5,6-dichloropyridin-3-sulfonamide (4.75 g) and stirring continued for 12 hours. The reaction mixture was quenched by addition of water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was wet-milled with 1:1 petroleum ether and ethyl acetate (50 mL) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δ ppm1.69-1.94 (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 / z380.1 (M-H) - . Example 22E N-((5-chloro-6-((4-fluoro-1-(2-methoxyethyl)piperidin-4-yl)methoxy)pyridin-3-yl)sulfonyl)-4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 1Q (0.075 g), Example 22D (0.036 g), N, N-dimethylpyridine-4-amine (0.039 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) was stirred in dichloromethane (1.0 mL). After stirring for 16 hours, the reaction was loaded onto a silicone gel (Teledyne Isco RediSep ® RF GOLD ® , 40 g) and ionization over 30 minutes using a gradient of 1% to 4% dichloromethane / methanol to give the title compound. 1 H NMR (600 MHz, pyridine- d 5 ) δppm 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, 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 / z1077.65 (M+H) + . Example 23 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-methyltetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide The title compound was prepared following the procedure of the last step of Example 21 and replaced Example 21G with Example 21H. The crude product was purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-70% acetonitrile / water (+ 0.1% trifluoroacetic acid). 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z1023.67 (M+H) + . Example 24 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-methoxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 24A N-benzyl-3-pendicular oxycyclobutanecarboxylate Add to a solution of 3-pendicular oxycyclobutanecarboxylic acid (5 g) in tetrahydrofuran (50 mL) at 0°C N, N'-carbonyldiimidazole (8.53 g). The reaction mixture was stirred at 20°C for 1.5 hours and then phenylmethylamine (5.75 mL) was added at 20°C and the reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was wet-milled with 20:1 ethyl acetate / petroleum ether (1 L) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 24B (1 s,3 s)- N-benzyl-3-hydroxycyclobutanecarboxylamide To a solution of Example 24A (5 g) in methanol (50 mL) at 0°C, sodium borohydride (1.396 g) was added to a solution of Example 24A (5 g) in methanol (50 mL), and the reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was wet-milled with 15:1 ethyl acetate / petroleum ether (1 L) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 24C (1 s,3 s)- N-benzyl-3-methoxycyclobutanecarboxylamide To a solution of Example 24B (8 g) in methyl ethyl ketone (100 mL) was added silver oxide (18.06 g) and methyl iodide (7.31 mL) at 20°C, and the reaction mixture was stirred at 70°C for 24 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was quenched with addition of water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by column chromatography (dissolved with 3 / 1 petroleum ether / ethyl acetate to ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 24D N-benzyl-1-((1 s,3 s)-3-methoxycyclobutyl)methylamine To a solution of Example 24C (5 g) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (1.731 g) at 0°C. The reaction mixture was stirred at 70°C for 2 hours. To the reaction mixture were added water (1.8 mL), 15% aqueous sodium hydroxide solution (1.8 mL) and water (3×1.8 mL). The mixture was filtered through diatomaceous earth and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 24E ((1 s,3 s)-3-methoxycyclobutyl)methylamine 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 under hydrogen atmosphere for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 24F 4-(((((1) s,3 s)-3-methoxycyclobutyl)methyl)amine)-3-nitrobenzenesulfonamide To Example 24E (1.50 g) at 20°C N, Add to the solution of N-dimethylformamide (15 mL) N, N-diisopropylethylamine (4.55 mL) and 4-chloro-3-nitrobenzenesulfonamide (2.46 g). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched by addition of water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was prepared by preparative HPLC (Welch Xtimate C18 250 x 50 mm 10 μm, mobile phase: A: 10 mM NH 4 HCO 3 / H 2 O; B: acetonitrile) purified to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 24G 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,3 s)-3-methoxycyclobutyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.040 g), Example 24F (0.017 g), N, N-dimethylpyridine-4-amine (0.021 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.022 g) was stirred in dichloromethane (0.6 mL) for 3 days. The reaction was loaded onto a silicone gel (agela, 40 g) and dissolved over 30 minutes using a gradient of 0.5% to 4.5% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 / z1009.82 (M+H) + . Example 25 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 25A ( S)-(3,4-dihydrogen-2 H-piperan-2-yl)methanol Contains racemic (3,4-dihydrogen-2 Add dichloromethane (250 mL) to a flask of H-piperan-2-yl)methanol (25.8) and N, N-dimethylpyridin-4-amine (32.0 g). Place the flask in an ice bath. After 15 minutes, pure acetyl chloride (16.1 mL) was added and the reaction was stirred in an ice bath for 1 hour. The reaction mixture was poured into a separate 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 by flash chromatography (330 g silicon dioxide column, 0-60% ethyl acetate / heptane) to obtain racemic acetic acid (3,4-dihydrogen-2 H-piperan-2-yl)methyl ester. To a flask containing water (1 L), tripopotassium phosphate (4.48 g) and potassium dihydrogen phosphate (4.28 g) were added, and the mixture was stirred until all solids dissolved. Add to the solution at ambient temperature Racemic acetic acid (3,4-dihydrogen-2 in acetone (10 mL) H-piperan-2-yl)methyl ester (10.0 g) followed by addition of porcine pancreatic lipase (75 mg). In another flask, set the same reaction at twice the size. The reaction was stirred at ambient temperature for 18 hours, and then the two were combined into 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 by flash chromatography (80 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). 3-(4-(trifluoromethyl)phenyl)propionic acid for a small amount of material, N, N-dimethylpyridine-4-amine and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride treatment to obtain ( S)-3-(4-(trifluoromethyl)phenyl)propionic acid (3,4-dihydro-2 H-piperan-2-yl)methyl ester. ChiralPak AD-H, 5-50% CH 3 OH, 3 mL / min, 10 min method, 150 bar CO 2 ) The ee of the ester was determined to be 93%. The residence time of the primary enantiomer was 1.26 minutes and the residence time of the secondary enantiomer was 1.34 minutes. Example 25B ( S)-2-((benzyloxy)methyl)-3,4-dihydro-2 H-Peram To a flask containing sodium hydride (60 wt% in mineral oil, 1.104 g) was added tetrahydrofuran (60.0 mL). The slurry was cooled in an ice bath and a solution of Example 25A (2.100 g) in tetrahydrofuran (3 mL) was added dropwise, followed by tetrahydrofuran (2 mL). The reaction was stirred in an ice bath for 15 minutes. Pure (bromomethyl)benzene (3.50 mL) was added and the ice bath was removed. The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was placed in an ice bath and carefully quenched by dropwise addition of 1:1 water / aqueous saturated ammonium chloride solution (80 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (80 g silicon dioxide column, 0-5% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 25C (3 R,6 S)-6-((benzyloxy)methyl)tetrahydro-2 H-哌喃-3-醇 To a solution of Example 25B (3.60 g) in tetrahydrofuran (50.0 mL) was added dropwise at 0°C for 1 hour. 9-boron bicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 75.0 mL). 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 solution (25 mL) was carefully added to the mixture at 0°C, followed by 30% aqueous hydrogen peroxide solution (32 mL). 