WO2018178226A1

WO2018178226A1 - Mcl-1 inhibitors and methods of use thereof

Info

Publication number: WO2018178226A1
Application number: PCT/EP2018/058054
Authority: WO
Inventors: Martin John Packer; David Robert PERKINS; Steven Swallow; Alexander Hird; Qing Ye; Bo Peng; Xiaolan Zheng; Jeffrey Johannes; Scott MLYNARSKI; Michelle Lamb; Hoan Huynh; Daniel William ROBBINS
Original assignee: Astrazeneca Ab
Priority date: 2017-03-31
Filing date: 2018-03-29
Publication date: 2018-10-04
Also published as: TW201904976A

Abstract

Disclosed are Mcl-1 inhibitors, pharmaceutical compositions comprising the same and methods of using the same.

Description

MCL-1 INHIBITORS AND METHODS OF USE THEREOF

Background

Myeloid Cell Leukemia 1 (Mcl-1 ) is an important anti-apoptotic member of the BCL-2 family of proteins and a master regulator of cell survival. Amplification of the MCL1 gene and/or overexpression of the Mcl-1 protein has been observed in multiple cancer types and is commonly implicated in tumor development. In fact, MCL1 is one of the most frequently amplified genes in human cancer. In many malignancies, Mcl-1 is a critical survival factor and it has been shown to mediate drug resistance to a variety of anti-cancer agents.

Mcl-1 promotes cell survival by binding to pro-apoptotic proteins like Bim, Noxa, Bak, and Bax and neutralizing their death-inducing activities. Inhibition of Mcl-1 thereby releases these pro-apoptotic proteins, often leading to the induction of apoptosis in tumor cells dependent on Mcl-1 for survival. Therapeutically targeting Mcl-1 alone or in combination with other therapies, therefore, is a promising strategy to treat a multitude of malignancies and to overcome drug resistance in many human cancers.

Summary

In some embodiments, disclosed is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

W is NH or CH;

^"" is a single bond when W is NH or a double bond when W is CH;

Z is S or CH₂;

Y is selected from S, NH, NCH₃ and NCH₂CH₃; and X isCHaor

In some embodiments, disclosed is a compound of Formula (la) or (lb), or a pharmaceuticall acceptable salt thereof:

wherein

Wis NH orCH;

^"" is a single bond when W is NH or a double bond when W is CH;

ZisSorCH₂;

Y is selected from S NH, NCH₃ and NCH₂CH₃; and

X isCHaor

In some embodiments, disclosed is a compound of Formula (II), or a pharmaceutically acceptable salt thereof:

(II) wherein

D is NH or CH;

^"""" is a single bond when D is NH or a double bond when D is CH;

B is S or CH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

In some embodiments, disclosed is a compound of Formula (lla) or (lib), or a pharmaceuticall acceptable salt thereof:

(lib) wherein

D is NH or CH;

^"""" is a single bond when D is NH or a double bond when D is CH;

B is S or CH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

In some embodiments, disclosed is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein J is NH or CH;

^"""" is a single bond when J is NH or a double bond when J is CH;

G is S or CH₂; and

E is selected from S, NH and NCH₃.

In some embodiments, disclosed is a compound of Formula (Ilia) or (lllb), or a pharmaceutically acce table salt thereof:

wherein

J is NH or CH;

^"" is a single bond when J is NH or a double bond when J is CH;

G is S or CH₂; and

E is selected from S, NH and NCH₃.

In one embodiment, disclosed is 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is (S_a)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is (f?_a)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient, carrier or diluent.

In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is the use of a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising 17-chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof and a pharmaceutical excipient, carrier or diluent.

In one embodiment, disclosed is a pharmaceutical composition comprising (S_a)-17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]ph

2,9-dithia-5,6,12,13,22^entaazaheptacyclo[27.7.1 J

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof and a pharmaceutical excipient, carrier or diluent. In one embodiment, disclosed is a pharmaceutical composition comprising (f?_a)-1 - chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa- 2,9-dithia-5,6,12,13,22^entaazaheptacyclo[27 .1 J ⁴'^{7 11}'¹^0¹⁶'² 0²⁰'²^ 0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of (S_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of (f?_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a compound of 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a compound of (S_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer. In one embodiment, disclosed is a compound of (f?_a)-1 -chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is the use of 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

In one embodiment, disclosed is the use of (S_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

In one embodiment, disclosed is the use of (f?_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising (S_a)-17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa- 2,9-dithia-5,6,12,13,22^entaazaheptacyclo[27.7.1 J

pharmaceutically acceptable salt thereof, for use in treating cancer. In one embodiment, disclosed is a pharmaceutical composition comprising (f?_a)-1 -chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

Detailed Description

Compounds

In some embodiments, disclosed is a compound of Formula (I), or a pharmaceutically

wherein

W is NH or CH;

^"" is a single bond when W is NH or a double bond when W is CH;

Z is S or CH₂;

Y is selected from S NH, NCH₃ and NCH₂CH₃ ; and

In some embodiments, disclosed is a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt thereof:

wherein

W is NH or CH;

^"""" is a single bond when W is NH or a double bond when W

Z is S or CH₂;

Y is selected from S NH and NCH₃; and

In some embodiments, W is NH.

In some embodiments, W is CH.

In some embodiments, ^""" is a single bond when W is NH.

In some embodiments, is a double bond when W is CH.

In some embodiments, Y is S.

In some embodiments, Y is NH.

In some embodiments, Y is NCH₃.

In some embodiments, Y is NCH₂CH₃.

In some embodiments, X is CH .

In some embodiments, X is

In some embodiments, X is CH₃, W is NH, Z is S, Y is S, NCH₃ or NCH₂CH₃ and is a single bond.

In some embodiments, X is CH₃, W is NH, Z is S, Y is S and is a single bond. In some embodiments, X is CH₃, W is NH, Z is S, Y is NCH₃ and ^"""" is a single bond. In some embodiments, X is CH₃, W is NH, Z is S, Y is NCH₂CH₃ and ^"""" is a single bond.

In some embodiments, X

W is NH, Z is S, Y is NH or , and ^"" is a single bond

In some embodiments, X is

, W is CH, Z is S or CH_2jY is

S and ^"""" is a double bond.

In some embodiments, W is NH, Z is S, Y is S, X is CH₃ and ^""" is a single bond.

In some embodiments, W is CH, Z is CH₂, Y is NH, X is CH₃ and ^"" is a double bond.

In some embodiments, W is NH, Z is S, Y is NCH₃, X is CH and ^*"* is a single bond.

In some embodiments, W is NH, Z is S, Y is NH, X is

and ^" is a single bond.

In some embodiments, W is CH, Z is CH₂, Y is NH, X is

and ^"" is a double bond.

In some embodiments, W is CH, Z is S, Y is S, X is

and is a double bond.

In some embodiments, W is CH, Z is CH₂, Y is S, X is

and ^"" is a double bond. In some embodiments, W is NH, Z is S, Y is NCH₃, X is

and ^"" is a single bond.

In some embodiments, W is CH, Z is CH₂, Y is S, X is CH₃ and and ^"" is a double bond.

wherein

D is NH or CH;

^"" is a single bond when D is NH or a double bond when D is CH;

B is S or CH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

In some embodiments, disclosed is a compound of Formula (lla) or (lib), or a pharmaceutically acceptable salt thereof:

wherein

D is NH or CH;

^"" is a single bond when D is NH or a double bond when D is CH;

B is S or CH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

In some embodiments, D is NH.

In some embodiments, D is CH.

In some embodiments, B is S.

In some embodiments, B is CH₂.

In some embodiments, A is S.

In some embodiments, A is NH.

In some embodiments, A is NCH₃

n some embodiments, ^""" is a single bond when D is NH.

n some embodiments, ^""" is a double bond when D is CH.

n some embodiments, D is NH, Z is S, A is S, NCH₃ or NCH₂CH₃ and ^"" is a single bond.

n some embodiments, D is NH, Z is S, A is S and — ^' is a single bond.

n some embodiments, D is NH, Z is S, A is NCH₃ and ^"" is a single bond.

n some embodiments, D is NH, Z is S, A is NCH₂CH₃ and ^"" is a single bond n some embodiments, D is NH, B is S, A is S and ^" is a single bond.

n some embodiments, D is NH, B is S A is NCH₃ and ^"" is a single bond.

n some embodiments, D is CH, B is CH₂, A is NH and ^"""" is a double bond.

n some embodiments, D is CH, B is CH₂, A is S and ^" ^""" is a double bond. In some embodiments, disclosed is a compound of Formula (III), or a pharmaceutically acceptable salt thereof:

(III)

wherein

J is NH or CH;

^"" is a single bond when J is NH or a double bond when J is CH;

G is S or CH₂; and

E is selected from S, NH and NCH₃.

In some embodiments, disclosed is a compound of Formula (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof:

(Ilia) \

N

N-N

/

(1Mb)

wherein

J is NH or CH;

^"" is a single bond when J is NH or a double bond when J is CH;

G is S or CH₂; and

E is selected from S, NH and NCH₃.

In some embodiments, J is NH.

In some embodiments, J is CH.

In some embodiments, G is S.

In some embodiments, G is CH₂.

In some embodiments, E is S.

In some embodiments, E is NH.

In some embodiments, E is NCH₃.

In some embodiments, ^""" is a single bond when J is NH.

In some embodiments, ^""" is a double bond when J is CH.

In some embodiments, J is NH, G is S, E is NH or NCH₃ and ^"" is a single bond.

In some embodiments, J is CH, G is S or CH₂, E is NH, S or NCH₃ and ^"" is a double bond.

n some embodiments J is NH, G is S, E is NH and ^"" is a single bond.

n some embodiments J is CH, G is CH₂. E is NF and ^"" is a double bond.

n some embodiments J is CH, G is S, E is NH and ^"" is a double bond.

n some embodiments J is CH, G is CH₂, E is S and ^"" is a double bond.

n some embodiments J is NH, G is S, E is NCH₃ and ^""" is a single bond. In one embodiment, disclosed is 17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20 23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin- 1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is (f?_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin- 1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

In some embodiments, disclosed are the compounds of Table 1 , and pharmaceutically acceptable salts thereof:

Table 1

(fla)-17-Chloro-5, 12,14,22-tetramethyl-28- oxa-9-thia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1.1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0

20,24 ₀30,35_{]octatriaconta}.

1(37),4(38),6,11(15), 13,16, 18,20,23,29,35- undecaene-23-carboxylic acid

17-Chloro-5, 12,14,22-tetramethyl-28-oxa-

( NH 2,9-dithia-5,6,12,13,22,31- hexaazaheptacyclo[27.7.1.1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0

20,24 ₀30,35_{]octatriaconta}.

1(37),4(38),6,11(15), 13,16, 18,20,23,29,35- undecaene-23-carboxylic acid

N-N

(S_a)-17-Chloro-5,12,14,22-tetramethyl-28- oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1.1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0

20,24 ₀30,35_{]octatriaconta}.

1(37),4(38),6,11(15), 13,16, 18,20,23,29,35- undecaene-23-carboxylic acid

(fl_a)-17-Chloro-5,9,12,14,22-pentamethyl-

28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0

20,24. o³°.³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,

16,18,20,23,29,31 , 33,35-tridecaene-23- carboxylic acid

17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,12,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

1 (37),4(38),6,1 1 (15), 13,16, 18,20,23,29,31 , 33,35-tridecaene-23-carboxylic acid

(S_a)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,12,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

(fla)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,12,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,13,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33, 35-tridecaene-23-carboxylic acid

(S_a)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,13,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33, 35-tridecaene-23-carboxylic acid

(fla)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,13,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33, 35-tridecaene-23-carboxylic acid

17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,12,22-trimethyl-28- oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

(S_a)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l - yl]phenoxy}methyl)-5,12,22-trimethyl-28- oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶·²¹.

Q20.24 ₀30,35_{] octatri aco nta}.

(fla) - 17-chloro-5, 12,14,22-tetramethyl-28- oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶·²¹.

₀2o,24 ₀3o,35] octatriaconta-

O H

\

N-N

/

The language "pharmaceutically acceptable salt" includes acid addition or base salts that retain the biological effectiveness and properties of any of the compounds disclosed herein which typically are not biologically or otherwise undesirable. In many cases, the compounds disclosed herein are capable of forming acid and/or base salts by virtue of the presence of basic and/or carboxyl groups or groups similar thereto. In one embodiment, the pharmaceutically acceptable salt includes quaternary ammonium salts.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide,

bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,

chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate/hydrogen

phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, sulfate/hydrogensulfate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid,

sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonia and salts of ammonium and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na⁺, Ca²⁺, Mg²⁺, or K⁺ hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a

stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); Berge et al., "J. Pharm. Sci., 1977, 66, 1 -19 and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms for the compounds disclosed herein. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom of the same element but with differing mass number. Examples of isotopes that can be incorporated into any of the comounds disclosed herein and their salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ³⁵S and ¹²⁵l. The compounds disclosed herein may include various isotopically labeled compounds into which radioactive isotopes, such as, ³H, ¹¹C, ¹⁴C, ³⁵S and ³⁶CI are present. Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.

The compounds disclosed herein may have different isomeric forms. The language "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations which may exist for any of the compounds disclosed herein. In particular, the compounds disclosed herein possess axial chirality, by virtue of restricted rotation around a biaryl bond and as such may exist as mixtures of enantiomers/atropisomers with enantiomeric excess between about 0% and >98% e.e. When a compound is a pure enantiomer, the stereochemistry at each chiral center may be specified by either R_a or S_a. Such designations may also be used for mixtures that are enriched in one enantiomer. Further description of atropisomerism and axial chirality and rules for assignment of configuration can be found in Eliel, E.L. & Wilen, S. H. 'Stereochemistry of Organic Compounds' John Wiley and Sons, Inc. 1994. Resolved

compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. The present disclosure is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active {Ra)- and (S_a)-isomers may be prepared using chiral synthons, chiral reagents or chiral catalysts, or resolved using conventional techniques well known in the art, such as chiral HPLC.

Also disclosed herein the Intermediates 1 -149 in the Examples, and salts thereof.

Pharmaceutical Compositions

In some embodiments, disclosed are pharmaceutical compositions comprising a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (1Mb), and a pharmaceutically acceptable excipient, carrier or diluent.

2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.^

In one embodiment, disclosed is a pharmaceutical composition comprising (fl_a)-17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]ph

2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1 ^ 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

The language "pharmaceutically acceptable excipient, carrier or diluent" includes compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as ascertained by one of skill in the art.

The disclosed compositions may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, as a finely divided powder or a liquid aerosol), for administration by insufflation (for example, as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The disclosed compositions may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their

disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p-hydroxybenzoate; anti-oxidants such as ascorbic acid; coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1 ,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The compounds disclosed herein may be administered once, twice, three times a day or as many times in a 24 hour period as medically necessary. In some embodiments, the compounds disclosed herein may be administered daily, once a week, twice a week, 3 times a week, 4 times a week, 5 times a week or 6 times a week. One of skill in the art would readily be able to determine the amount of each individual dose based on the subject. In some embodiments, the compounds disclosed herein are administered in one dosage form. In some embodiments, the disclosed compounds are administered in multiple dosage forms.

Method of Use

In one aspect, disclosed are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I), (la), (lb), (II), (I la), (lib), (III), (Ilia) or (1Mb), or a pharmaceutically acceptable salt thereof. In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof.

In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof an effective amount of (S_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof.

In one aspect, disclosed is a compound of Formula (I), (la), (lb), (II), (I la), (lib), (III), (Ilia) or (1Mb), or a pharmaceutically acceptable salt thereof, for use in treating cancer.

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a compound of (f?_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one aspect, disclosed is the use of a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cancer.

In one embodiment, disclosed is the use of 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴- .0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

In one embodiment, disclosed is the use of (S_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴- .0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

In one embodiment, disclosed is the use of (f?_a)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴· .0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

In one aspect, disclosed are pharmaceutical compositions comprising a compound of Formula (I), (la), (lb), (II), (lla), (lib), (III), (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising 17-chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴- .0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising (S_a)-17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa- 2,9-dithia-5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴⁷.0¹¹ '¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

In one embodiment, disclosed is a pharmaceutical composition comprising (f?_a)-1 -chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid, or a

pharmaceutically acceptable salt thereof, for use in treating cancer.

The term "cancer" includes, but is not limited to, hematological malignancies such as acute myeloid leukemia, multiple myeloma, mantle cell lymphoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt's lymphoma, follicular lymphoma and solid tumors, for example, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer, neuroblastoma, prostate cancer, melanoma, pancreatic cancer, uterine, endometrial and colon cancer.

In one aspect, disclosed are methods for treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed is a compound ofdisclosed herein, or a pharmaceutically acceptable salt thereof in combination with anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in treating a cancer.

In one aspect, disclosed is the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

In one aspect, disclosed are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an anticancer agent, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

The language "in combination with" includes any compound disclosed herein, or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, or pharmaceutically acceptable salt thereof, sequentially, separately or simultaneously. In some aspects, any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, or pharmaceutically acceptable salt thereof, are administered in the same formulation, for example, in a fixed dose formulation. In some embodiments, any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, or

pharmaceutically acceptable salt thereof, are administered in separate formulations, and are administered at substantially the same time, sequentially or separately.

The language "anti-cancer agent" includes, but is not limited to, radiation, alkylating agents, angiogenesis inhibitors, antibodies, antibody-drug conjugates, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, other cell death activators (for example, other inhibitors of Bcl-2, Bcl-xL, Bcl-w, Bf 1-1 or Mcl inhibitors), activators of death receptor pathways (for example, FAS or TRAIL agonists), Bcr-Abl kinase inhibitors, BET (bromodomain) inhibitors, BiTE (Bi-Specific T-cell Engager) antibodies, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variable domain antibodies), leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, EGFR inhibitors, heat shock protein (HSP) inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, inhibitors of the inhibitors of apoptosis proteins (lAPs), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin (mTOR) inhibitors, AKT inhibitors, microRNA's, mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors, BRAF inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP

(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase inhibitors, proteosome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids (siRNAs), anti-CD20 compounds, topoisomerase inhibitors, and ubiquitin ligase inhibitors.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, cisplatin, carboplatin, carboquone, carmustine (BCNU), chlorambucil, CLORETAZINE® (laromustine, VNP 40101 M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, nitrosoureas, oxaliplatin, ranimustine, temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamide and the like.

Angiogenesis inhibitors include endothelial-specific receptor , (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, ALK inhibitors and the like. Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA), 5- azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1 -3-D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination with leucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, pemextred, raltitrexed, Ribavirin, triapine, trimetrexate, S-1 , tiazofurin, tegafur, TS- 1 , vidarabine, LIFT and the like.

Bcl-2 protein inhibitors include ABT-199, AT-101 ((-)gossypol), GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194, IPI-565, ABT-737, ABT-263, GX-070 (obatoclax), AMG-176, S63645 and the like.

Anti-CD20 compounds include rituximab and obinutuzumab.

Btk inhibitors include ibrutinib and acalabrutinib.

Bromodomain inhibitors include l-BET 762, OTX-015, CPI-203, LY294002 and the like.

CDK inhibitors include BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC- 286199, MCS-5A, PD0332991 , PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709, AZD4573 and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB® (lapatinib),

TAGRISSO (AZD9291 , osimertinib), and the like.

ALK inhibitors include crizotinib, ceritinib, and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2lgG3, AS HER2 bifunctional bispecific antibodies, mAB AR-209, mAB 2B-1 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE, anti- CD22-MCC-DM1 , CR-01 1 -vcMMAE, PSMA-ADC {e.g., MEDI3726), MEDI-547, SGN-19Am SGN-35, SGN-75 and the like.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors such as GSK923295A and the like. MEK inhibitors include trametinib (GSK1 120212), binimetinib (MEK162), selumetinib (AZD6244), cobimetinib (XL518), ARRY-142886, ARRY-438162, PD-325901 , PD-98059, and the like.

BRAF inhibitors include sorafenib, vemurafenib, dabrafenib, GDC-0879, LGX818 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, picoplatin and the like.

VEGFR inhibitors include AVASTIN (bevacizumab), ABT-869, AEE-788, ANGIOZYME™ (a ribozyme that inhibits angiogenesis (Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)), axitinib (AG-13736), AZD-2171 , CP-547,632, IM-862, MACUGEN

(pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib (PTK- 787, ZK-222584), SUTENT® (sunitinib, SU-1 1248), VEGF trap, ZACTIMA™ (vandetanib, ZD- 6474), GA101 , ofatumumab, ABT-806 (mAb-806), ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specific antibodies {e.g., MEDI0629) and C-met specific antibodies, and the like.

WEE1 inhibitors include AZD1775 and the like.

Antitumor antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin,

stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Inhibitors of DNA repair mechanisms such as CHK kinase; DNA-dependent protein kinase inhibitors; inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors) including ABT- 888 (veliparib), olaparib, KU-59436, AZD-2281 , AG-014699, BSI-201 , BGP-15, INO-1001 , ONO-2231 and the like; and Hsp90 inhibitors such as tanespimycin and retaspimycin.

Proteasome inhibitors include VELCADE® (bortezomib), KYPROLIS (carfilzomib), NINLARO (ixazomib), MG132, NPI-0052, PR-171 and the like.

Examples of immunologicals include interferons and other immune-enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1 a, ACT IMMUNE® (interferon gamma-1 b) or interferon gamma-n1 , combinations thereof and the like. Other agents include ALFAFERONE®, (IFN-a), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), decarbazine, denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®

(filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1 ),

PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)),

PROLEUKIN® (aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-lbritumomab tiuxetan) and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR®

(gemcitabine), TOMUDEX® (ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940 (109881 ), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone) and the like.

Additionally, the dendrimers of (I), (II), (III) and (IV) may be combined with other chemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly l:poly C12U, a synthetic RNA), APTOSYN® (exisulind), AREDIA®

(pamidronic acid), arglabin, L-asparaginase, atamestane (1 -methyl-3,17-dione-androsta-1 ,4- diene), AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE® (histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxydoxorubicin) ; O: Vincristine (ONCOVIN®) ; P: prednisone), CYPAT™ (cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor) or TransMID-107R™

(diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposome lotion),

discodermolide, DX-8951 f (exatecan mesylate), enzastaurin, EPO906 (epithilone B),

GARDASIL® (quadrivalent human papillomavirus (Types 6, 1 1 , 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®, GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101 , IL-13- PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-a, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide), lonafarnib, 5,10- methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941 ), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin), ONCONASE® (a

ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine), ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb (murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine

(Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN® (DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®

(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq (2-amino-3,4- dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazoline dihydrochloride), TNFERADE™

(adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER® or ZAVESCA® (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti- alphavbeta3 antibody), XCYTRIN® (motexafin gadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex), YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA® (zolendronic acid), zorubicin and the like.

In one aspect, disclosed are methods for inhibiting Mcl-1 in a subject in need thereof, comprising administering to the subject an effective amount of any of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof.

In one aspect, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting Mcl-1

In one aspect, disclosed is the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting Mcl-1 .

In one aspect, disclosed are pharmaceutical compositions comprising a disclosed herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting Mcl-1 .

The term "Mcl-1 " refers to Myeloid Cell Leukemia 1 , an anti-apoptotic member of the BCL-2 family of proteins.

The language "effective amount" includes an amount of a compound disclosed herein that will elicit a biological or medical response in a subject, for example, the reduction or inhibition of enzyme or protein activity related to Mcl-1 or cancer; amelioration of symptoms of cancer; or the slowing or delaying of progression of cancer. In some embodiments, the language "effective amount" includes the amount of a compound disclosed herein, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate cancer or inhibit Mcl- 1 , and/or reduce or inhibit the growth of a tumor or proliferation of cancerous cells in a subject.

The term "subject" includes warm-blooded mammals, for example, primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from cancer. In some embodiments, the subject is in need of treatment {e.g., the subject would benefit biologically or medically from treatment).

The language "inhibit," "inhibition" or "inhibiting" includes a decrease in the baseline activity of a biological activity or process. In some embodiments, the disclosed herein inhibit Mcl-1 .

The language "treat," "treating" and "treatment" includes the reduction or inhibition of enzyme or protein activity related to Mcl-1 or cancer in a subject, amelioration of one or more symptoms of cancer in a subject, or the slowing or delaying of progression of cancer in a subject. The language "treat," "treating" and "treatment" also includes the reduction or inhibition of the growth of a tumor or proliferation of cancerous cells in a subject.

Examples

Aspects of the present disclosure can be further defined by reference to the following non- limiting examples, which describe in detail preparation of certain compounds and intermediates of the present disclosure and methods for using compounds of the present disclosure. It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the present disclosure.

Unless stated otherwise:

(i) all syntheses were carried out at ambient temperature, i.e. in the range 17 to 25 ^QC and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;

(ii) evaporations were carried out by rotary evaporation or utilizing Genevac equipment or Biotage v10 evaporator under reduced pressure;

(iii) silica gel chromatography purifications were performed on an automated Teledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash® Companion® using prepacked RediSep Rf Gold™ Silica Columns (20-40 μιη, spherical particles), GraceResolv™ Cartridges (Davisil® silica) or Silicycle cartridges (40 - 63 μιη). (iv) chiral preparative chromatography was performed on a Waters Prep 100 SFC-MS instrument with MS- and UV- triggered collection or a Thar MultiGram III SFC instrument with UV collection.

(v) chiral analytical chromatography was performed on either a Waters X5 SFC-MS with UV detection or a Waters UPC2 SFC-MS with UV and ELSD detection.

(vi) yields, where present, are not necessarily the maximum attainable;

(vii) in general, the structures of end-products were confirmed by NMR spectroscopy; NMR chemical shift values were measured on the delta scale, using the solvent residual peak as the internal standard [proton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz), Bruker Avance 400 (400 MHz), Bruker Avance 300 (300 MHz) or Bruker DRX (300 MHz) instrument]; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal; AB d, AB doublet; AB q, AB quartet.

(viii) in general, end-products were also characterized by mass spectroscopy following liquid chromatography (UPLC); using a Waters UPLC fitted with a Waters SQ mass

spectrometer (Column temp 40 °C, UV = 220-300 nm or 190-400 nm, Mass Spec = ESI with positive/negative switching) at a flow rate of 1 mL/min using a solvent system of 97% A + 3% B to 3% A + 97% B over 1 .50 min (total run time with equilibration back to starting conditions, etc., 1 .70 min), where A = 0.1 % formic acid or 0.05% trifluoroacetic acid in water (for acidic work) or 0.1 % ammonium hydroxide in water (for basic work) and B = acetonitrile. For acidic analysis the column used was a Waters Acquity HSS T3 (1 .8 μιη, 2.1 x 50 mm), for basic analysis the column used was a Waters Acquity BEH C18 (1 .7 μιη, 2.1 x 50 mm). Alternatively, UPLC was carried out using a Waters UPLC fitted with a Waters SQ mass spectrometer (Column temp 30 °C, UV = 210-400 nm, Mass Spec = ESI with positive/negative switching) at a flow rate of

1 mL/min using a solvent gradient of 2 to 98% B over 1 .5 min (total run time with equilibration back to starting conditions 2 min), where A = 0.1 % formic acid in water and B = 0.1 % formic acid in acetonitrile (for acidic work) or A = 0.1 % ammonium hydroxide in water and B = acetonitrile (for basic work). For acidic analysis the column used was a Waters Acquity HSS T3 (1 .8 μιη, 2.1 x 30 mm), for basic analysis the column used was a Waters Acquity BEH C18 (1 .7 μιη, 2.1 x 30 mm) ; The reported molecular ion corresponds to the [M+H]+ unless otherwise specified; for molecules with multiple isotopic patterns (Br, CI, etc.) the reported value is the one obtained with highest intensity unless otherwise specified. (x) intermediate purity was assessed by thin layer chromatographic, mass spectroscopy, LCMS, UPLC/MS, HPLC and/or NMR analysis;

(xi) the following abbreviations have been used:

ACN acetonitrile

aq. aqueous

cone. concentrated

DCM dichloromethane

DEA diethylamine

DIPEA diisopropylethylamine

di-t-BPF 1 ,1 '-bis(di-te/t-butylphosphino)ferrocene

DMAP 4-dimethylaminopyridine

DMF Ν,Ν-dimethylform amide

DSC Differential Scanning Calorimetry

DTBAD di-te/t-butyl diazene-1 ,2-dicarboxylate

e.e. enantiomeric excess

equiv. equivalents

ES electrospray mode

EtOAc ethyl acetate

EtOH ethanol

HPLC high performance liquid chromatography

Inj. Injection

KOAc potassium acetate

IPA Isopropyl alcohol

LAH lithium aluminium hydride

LCMS liquid chromatography mass spectrometry

MeOH methanol

MS mass spectrometry

MPLC medium pressure liquid chromatography

MTBE methyl te/t-butyl ether

NaHMDS sodium hexamethyldisilazane

NaOH sodium hydroxide

NBS N-bromo succinimide

NMR nuclear magnetic resonance PE petroleum ether

PMB 4-methoxybenzyl

PPTS pyridinium p-toluenesulfonate

RBF round-bottom flask

RT room / ambient temperature

sat. saturated

SFC supercritical fluid chromatography

TBAF tetrabutylammonium fluoride

TBDPS te/t-butyldiphenylsilyl

TBDPSCI tert-butylchlorodiphenylsilane

TEA triethylamine

TFA trifluoroacetic acid

TGA Thermogravimetric analysis

THF tetrahydrofuran

THP tetrahydropyranyl

Tol. toluene

UPLC ultra-high performance liquid chromatography

wt% weight percent

XRPD Powder X-ray Diffraction

Intermediate 1 : Methyl 7-bromo-6-chloro-3-(3-methoxy-3-oxopropyl)-1 H-indole-2-carboxylate

2-Bromo-3-chloroaniline (600 g, 2.91 mol) and concentrated aqueous HCI (1500 mL, 49.4 mol) in water (1500 mL) were placed into a 4-necked RBF. The mixture was stirred overnight to give a solution. A solution of NaN0₂ (212 g, 3.07 mol) in water (720 mL) was added dropwise with stirring at 0-5 °C. After 1 .5 h, a solution of KOAc (4020 g, 40.9 mol) in water (6000 mL) and methyl 2-oxocyclopentane-1 -carboxylate (420 g, 2.95 mol) was added dropwise with stirring at 0-5 °C. The resulting solution was stirred at 0-5 °C for 0.5 h then for 2 h at RT. The solution was then extracted with 2 x10 L of DCM. The combined organic phases were washed with 1 x 5 L of brine. The solution was dried over anhydrous ^SC and concentrated to yield methyl 1 -((2-bromo-3-chlorophenyl)diazenyl)-2-oxocyclopentane-1 -carboxylate (1070 g, 100%, 97 wt%).

A solution of cone, sulfuric acid (1000 mL, 18.8 mol) in methanol (10000 mL) and methyl 1 -((2-bromo-3-chlorophenyl)diazenyl)-2-oxocyclopentane-1 -carboxylate (1400 g, 3.89 mol) were placed into a 4-necked RBF. The resulting solution was stirred at 70 °C in an oil bath for 2 h. The reaction mixture was cooled to 20 °C with a water/ice bath. The solids were collected by filtration. The solid was washed with 2 x 1 L of MeOH and then dried in an oven under reduced pressure to yield (E/Z)-dimethyl 2-(2-(2-bromo-3-chlorophenyl)hydrazono)hexanedioate (1200 g, 79%).

A solution of cone, sulfuric acid (2 L, 37.5 mol) in methanol (10 L) and (E/Z)-dimethyl 2- (2-(2-bromo-3-chlorophenyl)hydrazono)hexanedioate (1200 g, 2.96 mol, 1 .00 equiv.) were placed into a 4-necked RBF. The resulting solution was stirred for 72 h at 80 °C in an oil bath. The reaction mixture was cooled to 20 °C with a water/ice bath. The solids were collected by filtration, washed with 1 L of MeOH and then air-dried. The solid was then suspended in 2250 mL of MeOH, with stirring at 50 °C over 30 min. After cooling to 20 °C, the solid was collected by filtration and was washed with 500 mL of MeOH and then air-dried to yield methyl 7-bromo-6- chloro-3-(3-methoxy-3-oxopropyl)-1 H-indole-2-carboxylate (Intermediate 1 , 930 g, 84%) ; m/z (ES+), [M+H]⁺ = 374. ¹ H NMR (400 MHz, CHLOROFORM- of) δ 3.68 (t, 2H), 3.37 (t, 2H), 3.63 (s, 3H), 3.98 (s, 3H), 7.23 (d, 1 H), 7.61 (d, 1 H), 8.80 (s, 1 H).

Intermediate 2: (4-Bromo-1 ,3-dimethyl-1 H-pyrazol-5-yl)methanol

Bromine (20.4 mL, 396 mmol) was added dropwise over 10 min to a solution of (1 ,3- dimethyl-1 H-pyrazol-5-yl)methanol (50.0 g, 396 mmol) in DCM (800 mL) cooled to -10 °. The resulting mixture was stirred at 25 °C for 30 min. The reaction mixture was quenched with saturated Na₂S₂0₃ solution (30 mL). The layers were separated and the aq. phase was extracted with DCM (4 x 100 mL). The combined organic phases were dried over Na2S04, filtered and evaporated to afford 4-bromo-1 ,3-dimethyl-1 H-pyrazol-5-yl)methanol (Intermediate 2, 55.0 g, 67.7%) as a white solid, which was used without further purification; m/z (ES+),

[M+H]⁺ = 205. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.09 (s, 3H), 3.77 (s, 3H), 4.43 (d, 2H), 5.29 (t, 1 H).

Intermediate 3: 4-Bromo-5-((4-methox benzyloxy)methyl)-1 ,3-dimethyl-1 H-pyrazole

DMF (300 mL) was added to 4-bromo-1 ,3-dimethyl-1 H-pyrazol-5-yl)methanol

(Intermediate 2, 24.9 g, 121 mmol) and the solution was cooled to 0 °C. NaH (7.29 g, 182 mmol) (60% in oil) was added. The mixture was stirred at 0 °C for 20 min, allowed to warm to RT and stirred for 20 min. 1 -(Chloromethyl)-4-methoxybenzene (19.0 g, 121 mmol) and Nal (3.64 g, 24.3 mmol) were added and the mixture was stirred for 30 min and concentrated to dryness. EtOAc (500 mL) was added. The organic phase was washed with water (100 mL), brine (100 mL) and dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give 4-bromo-5-((4- methoxybenzyloxy)methyl)-1 ,3-dimethyl-1 H-pyrazole (Intermediate s, 37.0 g, 94%); m/z (ES+), [M+H]⁺ = 325. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.1 1 (s, 3H), 3.75 (s, 6H), 4.42 (s, 2H), 4.48 (s, 2H), 6.91 (d, 2H), 7.27 (d, 2H).

Intermediate 4: 5-(((4-Methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole

THF (1000 mL) was added to 4-bromo-5-((4-methoxybenzyloxy)methyl)-1 ,3-dimethyl- 1 H-pyrazole (Intermediate 3, 70.0 g, 215 mmol) and the resulting clear solution was cooled to - 78 °C. n-Butyl lithium (105 mL, 262 mmol) (2.5 M in hexane) was added at -78 °C under Ar. The mixture was stirred at -78 °C for 30 min. 2-lsopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (48.1 g, 258 mmol) was added. The mixture was stirred at -78 °C for 2 h, then slowly warmed to RT and stirred for 1 h. The mixture was concentrated to dryness and EtOAc (1000 mL) was added. The resulting solution was washed with water (3 x 200 mL), brine (200 mL) and dried over Na₂S04, filtered and concentrated to dryness. The crude product was purified by silica gel column chromatography (hexanes/EtOAc) to give 5-(((4-methoxybenzyl)oxy)methyl)-1 ,3- dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (Intermediate 4, 70.0 g, 87%); m/z (ES+), [M+H]⁺ = 373. ¹ H NMR (400 MHz, DMSO-ofe) 5 1 .18 (s, 12H), 2.20 (s, 3H), 3.71 (s, 3H), 3.73 (s, 3H), 4.39 (s, 2H), 4.65 (s, 2H), 6.90 (d, 2H), 7.23 (d, 2H).

Intermediate 5: 1 -((te/t-Butyldiphenylsilyl)oxy)propan-2-one

^_j OTBDPS

o

1 -Hydroxypropan-2-one (34.9 mL, 463 mmol) was dissolved in anhydrous DMF (150 mL) under Ar. Imidazole (34.1 g, 501 mmol) and DMAP (2.37 g, 19.3 mmol) were added and the solution was cooled to 0 °C. TBDPSCI (100 mL, 386 mmol) was added slowly. The mixture was stirred at 0 °C for 15 min, then at RT for 18 h under Ar. Water (1 L) was added and the aqueous phase was extracted with hexanes (4 x 200 mL). The combined organic phases were washed with brine, dried over Na₂S04, filtered and concentrated to give ~\ -{{tert- butyldiphenylsilyl)oxy)propan-2-one (Intermediate 5, 120 g, 100%). This material was used without further purification; m/z (ES+), [M+18]⁺ = 330. ¹ H NMR (400 MHZ, CHLOROFORM-D) δ 1 .12 (s, 9H), 2.20 (s, 3H), 4.17 (s, 2H), 7.36-7.49 (m, 6H), 7.62-7.70 (m, 4H).

Intermediate 6: Ethyl 5-((te/t-butyldiphenylsilyl)oxy)-2-hydroxy-4-oxopent-2-enoate

THF (1 .50 L) was added to potassium te/t-butoxide (69.0 g, 570 mmol) and the solution was cooled to 0 °C. Diethyl oxalate (78.1 g, 570 mmol) was added slowly, maintaining the temperature below 0 °C. The solution was stirred for 30 min at 0 °C. ~\ -{{tert- Butyldiphenylsilyl)oxy)propan-2-one (Intermediate 5, 150 g, 480 mmol) was added slowly, maintaining the temperature below 0 °C. The reaction mixture was stirred at 0 °C for 1 h, and then EtOAc (300 mL) was added. The resulting mixture was acidified with 1 N HCI to pH=2 to 3. The phases were separated and the aqueous phase was extracted with EtOAc (4 x 300 mL). The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated to dryness to give ethyl 5-((te/?-butyldiphenylsilyl)oxy)-2-hydroxy-4-oxopent-2- enoate (Intermediate 6, 160 g, 80%); m/z (ES-), [M-H]^" = 411 . ¹ H NMR (400 MHz,

CHLOROFORM-o δ 1 .13 (s, 9H), 1 .39 (t, 3H), 4.31 (s, 2H), 4.39 (q, 2H), 6.88 (s, 1 H) 7.39-7.44 (m, 6H), 7.65 - 7.68 (m, 4H).

Intermediates 7 & 8: Ethyl 3-(((te/t-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5- carboxylate (Intermediate 7) and ethyl 5-(((te/?-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate (Intermediate 8)

Intermediate 7 Intermediate 8

Ethyl 5-((te/t-butyldiphenylsilyl)oxy)-2-hydroxy-4-oxopent-2-enoate (Intermediate 6, 155 g, 375 mmol) was dissolved in 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (75 mL) and

trifluoroethanol (75 mL). The solution was cooled to 0 °C. Methyl hydrazine (19.0 mL, 361 mmol) was added dropwise. After addition, the ice bath was removed. The mixture was stirred at RT for 2 h and concentrated to dryness. EtOAc (500 mL) was added to the residue. The resulting organic solution was washed with water (100 mL), brine (100 mL) and dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel

chromatography (0 to 50% EtOAc in hexanes) to give two isomers: ethyl 3-{{{tert- butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5-carboxylate (Intermediate 7, 62.5 g, 64 wt% purity, 26% yield, eluted first); m/z (ES+), [M+H]⁺ = 423. ¹ H NMR (300 MHz,

CHLOROFORM-o δ 1 .09 (s, 9H), 1 .41 (t, 3H), 4.12 (s, 3H), 4.37 (q, 2H), 4.74 (s, 2H), 6.82 (s, 1 H), 7.37-7.50 (m, 6H), 7.65-7.80 (m, 4H) and ethyl 5-(((te/f-butyldiphenylsilyl)oxy)methyl)-1 - methyl-1 H-pyrazole-3-carboxylate (Intermediate 8, 70.2 g, 44% yield, eluted second); m/z (ES+), [M+H]⁺ = 423. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .05 (s, 9H), 1 .41 (t, 3H), 3.95 (s, 3H), 4.42 (q, 2H), 4.68 (s, 2H), 6.56 (s, 1 H), 7.37-7.50 (m, 6H), 7.61 -7.69 (m, 4H).

Intermediate 9: (5-(((te -Butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol

TBDPS

THF (800 mL) was added to ethyl 5-(((te -butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate (Intermediate 8, 160 g, 378 mmol) to give an orange solution. The solution was cooled to 0 °C and LAH (189 mL, 47.3 mmol) (2.0 M in THF) was added dropwise, maintaining the temperature below 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The mixture was diluted with diethyl ether (1600 mL) and water (14.4 mL) was added dropwise below 0 °C, followed by 15% aq. NaOH solution (14.4 mL), and water (43.0 mL). The resulting mixture was stirred at RT for 10 min. Anhydrous Na2S04 was added and the suspension was stirred for 15 min. The mass was filtered through a pad of diatomaceous earth and washed with diethyl ether. The filtrate was concentrated to obtain (5-(((te/?-butyldiphenylsilyl)oxy)methyl)-1 - methyl-1 H-pyrazol-3-yl)methanol (Intermediate 9, 140 g, 97%) ; m/z (ES+), [M+H]⁺ = 381 . ¹ H NMR (300 MHz, CHLOROFORM-c ) δ 1 .06 (s, 9H), 3.85 (s, 3H), 4.62 (s, 2H), 4.64 (s, 2H), 6.02 (s, 1 H), 7.35-7.53 (m, 6H), 7.62-7.72 (m, 4H).

Intermediate 10: (4-Bromo-5-((teri-butyldiphenylsilyloxy)methyl)-1 -methyl-1 H-pyrazol-3- yl)methanol

(5-(((te/t-Butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol

(Intermediate 9, 51 .3 g, 135 mmol) was dissolved in DCM (300 mL) to give a clear solution. This solution was cooled to 0 °C. NBS (25.2 g, 142 mmol) was added. After stirring at 0 °C for 1 .5 h, the mixture was washed with sat. NaHC03 (2 x 75 mL), 1 N NaOH (2 x 50 mL), dried over Na₂S04, filtered and concentrated to dryness. EtOAc (30 mL) was added to the residue to give a suspension. This suspension was stirred at RT for 15 min. The solids were collected by filtration, washed with EtOAc (10 mL) to give the first batch of product (48.8 g) as a white solid. The mother liquid was concentrated to dryness. The residue was purified by silica gel column chromatography (50% hexanes in DCM to 25% EtOAc in DCM) to give the second batch of product (2.30 g). The total amount of 4-bromo-5-(((te -butyldiphenylsilyl)oxy)methyl)-1 -methyl- 1 H-pyrazol-3-yl)methanol (Intermediate 10) was 51 .1 g (83%); m/z (ES+), [M+H]⁺ = 459. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .06 (s 9H) 3.93 (s, 3H) 4.64 (s, 2H) 4.69 (s, 2H) 7.36- 7.52 (m, 6H) 7.62-7.74 (m, 4H).

Intermediate 11 : 4-Bromo-5-((te/?-butyldiphenylsilyloxy)methyl)-1 -methyl-3-((tetrahydro-2H- pyran-2-yloxy) methyl)- 1 H-pyrazole

(4-Bromo-5-(((te -butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 10, 51 .1 g, 111 mmol) was dissolved in DCM (200 mL). 3,4-Dihydro-2H-pyran (12.2 mL, 133 mmol) was added, followed by addition of p-toluenesulfonic acid monohydrate (1 .06 g, 5.56 mmol). The resulting solution was stirred at RT for 4 h and washed with sat.

NaHC0₃ solution (50 mL), dried over Na₂S04, filtered and concentrated to dryness to give 4- bromo-5-((te -butyldiphenylsilyloxy)methyl)-1 -methyl-3-((tetrahydro-2H-pyran-2-yloxy)methyl)- 1 H-pyrazole (Intermediate 11 , 60.5 g, 100%), which was used without purification; m/z (ES+), [M+H]⁺ = 534. ¹ H NMR (300 MHz, CHLOROFORM-d) δ 1 .06 (s, 9H), 1 .44-1 .94 (m, 6H), 3.50- 3.75 (m, 1 H), 3.88-4.06 (m, 4H), 4.43 (AB d, 1 H), 4.62-4.89 (m, 4H), 7.32-7.55 (m, 6H), 7.58- 7.81 (m, 4H).

Intermediate 12: (4-Bromo-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-5- yl)methanol

4-Bromo-5-(((te -butyldiphenylsilyl)oxy)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazole (Intermediate 11 , 61 .0 g, 112 mmol) was dissolved in THF (200 mL). TBAF (135 mL, 135 mmol) (1 M in THF) was added. The mixture was stirred at RT for 20 min and concentrated to dryness. Water (200 mL) and EtOAc (200 mL) were added to the residue. The layers were separated. The aq. phase was extracted with EtOAc (5 x 100 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (4-bromo-1 - methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-5-yl)methanol (Intermediate 12, 33.4 g , 98%) as a sticky oil; m/z (ES+), [M+H]⁺ = 305. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .45-1 .96 (m, 7H), 3.56-3.62 (m, 1 H), 3.92-4.05 (m, 4H), 4.45 (AB d, 1 H), 4.65-4.77 (m, 3H), 4.78-4.82 (m, 1 H).

Intermediate 13: (1 -Methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-5- l)methanol

A mixture of (4-bromo-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-5- yl)methanol (Intermediate 12, 5.00 g, 16.4 mmol), palladium(ll) acetate (0.184 g, 0.82 mmol) and dicyclohexyl(2',6'-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphine (0.673 g, 1 .64 mmol) in 1 ,4- dioxane (40 mL) was evacuated and backfilled with N₂ 3 times. TEA (6.85 mL, 49.2 mmol) was added, followed by the slow addition of 4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (14.2 mL, 98.3 mmol) over 10 min. The resulting mixture was stirred at 75 °C for 1 h under N₂, then cooled to RT and concentrated to dryness. Ice water (100 mL) was added to the residue. The aq. phase was extracted with EtOAc (3 x 75 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column

chromatography (hexanes to EtOAc) to give (1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-5-yl)methanol

(Intermediate 13, 4.90 g, 85%) as a gray solid; m/z (ES+), [M+H]⁺ = 353. ¹ H NMR (300 MHz,

CHLOROFORM-oO δ 1 .32 (s, 12H), 1 .44-1 .75 (m, 5H), 1 .79-1 .95 (m, 1 H), 3.48-3.64 (m, 1 H), 3.87 (s, 3H), 3.98-4.1 1 (m, 1 H), 4.52 (AB d, 1 H), 4.73 (s, 2H), 4.85 (AB d, 1 H), 4.89-4.92 (m,

1 H).

Intermediate 14: Ethyl 5-(hydroxymethyl)-1 -methyl-1 H-pyrazole-3-carboxylate

Ethyl 5-(((teri-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-3-carboxylate

(Intermediate 8, 47.0 g, 1 1 1 mmol) was dissolved in THF (100 mL). TBAF (1 1 1 mL, 1 1 1 mmol) (1 M in THF) was added at RT. The mixture was stirred at RT for 1 h and concentrated to dryness. Water (400 mL) was added to the residue. The aq. phase was extracted with EtOAc (10 x 100 mL). The combined organic phases were dried over Na₂S04, filtered and

concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes to EtOAc) to give ethyl 5-(hydroxymethyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 14, 18.2 g, 89%) as a sticky oil; m/z (ES+), [M+H]⁺ = 185. ¹H NMR (300 MHz, CHLOROFORM-oO δ 1 .39 (t, 3H), 3.98 (s, 3H), 4.39 (q, 2H), 4.69 (s, 2H), 6.71 (s, 1 H).

Intermediate 15: Ethyl 1 -methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-1 H-pyrazole-3- carboxylate

Ethyl 5-(hydroxymethyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 14, 18.5 g, 100 mmol) was dissolved in DCM (150 mL). 3,4-Dihydro-2H-pyran (10.1 mL, 1 1 1 mmol) and p- toluenesulfonic acid monohydrate (0.96 g, 5.02 mmol) were added. The mixture was stirred at RT overnight and washed with sat. NaHC0₃ solution (50 mL), dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography

(hexanes to EtOAc) to give ethyl 1 -methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)-1 H-pyrazole- 3-carboxylate (Intermediate 15, 25.1 g, 93%); M/Z (ES+), [M+H]⁺ = 269. ¹ H NMR (300 MHz, CHLOROFORM-oO δ 1 .39 (t, 3H), 1 .47-1 .89 (m, 6H), 3.49-3.63 (m, 1 H), 3.78-3.91 (m, 1 H), 3.98 (s, 3H), 4.40 (q, 2H), 4.55 (AB d, 1 H), 4.62-4.67 (m, 1 H), 4.74 (AB d, 1 H), 6.78 (s, 1 H).

Intermediate 16 (1 -Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-3-yl)methanol

Ethyl 1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazole-3-carboxylate

(Intermediate 15, 25.1 g, 93.6 mmol) was dissolved in THF (100 mL) under N₂. The solution was cooled to 0 °C. LAH (35.1 mL, 70.2 mmol) (2M in THF) was added. The mixture was stirred at 0 °C for 20 min, then at RT for 30 min. The mixture was cooled to 0 °C, carefully quenched with 2.66 mL of water, 2.66 mL of 15% NaOH solution then 3 x 2.66 mL water. The resulting solution was stirred at 0 °C for 15 min, then RT for 20 min. Anhydrous Na2S04 (15 g) was added. The mixture was stirred at RT for 10 min, filtered and the solid cake was washed with EtOAc (200 mL). The combined organic phases were concentrated to dryness to give (1 -methyl- 5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-3-yl)methanol (Intermediate 16, 21 .2 g, 100%) as a colorless oil; m/z (ES+), [M+H]⁺ = 227. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .46-1 .90 (m, 6H), 3.46-3.63 (m, 1 H), 3.83-3.94 (m, 4H), 4.51 (AB d, 1 H), 4.63-4.80 (m, 4H), 6.24 (s, 1 H).

Intermediate 17: (4-Bromo-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-3- yl)methanol

(1 -Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-3-yl)methanol

(Intermediate 16, 21 .4 g, 94.4 mmol) was dissolved in DCM (150 mL) at 0 °C. NBS (16.8 g, 94.4 mmol) was added. After the mixture was stirred at 0 °C for 30 min, the ice bath was removed. The resulting suspension was stirred at RT for 1 h, then washed with KOH solution (21 .0 mL, 94.4 mmol) (4.5M in water). The layers were separated. The aq. phase was extracted with DCM (3 x 20 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes to EtOAc) to give (4-bromo-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H- pyrazol-3-yl)methanol (Intermediate 17, 27.4 g, 91 %) as a colorless oil; M/Z (ES+), [M+H]⁺ = 305. ¹ H NMR (500 MHz, CHLOROFORM-c/) δ 1 .47-1 .66 (m, 5H), 1 .67-1 .75 (m, 1 H), 1 .75-1 .88 (m, 1 H), 3.54-3.64 (m, 1 H), 3.83-3.97 (m, 4H), 4.56 (AB d, 1 H), 4.66 (s, 3H), 4.71 (AB d, 1 H).

Intermediate 18: (1 -Methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-3- l)methanol

A mixture of (4-bromo-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-3- yl)methanol (Intermediate 17, 9.40 g, 29.4 mmol), palladium(ll) acetate (0.331 g, 1 .47 mmol) and dicyclohexyl(2',6'-dimethoxy-[1 ,1 '-biphenyl]-2-yl)phosphane (1 .21 g, 2.94 mmol) in 1 ,4- dioxane (100 mL) was evacuated and backfilled with N₂ 3 times. TEA (12.3 mL, 88.3 mmol) was added, then 4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolane (17.1 mL, 1 18 mmol) was added very slowly. The resulting mixture was stirred at 70 °C under N₂. After 60 min, then cooled to RT and concentrated to dryness. Ice water (100 mL) was added. The resulting aq. phase was extracted with EtOAc (10 x 50 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography

(hexanes to EtOAc) to give (1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-3-yl)methanol (Intermediate 18, 7.00 g, 67%) as a gray oil; M/Z (ES+), [M+H]⁺ = 353. ¹ H NMR (300 M MHz, CHLOROFORM-c ) δ 1.33 (s, 12H), 1 .46-1 .89 (m, 6H), 3.47-3.63 (m, 1 H), 3.82-3.97 (m, 4H), 4.62-4.80 (m, 4H), 4.88 (AB d, 1 H).

Intermediates 19 and 20: 3-Mercaptonaphthalen-1 -ol (Intermedate 19) and 3- (acetylthio)naphthalen-l -yl acetate (Intermediate 20)

Intermediate 19 Intermediate 20

l₂ (38.7 g, 152 mmol) was added in one portion to a mixture of sodium 4- hydroxynaphthalene-2-sulfonate (75.0 g, 305 mmol), Ph₃P (320 g, 1220 mmol) and 18-crown-6 (24.2 g, 91 .4 mmol) in toluene (750 mL) at 20 °C under nitrogen. The resulting mixture was stirred at 100 °C for 17 h. 1 ,4-Dioxane (150 mL) and water (75 mL) were added and the mixture was stirred at 100 °C for a further 1 h. Na₂S0₄was added. The solids were removed by filtration and the filtrate was partially concentrated under vacuum to afford 3-mercaptonaphthalen-1 -ol (Intermediate 19, 360 g, 14 wt% in toluene). The product was used without further purification; m/z (ES ), [M-H] = 175.

Ac₂0 (162 mL, 1720 mmol) was added dropwise to a mixture of DMAP (3.49 g, 28.6 mmol), 3-mercaptonaphthalen-1 -ol (Intermediate 19, 360 g, 286 mmol, 14 wt% in toluene) and Et₃N (80 mL, 572 mmol) in DCM (1000 mL) at 0 °C over a period of 10 min under nitrogen. The resulting mixture was stirred at 0 °C for 30 min. The reaction mixture was diluted with DCM (200 mL), and washed sequentially with water (4 x 750 mL) and saturated brine (500 mL). The organic layer was dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc) to give 3-(acetylthio)naphthalen-1 -yl acetate (Intermediate 20, 40.0 g, 50% over 2 steps); m/z (ES+), [M+H]⁺ = 261 . ¹ H NMR (400 MHz, CHLOROFORM-c/ ) 5 2.48 (s, 3H), 2.49 (s, 3H), 7.34 (d, 1 H), 7.55-7.62 (m, 2H), 7.88-7.92 (m, 3H). Intermediate 21 : Methyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1 H-indole-2-carboxylate

Methyl 7-bromo-6-chloro-3-(3-methoxy-3-oxopropyl)-1 H-indole-2-carboxylate

(Intermediate 1 , 18.4 g, 49.1 mmol) was dissolved in THF (100 mL) under N₂. After cooling to 0 °C, borane tetrahydrofuran complex (246 ml, 246 mmol) (1 M in THF) was added slowly through a cannula under N₂ at 0 °C. The mixture was stirred at RT for 5.5 h. The reaction solvent was removed under vacuum. 200 mL of THF was added to the residue, followed by addition of Amberlite IRA743 free base (Aldrich) (20 g) very slowly at RT and then 4 mL of 10% HCI solution. The resulting suspension was stirred at RT overnight. The solids were removed by filtration and washed with methanol (100 mL). The filtrate was concentrated to dryness. EtOAc (500 mL) was added to the residue. The resulting organic phase was washed with sat. NaHC0₃ solution (200 mL). The aq. phase was further extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to ~ 300 mL volume to give a suspension. Hexanes (100 mL) was added. The solids were collected by filtration, washed with hexanes (100 mL) and dried to yield 10.0 g of the desired product. The mother liquid was concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc) to give 5.45 g of the desired product. Total amount of methyl 7-bromo-6- chloro-3-(3-hydroxypropyl)-1 H-indole-2-carboxylate (Intermediate 21 ) was 15.5 g (91 %); M/Z (ES+), [M+H]⁺ = 346. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .73 (quin, 2H), 3.04 (t, 2H), 3.40 (t, 2H), 3.89 (s, 3H), 4.43 (t, 1 H), 7.29 (d, 1 H), 7.74 (d, 1 H), 1 1 .45 (br s, 1 H).