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 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (120 g silicon dioxide column, 0-60% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.53 (M+H) + . Example 25D (2 S,5 R)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2 H-Peram The solution of Example 25C (1.000 g) in tetrahydrofuran (20.0 mL) was cooled in an ice bath. Solid sodium hydride (60% by weight in mineral oil, 0.270 g) was added and the mixture was stirred in an ice bath for 15 minutes. Pure methyl iodide (0.400 mL) was added and the reaction was allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by the addition of 0.1% aqueous trifluoroacetic acid solution (4 mL) and water (20 mL) followed by extraction of 5:1 ethyl acetate / heptane (2 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (40 g silicon dioxide column, 0-40% ethyl acetate / heptane) to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z237.46 (M+H) + . Example 25E 4-methylbenzenesulfonic acid ((2 S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl ester A solution of Example 25D (0.97 g) in tetrahydrofuran (10.00 mL) was added to contain Pd(OH) 2 In a flask of / C (20 wt% Pd, 50% moisture, 50 mg). The flask was purged with nitrogen and connected to a hydrogen balloon. The reaction was stirred at ambient temperature for 24 hours and then filtered and the mixture was concentrated. The residue was dissolved in dichloromethane (15 mL) and then added in sequence N, N-dimethylpyridine-4-amine (0.750 g), N-ethyl- N-isopropylprop-2-amine (1.500 mL) and 4-methylbenzene-1-sulfonyl chloride (0.800 g). The reaction was stirred at ambient temperature for 3 hours, and the mixture was then poured over water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (silicon dioxide, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z301.36 (M+H) + . Example 25F (2 S,5 R)-2-(azidomethyl)-5-methoxytetrahydro-2 H-Peram Example 25E (1.000 g), N, A mixture of N-dimethylformamide (6.00 mL) and sodium azide (1.000 g) was heated at 80°C for 18 hours. The reaction was allowed to cool to ambient temperature and poured over water (30 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z144.27 (M-N 2 +H) + . Example 25G 4-(((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide To a solution of Example 25F (0.57 g) in tetrahydrofuran (6.00 mL) was added water (0.076 mL) and triphenylphosphine (1.10 g) and the reaction was stirred at ambient temperature for 16 hours. Add to the reaction mixture N-ethyl- N-isopropylprop-2-amine (2.32 mL) and 4-fluoro-3-nitrobenzenesulfonamide (0.73 g) were stirred for 2 hours at ambient temperature. The reaction mixture was purified by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z346.39 (M+H) + . Example 25H 7,7-dimethyl-4,6,7,8-tetrahydro-2 H,5 H-1,3-benzodime cin-5-ketone To a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) over 10 minutes, boron trifluoride and diethyl ether (40.7 mL) were added to a solution of 5,5-dimethylcyclohexane-1,3-dione (15 g) and formaldehyde (19.92 g) in dichloromethane (600 mL) and the reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture is by adding saturated aqueous NaHCO 3 The solution was quenched, the organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in heptane / ethyl acetate (5:1), concentrated, treated with heptane (300 mL) and filtered. The residue is made of silicone (ISCO Gold) ® ) Chromatography and dissolved with a gradient of 0 to 16% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 5.13 (s, 2H), 4.43 (t, 2H), 2.28 (t, 2H), 2.22 (s, 2H), 1.08 (s, 6H). MS (DCI+) m / z183.1 (M+H) + . Example 25I 4'-Chloro-2-(hydroxymethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4 H)-Ke 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 to a solution of 1-bromo-4-chlorobenzene (30.3 g) in tetrahydrofuran (200 mL) at -78°C, keeping the temperature below -70°C. After stirring at -78°C for 30 minutes, a solution of Example 25H (24 g) in tetrahydrofuran (75 mL) was added dropwise, and the temperature was kept below -60°C. The reaction mixture was stirred at -78°C for one hour, warmed to ambient temperature and stirred for 12 hours. The reaction mixture was treated with 3 M aqueous HCl solution (80 mL) and stirred for 2 hours. Most of the organic solvent was removed and the resulting aqueous layer was extracted with ethyl acetate (three times). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. Residue through silicone gel (750 g BIOTAGE ® SNAP) chromatography was performed with a gradient of 5 to 22% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z247.2 (M+H) + . Example 25J 4'-chloro-2-(chloromethyl)-5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4 H)-Ke To a solution of Example 25I (15 g) in dichloromethane (800 mL), tetraethylammonium chloride (14.08 g) followed by triethylamine (11.85 mL). The reaction mixture was cooled to 0°C in 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 solution and brine, dried over magnesium sulfate, filtered and concentrated. Residue through silica gel (330 g ISCO Gold ® ) Chromatography and dissolved with a gradient of 0 to 35% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z283.1 (M+H) + . Example 25K ( R)-4'-chloro-2-(chloromethyl)-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-3-ol 45 minutes at -50°C S)-2-methyl-CBS- BH was added to a solution of zoboridine (20.96 g) in anhydrous tetrahydrofuran (230 mL) 3 -Tetrahydrofuran (1.0 M in tetrahydrofuran, 76 mL), and the solution was stirred for another 40 minutes. A solution of Example 25J (21 g) in anhydrous tetrahydrofuran (230 mL) was added dropwise via an addition funnel over a course of about 60 minutes. After addition, the reaction mixture was stirred at -50°C for 1.5 hours. The reaction mixture was quenched by dropwise addition of methanol (130 mL) at -50°C over about 20 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature overnight. Saturated aqueous NH 4 Cl solution (250 mL) was diluted, diluted with water and extracted with ethyl acetate. The organic layer is saturated with additional NH 4 The aqueous Cl solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is made of silicone (Teledyne Isco RediSep ® Rf GOLD ® 330 g) chromatography and dissolved with a gradient of 0 to 20% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z284.1 (M+H) + . Example 25L ( S)-4-(((( R)-4'-chloro-3-hydroxy-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)-3-(hydroxymethyl)piper -1-Triple grade butyl ester formate ( S)-3-(hydroxymethyl)piper A solution of -1-tri-butyl formate (1.71 g), Example 25K (2.15 g), sodium iodide (1.47 g) and potassium carbonate (2.084 g) in acetonitrile (15.08 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (80 g) and dissolved with a gradient of 0% to 70% ethyl acetate:ethanol / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z465.4 (M+H) + . Example 25M (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-Tripartic Butyl Formate To a solution of Example 25L (100 g) in dichloroethane (2150 mL), propane-1,3-diylbis(trifluoromethanesulfonate) (95 g) was added, followed by N 1 , N 1 , N 8 , N 8 -Tetramethylnaphthalene-1,8-diamine (122 g) (proton sponge), and the reaction mixture was heated to 50°C for 20 hours. The reaction mixture was cooled in an ice bath and filtered. The filtrate was washed with 1N aqueous HCl solution (1 L×3) and 1N aqueous NaOH solution (three times), dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed with 2 L 5% ethyl acetate / heptane, 4 L 10% ethyl acetate / heptane, followed by 6-8 L 20% ethyl acetate / heptane gradient over silicone gel (3 kg) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z505.3 (M+H) + . Example 25N (4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,3,4,4a,5,7,8,9,10a,11,12,13,15-40hydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazene heterocycloundelyne To a solution of Example 25M (90 g) in dichloromethane (713 mL) cooled in an ice bath, trifluoroacetic acid (206 mL) was added dropwise over approximately 20 minutes. The ice bath was removed and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (300 mL). The vigorously stirred solution is by adding saturated Na 2 CO 3 Neutralize aqueous solution (350 mL). Separate the organic layer with saturated Na 2 CO 3 The aqueous solution was washed four times, dried over sodium sulfate, filtered and concentrated to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) 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 / z405.3 (M+H) + . Example 25O 2-Bromo-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-yl)ethyl benzoate Equipped with a stirring rod, heating sleeve, nitrogen inlet and outlet and a 2L three-neck round bottom flask with ethyl 2-bromo-4-fluorobenzoate (44.4 g). Anhydrous dimethylsenolin (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 is mixed thoroughly, the temperature is raised to 60°C and the slurry is heated under nitrogen for 72 hours. The heating sleeve was removed and the reaction was cooled to 8°C with an ice / water bath. The flask is equipped with a 1 L feed funnel. Water (850 mL) was added dropwise to this cold reaction slurry via an addition funnel and the mixture was sonicated for 30 minutes. The mixture was subjected to mechanical stirring and vigorously stirred at ambient temperature for 1 hour. The precipitate was filtered through a Buchner funnel loaded with filter paper. The filtered solid was washed with water (2 x 500 mL) and allowed to dry on a filter for 16 hours. The solid was dissolved in ethyl acetate (600 mL) and water (300 mL) was added to the solution. Stir the biphasic solution for 1 hour. The layers were separated in a separatory funnel and the organic layers were 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 BIOTAGE was used via normal phase chromatography ® Snap Ultra 750 g silicone tube column, purified by gradient ionization of 0 to 30% ethyl acetate / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z631.46 (M+H) + . Example 25P 7-Oxidation 5-Bromo-1 H-pyrrolo[2,3- b]pyridine 5-bromo-1 at 25°C To a solution of H-pyrrolo[2,3-b]pyridine (10 g) in ethyl acetate (200 mL), 3-chloroperoxybenzoic acid (21.90 g) was added, followed by stirring 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. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 25Q 5-Bromo-6-Chloro-1 H-pyrrolo[2,3- b]pyridine To a solution of Example 25P (30 g) and 1,1,1,3,3,3-hexamethyldisisazane (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 another 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (3 x 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 the residue, which was wet-milled with ethyl acetate and petroleum ether (1:10, 100 mL) to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 12.05 (s, 1H), 8.41 (s, 1H), 7.63 - 7.54 (m, 1H), 6.51 - 6.45 (m, 1H). Example 25R 5-bromo-6-chloro-1-((2-(trimethylsilicate)ethoxy)methyl)-1 H-pyrrolo[2,3- b]pyridine At 0°C, to Example 25Q (15 g) N, Sodium hydride (3.11 g) was added portionwise to the solution in N-dimethylformamide (150 mL). The resulting mixture was stirred at 0°C for 1 hour, followed by dropwise addition of 2-(trimethylsilicon)ethoxymethyl chloride (13.79 mL) to N, Solution in N-dimethylformamide (50 mL). 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 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 10:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 25S N-(3-((5-bromo-1-((2-(trimethylsilicate)ethoxy)methyl)-1 H-pyrrolo[2,3- b]pyridin-6-yl)oxy)propyl)-4-methylbenzenesulfonamide At 0°C Sodium hydride (0.166 g) was added portion by portion to a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (0.349 g) in anhydrous tetrahydrofuran (5 mL). The resulting mixture was stirred at 0°C for 0.5 hours, followed by addition of Example 25R (0.5 g). 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 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 5:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 25T 1-Toluenesulfonyl-7-((2-(trimethylsilicate)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Oxyzacycloheptane To a solution of Example 25S (500 mg) in dimethylol (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 under microwave for 2 hours. After cooling to ambient temperature, the reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3 x 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 the residue which was purified by silicone tube column chromatography (dissolved with petroleum ether:ethyl acetate = 3:1) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 25U 7-((2-(trimethylsilicate)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Oxyzacycloheptane To a solution of sodium (0.291 g) in 1,2-dimethoxyethane (0.5 mL) under nitrogen (1.624 g). The mixture was stirred at 20°C for 1 hour until the formation of sodium / naphthalene was completed. A solution of Example 25T (1 g) in anhydrous tetrahydrofuran (10 mL) was then added to the above solution at -78°C. The resulting mixture was allowed to reach 20°C and stirred for 2 hours. The reaction was quenched by addition of water (200 mL) and extracted with ethyl acetate (3 x 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 the residue which was purified by preparative HPLC to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 25V 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[f]pyramid and [2,1-c][1,8,4] dioxazazene heterocycloundelyne-3(4 H,7 H,15 H)-yl)-2-(7-((2-(trimethylsilicate)ethoxy)methyl)-2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate Example 25U (79 g), (Example 1N) (26.6 g) and methanesulfonate [9,9-dimethyl-4,5-bis(diphenylphosphine)xon](2'-methylamino-1,1'-biphenyl-2-yl)palladium (II) (5.61 g) were fed into a 2L three-neck round bottom flask equipped with a mechanical stirrer, a Huber cooling reflux condenser, a Clayson head adapter, a nitrogen needle inlet and outlet through a separator to a bubbler and an oven-dried thermocouple. This solid was placed under a large stream of nitrogen and cesium carbonate (81 g) was then rapidly added to the reaction flask. The solids were mixed slowly with a mechanical stirrer and a large stream of nitrogen was continued to pass through the reaction flask for 60 minutes. Anhydrous toluene (833 mL) was fed into a 2 L round bottom flask equipped with stirring rods and separators. The solvent was bubbled under the surface of the solvent with a large stream of nitrogen for 60 minutes while stirring. The solvent was then transferred to a three-necked flask via a cannula and the reaction was heated to an internal temperature of 110°C under a stream of nitrogen for 16 hours. The reaction was cooled to ambient temperature and water (600 mL) was fed into the flask followed by pyrrolidine dithiamyl formate palladium scavenger (3 g). The mixture was stirred vigorously for 1 hour. The reaction was further diluted with ethyl acetate (400 mL), stirred for 30 minutes, and then filtered through a plug of diatomaceous earth. The filter cake was washed with ethyl acetate (2 x 500 mL). The filtrate was transferred to a separating funnel and the layers were separated. The organic layer was washed with water (200 mL) and subsequently brine (200 mL). The combined aqueous layers were stripped 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 BIOTAGE was used via normal phase chromatography ® Snap Ultra 1.5 kg silicone tube column, purified by gradient ionization of 0 to 50% ethyl acetate / heptane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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). Example 25W 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Ethyl benzoate Example 25V (69 g) was fed into a 2L three-neck flask equipped with a mechanical stirrer, a heating sleeve, a Clayson head adapter, a reflux condenser, a nitrogen inlet and outlet to the bubbler and a thermocouple. The solid was dissolved in anhydrous tetrahydrofuran (330 mL). To this solution was added ethylenediamine (53.5 mL) and tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 793 mL). The reaction was heated to an internal temperature of 66°C for 24 hours. The heating sleeve was removed and the reaction was cooled to 8°C in an ice / water bath. The mixture was quenched with water (200 mL). The reaction mixture was diluted with ethyl acetate (200 