Intermediate 22: Methyl 7-bromo-3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-1 H-indole-2- carboxylate

A 1 -liter flask was charged with methyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1 H-indole- 2-carboxylate (Intermediate 21 , 15.0 g, 43.3 mmol) and DCM (400 mL). The mixture was cooled to 0 °C. TBDPSCI (15.6 mL, 60.6 mmol) was added, followed by addition of imidazole (4.42 g, 64.9 mmol) and DMAP (0.264 g, 2.16 mmol) in portions. The mixture was allowed to warm to RT over 1 h and then stirred at RT for 16 h. The reaction mixture was diluted with DCM (200 mL) and water (200 mL). The layers were separated. The aq. layer was extracted with DCM (200 mL). The combined organic phases were washed with brine (150 mL), dried over MgSC , filtered and concentrated to dryness. The residue was purified by silica gel

chromatography (hexanes/EtOAc) to yield methyl 7-bromo-3-(3-((te/t- butyldiphenylsilyl)oxy)propyl)-6-chloro-1 H-indole-2-carboxylate (Intermediate 22, 25.3 g, 100%); M/Z (ES-), [M-H]^" = 582. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .09 (s, 9H), 1 .89 (t, 2H), 3.16 (t, 2H), 3.73 (t, 2H), 3.92 (s, 3H), 7.18 (d, 1 H), 7.31 -7.49 (m, 6H), 7.56 (d, 1 H), 7.60- 7.76 (m, 4H), 8.77 (br s, 1 H).

Intermediate 23: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4- methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate

A solution of 5-(((4-methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (Intermediate 4, 22.3 g, 59.8 mmol) in 1 ,4-dioxane (200 mL) and water (50 mL) was added to a solid mixture of methyl 7-bromo-3-(3-((te/t- butyldiphenylsilyl)oxy)propyl)-6-chloro-1 H-indole-2-carboxylate (Intermediate 22, 28.0 g, 47.9 mmol) and Cs₂C0₃ (31 .2 g, 95.7 mmol), followed by addition of dichloro[1 ,1 '-bis(di-te/t- butylphosphino)ferrocene]palladium(ll) (0.936 g, 1 .44 mmol). The mixture was degassed and refilled with N₂ three times. After stirring at 100 °C for 1 h, the mixture was cooled to RT, diluted with EtOAc (500 mL), washed with brine (200 mL), dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to yield (±) methyl 3-(3-((teri-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4-methoxybenzyl)oxy)methyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate (Intermediate 23, 35.9 g, 100%); M/Z (ES+), [M+H]⁺ = 750. ¹ H NMR (300 MHz, CHLOROFORM-c ) δ 1 .10 (s, 9H), 1 .93-1 .97 (m, 2H), 2.13 (s, 3H), 3.18-3.30 (m, 2H), 3.74-3.86 (m, 8H), 3.91 (s, 3H), 4.04-4.13 (m, 1 H), 4.20 (AB d, 1 H), 4.28 (AB d, 1 H), 4.38 (AB d, 1 H), 6.70-6.80 (m, 2H), 7.04-7.07 (m, 2H), 7.24 (d, 1 H), 7.30- 7.45 (m, 6H), 7.63 (d, 1 H), 7.66-7.73 (m, 4H), 8.79 (s, 1 H).

Intermediate 24: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4- methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

Cs₂C0₃ (24.7 g, 75.9 mmol) was added to a mixture of (±)-methyl 3-(3-((te/f- butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4-methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-1 H- pyrazol-4-yl)-1 H-indole-2-carboxylate (Intermediate 23, 38.0 g, 50.6 mmol) and methyl iodide (6.33 ml_, 101 mmol) in DMF (200 ml.) at RT. The mixture was stirred at RT overnight and concentrated to dryness. EtOAc (500 ml.) and water (500 ml.) were added to the residue. The layers were separated. The organic layer was dried over MgSC , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to yield (±) methyl 3-(3-((teri-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4-methoxybenzyl)oxy)methyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 24, 36.7 g, 95%); M/Z (ES+), [M+H]⁺ = 764. ¹ H NMR (300 MHz, METHANOL- 4) δ 1 .08 (s, 9H), 1 .81 -1 .99 (m, 2H), 2.02 (s, 3H), 3.03-3.20 (m, 2H), 3.45 (s, 3H), 3.70 (s, 3H), 3.73-3.79 (m, 2H), 3.80 (s, 3H), 3.92 (s, 3H), 4.06-4.35 (m, 4H), 6.54-6.72 (m, 2H), 6.82-7.01 (m, 2H), 7.20 (d, 1 H),7.34-7.51 (m, 6H) 7.60-7.70 (m, 5H).

Intermediate 25: (±) Methyl 3-(3-((teri-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (hydroxymethyl)-l ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((4-methoxybi oxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 24, 26.0 g, 34.0 mmol) was dissolved in a mixture of DCM (3000 mL) and water (30 mL). The mixture was cooled to 0 °C. 4,5-Dichloro-3,6-dioxocyclohexa-1 ,4-diene-1 ,2-dicarbonitrile (11 .6 g, 51 .0 mmol) was added in one batch. After stirring at RT for 2 days, CHCI₃ (500 mL) and sat. NaHC03 solution (200 mL) were added to the reaction mixture. Then the mixture was filtered through a pad of diatomaceous earth. The filtered layers were separated. The water layer was extracted with CHC (150 mL). The combined organic phases were washed with brine, dried over MgSC , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to yield (±)-methyl 3-(3-((te/?-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 25, 11 .5 g, 52%); M/Z (ES+), [M+H]⁺ = 644. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .02 (s, 9H), 1 .76-1 .92 (m, 5H), 3.04 (t, 2H), 3.40 (s, 3H), 3.67-3.79 (m, 5H), 3.86 (s, 3H), 4.06-4.20 (m, 1 H), 4.21 -4.42 (m, 1 H), 5.10 (br s, 1 H), 7.24 (d, 1 H), 7.35-7.54 (m, 6H), 7.60-7.70 (m, 5H).

Intermediate 26: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(iodomethyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

Thionyl chloride (0.47 mL, 6.46 mmol) was added to a solution of (±)-methyl 3-(3-((te/t- butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 25, 3.47 g, 5.39 mmol) in DCM (100 mL) at 0 °C. The mixture was then stirred at RT for 1 h, then cooled to 0 °C and diluted with 100 mL of DCM. Sat. NaHC0₃ solution (100 mL) was added. The layers were separated. The aq. layer was extracted with DCM (100 mL). The combined organic phases were dried over MgS04, filtered and concentrated to yield crude (±)-methyl 3-(3-((te/?-butyldiphenylsilyl)oxy)propyl)-6-chloro-7- (5-(chloromethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (3.57 g, 100%).

(±) Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(chloromethyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (3.57 g, 5.39 mmol) was dissolved in acetonitrile (100 mL). Sodium iodide (4.04 g, 26.9 mmol) was added. The resulting suspension was stirred at RT overnight. The solvent was removed under reduced pressure. The residue was diluted with water (50 ml.) and DCM (100 ml_). The layers were separated. The aq. layer was extracted with DCM (2 x 50 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel

chromatography (hexanes/EtOAc) to yield (±)-methyl 3-(3-((te/?-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(5-(iodomethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

(Intermediate 26, 3.01 g, 74.1 %); M/Z (ES+), [M+H]⁺ = 754. ¹ H NMR (300 MHz,

CHLOROFORM-oO δ 1 .12 (s, 9H), 1 .77-2.01 (m, 2H), 2.07 (s, 3H), 3.02-3.24 (m, 2H), 3.57 (s, 3H), 3.80 (t, 2H), 3.86 (s, 3H), 3.95 (s, 3H), 4.12 (s, 2H), 7.25 (d, 1 H), 7.34-7.55 (m, 6H), 7.58- 7.76 (m, 5H).

Intermediate 27: (±)-Methyl 6-chloro-3-(3-methoxy-3-oxopropyl)-7-(5-((4- methoxybenzyloxy)methyl)-1 ,3-dimeth l-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate

5-(((4-Methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (Intermediate 4, 18.9 g, 50.7 mmol) was dissolved in a mixture of 1 ,4-dioxane and water (4:1 , 35 ml_). Cs₂C0₃ (26.1 g, 80.1 mmol), methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl)-1 H-indole-2-carboxylate (Intermediate 1 , 15.0 g, 40.0 mmol) and dichloro[1 ,1 '-bis(di-te/t-butylphosphino)ferrocene] palladium(ll) (0.783 g, 1.20 mmol) were added, followed by additional 1 ,4-dioxane and water (340 ml_, 4:1 ). The mixture was degassed and filled with N₂ three times. The resulting brown clear mixture was placed in an oil bath preheated to 100 °C. The mixture was stirred at 100 °C for 3 h, then cooled to RT and concentrated to 100 ml_. EtOAc (200 ml.) and water (100 ml.) were added. The layers were separated and the aqueous phase was extracted with EtOAc (3 x 100 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (±)-methyl 6-chloro-3-(3-methoxy-3- oxopropyl)-7-(5-((4-methoxybenzyloxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 H-indole-2- carboxylate (Intermediate 27, 19.4 g, 90%); m/z (ES+), [M+H]⁺ = 540. ¹ H NMR (400 MHz, DMSO-ce) δ 1 .94 (s, 3H), 2.63 (t, 2H), 3.28-3.30 (m, 2H), 3.58 (s, 3H), 3.69 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 4.12 (AB d, 1 H), 4.19-4.23 (m, 3H), 6.71 -6.74 (m, 2H), 6.91 -6.94 (m, 2H), 7.25 (d, 1 H), 7.73 (d, 1 H), 10.98 (s, 1 H).

Intermediate 28: (±)-Methyl 6-chloro-3-(3-methoxy-3-oxopropyl)-7-(5-((4- methoxybenzyloxy)methyl)-1 ,3-dimeth l-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

lodomethane (3.19 g, 22.4 mmol) and Cs₂C0₃ (7.31 g, 22.4 mmol) were added to a solution of (±)-methyl 6-chloro-3-(3-methoxy-3-oxopropyl)-7-(5-(((4-methoxybenzyl)oxy)methyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate (Intermediate 27, 8.08 g, 14.9 mmol) in DMF (80 ml.) at RT. After stirring at RT for 4 h, the mixture was concentrated. DCM (100 ml.) and water (50 ml.) were added to the residue. The layers were separated. The aq. layer was extracted with DCM (2 x 150 ml_). The combined organic phases were dried over N^SC , filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes/EtOAc) yield (±)-methyl 6-chloro-3-(3-methoxy-3-oxopropyl)-7-(5-(((4- methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 28, 8.29 g, 100%); m/z (ES+), [M+H]⁺ = 554. ¹ H NMR (400 MHz, DMSO-c/e) δ 1 .92 (s, 3H), 2.62 (t, 2H), 3.25 (t, 2H), 3.38 (s, 3H), 3.57 (s, 3H), 3.69 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.13-4.19 (m, 3H), 4.30 (AB d, 1 H), 6.69-6.71 (m, 2H), 6.90-6.93 (m, 2H), 7.28 (d, 1 H), 7.76 (d, 1 H).

Intermediate 29: (±)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3- methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate

TFA (222 mL, 2888 mmol) was added in one portion to a solution of (±)-methyl 6-chloro- 3-(3-methoxy-3-oxopropyl)-7-(5-(((4-methoxybenzyl)oxy)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)- 1 -methyl-1 H-indole-2-carboxylate (Intermediate 28, 160 g, 289 mmol) in DCM (1200 mL) at 25 °C under nitrogen. The resulting mixture was stirred at 25 °C for 16 h and then concentrated to dryness. The residue was diluted with MeOH (1000 mL) to give a suspension. The solids were removed by filtration. 4M HCI in 1 ,4-dioxane (14.4 mL, 57.8 mmol) was add to the filtrate. The mixture was stirred at 70 °C for 16 h. Then the solution was concentrated to dryness to give a solid which was washed with MTBE (1000 mL) to give (±)-methyl 6-chloro-7-(5-(hydroxymethyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 29, 105 g, 84%); m/z (ES+), [M+H]⁺ = 434. ¹ H NMR (400 MHz, CHLOROFORM- d) δ 2.06 (s, 3H), 2.68 (t, 2H), 3.35 (t, 2H), 3.53 (s, 3H), 3.69 (s, 3H), 3.94 (s, 3H), 4.02 (s, 3H), 4.41 -4.48 (m, 2H), 7.24 (d, 1 H), 7.65 (d, 1 H).

Intermediate 29 (109 g, 252 mmol) was subjected to Pre-Packed Chiralpak IC^® column: 50 x 250 mm, 20 μιη; Temperature = RT; Mobile Phase: Heptane/EtOAc=70/30; UV detection @ 280 nm; Injected amount: 360 mg; Injection volume: 4 mL; Sample concentration (mg/mL): 90 mg/mL in DCM; Flow rate = 120 mL/min to give two enantiomers (/¾)-(-)-methyl 6-chloro-7- (5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1 -methyl-1 H- indole-2-carboxylate (Intermediate 30) and (S_a)-(+)-methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate

(Intermediate 31 ).

Intermediate 30, (fl_a)-(-)-enantiomer eluted first (42 g, 39%, >98% e.e.): m/z (ES+), [M+H]⁺ = 434. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ 2.06 (s, 3H), 2.68 (t, 2H), 3.35 (t, 2H), 3.53 (s, 3H), 3.69 (s, 3H), 3.94 (s, 3H), 4.02 (s, 3H), 4.41 -4.48 (m, 2H), 7.24 (d, 1 H), 7.65 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IC^® column, 4.6 x 50 mm, 5 μιη, Temperature = 40 °C, Mobile Phase: 20:80 /-PrOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .03 min, >98% e.e., [a]_D -27^Q (c = 0.1 , MeOH).

Intermediate 31 (desired) is (S_a)-(+)-enantiomer eluted second: (49 g, 45%, >98% e.e.) : m/z (ES+), [M+H]⁺ = 434. ¹ H NMR (400 MHz, CHLOROFORM-of) δ 2.06 (s, 3H), 2.68 (t, 2H), 3.35 (t, 2H), 3.53 (s, 3H), 3.69 (s, 3H), 3.94 (s, 3H), 4.02 (s, 3H), 4.41 -4.48 (m, 2H), 7.24 (d, 1 H), 7.65 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IC^® column, 4.6 x 50 mm, 5 μιη, Temperature = 40 °C, Mobile Phase 20:80 /-PrOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .43 min, 98% e.e., [a]_D +32^Q (c = 0.1 , MeOH).

Intermediate 32: Ethyl 5-(chloromethyl)-1 -methyl-1 H-pyrazole-3-carboxylate

A solution of ethyl 5-(hydroxymethyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 14, 20.8 g, 113 mmol) in DCM (217 mL) was cooled to 0 °C. Thionyl chloride (9.04 mL,

124 mmol) was added. The ice bath was removed. After stirring at RT for 30 min, the mixture was concentrated to dryness. DCM (50 mL) was added to the residue. The resulting solution was washed with sat. NaHC0₃ solution (2 x 20 mL), dried over Na₂S04, filtered and

concentrated to dryness to give ethyl 5-(chloromethyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 32, 21 .2 g, 93%); M/Z (ES+), [M+H]⁺ = 203. ¹ H NMR (300 MHz, CHLOROFORM- d) δ 1 .37 (t, 3H), 3.98 (s, 3H), 4.37 (q, 2H), 4.57 (s, 2H), 6.80 (s, 1 H).

Intermediate 33: 5-((Acetylthio)methyl)-1 -methyl-1 H-pyrazole-3-carboxylate

A mixture of ethyl 5-(chloromethyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 32, 4.52 g, 22.3 mmol), potassium iodide (3.70 g, 22.3 mmol) and potassium ethanethioate (5.09 g, 44.6 mmol) in CH₃CN (112 ml.) was stirred at RT overnight. The mixture was concentrated to dryness. Water (20 ml.) and DCM (40 ml.) were added to the residue. The layers were separated. The organic phase was dried over MgSC and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to yield ethyl 5- ((acetylthio)methyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 33, 5.01 g, 93%); M/Z (ES+), [M+H]⁺ = 243. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .40 (t, 3H), 2.40 (s, 3H), 3.92 (s, 3H), 4.15 (s, 2H), 4.40 (q, 2H), 6.74 (s, 1 H).

Intermediate 34: ((3-(Ethoxycarbonyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)triphenylphosphonium chloride

Triphenylphosphine (30.6 g, 117 mmol) was added to a solution of ethyl 5- (chloromethyl)-l -methyl-1 H-pyrazole-3-carboxylate (Intermediate 32, 21 .5 g, 106 mmol) in acetonitrile (400 ml_). The resulting mixture was stirred at reflux for 16 h. The solvent was removed under reduced pressure. The residue was triturated with EtOAc (100 ml_). The resulting solids were collected by filtration and washed with EtOAc (20 ml.) to give ((3- (ethoxycarbonyl)-l -methyl-1 H-pyrazol-5-yl)methyl)triphenylphosphonium chloride (Intermediate 34, 48.0 g, 97%) as a white solid; M/Z (ES+), [M-CI]⁺ = 429. ¹ H NMR (400 MHz, METHANOL-ok) δ 1 .32 (t, 3H), 2.95 (s, 2H), 4.30 (q, 2H), 4.88 (s, 3H), 6.42 (s, 1 H), 7.71 -7.86 (m, 12H), 7.94- 8.04 (m, 3H). Intermediate 35: 3-(((3-(Hydroxymethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)naphthalen-1 -ol

K2CO3 (26.6 g, 192 mmol) was added to a mixture of ethyl 5-(chloromethyl)-1 -methyl- 1 H-pyrazole-3-carboxylate (Intermediate 32, 26.0 g, 128 mmol) and 3-(acetylthio)naphthalen-1 - yl acetate (Intermediate 20, 35.1 g, 135 mmol) in MeOH (500 mL) under N₂. The resulting suspension was stirred at RT for 1 h under N₂. The mixture was filtered through a pad of diatomaceous earth and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc) to give a mixture of ethyl 5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate and methyl 5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate (29.0 g). This methyl ester and ethyl ester mixture was dissolved in THF (500 mL). The resulting solution was cooled to 0 °C. LiAIH₄ (3.21 g, 84.7 mmol) was added under N₂. After stirring at RT for 1 h, the reaction mixture was quenched with water (100 mL) at 0 °C and then adjusted to pH=5 with 1 N HCI solution. The layers were separated. The aq.

phase was extracted with EtOAc (3 x 500 mL). The combined organic phases were dried over Na₂S04, filtered and concentrate to afford 3-(((3-(hydroxymethyl)-1 -methyl-1 H-pyrazol-5- yl)methyl)thio)naphthalen-1 -ol (Intermediate 35, 23.0 g, 60%); M/Z (ES+), [M+H]⁺ = 301 . ¹ H NMR (400 MHz, DMSO-ofe) δ 3.77 (s, 3H), 4.28 (s, 2H), 4.36 (s, 2H), 6.15 (s, 1 H), 6.81 (s, 1 H), 7.35 (s, 1 H), 7.35-7.42 (m, 1 H), 7.43-7.51 (m, 1 H), 7.74 (d, 1 H), 8.05 (d, 1 H), 10.32 (s, 1 H).

Intermediate 36: 3-(((3-(Chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)naphthalen-1 -ol

Thionyl chloride (50.0 mL, 166 mmol) was added to a solution of 3-(((3-(hydroxymethyl)- 1 -methyl-1 H-pyrazol-5-yl)methyl)thio)naphthalen-1 -ol (Intermediate 35, 50.0 g, 166 mmol) in DMF (50 mL) and DCM (350 mL) at 0 °C under nitrogen dropwise. After addition, the light- yellow solution was warmed to RT and stirred for 30 min. Then the resulting solution was concentrated and the residue was cooled to 0 °C again. MeOH (500 mL) was added to the above residue. The resulting solution was stirred at 32 °C for 2 h. 300 mL of water was added to the mixture. Then most of MeOH was removed under reduced pressure. The resulting aq. phase was extracted with DCM (3 x 300 mL). The organic layers were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography

(hexanes/EtOAc) to afford 3-(((3-(chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio) naphthalen-1 -ol (Intermediate 36, 40.0 g, 75%); M/Z (ES+), [M+H]⁺ = 319. ¹ H NMR (400 MHz, DMSO-ofe) δ 3.81 (s, 3H), 4.39 (s, 2H), 4.62 (s, 2H), 6.26 (s, 1 H), 6.81 (s, 1 H), 7.36-7.50 (m, 3H), 7.74 (d, 1 H), 8.05 (d, 1 H), 10.35 (s, 1 H).

Intermediate 37: 3-(((3-((Acetylthio)methyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)naphthalen-1 - yl acetate

Potassium iodide (21 .0 g, 126. mmol) was added to a mixture of potassium

ethanethioate (60.0 g, 525 mmol) and 3-(((3-(chloromethyl)-1 -methyl-1 H-pyrazol-5- yl)methyl)thio)naphthalen-1 -ol (Intermediate 36, 40.0 g, 125 mmol) in MeCN (1000 mL) under nitrogen. The resulting mixture was stirred at RT for 16 h and then cooled to 0-5 °C. Acetic anhydride (27.7 mL, 294 mmol) was added. After stirring at 0-5 °C for 2 h, the reaction mixture was diluted with water (100 mL) and extracted with DCM (3 x 300 mL). The organic layers were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (PE/EtOAc) to give 3-(((3-((acetylthio)methyl)-1 -methyl-1 H-pyrazol-5- yl)methyl)thio)naphthalen-1 -yl acetate (Intermediate 37, 36.0 g, 72%); M/Z (ES+), [M+H]⁺ = 401 . ¹ H NMR (400 MHz, DMSO-ofe) δ 2.29 (s, 3H), 2.46 (s, 3H), 3.76 (s, 3H), 3.92 (s, 2H), 4.43 (s, 2H), 6.04 (s, 1 H), 7.36 (s, 1 H), 7.52-7.61 (m, 2H), 7.83-7.92 (m, 3H).

Intermediate 38: Ethyl 4-acetoxy-2-naphthoate

Sodium (50.3 g, 2.19 mol) was added to EtOH (2000 mL) at 25 °C under nitrogen. The resulting mixture was stirred at 50 °C for 2 h. A mixture of benzaldehyde (116 g, 1 .09 mol) and diethyl succinate (200 g, 1 .15 mol) in anhydrous ethanol (350 mL) was added dropwise over 2 h at 50 °C. The resulting mixture was stirred at reflux for 4 h. The solvent was removed under reduced pressure. The residue was diluted with water (3000 mL). The pH value of the solution was adjusted to 5-6 with cone. HCI. The mixture was extracted with EtOAc (3 x 1500 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to afford 3- (ethoxycarbonyl)-4-phenylbut-3-enoic acid (231 g, 90 %). This acid intermediate was dissolved in acetic anhydrous (700 mL). Sodium acetate (81 .0 g, 986 mmol) was added. The resulting solution was stirred at reflux for 3 h. After cooling to 40 °C, the mixture was diluted with water (3500 mL) and stirred for 1 .5 h. The brown tar was extracted with EtOAc (3 x 1500 mL). The combined organic extracts were washed with sat. NaHC0₃ solution (3 x 3000 mL), brine (2000 mL), dried over Na₂S04 and concentrated. The residue was purified by silica gel

chromatography (PE/EtOAc) to give ethyl 4-acetoxy-2-naphthoate (Intermediate 38, 102 g, 40%) as a solid; M/Z (ES+), [M+H]⁺ = 259. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ 1 .46 (t, 3H), 2.51 (s, 3H), 4.46 (q, 2H), 7.59-7.64 (m, 2H), 7.83-7.95 (m, 2H), 7.98-8.05 (m, 1 H), 8.52 (s, 1 H).

Intermediate 39: Ethyl 4-hydroxy-2-naphthoate

K2CO3 (88.0 g, 639 mmol) was added to a solution of ethyl 4-acetoxy-2-naphthoate

(Intermediate 38, 110 g, 426 mmol) in MeOH (1100 mL). The resulting suspension was stirred at RT for 30 min. The reaction mixture was poured into water (6000 mL). The aq. phase was extracted with EtOAc (4 x 1500 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to afford ethyl 4-hydroxy-2-naphthoate (Intermediate 39, 82.0 g, 89%) as a solid; M/Z (ES+), [M+H]⁺ = 217. ¹ H NMR (400 MHz, CHLOROFORM-c ) δ 1 .48 (t, 3H), 4.48 (q, 2H), 6.28 (br s, 1 H), 7.50-7.67 (m, 3H), 7.89-7.98 (m, 1 H), 8.21 -8.32 (m, 2H). Intermediate 40: Ethyl 4-(benzyloxy)-2-naphthoate

K2CO3 (28.8 g, 208 mmol) was added to a mixture of ethyl 4-hydroxy-2-naphthoate

(Intermediate 39, 30.0 g, 138 mmol) and (bromomethyl)benzene (28.5 g, 166 mmol) in CH₃CN (300 ml.) at 25 °C. After stirring at RT for 16 h, the reaction mixture was poured into water (1 L). The solution was extracted with EtOAc (3 x 250 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was triturated with petroleum ether to give a solid which was collected by filtration and dried under vacuum to give ethyl 4-(benzyloxy)-2- naphthoate (Intermediate 40, 33.6 g, 79%); M/Z (ES+), [M+H]⁺ = 307. ¹ H NMR (400 MHz, CHLOROFORM-oO δ 1 .48 (t, 3H), 4.47 (q, 2H), 5.34 (s, 2H), 7.33-7.42 (m, 1 H), 7.43-7.49 (m, 2H), 7.53 (s, 1 H), 7.56-7.63 (m, 4H), 7.90-7.99 (m, 1 H), 8.24-8.29 (m, 1 H), 8.34-8.43 (m, 1 H).

Intermediate 41 : (4-(Benzyloxy)naphthalen-2-yl)methanol

A solution of LiAIH₄ (6.24 g, 164 mmol) in THF (200 ml.) was added to a solution of ethyl 4-(benzyloxy)-2-naphthoate (Intermediate 40, 33.6 g, 109 mmol) at 0 °C under nitrogen. The resulting mixture was stirred at RT for 1 h. Na₂SO4.10H₂O (25.0 g) was added at 0 °C. The mixture was filtered through a pad of diatomaceous earth. The solvent was removed under reduced pressure to afford (4-(benzyloxy)naphthalen-2-yl)methanol (Intermediate 41 , 27.4 g, 95%) as a solid; M/Z (ES+), [M+H]⁺ = 265. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ 4.83 (s, 2H), 5.28 (s, 2H), 6.96 (s, 1 H), 7.34-7.60 (m, 8H), 7.76-7.86 (m, 1 H), 8.31 -8.38 (m, 1 H).

Intermediate 42: 4-(Benzyloxy)-2-naphthaldehyde

Manganese (IV) oxide (90.0 g, 1 .03 mol) was added to a solution of (4-(benzyloxy) naphthalen-2-yl)methanol (Intermediate 41 , 27.4 g, 103 mmol) in DCM (500 ml_). After stirring at RT for 16 h, the reaction mixture was filtered through a pad of diatomaceous earth. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (PE/EtOAc) to afford 4-(benzyloxy)-2-naphthaldehyde (Intermediate 42, 23.8 g, 88%); M/Z (ES+), [M+H]⁺ = 263. ¹ H NMR (400 MHz, CHLOROFORM-of) δ 5.28 (d, 2H), 7.29- 7.71 (m, 8H), 7.88-8.01 (m, 2H), 8.31 -8.43 (m, 1 H), 10.07 (s,1 H).

Intermediate 43: (E/Z) Ethyl 5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazole-3- carboxylate

OEt

Anhydrous THF (300 mL) was added to ((3-(ethoxycarbonyl)-1 -methyl-1 H-pyrazol-5- yl)methyl)triphenylphosphonium chloride (Intermediate 34, 26.7 g, 54.3 mmol) to give a suspension at 0 °C. NaH (2.17 g, 54.3 mmol) (60% in oil) was added under N₂. After stirring at 0 °C for 40 min, the mixture was cooled to -20 °C. 4-(Benzyloxy)-2-naphthaldehyde

(Intermediate 42, 13.0 g, 49.4 mmol) in THF (30.0 mL) was added at -30 to -20 °C slowly. After addition, the mixture was stirred at -10 °C for 2 h. Sat. NH₄CI solution (200 mL) was added to quench the reaction at -10 °C. The layers was separated. The aq. phase was extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc) to give a mixture of (E/Z) ethyl 5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 - methyl-1 H-pyrazole-3-carboxylate (Intermediate 43, 19.2 g, 94%); M/Z (ES+), [M+H]⁺ = 413.

Intermediate 44: (E/Z) (5-(2-(4-(Benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazol-3- yl)methanol

A mixture of (E/Z) ethyl 5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazole- 3-carboxylate (Intermediate 43, 23.5 g, 57.0 mmol) in anhydrous THF (160 mL) was cooled to 0 °C. LAH (21 .1 mL, 42.2 mmol) (2M in THF) was added at 0 °C. After stirring at 0 °C for 30 min and RT for 30 min under N₂, the reaction was quenched with 1 .60 mL of water, 1 .60 mL of 15% NaOH then 4.80 mL of water at 0 °C. The mixture was stirred at 0 °C for 15 min and RT for 30 min. Na₂S04 (50.0 g) was added. The suspension was filtered and the solid cake was washed with EtOAc (700 mL). The combined organic solution was concentrated to dryness. EtOAc (150 mL) was added to the residue and sonicated to give a suspension. The solids were collected by filtration and washed with EtOAc (20 mL) to give the first batch of product (11 .0 g). The mother liquid was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give the second batch of product (4.80 g). The total amount of (E/Z) (5-(2-(4-(Benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (intermediate 44) was 15.8 g (75%); M/Z (ES+), [M+H]⁺ = 371 . ¹ H NMR (300 MHz,

CHLOROFORM-o δ 3.95 (s, 3H), 4.70 (s, 2H), 5.33 (s, 2H), 6.51 (s, 1 H), 7.04-7.13 (m, 3H), 7.40-7.59 (m, 8H), 7.76-7.82 (m, 1 H), 8.28-8.33 (m, 1 H).

Intermediate 45: 3-(2-(3-(Hydroxymethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol

Pd/C (0.517 g, 4.86 mmol) (10% Pd on carbon) was added to a solution of (E/Z) (5-(2-(4- (benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 44, 18.0 g, 48.6 mmol) in THF (500 mL) and MeOH (500 mL). The mixture was degassed, filled with H₂ three times and stirred under an atmosphere of H₂ at 25 °C for 16 h. The reaction mixture was filtered through a pad of diatomaceous earth and the solid cake was washed with MeOH (3 x 100 mL) to give 3-(2-(3-(hydroxymethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol

(Intermediate 45, 11 .1 g, 81 %) as a solid; M/Z (ES+), [M+H]⁺ = 283. ¹ H NMR (300 MHz, DMSO-ce) δ 2.93-2.94 (m, 4H), 3.65 (s, 3H), 4.20 (d, 2H), 4.86 (t, 1 H), 6.03 (s, 1 H), 6.79 (s, 1 H), 7.22 (s, 1 H), 7.35-7.45 (m, 2H), 7.68-7.78 (m, 1 H), 8.01 -8.11 (m, 1 H), 10.04 (s, 1 H).

Intermediate 46: 3-(2-(3-((Acetylthio)methyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -yl acetate

Thionyl chloride (3.29 mL, 45.1 mmol) was added dropwise to 3-(2-(3-(hydroxymethyl)-1 - methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol (Intermediate 45, 10.6 g, 37.5 mmol) in THF (200 mL) at 0°C. The resulting mixture was stirred at 0-25 °C for 1 h. The reaction mixture was basified with sat. NaHC0₃ solution. The layers were separated. The aq. phase was extracted with DCM (3 x 300 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to afford 3-(2-(3-(chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol (10.0 g, 89%) as a white solid, which was used without further purification.

Potassium iodide (0.552 g, 3.32 mmol) was added to a mixture of 3-(2-(3-(chloromethyl)- 1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol (10.0 g, 33.3 mmol) and potassium

ethanethioate (22.8 g, 199 mmol) in MeCN (200 mL). After stirring at 40 °C for 16 h, the reaction mixture was diluted with water (100 mL). The resulting solution was extracted with EtOAc (3 x 75 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc) to afford 3-(2-(3- ((acetylthio)methyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -yl acetate (Intermediate 46, 7.70 g, 61 %); M/Z (ES+), [M+H]⁺ = 383. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ 2.37 (s, 3H), 2.49 (s, 3H), 2.95 (t, 2H), 3.09 (t, 2H), 3.66 (s, 3H), 4.13 (s, 2H), 6.04 (s, 1 H), 7.11 (d, 1 H), 7.47- 7.54 (m, 3H), 7.80-7.85 (m, 2H).

Intermediate 47: (E/Z) 3-(Azidomethyl)-5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H- pyrazole

A mixture of (E/Z) (5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazol-3- yl)methanol (Intermediate 44, 10.2 g, 27.5 mmol) was dissolved in DCM (100 mL) and cooled to 0 °C. Thionyl chloride (2.11 mL, 28.9 mmol) was added at 0 °C. After addition, the mixture was stirred at RT for 1 h. 0.1 equiv. of thionyl chloride was added again. After another 1 h at RT, the mixture was cooled to 0 °C, diluted with DCM (300 mL) and quenched with sat. NaHC0₃ (100 mL). The layers were separated. The organic phase was washed with sat. NaHC0₃ (2 x 50 mL), brine, dried over Na₂S04, filtered and concentrated to dryness to give a mixture of (E/Z) 5- (2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-3-(chloromethyl)-1 -methyl-1 H-pyrazole. This chloride intermediate was dissolved in acetonitrile (100 mL). Kl (4.57 g, 27.5 mmol) and sodium azide (8.94 g, 137 mmol) were added. After stirring at 85 °C for 2 h, the mixture was cooled to RT and filtered to remove inorganic salts which were washed with EtOAc (100 mL). The organic solution was concentrated to dryness. EtOAc (200 mL) was added to the residue. The organic phase was washed with water (50 mL), brine (20 mL), dried over Na₂S04, filtered and concentrated to dryness. The residue was sonicated in EtOAc (20 mL) to give a suspension. The solids were collected by filtration, washed with EtOAc (10 mL) to give the first batch of product. The mother liquid was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give the second batch of product. The total amount of (E/Z) 3- (azidomethyl)-5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazole (Intermediate 47) was 8.40 g (77% yield); M/Z (ES+), [M+H]⁺ = 396. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 3.95 (s, 3H), 4.34 (s, 2H), 5.31 (s, 2H), 6.51 (s, 1 H), 6.88 (d, 1 H), 7.02 (s, 1 H), 7.15 (d, 1 H), 7.34- 7.59 (m, 8H), 7.79-7.81 (m, 1 H). 8.27-8.30 (m, 1 H).

Intermediate 48: 3-(2-(3-(Aminomethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol

(E/Z) 3-(Azidomethyl)-5-(2-(4-(benzyloxy)naphthalen-2-yl)vinyl)-1 -methyl-1 H-pyrazole (Intermediate 47, 3.00 g, 7.59 mmol) was dissolved in EtOAc (37.9 mL) and MeOH (37.9 mL). The solution was degassed, re-filled with N₂, Pd/C (0.202 g) (10 wt% on C) was added. The black suspension was degassed, re-filling with H₂ three times. The mixture was stirred at RT under an atmosphere of H₂ for 16 h. 0.300 g of Pd/C was added again. After stirring at RT for total 49 h under H₂, the mixture was filtered through a pad of diatomaceous earth and the solid cake was washed with 10% MeOH in EtOAc (100 mL). The combined organic solution was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/DCM to 1 % Et₃N in MeOH/DCM(1 :10)) to give 3-(2-(3-(aminomethyl)-1 -methyl-1 H-pyrazol-5- yl)ethyl)naphthalen-1 -ol (Intermediate 48, 1 .73 g, 80%); M/Z (ES+), [M+H]⁺ = 282. ¹ H NMR (300 MHz, DMSO-ce) δ 2.82-3.01 (m, 4H), 3.54 (s, 2H), 3.63 (s, 3H), 6.01 (s, 1 H), 6.77 (s, 1 H), 7.20 (s, 1 H), 7.32-7.46 (m, 2H), 7.72 (d, 1 H),8.06 (d, 1 H).

Intermediate 49: 6-Bromo-8-methoxyqu

4-Bromo-2-methoxyaniline (50.0 g, 247 mmol) was added to a mixture of sodium 3- nitrobenzenesulfonate (86.8 g, 385 mmol) and propane-1 ,2,3-triol (108 g, 1 .18 mol) in cone. H₂SO4 (97 ml.) and water (75.7 ml.) at 0 °C over a period of 30 min under nitrogen. After stirring at 120 °C for 24 h and then cooling to RT, the reaction mixture was quenched slowly with 2M NaOH (1 L). The aq. solution was extracted with EtOAc (3 x 500 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to afford 6-bromo-8- methoxyquinoline (Intermediate 49, 60.0 g, 100%); M/Z (ES+), [M+H]⁺ = 237. ¹ H NMR (300 MHz, DMSO-ofe) δ 3.99 (s, 3H), 7.30 (d, 1 H), 7.58-7.60 (m, 1 H), 7.79 (s, 1 H), 8.28 (dd, 1 H), 8.86 (dd, 1 H).

Intermediate 50: 6-Bromoquinolin-8-ol

6-Bromo-8-methoxyquinoline (Intermediate 49, 59.0 g, 248 mmol) was added to 48% HBr solution (500 ml.) under nitrogen. After stirring at 145 °C for 24 h and then cooling to RT, the reaction mixture was quenched with 2M NaOH to adjust pH to 7. The aq. phase was extracted with EtOAc (3 x 500 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by crystallization from petroleum ether/MeOH to afford 6-bromoquinolin-8-ol (Intermediate 50, 35.0 g, 63%) as a brown solid; M/Z (ES+), [M+H]⁺ = 224. ¹ H NMR (300 MHz, METHANOL-c/4) δ 7.23 (s, 1 H), 7.52-7.59 (m, 2H), 8.21 (d, 1 H), 8.82 (d,1 H). Intermediate 51 : 6-Bromo-8-((4-methoxybenzyl)oxy)qu

K2CO3 (55.5 g, 402 mmol) was added portion wise to a mixture of 1 -(chloromethyl)-4- methoxybenzene (37.7 g, 241 mmol) and 6-bromoquinolin-8-ol (Intermediate 50, 45.0 g, 201 mmol) in DMF (500 mL) under nitrogen over a period of 5 min. The resulting mixture was stirred at 25 °C for 3 h, then diluted with water (3 L) and stirred at RT for further 30 min to give a suspension. The solids were collected by filtration, washed with water (3 x 500 mL), PE:EtOAc (10:1 , 3 x 500 mL) and dried under vacuum to give 6-bromo-8-((4-methoxybenzyl)oxy)quinoline (Intermediate 51 , 37.0 g, 54%); M/Z (ES+), [M+H]⁺ = 344. ¹ H NMR (300 MHz, DMSO-ofe) δ 3.79 (s, 3H), 5.26 (s, 2H), 7.01 (d, 2H), 7.38-7.50 (m, 3H), 7.56-7.71 (m, 1 H), 7.82 (s, 1 H), 8.30 (d, 1 H), 8.74-9.00 (m, 1 H).

Intermediate 52: Ethyl 5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate

Pd₂(dba)₃ (1 .32 g, 1 .44 mmol) was added to a mixture of ethyl 5-((acetylthio)methyl)-1 - methyl-1 H-pyrazole-3-carboxylate (Intermediate 33, 9.70 g, 40.0 mmol), 6-bromo-8-((4- methoxybenzyl)oxy)quinoline (Intermediate 51 , 9.08 g, 26.4 mmol), 2-dicyclohexylphosphino- 2',4',6'-tri-iso-propyl-1 ,1 '-biphenyl (1 .32 g, 2.76 mmol) and K₂C0₃ (3.82 g, 27.7 mmol) in THF (200 mL) and water (50 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 23 h under nitrogen. After cooling to RT, the reaction solvent was removed under reduced pressure. Water (100 mL) and EtOAc (200 mL) were added into the residue. The resulting two layers were separated. The aq. layer was extracted with EtOAc (2 x 200 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc) to give ethyl 5-(((8-((4-methoxybenzyl)oxy)quinolin-6- yl)thio)methyl)-1 -methyl-1 H-pyrazole-3-carboxylate (Intermediate 52, 10.0 g, 82%); M/Z (ES+), [M+H]⁺ = 464. ¹ H NMR (400 MHz, DMSO-ofe) δ 1 .20 (t, 3H), 3.77 (s, 3H), 3.93 (s, 3H), 4.17 (q, 2H), 4.51 (s, 2H), 5.20 (s, 2H), 6.59 (s, 1 H), 6.95-7.04 (m, 2H), 7.22 (s, 1 H), 7.43-7.49 (m, 2H), 7.49-7.57 (m, 2H), 8.21 -8.23 (m, 1 H), 8.75-8.77 (m, 1 H).

Intermediate 53: (5-(((8-((4-Methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol- 3-yl)methanol

A solution ethyl 5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazole-3-carboxylate (Intermediate 52, 9.35 g, 20.2 mmol) in THF (100 mL) was cooled to -40 °C. LAH (12.1 mL, 24.2 mmol) (2M in THF) was added dropwise. After stirring at -40 °C for 3 h, the reaction was warmed up to 4 °C, quenched with 1 .00 mL of water , followed by 1 .00 mL of 15% NaOH solution and 3.00 mL of water. The mixture was stirred at RT for 20 min.

Na2S04 (10.0 g) was added. The resulting mixture was stirred at RT for 10 min. The mixture was filtered through a pad of diatomaceous earth and washed with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 53, 6.20 g, 73%); M/Z (ES+), [M+H]⁺ = 422. ¹ H NMR (400 MHz,DMSO-ofe) δ 3.78 (s, 6H), 4.28 (d, 2H), 4.46 (s, 2H) 4.90 (t, 1 H) 5.22 (s, 2H), 6.13 (s, 1 H), 6.94-7.05 (m, 2H), 7.23 (s, 1 H), 7.43-7.59 (m, 4H), 8.22 (dd, 1 H), 8.78 (dd, 1 H).

Intermediate 54: 6-(((3-(Chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)-8-((4- methoxybenzyl)oxy)quinoline

A mixture of (5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazol-3-yl)methanol (Intermediate 53, 3.40 g, 8.07 mmol), 2,6-lutidine (3.76 mL, 32.3 mmol), and lithium chloride (1 .71 g, 40.3 mmol) in DMF (27.3 mL) was cooled to 0 °C. Methanesulfonyl chloride (1 .25 ml, 16.1 mmol) was added dropwise. After addition, the ice bath was removed. The mixture was stirred at RT for 2 h. Water (100 mL) and EtOAc (200 mL) were added. The layers were separated. The organic phase was dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give 6-(((3- (chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)-8-((4-methoxybenzyl)oxy)quinoline

(Intermediate 54, 2.86 g, 81 %); M/Z (ES+), [M+H]⁺ = 440. ¹ H NMR (400 MHz, DMSO-ofe) δ 3.77 (s, 3H), 3.81 (s, 3H), 4.46 (s, 2H), 4.56 (s, 2H), 5.22 (s, 2H), 6.20 (s, 1 H), 6.99-7.10 (m, 2H), 7.23 (s, 1 H), 7.41 -7.59 (m, 4H), 8.20-8.22 (m, 1 H), 8.75-8.78 (m, 1 H).

Intermediate 55: S-((5-(((8-((4-Methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazol-3-yl) methyl) ethanethioate

Potassium iodide (1 .08 g, 6.50 mmol) and potassium ethanethioate (1 .48 g, 13.0 mmol) were added to a solution of 6-(((3-(chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)-8-((4- methoxybenzyl)oxy)quinoline (Intermediate 54, 2.86 g, 6.50 mmol) in CH₃CN (32.5 mL). After stirring at RT overnight, the reaction solvent was removed under reduced pressure. Water (30 mL) and DCM (50 mL) were added to the residue. The resulting two layers were separated. The organic phase was dried over MgSC and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give S-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl) ethanethioate (Intermediate 55, 3.00 g, 96%); M/Z (ES+), [M+H]⁺ = 480. ¹ H NMR (300 MHz, METHANOL-^) δ 2.25 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 3.96 (s, 2H), 4.25 (s, 2H), 5.36 (s, 2H), 5.79 (s, 1 H), 7.02 (d, 2H), 7.18 (d, 1 H), 7.46 (d, 1 H), 7.54 (d, 2H), 7.58-7.62 (m, 1 H), 8.26 (dd, 1 H), 8.81 -8.83 (m, 1 H).

Intermediate 56: (3-(((te/?-Butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-5-yl)methanol

Ethyl 3-(((teri-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5-carboxylate

(Intermediate 7, 23.5 g, 64 wt% purity, 35.6 mmol) was dissolved in THF (160 mL) and cooled to 0 °C. LiAIH₄ (17.8 mL, 35.6 mmol) (2M in THF) was added. The mixture was stirred at 0 °C for 2 h and then quenched with 1 .35 mL of water, followed by 1 .35 mL of 15% NaOH solution and 4.05 mL of water at 0 °C. After stirring at RT for 20 min, Na₂S0₄ (10.0 g) was added to the mixture. The solids were removed by filtration and washed with EtOAc (100 mL). The combined organic phases were concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (3-(((te/t-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H- pyrazol-5-yl)methanol (Intermediate 56, 13.1 g, 97%); M/Z (ES+), [M+H]⁺ = 381 . 1 H NMR (400 MHz, CHLOROFORM-oO δ 1 .08 (s, 9H), 3.84 (s, 3H), 4.64 (s, 2H), 4.72 (s, 2H), 6.21 (s, 1 H), 7.35-7.49 (m, 6H), 7.71 (m, 4H).

Intermediate 57: 3-(((te/t-Butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5-carbaldehyde

Manganese dioxide (50.0 g, 575 mmol) was added to a solution of {3-{{{tert- butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-5-yl)methanol (Intermediate 56, 19.5 g, 51 .2 mmol) in acetone (300 mL). After stirring at RT for 60 h, the suspension was filtered through a pad of diatomaceous earth. The filtrate cake was washed with 200 mL of acetone. The filtrate was concentrated. The residue was purified by silica gel chromatography

(PE/EtOAc) to afford 3-(((te -butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5- carbaldehyde (Intermediate 57, 16.0 g, 82%); M/Z (ES+), [M+H]⁺ = 379. ¹ H NMR (400 MHz, DMSO-ofe) δ 1 .02 (s, 9H), 4.06 (s, 2H), 4.71 (s, 2H), 6.99 (s, 1 H), 7.38-7.50 (m, 6H), 7.64-7.71 (m, 5H), 9.89 (s, 1 H).

Intermediate 58: 3-(((te -Butyldiphen lsilyl)oxy)methyl)-5-ethynyl-1 -methyl-1 H-pyrazole

K2CO3 (17.6 g, 127 mmol) was added to a mixture of 3-(((tert- butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazole-5-carbaldehyde (Intermediate 57, 16.2 g, 42.8 mmol) and dimethyl (1 -diazo-2-oxopropyl)phosphonate (12.3 g, 64.0 mmol) in MeOH (150 mL) at 0 °C in several portions under nitrogen. The resulting suspension was then stirred at RT for 1 h, then diluted with 50 mL of water and concentrated. Water (250 mL) was added to the resulting residue again. This aq. phase was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc) to afford 3- (((te/?-butyldiphenylsilyl)oxy)methyl)-5-ethynyl-1 -methyl-1 H-pyrazole (Intermediate 58, 10.0 g, 62%); M/Z (ES+), [M+H]⁺ = 375. ¹ H NMR (400 MHz, CHLOROFORM-of) δ 1 .09 (s, 9H), 3.52 (s, 1 H), 3.89 (s, 3H), 4.73 (s, 2H), 6.50 (s, 1 H), 7.28-7.46 (m, 6H), 7.70-7.74 (m, 4H).

Intermediate 59: 6-((3-(((te -Butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-5-yl)ethynyl)- 8-((4-methoxybenzyl)oxy)quinoline

6-Bromo-8-((4-methoxybenzyl)oxy)quinoline (Intermediate 51 , 2.66 g, 7.73 mmol), bis(triphenylphosphine)palladium(ll) chloride (0.542 g, 0.77 mmol), and copper(l) iodide (0.147 g, 0.770 mmol) were added to a solution of 3-(((teri-butyldiphenylsilyl)oxy)methyl)-5-ethynyl-1 - methyl-1 H-pyrazole (Intermediate 58, 3.76 g, 10.1 mmol) in DMF (26.6 mL). The mixture was degassed and re-filled with N₂. TEA (4.31 mL, 30.9 mmol) was added. After stirring at 80 °C under N₂ overnight, the mixture was cooled to RT and concentrated. EtOAc (100 mL) was added to the resulting residue. This organic phase was washed with sat. NH₄OH solution (40 mL), brine (30 mL) and dried over Na₂S04 and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give 6-((3-(((teri-butyldiphenylsilyl)oxy)methyl)-1 - methyl-1 H-pyrazol-5-yl)ethynyl)-8-((4-methoxybenzyl)oxy)quinoline (Intermediate 59, 4.41 g, 89%); M/Z (ES+), [M+H]⁺ = 638. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .09 (s, 9H), 3.81 (s, 3H), 3.95 (s, 2H), 4.76 (s, 2H), 5.43 (s, 2H), 6.57 (s, 1 H), 6.84-7.00 (m, 2H), 7.23-7.27 (m, 2H), 7.33-7.82 (m, 14H), 8.24-8.26 (m, 1 H), 9.08-9.10 (m, 1 H).

Intermediate 60: (5-((8-((4-Methoxybenzyl)oxy)quinolin-6-yl)ethynyl)-1 -methyl-1 H-pyrazol-3- yl)methanol

A solution of 6-((3-(((te/?-butyldiphenylsilyl)oxy)methyl)-1 -methyl-1 H-pyrazol-5- yl)ethynyl) -8-((4-methoxybenzyl)oxy)quinoline (Intermediate 59, 4.20 g, 6.58 mmol) in THF (26.3 mL) was cooled to 0 °C. TBAF (6.58 mL, 6.58 mmol) (1 M in THF) was added. The reaction was allowed to warm up to RT and stirred at RT for 1 h. The reaction solvent was removed under reduced pressure. The residue was re-dissolved in water (50 mL) and DCM (75 mL). The layers were separated. The organic phase was dried over dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography

(hexanes/DCM/10%MeOH in DCM) to (5-((8-((4-methoxybenzyl)oxy)quinolin-6-yl)ethynyl)-1 - methyl-1 H-pyrazol-3-yl)methanol (Intermediate 60, 2.45 g, 93%); M/Z (ES+), [M+H]⁺ = 400. ¹ H NMR (300 MHz CHLOROFORM-of) δ 3.81 (s, 3H), 3.99 (s, 3H), 4.69 (s, 2H), 5.41 (s, 2H), 6.51 (s, 1 H), 6.85-6.97 (m, 2H), 7.19 (s, 1 H), 7.48-7.58 (m, 3H), 7.63-7.65 (m, 1 H), 8.21 (br d, 1 H), 8.96-9.16 (m, 1 H).

Intermediate 61 : (5-(2-(8-((4-Methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methanol

Pd/C (300 mg) (10% wet base) was added to a solution of (5-((8-((4-Methoxybenzyl)oxy) quinolin-6-yl)ethynyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 60, 2.1 1 g, 5.28 mmol) in MeOH (26.0 mL) and DCM (1 1 mL). The suspension was degassed, re-filled with H₂ three times and stirred at RT under an atmosphere of H₂ for 3.5 h. The mixture was filtered through a pad of diatomaceous earth and the solid cake was washed with 10% MeOH in DCM (50 mL). The combined organic solution was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/DCM to 1 % Et₃N in MeOH/DCM(1 :10)) to give (5-(2-(8-((4- methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 61 , 1 .50 g, 70%); M/Z (ES+), [M+H]⁺ = 404. ¹ H NMR (300MHz, METHANOL-^) δ 2.91 -3.04 (m, 2H), 3.05-3.12 (m, 2H), 3.51 (s, 3H), 3.78 (s, 3H), 4.46 (s, 2H), 5.28 (s, 2H), 6.06 (s, 1 H), 6.86- 6.95 (m, 2H), 7.07 (s, 1 H), 7.24 (s, 1 H), 7.41 -7.59 (m, 3H), 8.19 (dd, 1 H), 8.72 (dd, 1 H).

Intermediate 62: 6-(2-(3-(Chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)-8-((4- methoxybenzyl)oxy)quinoline

A mixture of (5-(2-(8-((4-methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methanol (Intermediate 61 , 1 .50 g, 3.72 mmol), 2,6-lutidine (2.16 mL, 18.6 mmol), and lithium chloride (0.95 g, 22.3 mmol) in DMF (12.1 mL) were stirred at RT. Methanesulfonyl chloride (0.58 mL, 7.44 mmol) was added dropwise. After stirring at RT overnight, H₂0 (50 mL) and EtOAc (200 mL) were added to the reaction mixture. The layers were separated. The organic phase was dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give 6-(2-(3-(chloromethyl)-1 -methyl-1 H-pyrazol- 5-yl)ethyl)-8-((4-methoxybenzyl)oxy)quinoline (Intermediate 62, 1 .34 g, 85%); M/Z (ES+),

[M+H]⁺ =422. ¹ H NMR (300 MHz CHLOROFORM-c/) δ 2.87-2.99 (m, 2H), 3.01 -3.09 (m, 2H), 3.60 (s, 3H), 3.82 (s, 3H), 4.56 (s, 2H), 5.37 (s, 2H), 6.10 (s, 1 H), 6.88-6.93 (m, 3H), 7.15 (s, 1 H), 7.46-7.50 (m, 3H), 8.09-8.12 (m, 1 H), 8.97-8.90 (m, 1 H).

Intermediate 63: S-((5-(2-(8-((4-Methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methyl) ethanethioate

A mixture of 6-(2-(3-(Chloromethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)-8-((4- methoxybenzyl) oxy)quinoline (Intermediate 62, 1 .34 g, 3.18 mmol), sodium iodide (0.48 g, 3.18 mmol) and potassium ethanethioate (0.73 g, 6.35 mmol) in CH₃CN (15.9 mL) was stirred at RT overnight. The reaction solvent was removed under reduced pressure. The residue was re- dissolved in H₂0 (20 mL) and DCM (40 mL). The layers were separated. The organic phase was dried over MgSC and concentrated. The residue was purified by silica gel

chromatography (hexanes/EtOAc) to yield S-((5-(2-(8-((4-methoxybenzyl)oxy)quinolin-6- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl) ethanethioate (Intermediate 63, 1 .27 g, 87%) ; M/Z (ES+), [M+H]⁺ = 462. ¹ H NMR (300 MHz CHLOROFORM-c ) δ 2.35 (s, 3H), 2.87-2.99 (m, 2H), 3.01 -3.06 (m, 2H), 3.57 (s, 3H), 3.82 (s, 3H), 4.10 (s, 2H), 5.37 (s, 2H), 5.99 (s, 1 H), 6.87-6.93 (m, 3H), 7.15 (s, 1 H), 7.46-7.50 (m, 3H), 8.09-8.13 (m, 1 H), 8.97-8.90 (m, 1 H).

Intermediate 64: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((((5-(2-(8- ((4-methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

A mixture of (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (iodomethyl) -1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 26,1 .38 g, 1 .84 mmol) and S-((5-(2-(8-((4-methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl-1 H- pyrazol-3-yl) methyl) ethanethioate (Intermediate 63, 706 mg, 1 .53 mmol) in MeOH (15 ml.) was degassed and re-filled with N₂ three times. K₂C0₃ (423 mg, 3.06 mmol) was added. After stirring at RT for 4 h under N₂, the mixture was concentrated to dryness and EtOAc (100 ml.) was added. The organic phase was washed with water, dried over Na₂S04 and concentrated. The residue was purified by silica gel column chromatography (hexanes/DCM to 10% MeOH in DCM) to give (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((((5-(2-(8-((4- methoxybenzyl)oxy) quinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 64, 1 .51 g, 94%); M/Z (ES+), [M+H]⁺ = 1045. ¹ H NMR (300MHz, CHLOROFORM-c/) δ 1 .08 (s, 9H), 1 .83-1 .95 (m, 2H), 2.04 (s, 3H), 2.72-2.81 (m, 2H), 2.88-2.99 (m, 2H), 3.04-3.14 (m, 2H), 3.44 (s, 3H), 3.46- 3.58 (m, 7H), 3.71 -3.79 (m, 5H), 3.81 (s, 3H), 3.87 (s, 3H), 5.35 (s, 2H), 5.64 (s, 1 H), 6.84-6.93 (m, 3H), 7.08 (s, 1 H), 7.19 (d, 1 H), 7.33-7.51 (m, 9H), 7.52-7.62 (m, 1 H), 7.67-7.70 (m, 4H), 8.09-8.1 1 (m, 1 H), 8.99-9.01 (m, 1 H).