mL) and then partitioned in a separatory funnel. The organic layer was washed with water (200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate (100 g), filtered and concentrated in vacuo to give the crude product. The residue was suspended in 1:1 methyltributyl ether:heptane (400 mL), sonic treatment for 30 minutes, followed by vigorous stirring for 1 hour. The solid was filtered off and the filter cake was washed with 1:1 methyltributyl ether heptane (50 mL). The solid was dried over a Buchner funnel to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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). Example 25X 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,12,13-decahydrobenzo[ f]Pyr and [2,1- c][1,8,4] Dioxazazenecycloundelyne-3(4 H,7 H,15 H)-based)-2-(2,3,4,7-tetrahydro-1 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrox-1-yl)benzoic acid Example 25W (58.7 g) was fed into a 5L three-neck flask equipped with a mechanical stirrer, a heating sleeve, a reflux condenser, a Clayson adapter, a nitrogen inlet and outlet to the bubbler and a thermocouple. Dissolve the residue in 1,4-dioxide Stir in alkane (991 mL) and methanol (496 mL) and stir at ambient temperature for 5 minutes. Subsequently, lithium hydroxide (18.99 g) and water (496 mL) were added and the reaction was heated to an internal temperature of 75°C for 16 hours. The heating sleeve 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 adding saturated aqueous ammonium chloride solution (100 mL). The mixture was diluted with dichloromethane (300 mL) and the layers were partitioned in a separatory funnel. The aqueous layer was extracted with dichloromethane (2 x 100 mL) and the organic layer was laminated 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 via a silicone cartridge (Teledyne Isco RediSep ® RF GOLD ® , 330 g) normal phase chromatography, purified with 0 to 10% methanol / dichloromethane to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z712.29 (M+H) + . Example 25Y 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 25G (50 mg) in dichloromethane (0.80 mL) N-ethyl- N-isopropylprop-2-amine (0.10 mL), Example 25X (88 mg), N, N-dimethylpyridine-4-amine (37 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (44 mg) was treated and the mixture was stirred for 18 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1039.65 (M+H) + . Example 26 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-methoxytetrahydro-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamid Example 26A 1,6-dioxaspiro[2.5]octane To a solution of trimethyl iodine oxide (28.6 g) in dimethylzolithium (150 mL) at 25°C, sodium hydride (5.19 g) was added portion by portion. The resulting mixture was stirred at 25°C for 1 hour, and then dihydro-2 was added dropwise H-piperan-4(3H)-one (10 g). The resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (100 mL) and extracted with methyl tributyl ether (3 x 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, CDCl 3 ) δppm 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). Example 26B (4-Methoxytetrahydro-2 H-piperan-4-yl)methanol To a solution of Example 26A (5 g) in methanol (50 mL) at 25°C, trifluoroacetic acid (6.75 mL) was added to a solution of Example 26A (5 g) in methanol (50 mL) and the reaction was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (20 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silicone tube column chromatography (dissolved with 1:1 to 0:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CD 3 OD-d 4 ) δppm 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). Example 26C 4-methylbenzenesulfonic acid (4-methoxytetrahydro-2 H-piperan-4-yl)methyl ester To a solution of Example 26B (4 g) in dichloromethane (50 mL) at 0°C, triethylamine (7.63 mL), 4-dimethylamine pyridine (0.334 g) and p-toluenesulfonyl chloride (7.82 g). The resulting mixture was stirred at 25°C for 12 hours. The mixture was quenched by addition of water (50 mL) and extracted with dichloromethane (3 x 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 silicone tube column chromatography (dissolved with 5:1 to 1:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 26D 4-(azidomethyl)-4-methoxytetrahydro-2 H-Peram At 25°C, to Example 26C (6 g) N, Sodium azide (2.86 g) and potassium iodide (3.32 g) were added to the solution in N-dimethylformamide (60 mL). The resulting mixture was heated to 80°C and stirred for 12 hours. After cooling to ambient temperature, the reaction mixture was quenched by addition of water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (3 x 50 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate concentrated. The residue was purified by silicone tube column chromatography (dissolved with 10:1 to 3:1 petroleum ether:ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 26E (4-Methoxytetrahydro-2 H-piperan-4-yl)methylamine The mixture of Example 26D (3 g) and palladium / carbon (1.87 g) in methanol (50 mL) was degassed and purged three times with hydrogen. The resulting mixture was stirred at 25°C under a hydrogen atmosphere for 6 hours. 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, diacetium- d 6 ) δppm 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). Example 26F 4-(((4-methoxytetrahydro-2 H-piperan-4-yl)methyl)amine)-3-nitrobenzenesulfonamide To Example 26E (2 g) at 25°C N, Add to the solution of N-dimethylformamide (20 mL) N, N-diisopropylethylamine (4.81 mL) and 4-chloro-3-nitrobenzenesulfonamide (3.26 g). The resulting mixture was heated to 80°C and stirred for 12 hours. The reaction was allowed to cool to ambient temperature and quenched by addition of water (60 mL). The resulting suspension was filtered and the cake was wet-milled with ethyl acetate to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 26G 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((4-methoxytetrahydro-2 H-piperan-4-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.075 g), Example 26F (0.035 g), N, N-dimethylpyridine-4-amine (0.039 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.040 g) was stirred in dichloromethane (1.0 mL). After stirring for 3 days, the reaction was loaded onto a silica gel (agela, 40 g) and dissolved over 30 minutes using a gradient of 0.5% to 4.5% dichloromethane / methane to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 (dd, 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). Example 27 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 27A (((3 R,6 S)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-yl)oxy)(trial butyl)dimethylsilane The title compound was synthesized following the procedure of Example 12D and Example 25C was replaced by Example 12C. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z337.55 (M+H) + . Example 27B 4-methylbenzenesulfonic acid ((2 S,5 R)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methyl ester The title compound was synthesized according to the procedure of Example 12E and replaced Example 12D with Example 27A. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z401.45 (M+H) + . Example 27C (((3 R,6 S)-6-(azidomethyl)tetrahydro-2 H-piperan-3-yl)oxy)( Tri-butyl)dimethylsilane The title compound was followed by the procedure of Example 12F, and Example 27B was synthesized instead of Example 12E. 1 H NMR (600 MHz, CDCl 3 ) δppm 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). Example 27D ((2 S,5 R)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methylamine The title compound was synthesized following the procedure of Example 12G and Example 27C was used instead of Example 12F. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z246.38 (M+H) + . Example 27E 4-(((((2) S,5 R)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide Example 27D (150.0 mg) in dichloromethane (2.00 mL) N-ethyl- N-isopropylprop-2-amine (0.300 mL) and 4-fluoro-3-nitrobenzenesulfonamide (180 mg). The reaction was stirred at ambient temperature for 2 hours and subsequently purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z446.41 (M+H) + . Example 27F 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S,5 R)-5-hydroxytetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 27E (60 mg), Example 1Q (80 mg), N, N-dimethylpyridine-4-amine (20 mg), N-ethyl- N-isopropylprop-2-amine (0.080 mL) and N 1-((ethylimine)methylene)- N 3 , N 3 The mixture of -dimethylpropane-1,3-diamine hydrochloride (33 mg) was stirred at ambient temperature for 16 hours. The reaction mixture was purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane). The solubilized products containing the tertiary butyldimethylsilicon protected were combined and concentrated. The residue was dissolved in dichloromethane (4 mL) and placed in an ice bath. After 5 minutes, trifluoroacetic acid (0.8 mL) was added, followed by water (0.2 mL), and the reaction was stirred in an ice bath for 30 minutes, followed by stirring at ambient temperature for 1 hour. The reaction mixture was concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm, 5-75% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1025.68 (M+H) + . Example 28 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-(N- lynyl)cyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 28A (((1 r,4 r)-4-(N- 3-butyl ester To (((1 r,4 r)-4-aminecyclohexyl)methyl)aminoformate tertiary butyl ester (10 g) in N, To the mixture in N-dimethylformamide (88 mL), 1-bromo-2-(2-bromoethoxy)ethane (11.17 g) and triethylamine (13.43 mL) were added, and the mixture was heated to 75°C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was concentrated from diethyl ether / heptane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z299.3 (M+H) + . Example 28B ((1 r,4 r)-4-(N- lynyl)cyclohexyl)methylamine In four parts, Example 28A (9.04 g) is used in two To the mixture of alkyl (180 mL) HCl (4.0 M in 2 37.8 mL). The reaction mixture was stirred for 16 hours, followed by addition of methanol and additional HCl (4.0 M in 2 60 mL). After stirring for another 2 hours, the reaction mixture was concentrated and the resulting residue was concentrated three times with diethyl ether and then dried in vacuo to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z199.1 (M+H) + . Example 28C 4-(((1 r,4 r)-4-(N- lynyl)cyclohexyl)methyl)amine)-3-nitrobenzenesulfonamide Example 28B (5.4 g), N, The mixture of N-diisopropylethylamine (9.5 mL) and 4-fluoro-3-nitrobenzenesulfonamide (5.7 g) in tetrahydrofuran (300 mL) was stirred at ambient temperature for 16 hours. The reaction was diluted with methyl tributyl ether and concentrated. The residue was dissolved in a mixture of dichloromethane and methanol and washed with saturated aqueous ammonium chloride solution, brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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 / z399.17 (M+H) + . Example 28D 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-(N- lynyl)cyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.100 g), Example 28C (0.053 g), N, N-dimethylpyridine-4-amine (0.051 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.054 g) was stirred in dichloromethane (1.4 mL). After stirring for 3 days, the reaction was used N 1 , N 1 -dimethylethane-1,2-diamine (0.031 mL), loaded onto a silica gel (agela, 40 g) and dissolved in a gradient of 0.5% to 9% dichloromethane / methanol over 30 minutes. The soluble ionis containing the product was concentrated, dissolved in 1:1 dimethylolite / methanol (3 mL), and purified by Gilson HPLC (Luna 10 mmC18(2) 250 x 50 mm column using a gradient of 10% to 85% acetonitrile / water containing 0.1% trifluoroacetic acid over 30 minutes) to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 / z1092.94 (M+H) + . Example 29 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S)-4-methoxytetrahydrofuran-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamide Example 29A ( S)-2-((benzyloxy)methyl)ethylene oxide Add sodium hydride (2.160 g) to ( R) A solution of ethylene oxide-2-ylmethanol (1.792 mL) in tetrahydrofuran (27.0 mL) was stirred for 30 minutes. After the bubble was stopped, (bromomethyl)benzene (6.42 mL) and tetrabutylammonium iodide (0.997 g) were then added, and the mixture was stirred for 16 hours while warming to ambient temperature. The reaction was carefully quenched with water and partitioned into ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were concentrated and purified by flash chromatography (80 g silicone, 0-20% ethyl acetate / hexane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z206.4(M+H+CH 3 CN) + . Example 29B ( S)-1-(benzyloxy)penta-4-ynde-2-ol To a solution of Example 29A (3.336 g) in dimethylol (40.6 mL) was added in several parts of acetylene lithium ethylenediamine miscompound (2.99 g) at 15°C. After 1 hour, the reaction was quenched by brine solution and acidified with 5N aqueous HCl solution. The aqueous layer was extracted with ethyl acetate and the combined organic parts were washed with 5% aqueous sodium bicarbonate solution and brine solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (0-30% ethyl acetate / heptane) to give the title compound. MS (DCI+) m / z208.2 (M+NH 4 ) + . Example 29C ( S)-5-((benzyloxy)methyl)dihydrofuran-3(2H)-one 1-oxidized 3,5-dichloropyridine (1.724 g), methanesulfonic acid (0.409 mL), and triphenylphosphine (i) (0.194 g) were added to a solution of Example 29B (1 g) in 1,2-dichloroethane (10.5 mL) in this order at ambient temperature. The reaction was stirred at ambient temperature for 15 hours. After completion, the mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 29D (5 S)-5-((benzyloxy)methyl)tetrahydrofuran-3-ol To a solution of Example 29C (400 mg) in methanol (6.5 mL) was added sodium borohydride (183 mg) in small portions at 0°C. After the addition was completed, the mixture was allowed to warm to ambient temperature and stirred for 1 hour. The reaction was then carefully quenched with water and the mixture was concentrated. To the aqueous residue was added ethyl acetate (10 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated to give the title compound. MS (APCI+) m / z209.4 (M+H) + . Example 29E (2 S)-2-((benzyloxy)methyl)-4-methoxytetrahydrofuran To Example 29D (404 mg) in tetrahydrofuran (5.5 mL) was added sodium hydride (116 mg) and 18-crown-6 (256 mg) at 0°C. The mixture was stirred for 30 minutes, followed by slowly adding methyl iodide (182 μL). The mixture was stirred for 16 hours and then quenched with brine solution and extracted with ethyl acetate. The organic layers were combined, 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 / z223.3 (M+H) + . Example 29F ((2 S)-4-methoxytetrahydrofuran-2-yl)methanol To the high-pressure vial equipped with a stirring rod, Pd / 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 with diatomaceous earth / polyethylene sintered disk and washed with methanol. The filtrate was concentrated to give the title compound. MS (APCI+) m / z133.2 (M+H) + . Example 29G methanesulfonic acid ((2 S)-4-methoxytetrahydrofuran-2-yl)methyl ester A solution of Example 29F (167 mg) and triethylamine (0.53 mL) in dichloromethane (6.3 mL) was cooled to 0°C. Add messulfonyl chloride (127 μL) dropwise. The mixture was stirred at 0°C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was concentrated to give the title compound. MS (APCI+) m / z211.3 (M+H) + . Example 29H ((2 S)-4-methoxytetrahydrofuran-2-yl)methylamine Example 29G (266 mg) was dissolved in N, To N-dimethylformamide (6.3 mL), sodium azide (164 mg) was added in one go. The mixture was allowed to warm to 40°C and stirred for 18 hours. The mixture was cooled, then diluted with water, and extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and the filtrate 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. The filtrate was concentrated to give the title compound. MS (APCI+) m / z132.2 (M+H) + . Example 29I 4-(((((2) S)-4-methoxytetrahydrofuran-2-yl)methyl)amine)-3-nitrobenzenesulfonamide Example 29H (166 mg) in tetrahydrofuran (12.7 mL) at ambient temperature N, N-diisopropylethylamine (0.66 mL) treatment. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (279 mg). The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated and the residue was purified by flash chromatography (0-10% methanol / dichloromethane) to give the title compound. MS (APCI+) m / z332.1 (M+H) + . Example 29J 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) S)-4-methoxytetrahydrofuran-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide 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-dimethylamine propyl)-3-ethylcarbodiimide hydrochloride (19.92 mg) and 4-dimethylamine pyridine (12.69 mg). The mixture was stirred at ambient temperature for 16 hours. The residue after evaporation of the solvent was purified by reverse phase HPLC (250x50 mm C18 LUNA column; 20-75% acetonitrile / water + 0.1% trifluoroacetic acid) to give the title compound. The ratio of cis isomers to trans isomers is 2:1. 1 H NMR (600 MHz, pyridine- d 5 ) δppm 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 / z1025.7 (M+H) + . Example 30 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((1) r,3 r)-3-methoxycyclobutyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 30A 4-(((1) r,3 r)-3-methoxycyclobutyl)amine)-3-nitrobenzenesulfonamide (1) in tetrahydrofuran (10 mL) at ambient temperature r,3 r)-3-methoxycyclobutane-1-amine (100 mg) N, N-diisopropylethylamine (518 μL) treatment. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (218 mg). The reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated and the residue was purified by flash chromatography (0-10% methanol / dichloromethane) to give the title compound. MS (ESI+) m / z603.2 (2M+H) + . Example 30B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((1) r,3 r)-3-methoxycyclobutyl)amine)-3-nitrophenyl)sulfonyl)benzolamide The title compound was synthesized following the procedure of the last step of Example 29 and Example 30A was used instead of Example 29I. 1 H NMR (600 MHz, pyridine- d 5 ) δppm 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 / z995.8 (M+H) + . Example 31 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamid Example 31A 4-(1-methylpiperidin-4-yl)-3-nitrobenzenesulfonyl 4-chloro-3-nitrobenzenesulfonamide (26 g) and 1-methylpiperidin-4-amine (28 g) at 90°C in 2 The suspension in alkane (100 mL) was stirred 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) and warmly loaded on silica gel and dissolved with 20% methanol / dichloromethane to give the title compound. 1 H NMR (400 MHz, diacetium- d 6 ) δppm 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). Example 31B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzolamide Example 1Q (0.050 g), Example 31A (0.021), N, N-dimethylpyridine-4-amine (0.026 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.027 g) was stirred in dichloromethane (0.70 mL). After stirring for 3 days, the reaction was loaded onto a silica gel (Teledyne Isco RediSep ® RF GOLD ® , 24 g) and ionization over 30 minutes using a gradient of 0.5% to 10% dichloromethane / methanol. The soluble ionis containing the product was concentrated, dissolved in 1:1 dimethylolite / methanol (2 mL) and purified over 30 minutes via Gilson HPLC (Luna 10 mmC18(2) 250 x 50 mm column using 10% to 75% acetonitrile / water containing 0.1% trifluoroacetic acid) to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 / z108.81 (M+H) + . Example 32 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzamidine Example 32A 4-(hydroxymethyl)cyclohexanone 1,4-dioxaspiro[4.5]dec-8-ylmethanol (10 g) in 1,4-dioxide Add to the mixture of alkyl (60 mL) in 2 3 M hydrogen chloride in alkyl (60 mL). After stirring at ambient temperature for 6 hours, the mixture was basified with 2N aqueous sodium hydroxide solution to pH=8 and extracted with dichloromethane (three times). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silicone tube column chromatography (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32B 4-(hydroxymethyl)-1-methylcyclohexanol To a mixture of Example 32A (10 g) in tetrahydrofuran (200 mL) was added dropwise at 0°C. 3 M methylmagnesium bromide (78 mL). After stirring at ambient temperature for 2 hours, the mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (five 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 silicone tube column chromatography (200:1 to 3:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32C 4-methylbenzenesulfonic acid ((1 s,4 s)-4-hydroxy-4-methylcyclohexyl)methyl ester 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. Add ice cold water. The mixture was extracted with dichloromethane (three times), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silicone tube column chromatography (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32D 4-methylbenzenesulfonic acid ((1 r,4 r)-4-hydroxy-4-methylcyclohexyl)methyl ester 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. Add ice cold water. The mixture was extracted with dichloromethane (three times), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silicone tube column chromatography (50:1 to 10:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32E (1 r,4 r)-4-(azidomethyl)-1-methylcyclohexanol To Example 32D (8.75 g) at 25°C N, Sodium azide (4.77 g) was added to the mixture in N-dimethylformamide (13 mL). The reaction mixture was stirred at 80°C for 12 hours. After cooling the mixture to 25°C, the mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silicone tube column chromatography (20:1 to 1:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32F (1 r,4 r)-4-(aminomethyl)-1-methylcyclohexanol To a mixture of Example 32E (4.25 g) in methanol (85 mL), Reynished nickel (0.147 g). The reaction mixture was stirred at ambient temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 32G 4-(((((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrobenzenesulfonamide 4-fluoro-3-nitrobenzenesulfonamide (1 g) and Example 32F (0.781 g) in N, For stirring mixture in N-dimethylformamide (9 mL) N, N-diisopropylethylamine (1.586 mL) treatment. The mixture was stirred at 40°C for 2 hours and the crude mixture was subsequently diluted with water (75 mL). The viscous suspension was stirred for several minutes, filtered and washed with water and diethyl ether to give the title compound. MS (ESI+) m / z344 (M+H) + . Example 32H 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) r,4 r)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide)benzolamide Example 1Q (0.050 g), Example 32G (0.024 g), N, N-dimethylpyridine-4-amine (0.026 g) and N 1 -((ethylimine)methylene)- N 3 , N 3 A solution of -dimethylpropane-1,3-diamine hydrochloride (0.027 g) was stirred in dichloromethane (0.70 mL). After stirring for 3 days, the reaction was used N 1 , N 1 -Dimethylethane-1,2-diamine (0.015 mL) quenched. The reaction was loaded onto a silicone gel (agela, 40 g) and dissolved over 30 minutes using a gradient of 0.5% to 6% dichloromethane / methanol to give the title compound. 1 H NMR (400 MHz, pyridine- d 5 ) δppm 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 / z1037.99 (M+H) + . Example 33 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide Example 33A ( R)-(3,4-dihydrogen-2 H-piperan-2-yl)methanol Title compounds follow the literature procedure (International Edition of Applied Chemistry 2015, 54, 13538-13544) Preparation. Optical rotation (observation) [α] D 25 = -78.93 (in chloroform c1.06); (Literature) [α] D 25 = -74.32 (in chloroform c1.07). Example 33B ( R)-2-((benzyloxy)methyl)-3,4-dihydro-2 H-Peram 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 Example 33A (1.5 g) was then added as a solution in tetrahydrofuran (2 mL). The reaction was stirred in an ice bath for 15 minutes. Pure bromotoluene (2.5 mL) was added, the ice bath was removed, and the reaction was stirred for 4 hours. The reaction mixture was again placed in an ice bath and carefully quenched with 1:1 aqueous saturated ammonium chloride solution and water (20 mL). The biphasic mixture was extracted with 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The crude material was purified using flash chromatography (40 g silicon dioxide column, 0-5% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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). Example 33C (3 S,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-ol To a solution of Example 33B (2.00 g) in tetrahydrofuran (24.0 mL) was added dropwise at 0°C for 1 hour. 9-boron bicyclo[3.3.1]nonane (0.5 M in tetrahydrofuran, 50.0 mL). 