Intermediate 65: (±)-Methyl 6-chloro-3-(3-hydroxypropyl)-7-(5-((((5-(2-(8-hydroxyquinolin-6- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate

TFA (6.00 mL, 77.9 mmol) was added to a solution of (±)-methyl 3-(3-((te/t-butyldiphenyl silyl)oxy)propyl)-6-chloro-7-(5-((((5-(2-(8-((4-methoxybenzyl)oxy)quinolin-6-yl)ethyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 64, 1 .51 g, 1 .44 mmol) in DCM (6.00 mL) at RT. After stirring at RT for 2 h, the reaction mixture was concentrated to dryness. The residue was re-dissolved in MeOH (7 mL). TEA (2 mL) was added slowly. The mixture was stirred for 30 min and concentrated to dryness. Water (20 mL) was added and the aqueous phase was extracted with DCM (3 x 30 mL). The combined organic phase were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes/DCM then 10% MeOH in DCM) to give (±)-methyl 6-chloro-3-(3-hydroxypropyl)-7-(5-((((5-(2-(8- hydroxyquinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H- pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 65, 890 mg, 90%); M/Z (ES+), [M+H]⁺ = 687. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .90-1 .97 (m, 2H), 2.04 (s, 3H), 2.75- 2.91 (m, 2H), 2.93-3.03 (m, 2H), 3.05-3.17 (m, 2H), 3.42-3.55 (m, 7H), 3.57 (s, 3H), 3.60-3.66 (m, 2H), 3.88 (s, 3H), 3.91 (s, 3H), 5.62 (s, 1 H), 7.1 1 (s, 1 H), 7.22-7.25 (m, 2H), 7.51 -7.55 (m, 1 H), 7.62 (d, 1 H), 8.22-8.24 (m, 1 H), 8.78-8.94 (m, 1 H).

Intermediate 66: (±)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12, 13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

A solution of triphenylphosphine (653 mg, 2.49 mmol) in toluene (13 mL) was stirred at 90 °C under N₂. A mixture of (±)-methyl 6-chloro-3-(3-hydroxypropyl)-7-(5-((((5-(2-(8- hydroxyquinolin-6-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H- pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 65, 855 mg, 1 .24 mmol) and di- te/t-butyl diazene-1 ,2-dicarboxylate (573 mg, 2.49 mmol) in THF (13 mL) was added into the PPh₃ solution under N₂ over 30 min via a syringe pump. After addition, the reaction was cooled to RT and concentrated to dryness. The residue was purified by silica gel column

chromatography (hexanes/DCM to in 10% MeOH/DCM with 1 % NH₄OH) to give (±)-methyl 17- chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰·³⁵] octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 66, 510 mg, 61 %); M/Z (ES+), [M+H]⁺ = 669. ¹ H NMR (300MHz, CHLOROFORM-c/) δ 2.03 (s, 3H), 2.20-2.40 (m, 1 H), 2.53 -2.71 (m, 1 H), 2.74 - 3.22 (m, 8H), 3.45-3.50 (m, 5H), 3.58 - 3.72 (m, 5H), 3.84 (s, 3H), 3.87 (s, 3H), 5.02 (s, 1 H), 6.24 (br s, 1 H), 6.77-6.94 (m, 1 H), 7.24-7.26 (m,1 H), 7.58-7.64 (m, 2H), 8.10-8.30 (m, 1 H), 8.99-9.23 (m, 1 H).

Intermediate 67: (±)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12, 13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate

(±) -Methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 66, 510 mg, 0.763 mmol) was dissolved in MeOH (3.81 mL) and acetic acid (3.81 mL). Sodium cyanoborohydride (479 mg, 7.62 mmol) was added. After stirring at 65 °C under N₂ for 3 h and then cooled to RT, the mixture was concentrated. The residue was re-dissolved in DCM (20 mL). This organic solution was washed with sat. Na₂C0₃ (2 x 10 mL), dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel column chromatography

(hexanes/DCM then 10% MeOH in DCM) to give (±)-methyl 17-chloro-5,12,14,22-tetramethyl- 28-oxa-9-thia-5,6,12,13,22,31 -hexaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

undecaene-23-carboxylate (Intermediate 67, 330 mg, 64%); M/Z (ES+), [M+H]⁺ = 673.

Intermediate 67 (330 mg, 0.491 mmol) was subjected to chiral SFC (Chiralpak AD^® column, 21 x 250 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 30:70 /-PrOH:C0₂, UV detection @ 254 nm, loading= 35 mg/inj, cone = 35 mg/mL, Diluent=MeOH/1 %TFA, flow rate = 60 mL/min, Outlet Pressure = 100 bar) to give two enantiomers (/¾)-methyl 17-chloro- 5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate (Intermediate 68a) and (Sa)-methyl 17-chloro-5,12, 14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate (Intermediate 68b)

and /

68a 68b

Intermediate 68a: (fl_a)-enantiomer eluted first (120 mg, 36%, >98% e.e.) : m/z (ES+), [M+H]⁺ = 673.

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak AD^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 40:60 /-PrOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .65 min, >98% e.e.

Intermediate 68b, (S_a)-enantiomer eluted second (100 mg, 30%, >98% e.e.) : m/z (ES+),

[M+H]⁺ = 673.

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak AD^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 40:60 /-PrOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .92 min, 97.2% e.e.

Intermediate 69: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

A mixture of S-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazol-3-yl) methyl) ethanethioate (Intermediate 55, 1 .92 g, 3.99 mmol) and (±)-methyl 3-(3- ((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(iodomethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 26, 3.01 g, 3.99 mmol) in MeOH (30 mL) and acetonitrile (30 mL) was degassed and re-filled with N₂ three times. Potassium carbonate (0.61 g, 4.39 mmol) was added to the mixture. After stirring at 50 °C under N₂ for 2 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes/EtOAc) to yield (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((((5- (((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

(Intermediate 69, 4.05 g, 95%); M/Z (ES+), [M+H]⁺ = 1063. ¹ H NMR (300 MHz, METHANOL-ok) δ 1 .09 (s, 9H), 1 .76-1 .96 (m, 2H), 2.01 (s, 3H), 2.99-3.19 (m, 2H), 3.30-3.40 (m, 2H), 3.44-3.56 (m, 5H), 3.64 (s, 3H), 3.68-3.77 (m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 4.07 (s, 2H), 5.20 (s, 2H), 5.28 (s, 1 H), 6.86-6.99 (m, 2H), 7.05 (s, 1 H), 7.13-7.22 (m, 1 H), 7.30-7.50 (m, 9H), 7.50-7.58 (m, 1 H), 7.58-7.80 (m, 5H), 8.16 (dd, 1 H), 8.78-8.80 (m, 1 H).

Intermediate 70: (±)-Methyl 6-chloro-3-(3-hydroxypropyl)-7-(5-((((5-(((8-hydroxyquinolin-6- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate

TFA (10 ml_, 129 mmol) was added to a solution of (±)-methyl 3-(3-((te/f- butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((((5-(((8-((4-methoxybenzyl)oxy)quinolin-6- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 69, 4.05 g, 3.81 mmol) in DCM (10 mL) at 0 °C. After stirring at 0°C for 2 h, the solvent was removed under reduced pressure. The residue was re-dissolved in DCM (300 mL). The organic phase was washed with sat. NaHC0₃ solution (100 mL), dried over Na₂S04 and concentrated to dryness. This residue was re-dissolved in methanol (30 mL) and DCM (30 mL). Et₃N (20 mL) was added. After stirring at RT for 2 h, the solvent was removed under reduced pressure. The residue was purified by silica gel

chromatography (hexane/EtOAc to 10% MeOH in EtOAc) to yield (±)-methyl 6-chloro-3-(3- hydroxypropyl)-7-(5-((((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

(Intermediate 70, 2.24 g, 83%); M/Z (ES+), [M+H]⁺ = 705. ¹ H NMR (300MHz, DMSO-ofe) δ 1 .60- 1 .80 (m, 2H), 1 .87 (s, 3H), 2.88-3.02 (m, 2H), 3.35-3.37 (m, 5H), 3.38-3.60 (m, 5H), 3.64 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H), 4.28 (s, 2H), 5.73 (s, 1 H), 7.03 (d, 1 H), 7.22 (d, 1 H), 7.31 (d, 1 H), 7.50-7.54 (m, 1 H), 7.71 (d, 1 H), 8.18 (dd, 1 H), 8.77 (dd, 1 H), 10.01 (br s, 1 H).

Intermediate 71 : (±)-Methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

A solution of triphenylphosphine (1 .49 g, 5.67 mmol) in toluene (50 mL) was stirred at 45 °C under N₂. A mixture of (±)-methyl 6-chloro-3-(3-hydroxypropyl)-7-(5-((((5-(((8- hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H- pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 70, 2.00 g, 2.84 mmol) and di- te/t-butyl diazene-1 ,2-dicarboxylate (1 .63 g, 7.09 mmol) in THF (10 mL) was added into the PPh₃ solution under N₂ over 30 min using a syringe pump. After addition, the reaction was cooled to RT and concentrated to dryness. The residue was purified by reverse-phase MPLC (130 g Teledyne ISCO C18 column, Redi Sep; eluted with 20% to 100% ACN/water/0.1 %TFA) to yield the product which was re-purified by silica gel chromatography (hexane/EtOAc to 10% MeOH in EtOAc) to yield (±)-methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-2,9-dithia- 5,6, 12,13,22,31 -hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹ '¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 71 , 1 .27 g, 66%); M/Z (ES+), [M+H]⁺ = 687. ¹ H NMR (300MHz, METHANOL-ok) δ 2.04 (s, 3H), 2.28 - 2.42 (m, 1 H), 2.49-2.61 (m, 1 H), 2.97 (d, 1 H), 3.22-3.32 (m, 3H), 3.47-3.60 (m, 2H), 3.65 (s, 3H), 3.83 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 3.90-4.12 (m, 2H), 4.12-4.32 (m, 2H), 4.99 (s, 1 H), 7.02 (s, 1 H), 7.13 (d, 1 H), 7.72 (s, 1 H), 7.80-7.90 (m, 2H), 8.63-8.65 (m, 1 H), 9.00 (dd, 1 H).

Intermediate 72: (±)-Methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-2,9-dithia- 5,6, 12,13,22,31 -hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹ '¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate

(±) -Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18, 20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 71 , 1 .43 g, 2.09 mmol) was dissolved in EtOH (50 mL) to give a yellow suspension. Cone, hydrogen chloride (0.87 mL, 10.4 mmol) was added. The mixture was cooled to 0 °C, then sodium cyanoborohydride (2.36 g, 37.6 mmol) was added. After stirring at RT for 20 h. A second batch of sodium cyanoborohydride (2.00 g) and cone, hydrogen chloride (0.87 mL, 10.4 mmol) were added. The mixture was stirred at RT for another 20 h. Cone. HCI (1 .6 mL) was added again. The reaction was continued at RT for 3 h and then quenched with sat. NaHC0₃ solution (100 mL), followed by addition of 5% NaOH solution (10 mL). The mixture was extracted with DCM/isopropanol (10/1 ) (3 x 100 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes/EtOAc). The obtained product was re-purified by reverse phase MPLC (C18 column, 40% to 100% ACN/water/0.1 % TFA) to yield (±)-methyl 17-chloro-5,12,14,22-tetramethyl-28- oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,35-undecaene-23-carboxylate (Intermediate 72, 0.89 g, 62%) as a white solid; M/Z (ES+), [M+H]⁺ = 691 .

Intermediate 72 (895 mg, 1 .29 mmol) was subjected to chiral SFC (Chiralpak IC^® column, 30 x 250 mm, 5 μπτι, Temperature = 40 °C, Mobile phase = 45:55 MeOH:C0₂, UV detection @ 254 nm, loading= 55 mg/inj, cone = 70 mg/mL, Diluent=MeOH/DCM, flow rate = 120 mL/min, Outlet Pressure = 100 bar) to give two enantiomers (f?_a)-methyl 17-chloro- 5,12,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate (Intermediate 73a) and (Sa)-methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-2,9-dithia-5,6, 12, 13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox late (Intermediate 73b)

73a 73b

Intermediate 73a is the (f?_a)-enantiomer which eluted first (360 mg, 40%, >98% e.e.): m/z

(ES+), [M+H]⁺ = 691 .

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IC^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 40:60 MeOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 2.77 min, >98% e.e.

Intermediate 73b is the (S_a)-enantiomer which eluted second (400 mg, 45%, >98% e.e.) : m/z (ES+), [M+H]⁺ = 691 . No NMR

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IC^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 40:60 MeOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 3.41 min, >98% e.e.

Intermediate 74: (S_a)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3- hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate

Borane-tetrahydrofuran complex (92.0 mL, 92.2 mmol) in THF (1 M) was added to a solution of (Sa)-methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3- methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 31 , 8.00 g, 18.4 mmol) in THF (60 mL) at RT. After stirring at RT for 4 h, the reaction mixture was cooled to 4 °C. A solution 4M of HCI in 1 ,4-dioxane (30 mL) and MeOH (30 mL) were added slowly. The stirring was continued for 20 min, then the mixture was concentrated. The residue was taken up in EtOAc (250 mL) and water (250 mL). The layers were separated and the aqueous phase was extracted with EtOAc (200 mL). The combined organic phases were washed with brine, dried over Na₂S04, filtered and concentrated to give desired (Sa)-methyl 6-chloro-7-(5- (hydroxymethyl)-l ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2- carboxylate, which was taken on without purification (Intermediate 74, 7.60 g, 100%) ; M/Z (ES+), [M+H]⁺ = 406. ¹ H NMR (400MHz, DMSO-ofe) δ 1 .65-1 .80 (m, 2H), 1 .88 (s, 3H), 2.93-3.06 (m, 2H), 3.30-3.52 (m, 5H), 3.85 (s, 3H), 3.86 (s, 3H), 4.12 (AB d, 1 H) 4.31 (AB d, 1 H), 7.27 (d, 1 H), 7.73 (d, 1 H).

Intermediate 75: (S_a)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

Diisopropylethylamine (5.42 mL, 31 .0 mmol) was added to a solution of (S_a)-methyl 6- chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H- indole-2-carboxylate (Intermediate 74, 5.04 g, 12.4 mmol) and methanesulfonic anhydride (5.41 g, 31 .0 mmol) in DCM (56.7 mL) at 4 °C. The ice bath was removed and the stirring was continued for 5 h. Then the solvent was evaporated under reduced pressure and the residue was taken up in 100 mL of MeCN (0.1 % formic acid) and 50 mL of water (0.1 % formic acid) at RT. After stirring at RT for 2 h, the reaction mixture was concentrated. The residue was re- dissolved in EtOAc (250 mL) and washed with water. The aq. phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (S_a)-methyl 6- chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 75, 4.99 g, 83%) ; M/Z (ES+), [M+H]⁺ = 484. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .87 (s, 3H), 1 .95-2.00 (m, 2H), 3.04-3.08 (m, 2H), 3.18 (s, 3H), 3.42 (s, 3H), 3.85 (s, 6H), 4.10-4.13 (m, 1 H), 4.24-4.30 (m, 3H), 5.13 (t, 1 H), 7.28 (d, 1 H), 7.75 (d, 1 H).

Intermediate 76: (S_a)-Methyl 6-chloro-7-(5-((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2-nitrophenylsulfonamido)methyl)-1 ,3-dimethyl- 1 H-pyrazol-4-yl)-1 -methyl-3-(3- methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

A solution of di-te/t-butyl azodicarboxylate (1 .31 g, 5.68 mmol) in DCM (5 mL) was added to a suspension of (S_a)-methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4- yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 75, 2.50 g, 5.17 mmol), 2-nitrobenzenesulfonamide (1 .04 g, 5.17 mmol) and triphenylphosphine (1 .49 g, 5.68 mmol) in DCM (30 mL) at 4 °C. The stirring was continued at 4 °C for 1 h. Then (5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol (Intermediate 53, 2.29 g, 5.42 mmol) and triphenylphosphine (1 .49 g, 5.68 mmol) were added, followed by addition of a solution of di-te/t-butyl azodicarboxylate (1 .31 g, 5.68 mmol) in DCM (5 mL) at 4 °C over 10 min. After stirring for 10 min, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (hexanes/EtOAc) to give (Sa)-methyl 6-chloro-7-(5- ((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)- 2-nitrophenylsulfonamido)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl) oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 76, 3.87 g, 70%); M/Z (ES+), [M+H]⁺ = 1071 . ¹ H NMR (500MHz, DMSO-ofe) δ 1 .82-2.03 (m, 5H), 2.97-3.13 (m, 2H), 3.13-3.23 (m, 4H), 3.38- 3.49 (m, 4H), 3.65 (s, 3H), 3.78 (s, 3H), 3.87(s, 3H), 4.01 (s, 3H), 4.14-4.31 (m, 4H), 4.33-4.46 (m, 1 H), 4.49-4.59 (m, 1 H), 5.22 (s, 2H), 5.36 (s, 1 H), 7.00 (d, 2H), 7.10 (d, 1 H), 7.18 (s, 1 H), 7.32 (s, 1 H), 7.43-7.71 (m, 8H), 8.13 (dd, 1 H), 8.79 (dd, 1 H).

Intermediate 77: (S_a)-Methyl 6-chloro-7-(5-((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 - methyl-1 H-pyrazol-3-yl)methyl)-2-nitrophenylsulfonamido)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)- 1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

TFA (3.77 mL, 49.0 mmol) was added to a solution of (S_a)-methyl 6-chloro-7-(5-((N-((5- (((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenylsulfonamido)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 76, 5.25 g, 4.90 mmol) in DCM (50 mL) at 4 °C. The ice bath was removed and the stirring was continued for 3 h. The reaction mixture was concentrated. The residue was re-dissolved in DCM (300 mL), washed with sat. NaHC0₃ (150 mL). The aq. phase was extracted with DCM (200 mL). The combined organic phases were washed with brine, dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/DCM to 20% MeOH in DCM) to give (Sa)-methyl 6-chloro-7-(5-((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)-2-nitrophenylsulfonamido)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl) oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 77, 4.20 g, 82%) ; M/Z (ES+), [M+H]⁺ = 951 . ¹ H NMR (500MHz, DMSO- ₆) δ 1 .88-2.03 (m, 5H), 2.98-3.1 1 (m, 2H), 3.15 (s, 3H), 3.33 (s, 3H), 3.41 (s, 3H), 3.69 (s, 3H), 3.87 (s, 3H), 4.01 (s, 2H), 4.13 (s, 2H), 4.20- 4.30 (m, 2H), 4.42 (AB d, 1 H), 4.53 (AB d, 1 H), 5.29 (s, 1 H), 6.99 (s, 1 H), 7.12 (d, 1 H), 7.21 (s, 1 H), 7.43-7.71 (m, 6H), 8.13-8.15 (m, 1 H), 8.78-8.80 (m, 1 H), 10.07 (s, 1 H).

Intermediate 78: (S_a)-Methyl 17-chloro-5,12,14,22-tetramethyl-9-(2-nitrobenzene-1 -sulfonyl)- 28-oxa-2-thia-5,6,9,12,13,22,31 heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰·³⁵] octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate

A suspension of (S_a)-methyl 6-chloro-7-(5-((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)- 1 -methyl-1 H-pyrazol-3-yl)methyl)-2-nitrophenylsulfonamido)methyl)-1 ,3-dimethyl-1 H-pyrazol-4- yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 77, 2.94 g, 3.09 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in acetonitrile (154 mL) was heated at 60 °C for 6 h under N₂. The reaction mixture was cooled to RT, filtered though a pad of diatomaceous earth which was washed with MeCN. The filtrate was concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (S_a)-methyl 17-chloro- 5,12,14,22-tetramethyl-9-(2-nitrobenzene-1 -sulfonyl)-28-oxa-2-thia-5,6,9,12,13,22,31 heptaazaheptacyclo[27.7.1 .1⁴·⁷.0^{11 15}.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,31 , 33,35-tridecaene-23-carboxylate (Intermediate 78, 1 .79 g, 68%); m/z (ES+), [M+H]⁺ = 855. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .89 (s, 3H), 2.04-2.18 (m, 1 H), 2.39-2.49 (m, 1 H), 3.24-3.30 (m, 1 H), 3.35-3.40 (m, 1 H), 3.44 (s, 6H), 3.60-3.80 (m, 3H), 3.84-3.98 (m, 8H), 4.12-4.20 (m, 2H), 4.59-4.61 (m, 2H), 6.42 (d, 1 H), 6.72 (s, 1 H), 7.38-7.72 (m, 6H), 7.79 (d, 1 H), 8.22 (dd, 1 H), 8.92 (dd, 1 H).

Intermediate 79: (S_a)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,31 ,33,35-tridecaene-23-carbox late

Potassium carbonate (1 .23 g, 8.88 mmol) and thiophenol (0.92 mL, 8.88 mmol) were added to a solution of (S_a)-methyl 17-chloro-5,12,14,22-tetramethyl-9-(2-nitrobenzene-1 - sulfonyl)-28-oxa-2-thia-5,6,9,12,13,22,31 heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰·³⁵] octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate

(Intermediate 78, 1 .52 g, 1 .78 mmol) in acetonitrile (20 mL) at RT. After stirring at RT overnight, the reaction mixture was diluted with DCM (60 mL) and filtered though a pad of diatomaceous earth which was washed with DCM (20 mL). The filtrate was concentrated. The residue was purified by silica gel chromatography (Hex to DCM to 10% MeOH in DCM) to give (S_a)-methyl 17-chloro-5,12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33,35 -tridecaene-23-carboxylate (Intermediate 79, 1 .05 g, 88%) ; m/z (ES+), [M+H]⁺ = 670. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .84 (s, 3H), 2.18 - 2.28 (m, 1 H), 2.34 - 2.42 (m, 1 H), 3.07-3.21 (m, 3H), 3.22-3.30 (m, 1 H), 3.34-3.45 (m, 5H), 3.72 (s, 3H), 3.78 (s, 3H), 3.86-3.94 (m, 4H), 3.96-4.05 (m, 1 H), 4.27-4.33 (m, 2H), 4.75 (s, 1 H), 6.92 (d, 1 H), 6.96 (s, 1 H), 7.34 (d, 1 H), 7.48-7.50 (m, 1 H), 7.89 (d, 1 H), 8.12 (dd, 1 H), 8.79 (dd, 1 H). Intermediate 80: (S_a)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,35-undecaene-23-carbox late

Sodium cyanoborohydride (830 mg, 1 .31 mmol) was added a solution of (S_a)-methyl 17- chloro-5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²\0²⁰'^¾ 0³⁰'³⁵^

undecaene-23-carboxylate (Intermediate 79, 220 mg, 0.33 mmol) in a mixture of MeOH (1 mL) and acetic acid (0.55 mL) at RT. The stirring was continued for 2 days. The reaction mixture was concentrated and the residue was partitioned between water (10 mL) and DCM (10 mL) and the pH was adjusted to 8-9 by adding sat. NH₄OH solution. Sat. NaCI solution (10 mL) was added to facilitate the phase separation. The layers were separated and the aq. phase was extracted with DCM (2 x 15 mL). The combined organic phases were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/10% MeOH in DCM) to give (S_a)-methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,35-undecaene-23-carboxylate (Intermediate 80, 184 mg, 83%); m/z (ES+), [M+H]⁺ = 674. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .69-1 .78 (m, 2H), 1 .89 (s, 3H), 2.00-2.17 (m, 2H), 2.55-2.57 (m, 2H), 2.98 3.14 (m, 3H), 3.17-3.35 (m, 4H), 3.42 (s, 3H), 3.47-3.56 (m, 2H), 3.58 (s, 3H), 3.62-3.71 (m, 1 H), 3.79 (s, 3H), 3.80 (s, 3H), 3.88 (s, 2H), 4.90 (s, 1 H), 5.1 1 (s, 1 H), 6.23 (s, 1 H), 6.47 (s, 1 H), 7.17 (d, 1 H), 7.78 (d, 1 H).

Intermediate 81 : (S_a)-Methyl 17-chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

A solution of (Sa)-methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13, 22,31 -heptaazaheptacyclo[27 .1 .1⁴'^{7 11}'¹^0

13,16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate (Intermediate 79, 1 15 mg, 0.17 mmol) and acetaldehyde (0.014 mL, 0.26 mmol) in DCM (0.84 mL) was stirred for 5 min at RT. Sodium triacetoxyborohydride (73.0 mg, 0.34 mmol) was added and the stirring was continued for 1 h. More acetaldehyde (50 uL) was added and the stirring was continued for another 2 h. The mixture was quenched with sat. NaHC0₃ (5 mL), diluted with water (5 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM to 10% MeOH in DCM) to give (S_a)-methyl 17-chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaaza heptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23, 29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 81 , 93.0 mg, 78%); m/z (ES+), [M+H]⁺ = 698. ¹ H NMR (400MHz, DMSO-ofe) δ 0.35 (t, 3H), 1 .74-1 .79 (m, 1 H), 1 .84-1 .90 (m, 4H), 2.13-2.24 (m, 1 H), 2.31 -2.41 (m, 1 H), 2.94-3.20 (m, 4H), 3.24-3.30 (m, 1 H), 3.35-3.45 (m, 4H), 3.74 (s, 3H), 3.78 (s, 3H), 3.86-3.95 (m, 4H), 4.10-4.18 (m, 1 H), 4.33 (q, 2H), 4.58 (s, 1 H), 6.90-7.09 (m, 2H), 7.28 (d, 1 H), 7.44-7.47 (m, 1 H), 7.94 (d, 1 H), 8.08 (dd, 1 H), 8.74 (dd, 1 H).

Intermediate 82: (S_a)-Methyl 17-chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate

Sodium cyanoborohydride (40.0 mg, 0.64 mmol) was added to a solution of (S_a)-methyl 17-chloro-9-ethyl-5,12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 -heptaazaheptacycio [27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33, 35-tridecaene-23-carboxylate (Intermediate 81 , 90.0 mg, 0.13 mmol) in acetic acid (2 ml.) at RT. The stirring was continued for 20 h. The reaction mixture was concentrated. The residue was partitioned between water (10 ml.) and DCM (10 ml.) and the pH was adjusted to 8-9 by adding sat. NH₄OH solution. Sat. NaCI solution (10 ml.) was added to facilitate the phase separation. The layers were separated and the aq. phase was extracted wit DCM (2 x 15 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/DCM to 20% MeOH in DCM) to give (S_a)- methyl 17-chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹·¹⁵.0⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate (Intermediate 82, 35.0 mg, 39%); M/Z (ES+), [M+H]⁺ = 702. ¹ H NMR (400MHz, DMSO-ofe) δ 0.53 (t, 3H), 1 .65-1 .71 (m, 2H), 1 .84-1 .94 (m, 4H), 2.00-2.18 (m, 3H), 3.00- 3.21 (m, 7H), 3.25-3.33 (m, 2H), 3.41 (s, 3H), 3.62 (s, 3H), 3.64-3.70 (m, 1 H), 3.75-3.91 (m, 10H), 4.64 (s, 1 H), 4.95 (s, 1 H), 6.32 (s, 1 H), 6.37 (s, 1 H), 7.14 (d, 1 H), 7.78 (d, 1 H).

Intermediate 83: (S_a)-Methyl 17-chloro-5,9,12,14,22-pentamethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

Formaldehyde (0.024 mL, 0.33 mmol, 37% in water) was added to a solution of (S_a)- methyl 17-chloro-5,12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 -heptaazaheptacyclo [27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²\0²⁰'^¾ 0³⁰'³⁵^^

35-tridecaene-23-carboxylate (Intermediate 79, 0.1 1 g, 0.16 mmol) in DCM (1 .5 mL) and acetic acid (0.019 mL, 0.33 mmol). Then sodium triacetoxyborohydride (70.0 mg, 0.33 mmol) was added at RT. After stirring at RT for 40 min, the reaction was quenched with sat. NaHC0₃ (5 mL), diluted with water (5 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/10% MeOH in DCM) to give (S_a)-methyl 17-chloro-5,9, 12,14,22- pentamethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 83, 103 mg, 92%); m/z (ES+), [M+H]⁺ = 684. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .80 (s, 3H), 1 .88 (s, 3H), 2.15-2.25 (m , 1 H), 2.41 -2.45 (m, 1 H), 2.85-2.90 (m, 2H), 3.00-3.08 (m, 1 H), 3.1 1 (AB d, 1 H), 3.33-3.41 (m, 2H), 3.44 (s, 3H), 3.72-3.82 (m, 7H), 3.91 (s, 3H), 4.24-4.48 (m, 4H), 7.07 (s, 1 H), 7.14 (d, 1 H), 7.28 (s, 1 H), 7.44-7.48 (m, 1 H), 7.98-8.13 (m, 2H), 8.73-8.75 (m, 1 H).

Intermediate 84: (S_a)-Methyl 17-chloro-5,9,12,14,22-pentamethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate

Sodium cyanoborohydride (0.22 g, 3.51 mmol) was added to a solution of (Sa)-methyl 17- chloro-5,9,12, 14,22-pentamethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²\0²⁰'^¾ 0³⁰'³⁵^^

35-tridecaene-23-carboxylate (Intermediate 83, 0.400 g, 0.58 mmol) in acetic acid (2.92 mL) under N₂. After stirring at RT for 90 h, the reaction mixture was concentrated and the residue was partitioned between water (10 mL) and DCM (10 mL) and the pH was adjusted to 8-9 by adding sat. NH4OH solution. The brine was added to facilitate the phase separation. The layers were separated and the aq. phase was extracted with DCM (3 x 15 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM to 10% MeOH in DCM) to give (S_a)-methyl 17-chloro-5,9, 12,14,22- pentamethyl-28-oxa-2-thia-5,6,9, 12, 13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'^¾ 0³⁰'³⁵^^

undecaene-23-carboxylate (Intermediate 84, 260 mg, 64%); M/Z (ES+), [M+H]⁺ = 688. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .60-1 .75 (m, 2H), 1 .82 (s, 3H), 1 .92 (s, 3H), 2.02-2.07 (m, 1 H), 2.20-2.27 (m, 1 H), 2.92-3.19 (m, 7H), 3.27-3.30 (m, 1 H), 3.37 (AB d, 1 H), 3.45 (s, 3H), 3.50-3.59 (m, 1 H), 3.65 (s, 3H), 3.81 (s, 3H), 3.86 (s, 3H), 3.90- 3.99 (m, 4H), 4.42 (s, 1 H), 4.98 (br s, 1 H), 6.31 (s, 1 H), 6.42 (s, 1 H), 7.19 (d, 1 H), 7.87 (d, 1 H).

Intermediate 85: (S_a)-Methyl 6-chloro-7-(5-formyl-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy- 3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate

Dess-Martin periodinane (860 mg, 2.03 mmol) was added to an ice cooled mixture of (Sa)-methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3- oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 31 , 800 mg, 1 .84 mmol) and sodium bicarbonate (0.774 g, 9.22 mmol) in DCM (15 ml_). After stirring at RT for 1 h, the reaction was diluted with DCM (10 ml_), washed with water, dried over Na2S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (Sa)-methyl 6-chloro-7-(5-formyl-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 85, 770 mg, 97%); M/Z (ES+), [M+H]⁺ = 432. ¹ H NMR (300 MHz, CHLOROFORM-c ) δ 2.13 (t, 3H), 2.69 (t, 2H), 3.37 (t, 2H), 3.51 (s, 3H), 3.70 (s, 3H), 3.95 (s, 3H), 4.26 (s, 3H), 7.31 (d, 1 H), 7.73 (d, 1 H), 9.42 (s, 1 H).

Intermediate 86: (S_a)-Methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)- 1 -methyl-1 H-indole-2-carboxylate

Sodium triacetoxyborohydride (559 mg, 2.64 mmol) was added to a mixture of 3-(2-(3- (aminomethyl)-l -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol (Intermediate 48, 495 mg, 1 .76 mmol) and (S_a)-methyl 6-chloro-7-(5-formyl-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3- oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 85, 760 mg, 1 .76 mmol) in 1 ,2- dichloroethane (15 mL) and the resulting suspension was stirred at RT overnight. The mixture was washed with sat. NaHC0₃ (2 x 10 mL) and the aq. phase was extracted with DCM (2 x 10 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (hexanes/DCM) to give (S_a)-methyl 6-chloro- 7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)- 1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 86, 630 mg, 51 %); M/Z (ES+), [M+H]⁺ = 697.

Intermediate 87: (S_a)-Methyl 7-(5-(((te/f-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro- 3-(3-methoxy-3-oxopropyl)-1 -meth l-1 H-indole-2-carboxylate

A solution of (Sa)-methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 - methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-3-(3-methoxy-3- oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 86, 630 mg, 0.90 mmol) and di-te/t- butyl dicarbonate (0.25 mL, 1 .08 mmol) in DCM (10 mL) was stirred at RT overnight and then concentrated. The residue was purified by silica gel chromatography (hexanes/DCM) to give (Sa)-methyl 7-(5-(((te -butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H- pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro-3-(3-methoxy-3- oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 87, 630 mg, 87%); M/Z (ES+), [M+H]⁺ = 797. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .34 (s, 9H), 2.10 (s, 3H), 2.58-2.73 (m, 3H), 2.75-2.98 (m, 4H), 3.22 (s, 3H), 3.31 -3.42 (m, 2H), 3.52 (s, 3H), 3.70 (s, 3H), 3.93 (s, 6H), 3.99-4.28 (m, 2H), 4.60 (AB d, 1 H), 5.53 (s, 1 H), 6.27 (s, 1 H), 7.18 (s, 1 H), 7.25-7.27 (m, 1 H), 7.36-7.52 (m, 2H), 7.64 (d, 1 H), 7.68-7.76 (m, 1 H), 8.20-8.33 (m, 1 H). Intermediate 88: (S_a)-Methyl 7-(5-(((te/f-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro- 3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carbox late

Borane tetrahydrofuran complex (3.20 mL, 3.20 mmol) (1 M in THF) was added to a solution of (Sa)-methyl 7-(5-(((te -butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 - methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro-3-(3- methoxy-3-oxopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 87, 510 mg, 0.64 mmol) in THF (5 mL) and the resulting solution was stirred at RT for 7 h. Methanol (10 mL) was carefully added to quench the reaction and the mixture was evaporated. The residue was stirred in MeOH (10 mL) overnight and the solution was evaporated again. The residue was purified by silica gel chromatography (hexanes/DCM) to give (S_a)-methyl 7-(5-(((te/t-butoxycarbonyl)((5-(2- (4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl- 1 H-pyrazol-4-yl)-6-chloro-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 88, 0.47 g, 96%); M/Z (ES+), [M+H]⁺ = 769. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .34 (s, 9H), 1 .92-1 .99 (m, 2H), 2.12 (s, 3H), 2.70-2.94 (m, 4H), 3.08-3.20 (m, 2H), 3.23 (s, 3H), 3.48 (m s, 3H), 3.67 (t, 2H), 3.87-3.96 (m, 7H), 3.98-4.25 (m, 2H), 4.59 (AB d, 1 H), 5.53 (s, 1 H), 6.25 (s, 1 H), 7.17 (s, 1 H), 7.25-7.26 (d, 1 H), 7.37-7.51 (m, 2H), 7.63 (d, 1 H), 7.67-7.75 (m, 1 H), 8.18- 8.29 (m, 1 H).

Intermediate 89: (S_a)-Methyl 7-(5-(((te/f-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro- 3-(3-iodopropyl)-1 -methyl-1 H-indole-2-carboxylate

Methyltriphenoxyphosphonium iodide (81 1 mg, 1 .79 mmol) was added to an ice cooled solution of (Sa)-methyl 7-(5-(((te -butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 - methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro-3-(3- hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 88, 0.46 g, 0.60 mmol) in DMF (5 ml_). After stirring at 0 °C for 10 min, the mixture was quenched with water (20 ml.) and extracted with EtOAc (3 x 15 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography

(hexanes/DCM) to give (Sa)-methyl 7-(5-(((teri-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro- 3-(3-iodopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 89, 0.48 g, 91 %); M/Z (ES+), [M+H]⁺ = 879. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .32 (s, 9H), 2.10 (s, 3H), 2.15-2.28 (m, 2H), 2.75-2.99 (m, 4H), 3.06-3.19 (m, 5H), 3.26 (t, 2H), 3.52 (s, 3H), 3.86-4.00 (m, 7H), 4.14- 4.31 (m, 2H), 4.59 (AB d, 1 H), 5.68 (s, 1 H), 6.17 (s, 1 H), 7.18 (s, 1 H), 7.26-7.28 (m, 1 H), 7.35- 7.51 (m, 2H), 7.60-7.81 (m, 2H), 8.21 -8.31 (m, 1 H).

Intermediate 90: (S_a)-9-te/t-Butyl 23-methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa- 5,6,9, 12,13,22-hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-9,23-dicarboxylate

A suspension of (Sa)-methyl 7-(5-(((te/t-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-6-chloro- 3-(3-iodopropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 89, 0.47 g, 0.53 mmol) and potassium carbonate (0.22 g, 1 .60 mmol) in acetonitrile (150 ml.) was stirred at 60 °C for 10 h and allowed to cool to RT. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (hexanes/10% MeOH in DCM) to give (S_a)-9-te/t-butyl 23-methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo [27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33, 35-tridecaene-9,23-dicarboxylate (Intermediate 90, 0.28 g, 70%); M/Z (ES+), [M+H]⁺ = 751 . ¹ H NMR (300MHz, CHLOROFORM-c/) δ 1 .42 (s, 9H), 2.08 (s, 3H), 2.08-2.15 (m, 1 H), 2.37-2.57 (m, 1 H), 2.70-2.83 (m, 2H), 2.86-3.04 (m, 2H), 3.13-3.49 (m, 7H), 3.54 (s, 3H), 3.58-3.87 (m, 2H), 3.93 (s, 3H), 4.00 (s, 3H), 4.08-4.33 (m, 2H), 5.14 (s, 1 H), 5.78 (s, 1 H), 6.81 -6.84 (m, 1 H), 7.19 (s, 1 H), 7.41 -7.56 (m, 3H), 7.68-7.81 (m, 1 H), 8.24-8.41 (m, 1 H).

Intermediate 91 : (S_a)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-5,6,9, 12, 13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

4M HCI in 1 ,4-dioxane (2 ml_, 8.00 mmol) was added a solution of (S_a)-9-te/t-butyl 23- methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33, 35-tridecaene-9,23-dicarboxylate (Intermediate 90, 0.28 g, 0.37 mmol) and triethylsilane (0.24 ml_, 1 .49 mmol) in 1 ,4-dioxane (2 mL). The mixture was stirred at RT for 1 h and concentrated to give (S_a)-methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-5,6,9, 12, 13,22- hexaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33, 35-tridecaene-23-carboxylate (Intermediate 91 , 0.25 g, 99%) as a HCI salt; M/Z (ES+), [M+H]⁺ = 651 . ¹ H NMR (300MHz, CHLOROFORM-c/) δ 2.15 (s, 3H), 2.18-2.25 (m, 1 H), 2.32-2.45 (m, 1 H), 2.7-2.83 (m, 2H), 2.95-3.07 (m, 5H), 3.15- 3.34 (m, 3H), 3.42-3.69 (m, 6H), 3.73-3.89 (m, 5H), 4.14-4.31 (m, 5H), 5.64 (s, 1 H), 5.74 (s, 1 H), 6.94 (d, 1 H), 7.41 -7.62 (m, 3H), 7.73-7.82 (m, 1 H), 8.33-8.46 (m, 1 H).

Intermediate 92: (S_a)-Methyl 17-chloro-5,9,12,14,22-pentamethyl-28-oxa-5,6,9,12, 13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

Sodium triacetoxyborohydride (23.0 mg, 0.1 1 mmol) was added to a mixture of (S_a)- methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²\0²⁰'^¾ 0³⁰'³⁵^^

35-tridecaene-23-carboxylate HCI salt (Intermediate 91 , 46.0 mg, 0.07 mmol), sodium acetate (7.16 mg, 0.09 mmol) and formaldehyde (37% in water) (10.8 μΙ_, 0.15 mmol) in 1 ,2- dichloroethane (1 ml_). After stirring at RT for 1 h, the mixture was treated with sat. NaHC03 (1 ml.) and extracted with DCM (3 x 5 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/10% MeOH in DCM) to give (S_a)-methyl 17-chloro-5,9,12,14,22-pentamethyl-28-oxa- 5,6,9, 12,13,22-hexaazaheptacyclo[27.7.1 .1⁴-⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18, 20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 92, 47.0 mg, 97%); M/Z (ES+), [M+H]⁺ = 665. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .99 (s, 3H), 2.03 (s, 3H), 2.16-2.33 (m, 1 H), 2.36-2.48 (m, 1 H), 2.80-3.25 (m, 8H), 3.30-3.44 (m, 1 H), 3.48- 3.63 (m, 7H), 3.75-3.88 (m, 5H), 3.91 (s, 3H), 4.95 (s, 1 H), 6.17 (s, 1 H), 7.03-7.06 (m, 2H), 7.36- 7.46 (m, 2H), 7.55 (d, 1 H), 7.60-7.72 (m, 1 H), 8.08-8.27 (m, 1 H).

Intermediate 93: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 H-indole- 2-carboxylate

A mixture of Cs₂C0₃ (4.57 g, 14.0 mmol), methyl 7-bromo-3-(3-((te/t- butyldiphenylsilyl)oxy) propyl)-6-chloro-1 H-indole-2-carboxylate (Intermediate 22, 3.57 g, 6.10 mmol) and dichloro[1 ,1 '-bis(di-te -butylphosphino)ferrocene]palladium(ll) (0.12 g, 0.18 mmol) in 1 ,4-dioxane (40.7 ml.) and water (10.2 ml.) was degassed, re-filled with N₂ three times and heated to 100 °C under N₂. A solution of (1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-5-yl)methanol (Intermediate 13, 2.79 g, 7.93 mmol) in 1 ,4-dioxane (10.2 ml.) was degassed, re-filled with N₂ and added slowly to the mixture above over 45 min at 100 °C via a syringe pump. After addition, the reaction was stirred at 100 °C for 30 min under N₂, then cooled to RT and concentrated to dryness. Water (100 ml.) was added to the residue and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((teri- butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran- 2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate (Intermediate 93, 3.34 g, 72%); M/Z (ES+), [M+H]⁺ = 730. ¹ H NMR (300MHz, CHLOROFORM-of) δ 1 .1 1 (s, 9H), 1 .32-1 .76 (m, 6H), 1 .86-1 .94 (m, 2H), 3.1 1 -3.27 (m, 3H), 3.77 (t, 2H), 3.84 (s, 3H), 4.10 (s, 3H), 4.33-4.56 (m, 4H), 4.61 -4.80 (m, 2H), 7.23 (d, 1 H), 7.31 -7.51 (m, 6H), 7.62 (d, 1 H), 7.69-7.72 (m, 4H), 8.83 (br s, 1 H).

Intermediate 94: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate

(±) Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hydroxymethyl)-1 - methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate

(Intermediate 93,13.5 g, 14.8 mmol) was dissolved in DMF (30 mL). Cs₂C0₃ (9.64 g, 29.6 mmol) and Mel (1 .85 mL, 29.6 mmol) were added. After stirring at RT for 2 h, the mixture was concentrated. Water (100 mL) was added to the residue and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography

(hexanes/EtOAc) to give (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 94, 10.0 g, 86%) which was taken on without purification; M/Z (ES+), [M+H]⁺ = 744. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .1 1 (s, 9H), 1 .29-1 .68 (m, 5H), 1 .77-1 .94 (m, 3H), 2.67-3.16 (m, 4H), 3.54-3.59 (m, 3H), 3.71 -3.80 (m, 2H), 3.83 (s, 3H), 4.07 (s, 3H), 4.20-4.32 (m, 2H), 4.43-4.78 (m, 4H), 7.21 (d, 1 H), 7.32-7.49 (m, 6H), 7.61 (d, 1 H), 7.68-7.73 (m, 4H). Intermediate 95: (±)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H- yl)oxy)methyl)-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate

(±) -Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hydroxymethyl)-1 - methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 94, 10.0 g, 12.7 mmol) was dissolved in THF (50 ml_). TBAF (15.3 ml_, 15.3 mmol) (1 M in THF) was added. After stirring at RT for 1 h, the mixture was

concentrated to dryness. EtOAc (100 ml.) was added to the residue and the resulting organic solution was washed with water (20 ml_), dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (±)-methyl 6-chloro-7-(5-(hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)- 1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 95, 6.05 g, 92%); M/Z (ES+), [M+H]⁺ = 506. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 0.85-1 .76 (m, 6H), 1 .85-2.00 (m, 2H), 2.76-3.35 (m, 4H), 3.53-3.57 (m, 3H), 3.60-3.72 (m, 2H), 3.92 (s, 3H), 4.06 (s, 3H), 4.18-4.80 (m, 5H), 7.24 (d, 1 H), 7.62 (d, 1 H).

Intermediate 96: (±)-Methyl 6-chloro-7-(5-(iodomethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2- carboxylate

(±)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy) methyl)-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 95, 3.15 g, 6.09 mmol) was dissolved in anhydrous THF (120 mL) at 0 °C.

Diisopropylethylamine (3.72 mL, 21 .3 mmol) and methanesulfonic anhydride (2.92 g, 16.7 mmol) were added. Then the ice bath was removed. After stirring at RT for 1 h, the mixture was cooled to 0 °C and sodium iodide (4.56 g, 30.4 mmol) was added. The stirring was continued at

0 °C for 3 h. The reaction mixture was allowed to warm to RT and concentrated to dryness. Ice water (50 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with 0.5M HCI solution (2 x 12 mL), brine, dried over Na2S04, filtered and concentrated to give (±)-methyl 6-chloro-7-(5-(iodomethyl)-1 -methyl-3-(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H- indole-2-carboxylate (Intermediate 96, 4.30 g, 100%), which was taken on without purification; M/Z (ES+), [M+H]⁺ = 694. ¹ H NMR (300MHz, CHLOROFORM-of) δ 0.94-1 .60 (m, 6H), 2.08-2.18 (m, 2H), 2.72-3.40 (m, 7H), , 3.65-3.67 (m, 3H), 3.93 (s, 3H), 3.96 (s, 3H), 4.07-4.37 (m, 5H), 4.41 -4.62 (m, 2H), 7.26 (d, 1 H), 7.62 (d, 1 H).

Intermediate 97: (±)-Methyl 6-chloro-7-(5-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 - methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-

1 H-pyrazol-4-yl)-1 -methyl-3-(3-( methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

Methanol (58.5 mL) was added to a mixture of 3-(((3-((acetylthio)methyl)-1 -methyl-1 H- pyrazol-5-yl)methyl)thio)naphthalen-1 -yl acetate (Intermediate 37, 2.34 g, 5.85 mmol), triphenylphosphine (0.12 g, 0.44 mmol) and (±)-methyl 6-chloro-7-(5-(iodomethyl)-1 -methyl-3- (((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy) propyl)-1 H-indole-2-carboxylate (Intermediate 96, 4.05 g, 5.85 mmol). The resulting clear mixture was cooled to 0 °C, degassed and re-filled with N₂ three times. K₂C0₃ (2.35 g, 16.9 mmol) was added. After stirring at 0 °C under N₂ for 70 min, the mixture was concentrated. Sat. NH4CI solution (50 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (±)-methyl 6-chloro-7-(5-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H- pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 97, 4.22 g, 93%); M/Z (ES+), [M+H]⁺ = 882. ¹ H NMR (300 MHz, CHLOROFORM-d) δ 1 .10-1 .50 (m, 6H) 2.07-2.17 (m, 2H), 2.79-3.26 (m, 6H), 3.39-3.74 (m, 1 1 H), 3.85-4.00 (m, 8H), 4.20-4.37 (m, 3H), 4.51 -4.66 (m, 2H), 5.49-5.52 (m, 1 H), 6.73 (s, 1 H), 7.19 (d, 1 H), 7.36 (s, 1 H), 7.42-7.60 (m, 3H), 7.64-7.77 (m, 1 H), 8.1 1 -8.27 (m, 1 H).

Intermediate 98: (±)-Methyl 17-chloro-5,12,22-tn^'methyl-14-{[(oxan

dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹ ^

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

A suspension of potassium carbonate (1 .50 g, 10.8 mmol) in anhydrous acetonitrile (400 mL) was degassed, re-filled with N₂ and heated to 80-85 °C in an oil bath. (±)-methyl 6- chloro-7-(5-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 97, 4.78 g, 5.42 mmol) was dissolved in 20 mL of acetonitrile, degassed and re-filled with N₂. This solution was slowly added to the K₂C0₃ suspension above over 10 h under N₂ via a syringe pump. After addition, the stirring was continued at 75 to 85 °C for 12 h, then the mixture was cooled to RT. The solids were removed by filtration and washed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure. Methanol (10 mL) was added to the resulting residue and sonicated for 5 min to form a suspension. The solids were collected by filtration and washed with MeOH (5 mL) and EtOAc (5 mL) to give the first batch of product (3.70 g). The mother liquid was concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give the second batch of product. The second batch of product was triturated in EtOAc (2 mL). The resulting solids were collected by filtration and washed with EtOAc (2 mL). The total isolated amount of (±)-methyl 17-chloro-5,12,22-trimethyl- 14-{[(oxan-2-yl)oxy]methyl}-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,

1 1 (15),13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 98) was 3.90 g (91 %); M/Z (ES+), [M+H]⁺ = 786. ¹ H NMR (300 MHz, DMSO-ofe) δ 0.76-1 .42 (m, 6H), 2.10-2.25 (m, 1 H), 2.30-2.40 (m, 1 H), 2.81 -3.25 (m, 5H), 3.31 -3.40 (m, 2H), 3.43-3.57 (m, 4H), 3.65 (s, 3H), 3.74-3.89 (m, 7H), 3.88-3.98 (m, 1 H), 4.06-4.50 (m, 5H), 4.76-4.77 (m, 1 H), 6.52 (s, 1 H), 6.98-7.03 (m, 1 H), 7.41 (d, 1 H), 7.44-7.59 (m, 2H), 7.67-7.86 (m, 2H), 8.06-8.20 (m, 1 H).

Intermediate 99: (±)-Methyl 17-chloro-14-(hydroxymethyl)-5,12,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴-⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

(±)-Methyl 17-chloro-5,12,22-trimethyl-14-{[(oxan-2-yl)oxy]methyl}-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6, 1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 98, 3.96 g, 5.04 mmol) was dissolved in DCM (15 mL) and MeOH (15 mL) to result in a light brown solution, degassed and re-filled with N₂. HCI (1 .26 mL, 5.04 mmol) (4M in 1 ,4-dioxane) was added. After stirring at RT under N₂ for 2 h, the mixture was concentrated to dryness. MeOH (5 mL) was added to the residue and the resulting solution was sonicated for 10 min to give a suspension. The solids were collected by filtration and washed with EtOAc (5 mL) to give the first batch of product (3.00 g). The mother liquid was concentrated to dryness. MeOH (1 mL) was added to the residue and sonicated for 10 min. The resulting second batch of solids were collected by filtration and washed with EtOAc (2 mL). The total amount of (±)-methyl 17-chloro-14- (hydroxymethyl)-5,12,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵] octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 99) was 3.50 g (91 %) ; M/Z (ES+), [M+H]⁺ = 702. ¹ H NMR (300 MHz, DMSO-ofe) 5 2.1 1 -2.41 (m, 2H),

2.86- 2.96 (m, 1 H), 3.02-3.29 (m, 4H), 3.34-3.53 (m, 5H), 3.64 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H),

3.87- 4.01 (m, 1 H), 4.07-4.27 (m, 4H), 4.71 -4.75 (m, 1 H), 4.82 (s, 1 H), 6.53 (s, 1 H), 7.01 (d, 1 H), 7.41 (s, 1 H), 7.45-7.57 (m, 2H), 7.68-7.80 (m, 2H), 8.06-8.21 (m, 1 H).

Intermediate 100: (±)-Methyl 17-chloro-14-{[(methoxysulfonyl)oxy]methyl}-5,12,22-trimethyl-28- oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyd

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

(±) -Methyl 17-chloro-14-(hydroxymethyl)-5,12,22-trimethyl-28-oxa-2,9-dithia-5,6,12, 13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹^ ^

13,16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate (Intermediate 99, 300 mg, 0.43 mmol) was dissolved in THF (6 mL) to result in a clear solution. DIPEA (0.075 mL, 0.43 mmol) and methanesulfonic anhydride (74.4 mg, 0.43 mmol) were added. After stirring at RT for 30 min, the mixture was diluted with EtOAc (10 mL), washed with water, dried over Na2S04, filtered and concentrated to dryness to give (±)-methyl 17-chloro-14-{[(methoxysulfonyl)oxy]methyl}-5,12,22- trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^ 0²⁰'²⁴.0³⁰ ^ octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate

(Intermediate 100, 330 mg, 99%) ; M/Z (ES+), [M+H]⁺ = 780. ¹ H NMR (300 MHz,

CHLOROFORM-of) 5 2.17-2.35 (m, 1 H), 2.35-2.56 (m, 1 H), 2.65 (s, 3H), 2.77-2.91 (m, 1 H), 3.16-3.35 (m, 4H), 3.46-3.57 (m, 1 H), 3.60 (s, 3H), 3.62-3.68 (m, 1 H), 3.73 (s, 3H), 3.77-3.85 (m, 2H), 3.86-3.98 (m, 7H), 4.86 (s, 1 H), 4.96-5.1 1 (m, 2H), 6.26 (s, 1 H), 6.86-7.02 (m, 1 H), 7.46-7.64 (m, 4H), 7.69-7.76 (m, 1 H), 8.24-8.37 (m, 1 H). Intermediate 101 : 4-(4-Hydroxyphen l)-N,N-dimethylpiperazine-1 -sulfonamide

DIPEA (1 1 .8 mL, 67.3 mmol) was added to a suspension of 4-(piperazin-1 -yl)phenol (10.0 g, 56.1 mmol) in 1 ,4-dioxane (200 mL) under nitrogen at 0 °C, followed by dropwise addition of dimethylsulfamoylchloride (6.28 mL, 58.9 mmol). After 10 min, the ice bath was removed and the mixture was stirred at RT for 67 h. The mixture was concentrated and water (700 mL) was added to the residue. The mixture was sonicated for 15 min to result in a brown suspension. The solids were collected by filtration and washed with water and then diethyl ether to give 4-(4-hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 12.9 g, 81 %); M/Z (ES+), [M+H]⁺ = 286. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.78 (s, 6H), 2.20-2.30 (m, 4H), 2.91 -3.04 (m, 4H), 6.51 -6.68 (m, 2H), 6.72-6.90 (m, 2H), 8.86 (s, 1 H).

Intermediate 102: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox late

4-(4-Hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 134 mg, 0.47 mmol) was dissolved in anhydrous DMF (2.50 mL) under N₂. NaH (20.5 mg, 0.51 mmol) (60% in oil) was added at RT under N₂. The mixture was stirred at RT for 20 min. A solution of (±)-methyl 17-chloro-14-{[(methoxysulfonyl)oxy]methyl}-5,12,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16, 18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 100, 330 mg, 0.43 mmol) in anhydrous DMF (5 mL) was added. The mixture was stirred at 100 °C for 2 h under N₂. LCMS still showed some mesylate starting material. Another flask was dried under N₂. 0.4 equiv. of 4-(4-hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide in anhydrous DMF (1 mL) was added, followed by addition of NaH (0.45 equiv., 60% in oil). The mixture was stirred at RT for 10 min. This solution was then added to the mixture above. After stirring at 100 °C for 15 min, the reaction mixture was allowed to cool to RT and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 17-chloro- 14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6, 1 1 (15),13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 102, 170 mg, 41 %); M/Z (ES+), [M+H]⁺ = 969. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.10-2.30 (m, 1 H), 2.32-2.49 (m, 1 H), 2.69-2.81 (m, 1 H), 2.86 (s, 6H), 3.1 1 -3.67 (m, 16H), ), 3.70 (s, 3H), 3.76-3.81 (m, 2H), 3.82-3.88 (m, 5H), 3.90 (s, 3H), 4.74-4.97 (m, 3H), 6.21 -6.31 (m, 1 H), 6.63-6.83 (m, 4H), 6.84-6.95 (m, 1 H), 7.44-7.61 (m, 4H), 7.61 -7.79 (m, 1 H), 8.23-8.38 (m, 1 H).