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 solution (15 mL) was carefully added to the mixture at 0°C, followed by 30% aqueous hydrogen peroxide solution (16 mL). 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 3:1 ethyl acetate / heptane (2 x 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (40 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.08 (M+H) + . Example 33D (2 R,5 S)-2-((benzyloxy)methyl)-5-methoxytetrahydro-2 H-Peram 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, pure methyl iodide (0.600 mL) was added and stirring continued for 16 hours. The reaction mixture was poured over aqueous saturated ammonium chloride solution (20 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 25 mL). The organic layers were combined, dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by flash chromatography (40 g silicon dioxide column, 0-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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 / z237.40 (M+H) + . Example 33E ((2 R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methanol A solution of Example 33D (0.94 g) in ethyl acetate (8.00 mL) was added to containing Pd(OH) 2 Flask of / C (20% by weight Pd, 50% moisture, 50 mg). The flask was purged with nitrogen and connected to a hydrogen balloon. The reaction was stirred at ambient temperature for 9 hours. The mixture was filtered and the filtrate was concentrated to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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). Example 33F 4-(((2 R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)-3-nitrobenzenesulfonamide 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 at ambient temperature for 20 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.377 g) was added in one go. After 1 hour the reaction was quenched by the addition of 1 M aqueous hydrochloric acid (10 mL) and the mixture was extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate concentrated. The residue was purified by flash chromatography (24 g silicon dioxide column, 20-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z347.45 (M+H) + . Example 33G 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-(((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methoxy)-3-nitrophenyl)sulfonyl)benzolamide To a solution of Example 33F (29 mg) in dichloromethane (0.500 mL), Example 1Q (60 mg) was added sequentially. N-ethyl- N-isopropylprop-2-amine (0.05 mL), N, N-dimethylpyridine-4-amine (15 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (24 mg). The reaction was stirred at ambient temperature for 6 hours, then concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1040.69 (M+H) + . Example 34 N-((3-chloro-4-(((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide Example 34A 3-chloro-4-(((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)benzenesulfonamide Example 13G (41.6 mg), 3-chloro-4-fluorobenzenesulfonamide (50 mg) and N-ethyl- N-isopropylprop-2-amine (0.10 mL) in 1,4-dioxide The solution in alkane (1.00 mL) was heated to 85°C for 3 days. The reaction mixture was purified by flash chromatography (12 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. LC / MS (APCI+) m / z335.36 (M+H) + . Example 34B N-((3-chloro-4-(((((2) R,5 S)-5-methoxytetrahydro-2 H-piperan-2-yl)methyl)amine)phenyl)sulfonyl)-4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-yl)benzolamide Example 34A (7 mg) in dichloromethane (0.50 mL) N-ethyl- N-isopropylprop-2-amine (10 μL), Example 1Q (12 mg), N, N-dimethylpyridine-4-amine (3 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (5 mg) was treated and the mixture was stirred for 16 hours. The reaction mixture was purified by flash chromatography (4 g silicon dioxide column, 0-5% methanol / ethyl acetate) to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z1028.65 (M+H) + . Example 35 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(2-methoxyethoxy)tetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 35A (2 R,5 S)-2-((benzyloxy)methyl)-5-(2-methoxyethoxy)tetrahydro-2 H-Peram The title compound was prepared following the procedure of Example 13D and substituted methyl iodide with 1-bromo-2-methoxyethane. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z281.03 (M+H) + . Example 35B 4-methylbenzenesulfonic acid ((2 R,5 S)-5-(2-methoxyethoxy)tetrahydro-2 H-piperan-2-yl)methyl ester The title compound was prepared following the procedure of Example 12E and Example 35A was used instead of Example 12D. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z345.43 (M+H) + . Example 35C (2 R,5 S)-2-(azidomethyl)-5-(2-methoxyethoxy)tetrahydro-2 H-Peram The title compound was prepared following the procedure of Example 12F and Example 35B was used instead of Example 12E. LC / MS (APCI+) m / z216.41 (M+H) + . Example 35D 4-(((((2) R,5 S)-5-(2-methoxyethoxy)tetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide To a solution of Example 35C (75 mg) in tetrahydrofuran (1.50 mL) was added water (0.075 mL) and triphenylphosphine (110 mg) and the reaction was stirred at ambient temperature for 3 hours. Add to the reaction mixture N-ethyl- N-isopropylprop-2-amine (0.20 mL) and 4-fluoro-3-nitrobenzenesulfonamide (77 mg), stirring continued for another hour at ambient temperature. The reaction mixture was purified by flash chromatography (24 g silicon dioxide column, 10-100% ethyl acetate / heptane) to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z390.23 (M+H) + . Example 35E 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(2-methoxyethoxy)tetrahydro-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide To a solution of Example 35D (44 mg) in dichloromethane (1.00 mL), Example 1Q (70 mg) was added sequentially. N-ethyl- N-isopropylprop-2-amine (0.06 mL), N, N-dimethylpyridine-4-amine (18 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (29 mg). The reaction was stirred at ambient temperature for 62 hours, then concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1083.74 (M+H) + . Example 36 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 36A 4-(((((1) s,4 s)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrobenzenesulfonamide (1 s,4 s)-4-(aminomethyl)-1-methylcyclohexanol (1.1 g) N, For solution in N-dimethylformamide (22.00 mL) N-ethyl- N-isopropylprop-2-amine (2.68 mL) and 4-chloro-3-nitrobenzenesulfonamide (1.82 g) were treated and the reaction was heated to 80°C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (4:1 petroleum ether / ethyl acetate) to give the title compound. 