Intermediate 103: (±)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

5,12,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox lic acid

(±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,12,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33, 35-tridecaene-23-carboxylate (Intermediate 102, 270 mg, 0.28 mmol) was dissolved in MeOH (2 mL), THF (2 mL) and water (2 mL). LiOH (33.3 mg, 1 .39 mmol) was added. After stirring at 70 °C under N₂ for 2 h, the mixture was allowed to cool to RT, neutralized with 6N HCI

(0.046 mL, 0.28 mmol) and concentrated to dryness. Water (3 mL) was added to the resulting residue to give a suspension. The solids were collected by filtration and washed with water (2 mL) and dried under air to give (±)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵] octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Intermediate 103, 200 mg, 75%); M/Z (ES+), [M+H]⁺ = 955. ¹ H NMR (300 MHz, METHANOL-^) δ 2.16-2.30 (m, 1 H), 2.32-2.46 (m, 1 H), 2.77-2.92 (m, 7H), 2.95-3.04 (m, 4H), 3.06-3.23 (m, 2H), 3.33-3.36 (m, 5H), 3.38-3.51 (m, 5H), 3.74 (s, 3H), 3.82-4.01 (m, 6H), 4.13 (AB d, 1 H), 4.72-4.80 (m, 3H) 6.47 6.60 (m, 3H), 6.67-6.81 (m, 3H), 7.33-7.42 (m, 2H), 7.44-7.56 (m, 2H), 7.64-7.73 (m, 1 H), 8.20-8.35 (m, 1 H).

Intermediate 104: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5- (iodomethyl)-l -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H- indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hydroxymethyl)-1 - methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 94, 1 .00 g, 1 .34 mmol) was dissolved in THF (6 mL) under N₂, cooled to 0 °C. DIPEA (0.59 mL, 3.36 mmol) and methanesulfonic anhydride (0.59 g, 3.36 mmol) were added. The mixture was stirred at 0 °C for 10 min and then RT for 2 h. Sodium iodide (2.01 g, 13.4 mmol) was added. The stirring was continued at 60 °C for 2 h. The mixture was allowed to cool to RT, diluted with EtOAc (40 mL) and washed with 0.5M aq. HCI solution (20 mL). The organic phase was dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) give (±)-methyl 3-{3-{{tert- butyldiphenylsilyl)oxy) propyl)-6-chloro-7-(5-(iodomethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 104, 1 .05 g, 91 %); M/Z (ES+), [M+H]⁺ = 854. ¹ H NMR (500 MHz, CHLOROFORM-of) δ 0.94-1 .02 (m, 1 H), 1 .12 (s, 9H), 1 .20-1 .56 (m, 5H), 1 .81 -1 .93 (m, 2H), 2.70-3.34 (m, 4H), 3.56-3.69 (m, 3H), 3.74- 3.81 (m, 2H), 3.84 (s, 3H), 3.95 (s, 3H), 4.08-4.25 (m, 3H), 4.30-4.62 (m, 2H), 7.21 (d, 1 H), 7.35-7.50 (m, 6H), 7.63 (d, 1 H), 7.70-7.72 (m, 4H).

Intermediate 105: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)m

yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate

4-(4-Hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 0.52 g, 1 .84 mmol) was dissolved in anhydrous DMF (2 mL) under N₂. Sodium hydride (88.0 mg, 2.21 mmol) (60% in oil) was added at RT. The mixture was stirred at RT for 15 min, then a solution of (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(iodomethyl)-1 - methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 104,1 .57 g, 1 .84 mmol) in DMF (8 mL) was added. After stirring at 80 °C under N₂ for 1 h, the reaction mixture was cooled to RT, quenched with water (100 mL) and extracted with 10% MeOH in EtOAc (3 x 20 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((teri-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-3- (((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 105, 1 .35 g, 73%); M/Z (ES+), [M+H]⁺ = 101 1 . ¹ H NMR (300 MHz,

CHLOROFORM-of) δ 0.92-1 .06 (m, 1 H), 1 .12 (s, 9H), 1 .18-1 .38 (m, 2H), 1 .38-1 .61 (m, 3H), 1 .79-1 .95 (m, 2H), 2.70-2.78 (m, 1 H), 2.87(s, 6H), 3.01 -3.16 (m, 6H), 3.31 -3.45 (m, 4H), 3.45- 3.59 (m, 3H), 3.77 (t, 2H), 3.83 (s, 3H), 4.06 (s, 3H), 4.21 -4.36 (m, 2H), 4.47-4.64 (m, 2H), 4.71 - 4.96 (m, 2H), 6.66-6.79 (m, 4H), 7.14-7.25 (m, 1 H), 7.34-7.49 (m, 6H), 7.62 (dd, 1 H), 7.69-7.73 (m, 4H). Intermediate 106: (±)-Methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-3-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 105, 1 .90 g, 1 .88 mmol) was dissolved in DCM (5 mL) and MeOH (5 mL). 4 M HCI in 1 ,4-dioxane (4.69 mL, 18.8 mmol) was added at RT. After stirring at RT for 1 h, the mixture was concentrated. Sat. aq. NaHC0₃ solution (50 mL) was added to the residue and it was extracted with 10% MeOH in EtOAc (3 x 20 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc) to give (±)-methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-3-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 106, 1 .16 g, 90%); M/Z (ES+), [M+H]⁺ = 689. ¹ H NMR (300 MHz, METHANOL- 4) δ 1 .70-1 .90 (m, 2H), 2.84 (s, 6H), 2.93-3.03 (m, 4H), 3.03-3.16 (m, 2H), 3.29-3.34 (m, 7H), 3.52-3.68 (m, 2H), 3.89 (s, 3H), 4.04 (s, 3H), 4.29-4.47 (m, 2H), 4.74 (d, 1 H), 4.95 (d, 1 H), 6.45 6.60 (m, 2H), 6.60-6.76 (m, 2H), 7.25 (d, 1 H), 7.73 (d, 1 H).

Intermediate 107: (±)-Methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-3-(iodomethyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

(±) -Methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-3- (hydroxymethyl)-l -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 106, 0.36 g, 0.52 mmol) was dissolved in anhydrous THF (18 mL). DIPEA (0.27 mL, 1 .57 mmol) and methanesulfonic anhydride (0.27 g, 1 .57 mmol) were added. The mixture was stirred at RT for 30 min under N₂, then sodium iodide (0.39 g, 2.61 mmol) was added. The stirring was continued at RT for 3 h. The mixture was filtered to remove inorganic salts. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 6-chloro-7-(5-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-3-(iodomethyl)-1 -methyl-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 107, 410 mg, 89%); M/Z (ES+), [M+H]⁺ = 877. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .92-2.05 (m, 2H), 2.77(s, 6H), 2.91 -3.03 (m, 4H), 3.00-3.10 (m, 2H), 3.18-3.27 (m, 4H), 3.30 (s, 3H), 3.35 (s, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 4.16 (s, 2H), 4.24 (t, 2H), 4.73 (AB d, 1 H), 4.93 (AB d, 1 H), 6.54-6.65 (m, 2H), 6.65-6.80 (m, 2H), 7.29-7.32 (d, 1 H), 7.69-7.87 (m, 1 H).

Intermediate 108: (±)-Methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-3-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H- indole-2-carboxylate

A mixture of 3-(((3-((acetylthio)methyl)-1 -methyl-1 H-pyrazol-5-yl)methyl)thio)naphthalen- 1 -yl acetate (Intermediate 37, 183 mg, 0.46 mmol) and triphenylphosphine (1 1 .9 mg, 0.05 mmol) in MeOH (6 ml.) was degassed and re-filled with N₂. (±)-Methyl 6-chloro-7-(5-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-3-(iodomethyl)-1 -methyl-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 107, 400 mg, 0.46 mmol) in MeOH (12 ml.) and THF (4 ml.) was added. The final mixture was degassed, refilled with N₂ and cooled to 0 °C. Potassium carbonate (158 mg, 1 .14 mmol) was added. The mixture was stirred at 0 °C under N₂ for 50 min. Then more 3-(((3-((acetylthio)methyl)-1 -methyl- 1 H-pyrazol-5-yl)methyl)thio)naphthalen-1 -yl acetate (37 mg, 0.09 mmol) and K₂C0₃ (28 mg, 0.20 mmol) were added again. The mixture was stored in a fridge overnight and concentrated to dryness. Water (10 ml.) was added to the residue and the resulting mixture was extracted with EtOAc (3 x 10 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc) to give a mixture of (±)-methyl 6-chloro-7-(5-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-3-((((5-(((4-hydroxynaphthalen-2- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl- 3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 108, 75 wt% purity) and byproduct (±)-methyl 6-chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-3-((((5-(((4-hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-(((5-(((4-hydroxynaphthalen-2- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)propyl)-1 -methyl-1 H-indole-2-carboxylate (400 mg) which was used directly in the next step; M/Z (ES+), [M+H]⁺ = 1065. Intermediate 109: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox late

K2CO3 (97.0 mg, 0.70 mmol) was added to anhydrous acetonitrile (30 mL). The resulting suspension was degassed, re-filled with N₂ and heated to 90 °C in an oil bath. (±)-Methyl 6- chloro-7-(5-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-3-((((5-(((4- hydroxynaphthalen-2-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 -methyl-1 H- pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate and

(Intermediate 108, 400 mg, 75 wt% purity, 0.28 mmol) was dissolved in acetonitrile (3 mL), degassed and re-filled with N₂. This solution was slowly added to the K₂C0₃ suspension over 6 h under N₂ via a syringe pump. After addition, stirring was continued at 90 °C overnight. The mixture was cooled to RT and concentrated. Water (20 mL) was added to the residue and it was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35- tridecaene-23-carboxylate (Intermediate 109, 0.21 g, 77%); M/Z (ES+), [M+H]⁺ = 969. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.13-2.29 (m, 1 H), 2.27-2.40 (m, 1 H), 2.67 (AB d, 1 H), 2.87 (s, 6H), 2.99-3.1 1 (m, 1 H), 3.13-3.35 (m, 6H), 3.43-3.57 (m, 3H), 3.57-3.70 (m, 6H), 3.73(s, 3H), 3.75-3.93 (m, 6H), 3.93-4.08 (m, 4H), 4.68-4.88 (m, 2H), 4.95 (s, 1 H), 6.25 (s, 1 H), 6.68-6.90 (m, 4H), 6.95 (d, 1 H), 7.43-7.59 (m, 4H), 7.61 -7.81 (m, 1 H), 8.25-8.37 (m, 1 H). Intermediate 110: (±)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox lic acid

(±) -Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo

[27.7.1 .1⁴'^{7 11}'¹^0¹⁶'²^0²⁰'^{24 30}'³⁵]octatriaconta-1 (37),4(38),6,1 1 ,14,16,^

tridecaene-23-carboxylate (Intermediate 109, 200 mg, 0.21 mmol) was dissolved in THF (1 mL), MeOH (1 mL) and water (1 mL). LiOH (24.7 mg, 1 .03 mmol) was added. After stirring at 80 °C under N₂ for 45 min, the mixture was allowed to cool to RT, neutralized with 6N HCI (0.17 mL, 1 .03 mmol) and concentrated to dryness. Water (3 mL) was added to the resulting residue to give a suspension. The solids were collected by filtration and washed with water (2 mL), MeOH (2 mL) and dried under suction to give (±)-17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6,12,13,22-pentaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Intermediate 110, 175 mg, 82%); M/Z (ES+), [M+H]⁺ = 955. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 2.15-2.25 (m, 1 H), 2.29-2.39 (m, 1 H), 2.78 (s, 6H), 2.87 (AB d, 1 H), 2.93-3.04 (m, 4H), 3.04-3.14 (m, 2H), 3.21 -3.27 (m, 5H), 3.37-3.51 (m, 5H), 3.69 (s, 3H), 3.87-3.90 (m, 4H), 3.98-4.13 (m, 1 H), 4.23 (s, 2H), 4.66-4.87 (m, 3H), 6.58-6.71 (m, 3H), 6.71 -6.80 (m, 2H), 7.10 (d, 1 H), 7.38 (s, 1 H), 7.41 -7.56 (m, 2H), 7.65-7.78 (m, 1 H), 7.85 (d, 1 H), 8.02-8.15 (m, 1 H).

Intermediate 111 : (±)-Methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H- pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

(±) -Methyl 6-chloro-7-(5-(iodomethyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2- carboxylate (Intermediate 96, 3.71 g, 5.35 mmol) was added to a mixture of triphenylphosphine (0.10 g, 0.40 mmol) and S-((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methyl) ethanethioate (Intermediate 46, 1 .95 g, 5.72 mmol) in methanol (100 ml_). The resulting clear mixture was cooled to 0 °C, degassed and re-filled with N₂. K₂C0₃ (1 .85 g, 13.4 mmol) was added. The suspension was degassed and re-filled with N₂ three times. After stirring at 0 °C under N₂ for 60 min, the mixture was concentrated. Sat. NH4CI solution (50 ml.) was added and the mixture was extracted with EtOAc (3 x 50 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give

(±)-methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy) propyl)-1 H-indole-2-carboxylate (Intermediate 111 , 4.32 g, 93%); m/z (ES+), [M+H]⁺ = 864. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 0.92-1 .57 (m, 6H), 2.06-2.14 (m, 2H), 2.72-2.96 (m, 4H), 2.96-3.26 (m, 6H), 3.31 -3.50(m, 4H), 3.52-3.69 (m, 7H), 3.86-3.99 (m, 6H), 4.20-4.39 (m, 3H), 4.40-4.67 (m, 2H), 5.56-5.57 (m, 1 H), 6.53 (s, 1 H), 7.16- 7.25 (m, 2H), 7.39-7.78 (m, 4H), 8.10-8.27 (m, 1 H).

Intermediate 112: (±)-Methyl 17-chloro-5,12,22-trimethyl-14-{[(oxan-2-yl)oxy]methyl}-28-oxa-9- thia-5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

K2CO3 (1 .38 g, 9.99 mmol) was added to anhydrous acetonitrile (400 ml_). The resulting suspension was degassed, re-filled with N₂ and heated to 100 °C in an oil bath under N₂. (±)-Methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)thio)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 111 , 4.32 g, 5.00 mmol) in anhydrous acetonitrile (20 ml.) was degassed and re-filled with N₂. This solution was slowly added to the K₂C0₃ suspension above over 15 h under N₂ via a syringe pump. After addition, the stirring was continued at 100 °C overnight. The mixture was cooled to RT and concentrated. Water (20 ml.) was added to the residue and it was extracted with EtOAc (3 x 30 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give the desired product which was further purified by trituration in MeOH (10 ml.) to obtain (±)-methyl 17-chloro-5,12,22-trimethyl-14-{[(oxan-2-yl)oxy]methyl}-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35 -tridecaene-23-carboxylate (Intermediate 112, 3.36 g, 85%); M/Z (ES+), [M+H]⁺ = 768. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 0.95-1 .59 (m, 6H), 2.09-2.26 (m, 1 H), 2.30-2.54 (m, 1 H), 2.70-3.12 (m, 6H), 3.13-3.60 (m, 10H), 3.68-3.72 (m, 4H), 3.83 (s, 3H), 3.90 (s, 3H), 4.18-4.32 (m, 1 H), 4.35-4.66 (m, 2H), 5.04-5.06 (m, 1 H), 5.82- 5.84 (m, 1 H), 6.84 (d, 1 H), 7.17-7.19 (m, 1 H), 7.39-7.58 (m, 3H), 7.66-7.84 (m, 1 H), 8.33-8.37 (m, 1 H).

Intermediate 113: (±)-Methyl 17-chloro-14-(hydroxymethyl)-5,12,22-trimethyl-28-oxa-9-thia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

(±)-Methyl 17-chloro-5,12,22-trimethyl-14-{[(oxan-2-yl)oxy]methyl}-28-oxa-9-thia- 5,6, 12, 13,22-pentaazaheptacyclo[27 .1 .1⁴^

1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 112, 3.36 g, 4.37 mmol) was dissolved in DCM (15 ml.) and MeOH (15 ml_). 4M HCI in 1 ,4-dioxane (2.19 ml_, 8.75 mmol) was added. After stirring at RT for 45 min, the mixture was concentrated to dryness. The residue was re-dissolved in 10% MeOH in DCM (800 ml.) and washed with 1 N NaOH (50 ml_). The organic phase was dried over Na₂S04, filtered and concentrated to give (±)-methyl 17-chloro-14-(hydroxymethyl)-5,12,22-trimethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35 -tridecaene-23-carboxylate (Intermediate 113, 3.00 g, 100%), which was taken on without purification; M/Z (ES+), [M+H]⁺ = 684. ¹ H NMR (300 MHz, CHLOROFORM-oO δ 2.13-2.25 (m, 1 H), 2.32-2.45 (m, 1 H), 2.69-2.87 (m, 3H), 2.89-3.08 (m, 2H), 3.13 (AB d, 1 H), 3.22-3.34 (m, 4H), 3.36-3.58 (m, 4H), 3.62-3.76 (m, 4H), 3.83 (s, 3H), 3.89 (s, 3H), 4.48 (s, 2H), 5.1 1 (s, 1 H), 5.81 (s, 1 H), 6.89 (d, 1 H), 7.19 (s, 1 H), 7.44-7.58 (m, 3H), 7.72-7.79 (m, 1 H), 8.25-8.43 (m, 1 H).

Intermediate 114: (±)-Methyl 17-chloro-14-{[(methanesulfonyl)oxy]methyl}-5,12,22-trimethyl-28- oxa-9-thia-5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ '¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

(±)-Methyl 17-chloro-14-(hydroxymethyl)-5_>12,22-trimethyl-28-oxa-9-thia-5,6_>12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0^{11 15}.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,31 , 33,35-tridecaene-23-carboxylate (Intermediate 113, 840 mg, 1 .23 mmol) was dissolved in THF (20 mL) and DCM (20 mL) to result in a suspension. DIPEA (0.43 mL, 2.46 mmol) and methanesulfonic anhydride (321 mg, 1 .84 mmol) were added. After stirring at RT for 30 min, the mixture was concentrated. The residue was re-dissolved in EtOAc (50 mL), washed with 1 N HCI solution (10 mL), dried over Na₂S04, filtered and concentrated to dryness to give (±)-methyl 17-chloro-14-{[(methanesulfonyl)oxy]methyl}-5,12,22-trimethyl-28-oxa-9-thia- 5,6,12,13, 22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13, 16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 114, 900 mg, 96%); M/Z (ES+), [M+H]⁺ = 762. ¹ H NMR (300 MHz, CHLOROFORM-d) δ 2.15-2.25 (m, 1 H), 2.33-2.48 (m, 1 H), 2.64 (s, 3H), 2.71 -2.89 (m, 3H), 2.89-3.07 (m, 2H), 3.15 (d, 1 H), 3.24-3.52 (m, 7H), 3.52-3.67 (m, 4H), 3.67-3.77 (m, 1 H), 3.86 (s, 3H), 3.92 (s, 3H), 5.04 (s, 2H), 5.09 (s, 1 H), 5.81 (s, 1 H), 6.87 (d, 1 H), 7.18 (s, 1 H), 7.43-7.60 (m, 3H), 7.74 (dd, 1 H), 8.27-8.44 (m, 1 H).

Intermediate 115: (±)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

5,12,22-trimethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,Ea33,35-tridecaene-23-carboxylic acid

4-(4-Hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 438 mg, 1 .53 mmol) was dissolved in anhydrous DMF (2 mL) under N₂. NaH (85.0 mg, 2.13 mmol) (60% in oil) was added at RT. The mixture was stirred at RT for 10 min. A solution of (±)-methyl 17- chloro-14-{[(methanesulfonyl)oxy]methyl}-5,12,22-trimethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0^{11 15}.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,31 , 33,35-tridecaene-23-carboxylate (Intermediate 114, 900 mg, 1 .18 mmol) in DMF (1 .5 mL) was added. The mixture was stirred at 60 °C for 1 h, then cooled to RT and concentrated to dryness. The residue was re-dissolved in water (5 mL), THF (5 mL) and MeOH (5 mL). LiOH (283 mg, 1 1 .8 mmol) was added. The mixture was degassed, re-filled with N₂ and stirred at 60 °C for 2 h. After cooling to RT, 6N HCI solution was added to the mixture to adjust pH to 6-7 and the mixture was then concentrated. Water (20 mL) was added and the mixture was extracted with DCM (3 x 50 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (±)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Intermediate 115, 830 mg, 74%) as a solid; M/Z (ES+), [M+H]⁺ = 937. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.10- 2.22 (m, 1 H), 2.29-2.42 (m, 1 H), 2.73-2.83 (m, 9H), 2.92-3.09 (m, 7H), 3.12-3.17 (m, 1 H), 3.20- 3.26 (m, 4H), 3.32-3.69 (m, 10H), 3.73-3.86 (m, 4H), 4.62 (AB d, 1 H), 4.76 (AB d, 1 H), 4.88 (s, 1 H), 6.07 (s, 1 H), 6.53 (d, 2H), 6.71 (d, 2H), 6.86 (d, 1 H), 7.21 (s, 1 H), 7.40-7.52 (m, 2H), 7.57 (d, 1 H), 7.72-7.74 (m, 1 H), 8.14-8.17 (m, 1 H), 13.22 (s, 1 H).

Intermediate 116: N-((5-(((8-((4-Methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazol-3-yl)methyl)-2-nitrobenzenesulfonamide

Di-te -butyl azodicarboxylate (601 mg, 2.61 mmol) was added to a suspension of (5- (((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methanol

(Intermediate 53, 1 .00 g, 2.37 mmol), 2-nitrobenzenesulfonamide (480 mg, 2.37 mmol) and triphenylphosphine (684 mg, 2.61 mmol) in DCM (15 ml.) at 0 °C under N₂. After stirring at 0 °C under N₂ for 1 h, the mixture was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6- yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2-nitrobenzenesulfonamide (Intermediate 116, 1 .24 g, 60 wt% purity, 52%) with 1 .26 equiv. of triphenylphosphine oxide; M/Z (ES+), [M+H]⁺ = 606. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 3.65 (s, 3H), 3.80 (s, 3H), 3.97 (s, 2H), 4.19 (d, 2H), 5.34 (s, 2H), 5.68-5.86 (m, 2H), 6.81 -7.01 (m, 3H), 7.23 (d, 1 H), 7.37-7.61 (m, 3H), 7.61 - 7.75 (m, 2H), 7.75-7.84 (m, 1 H), 7.96-8.15 (m, 2H), 8.94-8.98 (m, 1 H).

Intermediate 117: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((N-((5-(((8- ((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol- 4-yl)-1 -methyl-1 H-indole-2-carbox late

Di-te/t-butyl azodicarboxylate (255 mg, 1 .1 1 mmol) was added to a suspension of N-((5- (((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrobenzenesulfonamide (Intermediate 116, 746 mg, 60 wt% purity, 0.74 mmol), (±)-methyl 3- (3-((te/t-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(hy

2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 94, 550 mg, 0.74 mmol) and triphenylphosphine (388 mg, 1 .48 mmol) in DCM (6 ml.) at RT under N₂. After stirring at RT for 1 h under N₂, more di-te -butyl azodicarboxylate (85.1 mg) was added. The reaction was continued for 30 min. The mixture was washed with water, dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel

chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(5-(((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol- 3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 117, 1 .10 g, calculated >1 12 % yield due to triphenylphosphine oxide contamination) which was taken on without further purification; M/Z (ES+), [M+H]⁺ = 1331 .

Intermediate 118: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (hydroxymethyl)-5-(((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H- pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H- indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol- 4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 117, 568 mg, 0.26 mmol) was dissolved in MeOH (10 mL). PPTS (19.0 mg, 0.08 mmol) was added. The mixture was stirred at 70 °C under N₂ for 24 h, cooled to RT and concentrated to dryness. EtOAc (50 mL) was added to the residue and the resulting organic solution washed with water, dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc to 5% MeOH in EtOAc) to give (±)-methyl 3-(3-((te - butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-(hydroxymethyl)-5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 118, 280 mg, 82%) ; M/Z (ES+), [M+H]⁺ = 1247. ¹ H NMR (300 MHz,

CHLOROFORM-oO δ 1 .08 (s, 9H), 1 .79-1 .90 (m, 2H), 2.95-3.14 (m, 2H), 3.30 (s, 3H), 3.52 (s, 3H), 3.70-3.88 (m, 10H), 3.94 (s, 3H), 4.12-4.20 (m, 2H), 4.41 -4.58 (m, 3H), 4.61 -4.74 (m, 1 H), 5.27 (s, 1 H), 5.33 (s, 2H), 6.81 -6.94 (m, 3H), 6.99-7.08 (m, 2H), 7.13-7.23 (m, 1 H), 7.24-7.57 (m, 12H), 7.67-7.69 (m, 5H), 7.89-7.92 (m, 1 H), 8.92-8.96 (m, 1 H).

Intermediate 119: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((N-((5-(((8- ((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((methylsulfonyl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carbox late

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-(hydroxymethyl)-5-(((N- ((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 118 3.12 g, 2.51 mmol) was dissolved in DCM (15 mL). DIPEA (0.66 mL, 3.77 mmol) was added. The solution was cooled to 0 °C. Methanesulfonic anhydride (656 mg, 3.77 mmol) was added. After stirring at 0 °C for 5 min and then RT for 30 min, the mixture was washed with water, dried over Na₂S04, filtered and concentrated to dryness to give (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((methylsulfonyl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 119, 3.30 g, 100%); M/Z (ES+), [M+H]⁺ = 1325. ¹ H NMR (300 MHz, CHLOROFORM-c ) δ 1 .09 (s, 9H), 1 .78-1 .90 (m, 2H), 2.61 (s, 3H), 3.00-3.13 (m, 2H), 3.28 (s, 3H), 3.50 (s, 3H), 3.70-3.88 (m, 10H), 3.98 (s, 3H), 4.10-4.21 (m, 2H), 4.52 (AB d, 1 H), 4.68 (AB d, 1 H), 4.96-5.16 (m, 2H), 5.27 (s, 1 H), 5.32 (s, 2H), 6.82-6.98 (m, 3H), 6.99- 7.15 (m, 2H), 7.22-7.29 (m, 2H), 7.33-7.48 (m, 10H), 7.49-7.62 (m, 1 H), 7.66-7.71 (m, 5H), 7.86- 7.90 (m, 1 H), 8.94-8.95 (m, 1 H).

Intermediate 120: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

4-(4-Hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 1 .15 g, 4.02 mmol) was dissolved in anhydrous DMF (10 ml_). NaH (161 mg, 4.02 mmol) (60% in oil) was added at RT under N₂. The mixture was stirred at RT for 20 min. A solution of (±)-methyl 3- (3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-3-(((methylsulfonyl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 119, 3.30 g, 2.51 mmol) in anhydrous DMF (2 ml.) and Kl (42.0 mg, 0.25 mmol) were added. After stirring at 20 °C for 15 min, the reaction mixture was concentrated to dryness. Water (50 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(((N-((5-(((8-((4- methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 120, 2.80 g, 72%) (molecular weight exceeded UPLC detection limit); ¹ H NMR (300 MHz, CHLOROFORM-oO δ 1 .08 (s, 9H), 1 .77-1 .91 (m, 2H), 2.85 (s, 6H), 2.97-3.22 (m, 6H), 3.30 (s, 3H), 3.35-3.58 (m, 6H), 3.68-3.86 (m, 10H), 3.97 (s, 3H), 4.17-4.28 (m, 3H), 4.46 (AB d, 1 H), 4.70 (AB d, 1 H), 4.78-4.87 (m, 1 H), 4.89-5.07 (m, 1 H), 5.25 (s, 1 H), 5.32 (s, 2H), 6.55-6.58 (m, 2H), 6.87-6.96 (m, 3H), 6.98-7.08 (m, 2H), 7.17-7.28 (m, 3H), 7.28-7.56 (m, 1 1 H), 7.61 -7.73 (m, 5H), 7.84-7.89 (m, 1 H), 8.03 (s, 1 H), 8.92-8.94 (m, 1 H).