1 H NMR (400 MHz, CDCl 3 ) δppm 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). Example 36B 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((1) s,4 s)-4-hydroxy-4-methylcyclohexyl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide) The title compound was prepared by following the procedure of Example 35E, replacing Example 35D with Example 36A and taking 22 hours of reaction time. 1 H NMR (500 MHz, diacetium- d 6 ) δppm 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 / z1038.37 (M+H) + . Example 37 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(N- lyl)tetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 37A (3 R,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-ol Example 12C (1.00 g) at ambient temperature in 1,4-Bit Benzo[ d][1,3] m-dioxolene-5-carboxylic acid (0.747 g) and 2-(diphenylphosphine)pyridine (1.445 g). After 5 minutes, add ( E) A solution of diethyl diazene-1,2-dicarboxylate (40% by weight in toluene, 2.500 mL) was continued for 16 hours. Concentrate the reaction mixture to remove most of the 1,4-dioxide alkyl. The resulting residue was diluted with 3:1 ethyl acetate / heptane (25 mL) and washed with 1 M aqueous hydrochloric acid (2 x 20 mL). The organic layer was dried over magnesium sulfate, filtered, the filtrate was concentrated, and then purified by flash chromatography (40 g silicon dioxide 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 the solution and the reaction was stirred at ambient temperature for 7 hours. The reaction mixture was poured over 1 M aqueous hydrochloric acid solution (10 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z223.01 (M+H) + . Example 37B (((3 R,6 R)-6-((benzyloxy)methyl)tetrahydro-2 H-piperan-3-yl)oxy)(trial butyl)dimethylsilane To a solution of Example 37A (0.275 g) in dichloromethane (4.00 mL) was added 1 H-imidazole (0.180 g) and tertiary butchlorodimethylsilane (0.200 g, 1.324 mmol). The reaction was stirred at ambient temperature for 48 hours. The reaction mixture was poured over water (20 mL) and extracted with 3:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z337.16 (M+H) + . Example 37C 4-methylbenzenesulfonic acid ((2 R,5 R)-5-((triple-level butadiene methylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methyl ester Example 37B (0.40 g) in tetrahydrofuran (5.00 mL) added to Pd(OH) 2 / C (20% Pd, 50% moisture, 0.04 g). 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 and the filtrate was concentrated and dissolved in tetrahydrofuran (7.00 mL). Add to solution N-ethyl- N-isopropylprop-2-amine (0.45 mL), N, N-dimethylpyridin-4-amine (0.225 g) and 4-methylbenzene-1-sulfonyl chloride (0.227 g) were stirred at ambient temperature. After 3 hours, the reaction mixture was concentrated and the residue was purified by flash chromatography (40 g silicon dioxide column, 0-40% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z401.03 (M+H) + . Example 37D (((3 R,6 R)-6-(azidomethyl)tetrahydro-2 H-piperan-3-yl)oxy)(trial butyl)dimethylsilane To Example 37C (0.37 g) N, Sodium azide (0.200 g) was added to the solution in N-dimethylformamide (2.00 mL). The reaction was heated at 80°C for 21 hours. The reaction was allowed to cool to ambient temperature and poured over water (20 mL) and extracted with 5:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were washed with water (3 x 10 mL), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (12 g silicon dioxide column, 0-40% ethyl acetate / heptane) to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z244.01 (M-N 2 +H) + . Example 37E (((2 R,5 R)-5-((tributyldimethylsilicon)oxy)tetrahydro-2 H-piperan-2-yl)methyl)aminoformate tertiary butyl ester A solution of Example 37D (0.125 g) in tetrahydrofuran (3.07 mL) was added to a Raney-Ni 2800 water slurry (79.3 mg) in a 20 mL glass lined reactor. Purge the reactor with nitrogen. The mixture was stirred under hydrogen (50 psi) at 25°C. After 20 hours, the reactor was aerated and the reaction mixture was filtered and concentrated. The residue was dissolved in tetrahydrofuran (2.00 mL), followed by water (0.5 mL), di-tertiary butyl dicarbonate (0.089 g) and sodium bicarbonate (0.07 g). The reaction was stirred at ambient temperature for 20 hours, then poured on water (10 mL) and extracted with 4:1 ethyl acetate / heptane (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (24 g silicon dioxide column, 0-100% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (600 MHz, CDCl 3 ) δppm 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 / z246.02 (M-CO 2 -Triple Butyl+H) + . Example 37F (3 R,6 R)-4-methylbenzenesulfonic acid 6-(((tertiary butoxycarbonyl)amine)methyl)tetrahydro-2 H-piperan-3-yl ester To a solution of Example 37E (0.133 g) in tetrahydrofuran (1.00 mL) was added tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.8 mL) and the reaction was stirred at ambient temperature for 18 hours. The reaction mixture was poured over water (10 mL) and extracted with 4:1 ethyl acetate / heptane (2 x 10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (1.00 mL) and then added in sequence N, N-dimethylpyridine-4-amine (0.050 g), N-ethyl- N-isopropylprop-2-amine (0.150 mL) and 4-methylbenzene-1-sulfonyl chloride (0.073 g). The reaction was stirred at ambient temperature for 2 hours, and the reaction mixture was subsequently purified by flash chromatography (12 g silicon dioxide column, 0-100% ethyl acetate / heptane). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, CDCl 3 ) δppm 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 / z286.04 (M-CO 2 -Triple Butyl+H) + . Example 37G 4-(((((2) R,5 S)-5-(N- lyl)tetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrobenzenesulfonamide To Example 37F (80 mg) in 1,4-Bi Add to the solution of alkyl (1.00 mL) line (0.100 mL) and potassium carbonate (60 mg). The reaction was heated to 100°C and stirred for 5 days. The reaction was cooled to ambient temperature and poured over water (10 mL) and extracted with 3:1 chloroform / 2-propanol. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The residue was treated with hydrochloric acid (3 M in cyclopentylmethyl ether, 3 mL) and the reaction was stirred at ambient temperature for 60 hours. The reaction was concentrated to dryness, then dissolved in dichloromethane (1.00 mL) and added N-ethyl- N-isopropylprop-2-amine (0.400 mL) followed by addition of 4-fluoro-3-nitrobenzenesulfonamide (500 mg). The reaction was stirred at ambient temperature for 2 hours and then concentrated. The residue was dissolved in dimethylsubic acid (3 mL) and subsequently purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+0.1% trifluoroacetic acid)). The soluble idiots containing the desired product were combined and concentrated to give the title compound. 1 H NMR (500 MHz, pyridine- d 5 ) δppm 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 / z401.46 (M+H) + . Example 37H 4-((4a S,10a R)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7 H,12 H-benzo[ f]Pyr and [2,1- c][1,8] Dioxa[4] Azacycloundelyne-3(4 H)-based)-2-(3,4-dihydrogen-2 H-pyrrolo[3',2':5,6]pyridino[2,3- b][1,4] Nitrogen-1(7 H)-Basic)- N-((4-((((((2) R,5 S)-5-(N- lyl)tetrahydrogen-2 H-piperan-2-yl)methyl)amine)-3-nitrophenyl)sulfonyl)benzolamide Example 37G (18 mg) in dichloromethane (1.00 mL) N-ethyl- N-isopropylprop-2-amine (0.026 mL), Example 1Q (31 mg), N, N-dimethylpyridine-4-amine (8 mg) and N 1 -((ethylimine)methylene)- N 3 , N 3 -Dimethylpropane-1,3-diamine hydrochloride (12 mg) was treated and stirred at ambient temperature for 18 hours. The reaction mixture was concentrated and purified using reverse phase HPLC (Luna 10 mmC18(2) 250 x 50 mm column, 10-100% acetonitrile / water (+ 0.1% trifluoroacetic acid)) to give the title compound. 1 H NMR (600 MHz, diacetium- d 6 ) δppm 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 / z1095.14 (M+H) + . Example 38 N-((3-chloro-4-(((1r,4r)-4-(N- lynyl)cyclohexyl)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]pyramid [2,1-c][1,8]dioxa[4]azetanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyridino[2,3-b][1,4] Nitrox-1(7H)-yl)benzolamide Example 38A ((1r,4r)-4-(N- lynyl)cyclohexyl)methanol Towards((1 r,4 r)-4-(hydroxymethyl)cyclohexyl)aminoformate tertiary butyl ester (17.5 g) in 1,4-dioxide Add hydrochloric acid (4M in 1,4-dioxide to the solution of alkyl (100 mL) 95 mL in alkyl) and the reaction was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and the crude material was dissolved in acetonitrile (200 mL). Add to the solution in sequence N-ethyl- N-isopropylprop-2-amine (66.6 mL) and 1-bromo-2-(2-bromoet...

Claims

1. A 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyro[2,1-c][1,8]dioxa[4]azacycloundecanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azido-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-piperan-2-yl)methyl)amino)-3-nitrophenyl)sulfonylurea)benzamide or a pharmaceutically acceptable salt thereof.

2. A 4-((4aS,10aR)-14-(4-chlorophenyl)-12,12-dimethyl-1,2,4a,5,8,9,10a,11,13,15-decahydro-7H,12H-benzo[f]pyro[2,1-c][1,8]dioxa[4]azacycloundecanyne-3(4H)-yl)-2-(3,4-dihydro-2H-pyrrolo[3',2':5,6]pyrido[2,3-b][1,4]azido-1(7H)-yl)-N-((4-((((2S,5R)-5-methoxytetrahydro-2H-piperan-2-yl)methyl)amino)-3-nitrophenyl)sulfonylurea)benzamide.