Intermediate 121 : (±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3- hydroxypropyl)-1 -meth l-1 H-indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(((N-((5-(((8-((4-methoxybenzyl)oxy) quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 - methyl-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 120, 2.75 g,1 .82 mmol) was dissolved in THF (10 mL). TBAF (1 .86 ml, 1 .86 mmol) (1 M in THF) was added. The mixture was stirred at RT for 2 h and diluted with EtOAc (100 ml_). The organic phase was washed with water, brine, dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 5% MeOH in EtOAc) to give (±)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(((N- ((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H- indole-2-carboxylate (Intermediate 121 , 2.06 g, 80%); M/Z (ES+), [M+H]⁺ = 1276. ¹ H NMR (300 MHz, CHLOROFORM-oO δ 1 .79-1 .96 (m, 2H), 2.86 (s, 6H), 2.95-3.21 (m, 6H), 3.31 (s, 3H), 3.35-3.42 (m, 7H), 3.42-3.63 (m, 2H), 3.75-3.82 (m, 5H), 3.92 (s, 3H), 3.98(s, 3H), 4.14-4.23 (m, 2H), 4.48 (AB d, 1 H), 4.62-4.75 (m, 1 H), 4.77-4.86 (m, 1 H), 4.90-5.01 (m, 1 H), 5.25 (s, 1 H), 5.35 (s, 2H), 6.56 (d, 2H), 6.67-6.80 (m, 2H), 6.87-6.95 (m, 3H), 6.98-7.10 (m, 2H), 7.20-7.28 (m, 1 H),7.29-7.38 (m, 2H), 7.45-7.48 (m, 4H), 7.63-7.77 (m, 1 H), 7.94-7.97 (m, 1 H), 8.95-8.96 (m, 1 H).

Intermediate 122: (±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl- 3-(3-((methylsulfonyl)ox ropyl)-1 H-indole-2-carboxylate

(±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5- (((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)- 2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H- indole-2-carboxylate (Intermediate 121 , 1 .83 g, 1 .44 mmol) was dissolved in anhydrous DCM (10 mL) and cooled to 0 °C. DIPEA (0.38 mL, 2.16 mmol) and methanesulfonic anhydride (352 mg, 2.02 mmol) were added. After stirring at RT for 20 min, the mixture was washed with 0.5N aq. HCI (10 mL), sat. NaHC0₃ (10 mL), dried over Na₂S04, filtered and concentrated to give (±)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(((N- ((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)-2- nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy) propyl)-1 H-indole-2-carboxylate (Intermediate 122, 2.00 g, 100%); M/Z (ES+), [M+H]⁺ = 1354. ¹ H NMR (300 MHz, CHLOROFORM-c ) δ 2.05-2.15 (m, 2H), 2.86 (s, 6H), 2.93 (s, 3H), 3.02-3.23 (m, 6H), 3.28-3.57 (m, 10H), 3.79-3.82 (m, 5H), 3.93 (s, 3H), 3.97(s, 3H), 4.14-4.21 (m, 4H), 4.48 (AB d, 1 H), 4.70 (AB d, 1 H), 4.81 (AB d, 1 H), 4.95 (AB d, 1 H), 5.26 (s, 1 H), 5.35 (s, 2H), 6.55-6.58 (m, 2H), 6.67-6.78 (m, 2H), 6.86-6.93 (m, 3H), 7.02-7.15 (m, 2H), 7.30-7.42 (m, 3H), 7.41 -7.53 (m, 4H), 7.68-7.76 (m, 1 H), 7.92-7.96 (m, 1 H), 8.93-8.95 (m, 1 H).

Intermediate 123: (±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)pro l)-1 H-indole-2-carboxylate

(±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5- (((N-((5-(((8-((4-methoxybenzyl)oxy)quinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)- 2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl) oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 122, 2.00 g, 1 .44 mmol) was dissolved in DCM (5 mL) and then TFA (5.56 mL, 72.2 mmol) was added. After stirring at RT for 1 h, the mixture was concentrated to dryness. DCM (50 mL) was added to the residue and the solution was washed with sat. NaHC0₃ (40 mL) and brine, dried over Na₂S04, filtered and concentrated to dryness to give (±)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-^

yl)methyl)-2-nitrophenyl) sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 123, 1 .90 g, >100% calculated yield due to impurities) which was taken on without purification; M/Z (ES+), [M+H]⁺ = 1234. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.02-2.13 (m, 2H), 2.86 (s, 6H), 2.94 (s, 3H), 3.00-3.14 (m, 6H), 3.32-3.51 (m, 10H), 3.65-3.83 (m, 2H), 3.93 (s, 3H), 4.00 (s, 3H), 4.1 1 -4.30 (m, 4H), 4.55 (AB d, 1 H), 4.71 (AB d, 1 H), 4.83 (AB d, 1 H), 4.96 (AB d, 1 H), 5.22 (s, 1 H), 6.56- 6.59 (m, 2H), 6.70-6.80 (m, 2H), 6.99 (s, 1 H), 7.04-7.14 (m, 2H), 7.29-7.38 (m, 2H), 7.42-7.56 (m, 3H), 7.73 (d, 1 H), 7.98 (d, 1 H), 8.75-8.78 (m, 1 H).

Intermediate 124: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-9-(2-nitrobenzene-1 -sulfonyl)-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox late

A solution of (±)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(((N-((5-(((8-hydroxyquinolin-6-yl)thio)methyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)-2-nitrophenyl)sulfonamido)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 123, 1 .78 g, 1 .44 mmol) in acetonitrile (10 mL) was slowly added to a suspension of K₂C0₃ (598 mg, 4.32 mmol) in anhydrous acetonitrile (120 mL) under N₂ at 90 °C over 12 h via a syringe pump. After addition, the stirring was continued at 90 °C overnight. The mixture was cooled to RT and concentrated. Water (20 mL) was added to the residue and the mixture was extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-9-(2- nitrobenzene-1 -sulfonyl)-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵] octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 124, 1 .32 g, 74%); M/Z (ES+), [M+H]⁺ = 1 138. ¹ H NMR (300 MHz, CHLOROFORM- /) δ 2.12-2.35 (m, 1 H), 2.58-2.66 (m, 1 H), 2.86 (s, 6H), 2.96-3.1 1 (m, 4H), 3.30-3.59 (m, 13H), 3.61 -3.77 (m, 3H), 3.83-4.02 (m, 5H), 4.1 1 (s, 3H), 4.33-4.54 (m, 2H), 4.70 (s, 1 H), 4.80 (AB d, 1 H), 4.92 (AB d, 1 H), 6.36 (d, 1 H), 6.47-6.57 (m, 3H), 6.64-6.75 (m, 2H), 7.40-7.55 (m, 5H), 7.60 (d, 1 H), 7.87- 8.00 (m, 1 H), 8.06-8.08 (m, 1 H), 9.02-9.04 (m, 1 H).

Intermediate 125: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox late

Acetonitrile (40 mL) was added to (±)-methyl 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l -yl]phenoxy}methyl)-5,12,22-trimethyl-9-(2-nitrobenzene-1 - sulfonyl)-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵] octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate

(Intermediate 124, 1 .32 g, 1 .14 mmol) to give a suspension. Potassium carbonate (789 mg, 5.71 mmol) was added, followed by addition of thiophenol (0.59 mL, 5.71 mmol). The suspension was stirred at RT for 1 h. The reaction mixture was concentrated and DMF (3 mL) was added. After stirring at RT for 2 h, the mixture was concentrated, diluted with water (100 mL), extracted with EtOAc (5 x 50 mL), dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 125, 890 mg, 72%); M/Z (ES+), [M+H]⁺ = 953. ¹ H NMR (300 MHz, CHLOROFORM- /) δ 2.35-2.59 (m, 2H), 2.86 (s, 6H), 2.98-3.09 (m, 4H), 3.15-3.29 (m, 1 H), 3.31 -3.44 (m, 6H), 3.46-3.66 (m, 6H), 3.78 (s, 3H), 3.88-3.93 (m, 4H), 3.96-4.09 (m, 6H), 4.78 (AB d, 1 H), 4.90 (AB d, 1 H), 5.12 (s, 1 H), 6.55-6.65 (m, 2H), 6.65-6.82 (m, 3H), 7.00 (d, 1 H), 7.36 (s, 1 H), 7.39-7.48 (m, 1 H), 7.64 (d, 1 H), 7.97-8.00 (m, 1 H), 8.92-8.94 (m, 1 H).

Intermediate 126: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox late

Sodium cyanoborohydride (158 mg, 2.52 mmol) was added to a solution of (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa- 2-thia-5,6,9, 12,13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³⁵]octatriaconta^ 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 125, 400 mg, 0.42 mmol) in MeOH (7 mL) and acetic acid (3.50 mL) at RT to result in a white suspension. After stirring at RT for 7 h, MeOH (5 mL), acetic acid (1 mL) and DCM (18 mL) were added. After stirring at RT overnight, more sodium cyanoborohydride (26 mg) was added. The stirring was continued at RT for 30 h. The mixture was concentrated and sat. NH4OH solution (10 mL) was added. The aq. phase was extracted with DCM (4 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22- trimethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate (Intermediate 126,

230 mg, 57%); m/z (ES+), [M+H]⁺ = 957. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .83-2.01 (m,

2H), 2.05-2.24 (m, 2H), 2.73 (t, 2H), 2.86 (s, 6H), 2.99-3.07 (m, 4H), 3.07-3.15 (m, 1 H), 3.20

(AB d, 1 H), 3.30-3.59 (m, 14H), 3.64 (s, 3H), 3.66-3.76 (m, 3H), 3.82 (s, 3H), 4.01 (s, 3H), 4.84

(AB d, 1 H), 4.94 (AB d, 1 H), 5.31 (s, 1 H), 6.17 (s, 1 H), 6.61 -6.69 (m, 2H), 6.69-6.76 (m, 3H),

7.15 (d, 1 H), 7.56 (d, 1 H).

Intermediate 126 (230 mg, 0.24 mmol) was subjected to HPLC (Lux Amylose-2 column, 21 x 250 mm, 5 μιη, Temperature = RT, Mobile phase = 40:60 33% ACN in EtOH with 0.1 % DEA:hexane with 0.1 % DEA, UV detection @ 254 nm, loading= 20 mg/inj, cone = 60 mg/mL in MeOH/ACN, flow rate = 20 mL/min) to give two enantiomers.

Intermediate 127a: (S_a)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox late

(Sa)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12, 22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35- undecaene-23-carboxylate (Intermediate 127a) was the first eluting enantiomer (60.0 mg, 16%, >98% e.e.); m/z (ES+), [M+H]⁺ = 957. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .83-2.01 (m, 2H), 2.05-2.24 (m, 2H), 2.73 (t, 2H), 2.86 (s, 6H), 2.99-3.07 (m, 4H), 3.07-3.15 (m, 1 H), 3.20 (AB d, 1 H), 3.30-3.59 (m, 14H), 3.64 (s, 3H), 3.66-3.76 (m, 3H), 3.82 (s, 3H), 4.01 (s, 3H), 4.84 (AB d, 1 H), 4.94 (AB d, 1 H), 5.31 (s, 1 H), 6.17 (s, 1 H), 6.61 -6.69 (m, 2H), 6.69-6.76 (m, 3H),

7.15 (d, 1 H), 7.56 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: HPLC: Lux Amylose-2 column, 4.6 x 50 mm, 5 μιη, Temperature = RT, Mobile phase = 20:80 33% ACN in EtOH with 0.1 % DEA:hexane with 0.1 % DEA, UV detection at 254 nm, flow rate = 1 .0 mL/min, Retention time of 1 .63 min, >98% ee.

Intermediate 128: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,9,12,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox late

Formaldehyde (0.10 mL, 1 .36 mmol, 37 wt% in water) was added to a solution of (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22- trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazah

octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylate

(Intermediate 125, 433 mg, 0.45 mmol) in DCM (5 mL), followed by addition of sodium triacetoxyborohydride (192 mg, 0.91 mmol) at RT. The stirring was continued for 50 min. The reaction mixture was quenched with sat. NaHC0₃ (5 mL), diluted with water (5 mL), extracted with DCM (3 x 10 mL). The combined organic phases were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc to 10% MeOH in EtOAc) to give (±)-methyl 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,9,12,22-tetramethyl-28-oxa-2-thia- 5,6,9,12,13,22,31 -heptaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 , 33, 35-tridecaene-23-carboxylate (Intermediate 128, 360 mg, 82%); M/Z (ES+), [M+H]⁺ = 967. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 2.01 (s, 3H), 2.42-2.54 (m, 1 H), 2.57-2.72 (m, 1 H), 2.86 (s, 6H), 2.96-3.22 (m, 7H), 3.33-3.40 (m, 4H), 3.44- 3.62 (m, 5H), 3.85 (s, 3H), 3.92-4.03 (m, 7H), 4.16-4.28 (m, 2H), 4.62-4.73 (m, 2H), 4.78-4.88 (m, 1 H), 6.60 (d, 2H), 6.73 (d, 2H), 6.89 (s, 1 H), 7.12 (d, 1 H), 7.23 (s, 1 H). 7.36-7.40 (m, 1 H), 7.61 -7.73 (m, 1 H), 7.86-7.97 (m, 1 H), 8.86-8.87 (m, 1 H).

Intermediate 129: (±)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,9,12,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox late

Sodium cyanoborohydride (187 mg, 2.98 mmol) was added to a clear yellow solution of (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,9,12,22- tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

-tridecaene-23-carboxylate (Intermediate 128, 360 mg, 0.37 mmol) in MeOH (5 mL), DCM (2 mL) and acetic acid (2 mL) at RT. After stirring at RT for 20 h, the mixture was concentrated and sat. NH₄OH solution (10 mL) was added. The aq. phase was extracted with DCM (4 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc). The fractions containing product were concentrated and re-purified by reverse column chromatography (C18, 100% 0.1 % TFA in water to 100% 0.1 % TFA in ACN over 15 min) to give (±)-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,9, 12,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylate as a TFA salt

(Intermediate 129, 220 mg, 60%) ; m/z (ES+), [M+H]⁺ = 971 . ¹ H NMR (300 MHz, METHANOL- d₄) δ 1 .90-2.09 (m, 2H), 2.12-2.28 (m, 2H), 2.75 (s, 3H), 2.77-2.84 (m, 2H), 2.86 (s, 6H), 3.05- 3.18 (m, 1 H), 3.18-3.27 (m, 4H), 3.34-3.57 (m, 10H), 3.62-3.74 (m, 7H), 3.88 (s, 3H), 3.97 (s, 2H), 4.1 1 (s, 3H), 4.27-4.46 (m, 2H), 4.91 (AB d, 1 H), 5.00 (AB d, 1 H), 5.56 (s, 1 H), 6.09 (s, 1 H), 6.63 (d, 2H), 6.92 (s, 1 H), 6.98 (d, 2H), 7.26 (d, 1 H), 7.79 (d, 1 H).

Intermediate 129 (220 mg, 0.20 mmol) was subjected to chiral HPLC (Lux Amylose-2 column, 21 x 250 mm, 5 μιη, Temperature = RT, Mobile phase = 40:60 33% ACN in EtOH with 0.1 % DEA:hexane with 0.1 % DEA, UV detection @ 254 nm, loading= 20 mg/inj, cone = 60 mg/mL in MeOH/ACN, flow rate = 20 mL/min) to give two enantiomers.

Intermediate 130a: (S_a)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,9,12,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox late

(Sa)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,9,12,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

undecaene-23-carboxylate (Intermediate 130a) was the first eluting enantiomer (77.0 mg, 38%, >98% e.e.); m/z (ES+), [M+H]⁺ = 971 . ¹ H NMR (300 MHz, METHANOL-ok) δ 1 .75-1 .89 (m, 2H), 1 .98 (s, 3H), 2.03-2.13 (m, 1 H), 2.17-2.34 (m, 1 H), 2.55-2.60 (m, 2H), 2.83 (s, 6H), 2.93- 2.99 (m, 4H), 3.10-3.30 (m, 1 1 H), 3.37-3.49 (m, 2H), 3.56-3.63 (m, 2H), 3.68 (s, 3H), 3.72-3.83 (m, 4H), 3.90 (s, 3H), 3.97 (s, 3H), 4.70 (s, 1 H), 4.78-4.80 (m, 1 H), 4.84-4.93 (m, 1 H), 6.28-6.47 (m, 4H), 6.57-6.72 (m, 2H), 7.09 (d, 1 H), 7.67 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: HPLC: Lux Amylose-2 column, 4.6 x 50 mm, 5 μιη, Temperature = RT, Mobile phase = 20:80 33% ACN in EtOH with 0.1 % DEA:hexane with 0.1 % DEA, UV detection at 254 nm, flow rate = 1 .0 mL/min, Retention time of 1 .35 min, >98% e.e. Intermediate 131 : (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (hydroxymethyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 H-indole- 2-carboxylate

A mixture of Cs₂C0₃ (7.1 1 g, 21 .8 mmol), methyl 7-bromo-3-(3-((te/t- butyldiphenylsilyl)oxy)propyl)-6-chloro-1 H-indole-2-carboxylate (Intermediate 22, 5.55 g, 9.49 mmol) and dichloro[1 ,1 '-bis(di-te -butylphosphino)ferrocene]palladium(ll) (0.19 g, 0.28 mmol) in 1 ,4-dioxane (63.2 ml.) and water (15.8 ml.) was degassed, re-filled with N₂ three times and heated to 95 °C. A solution of (1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazol-3-yl)methanol (Intermediate 18, 4.34 g, 12.3 mmol) in 1 ,4-dioxane (15.8 ml.) was degassed, re-filled with N₂ and added slowly to the mixture above over 45 min at 95 °C via a syringe pump. After addition, the reaction was stirred at 95 °C for 60 min, then cooled to RT and concentrated to dryness. Water (100 ml.) was added to the residue and the mixture was extracted with EtOAc (3 x 100 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((te - butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-(hydroxymethyl)-1 -methyl-5-(((tetrahydro-2H-pyran- 2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 H-indole-2-carboxylate (Intermediate 131 , 4.00 g, 58%); M/Z (ES+), [M+H]⁺ = 730. ¹ H NMR (300 MHz, CHLOROFORM-of) 5 1 .1 1 (s, 9H), 1 .36-1 .80 (m, 6H), 1 .87-1 .98 (m, 2H), 3.13-3.39 (m, 3H), 3.71 -3.81 (m, 3H), 3.85 (s, 3H), 4.05-4.07 (m, 3H), 4.26- 4.77 (m, 5H), 7.22 (d, 1 H), 7.32-7.49 (m, 6H), 7.62 (d, 1 H), 7.69-7.70 (m, 4H), 8.90-8.95 (m, 1 H).

Intermediate 132: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (hydroxymethyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate

(±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-(hydroxymethyl)-1 - methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)m

(Intermediate 131 , 10.8 g, 14.8 mmol) was dissolved in DMF (20 mL). Cs₂C0₃ (5.06 g, 15.5 mmol) and Mel (0.97 mL, 15.5 mmol) were added. After stirring at RT for 2 h, the mixture was concentrated. Water (100 mL) was added to the residue and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (hydroxymethyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 132, 9.70 g, 88%); M/Z (ES+), [M+H]⁺ = 744. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .1 1 (s, 9H), 1 .33-1 .74 (m, 6H), 1 .80-1 .95 (m, 2H), 3.03-3.17 (m, 3H), 3.27-3.72 (m, 4H), 3.72-3.87 (m, 5H), 4.02-4.03 (m, 3H), 4.05-4.24 (m, 1 H), 4.33-4.63 (m, 4H), 7.20 (d, 1 H), 7.34-7.49 (m, 6H), 7.62 (d, 1 H), 7.69-7.72 (m, 4H).

Intermediate 133: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (iodomethyl)-l -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H- indole-2-carboxylate

A mixture of (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3- (hydroxymethyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 132, 9.04 g, 12.1 mmol) and DIPEA (3.18 mL, 18.2 mmol) in THF (30 mL) was cooled to 0 °C. Methanesulfonic anhydride (2.75 g, 15.8 mmol) was added. The mixture was stirred at 0 °C for 5 min and then at RT for 30 min. Sodium iodide (8.19 g, 54.6 mmol) was added. The resulting suspension was stirred at 50 °C for 2 h. After cooling to RT, the mixture was filtered to remove inorganic salts. The filtrate was concentrated to dryness. EtOAc (100 mL) and water (100 mL) were added to the residue. The layers was separated. The aq. phase was extracted with EtOAc (3 x 20 mL). The combined organic phases was dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel column

chromatography (hexanes/EtOAc) to give (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(3-(iodomethyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 - methyl-1 H-indole-2-carboxylate (Intermediate 133, 9.80 g, 94%); M/Z (ES+), [M+H]⁺ = 854. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .12 (s, 9H), 1 .35-1 .74 (m, 6H), 1 .82-1 .99 (m, 2H), 3.05- 3.21 (m, 3H), 3.32-3.80 (m, 4H), 3.72-3.86 (m, 5H), 4.00-4.03 (m, 3H), 4.06-4.48 (m, 4H), 4.52- 4.70 (m, 1 H), 7.22 (d, 1 H), 7.32-7.50 (m, 6H), 7.59-7.76 (m, 5H).

Intermediate 134: (±)-Methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-5-(((tetrahydro-2H-pyran-2- yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate

4-(4-Hydroxyphenyl)-N,N-dimethylpiperazine-1 -sulfonamide (Intermediate 101 , 1 .88 g, 6.60 mmol) was dissolved in anhydrous DMF (10 ml) under N₂. NaH (0.28 g, 6.88 mmol) (60 wt% in oil) was added at RT. The mixture was stirred at RT for 15 min. Then (±)-methyl 3-(3- ((te -butyldiphenylsilyl)oxy)propyl)-6-chloro-7-(3-(iodomethyl)-1 -methyl-5-(((tetrahydro-2H- pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 133, 4.90 g, 5.74 mmol) in DMF (10 mL) was added. After stirring at 55 °C under N₂ for 30 min, the mixture was cooled to RT and then concentrated to dryness. Water (150 mL) was added to the residue to give a suspension. This suspension was stirred at RT for 15 min. The solid was collected by filtration and re-dissolved in DCM (100 mL). The resulting organic solution was dried over Na₂S04, filtered and concentrated to dryness to give an off-white solid. This solid was washed with hexanes (50 mL) to give (±)-methyl 3-(3-((te -butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-5- (((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 134, 5.50 g, 95%); M/Z (ES+), [M+H]⁺ = 101 1 . ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .1 1 (s, 9H), 1 .34-1 .75 (m, 6H), 1 .78-1 .96 (m, 2H), 2.85 (s, 6H), 2.95-3.05 (m, 4H), 3.06-3.17 (m, 3H), 3.29-3.42 (m, 4H), 3.46-3.47 (m, 3H), 3.61 -3.80 (m, 3H), 3.83 (s, 3H), 4.03-4.05 (m, 3H), 4.08-4.49 (m, 2H), 4.55-4.66 (m, 1 H), 4.75-4.89 (m, 1 H), 4.89-5.04 (m, 1 H), 6.60-6.64 (m, 2H), 6.67-6.73 (m, 2H), 7.18 (d, 1 H), 7.33-7.49 (m, 6H), 7.56 (d, 1 H), 7.65- 7.76 (m, 4H).

Intermediate 135: (±)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate

MeOH (10 mL) was added to (±)-methyl 3-(3-((te/t-butyldiphenylsilyl)oxy)propyl)-6- chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-5- (((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 134, 3.00 g, 2.97 mmol) to give a white suspension. 4M HCI in 1 ,4-dioxane (4 mL, 16.0 mmol) was added. The mixture was stirred at RT for 1 h and concentrated to dryness. Sat. NaHC0₃ (50 mL) was added and the mixture was extracted with EtOAc (4 x 60 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (±)-methyl 6-chloro- 7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-(hydroxymethyl)-1 -methyl- 1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2-carboxylate (Intermediate 135, 1 .80 g, 88%); M/Z (ES+), [M+H]⁺ = 689. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .89-2.00 (m, 2H), 2.85 (s, 6H), 2.99-3.07 (m, 4H), 3.08-3.20 (m, 2H), 3.31 -3.41 (m, 4H), 3.47 (s, 3H), 3.56-3.63 (m, 2H), 3.92 (s, 3H), 4.08 (s, 3H), 4.41 -4.54 (m, 2H), 4.68-4.82 (m, 1 H), 4.83-5.02 (m, 1 H), 6.47-6.63 (m, 2H), 6.68-6.74 (m, 2H), 7.22 (d, 1 H), 7.60 (d, 1 H).

Intermediate 135 (1 .40 g, 2.03 mmol) was subjected to chiral SFC (Chiralpak IA^® column, 30 x 250 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 40:60 EtOH with 0.2% NH₄OH:C0₂, UV detection @ 254 nm, loading= 125 mg/inj, cone = 100 mg/mL in MeOH/DCM, flow rate = 100 mL/min, Outlet Pressure = 100 bar) to give two enantiomers. Intermediate 136b: (Sa)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate

(Sa)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)- 5-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl-1 H-indole-2- carboxylate (Intermediate 136b) was the second eluting enantiomer (0.63 g, 45%, >98% e.e.) ; M/Z (ES+), [M+H]⁺ = 689. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 1 .89-2.00 (m, 2H), 2.82 (s, 6H), 2.99-3.07 (m, 4H), 3.08-3.20 (m, 2H), 3.31 -3.41 (m, 4H), 3.44 (s, 3H), 3.56-3.63 (m, 2H), 3.89 (s, 3H), 4.04 (s, 3H), 4.41 -4.54 (m, 2H), 4.73 (AB d, 1 H), 4.89 (AB d, 1 H), 6.47-6.63 (m, 2H), 6.68-6.74 (m, 2H), 7.19 (d, 1 H), 7.57 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IA^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase= 30:70 EtOH with 0.2% NH₄OH:C0₂, UV detection at 254 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .76 min, >98% e.e.

Intermediate 137: (Sa)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3- yl)methyl)amino)methyl)-1 -methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)- 1 H-indole-2-carboxylate

O

/

N-S-N

O \

Methanesulfonic anhydride (372 mg, 2.13 mmol) was added to a mixture of DIPEA (0.50 mL, 2.84 mmol) and (S_a)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 - yl)phenoxy)methyl)-5-(hydroxymethyl)-1 -methyl-1 H-pyrazol-4-yl)-3-(3-hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 136b, 490 mg, 0.71 mmol) in DCM (10 mL) at 0 °C. The mixture was allowed to warm to RT, stirred at RT for 30 min and then washed with water (5 mL), sat. NaHC0₃. The organic phase was dried over Na₂S04, filtered and concentrated to dryness to give (Sa)-methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)- 1 -methyl-5-(((methylsulfonyl)oxy)methyl)-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy) propyl)-1 H-indole-2-carboxylate, which was taken on without purification. Acetonitrile (10 mL) and THF (3 mL) were added to this di-mesylate intermediate to give a suspension. 3-(2-(3- (Aminomethyl)-1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -ol (Intermediate 48, 200 mg, 0.71 mmol) and DIPEA (0.19 mL, 1 .07 mmol) were added. The mixture was stirred at 50 °C for 4 h and then concentrated to dryness. The residue was re-dissolved in EtOAc (30 mL) and washed with water, brine, dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (S_a)- methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-5-((((5-(2-(4- hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 -methyl-1 H- pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 137, 458 mg, 63%); M/Z (ES+), [M+H]⁺ = 1030. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .84-1 .96 (m, 2H), 2.73-2.84 (m, 10H), 2.89-2.97 (m, 4H), 2.98-3.07 (m, 2H), 3.1 1 (s, 3H), 3.17-3.25 (m, 4H), 3.29-3.30 (m, 1 H), 3.30-3.44 (m, 6H), 3.46-3.59 (m, 4H), 3.83 (s, 3H), 3.89 (s, 3H), 4.1 1 -4.25 (m, 2H), 4.55-4.67 (AB d, 1 H), 4.76-4.92 (AB d, 1 H), 5.60 (s, 1 H), 6.44 (d, 2H), 6.66 (d, 2H), 6.75 (s, 1 H), 7.1 1 (s, 1 H), 7.25 (d, 1 H), 7.31 -7.47 (m, 2H), 7.64-7.75 (m, 2H), 8.04-8.07 (d, 1 H), 10.00 (s, 1 H). Intermediate 138: (Sa)-Methyl 7-(5-(((te -butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-3-((4-(4-(N,N- dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-1 H-pyrazol-4-yl)-6-chloro-1 -methyl- 3-(3-((methylsulfonyl)oxy ropyl)-1 H-indole-2-carboxylate

(Sa)-Methyl 6-chloro-7-(3-((4-(4-(N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)- 5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-1 - methyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 137, 435 mg, 0.42 mmol) was dissolved in DCM (4 mL). Di-te t-butyl dicarbonate (0.12 mL, 0.51 mmol) was added. After stirring at RT for 2 h, the mixture was washed with water, dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (Sa)-methyl 7-(5-(((te/t-butoxycarbonyl)((5- (2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-3-((4-(4- (N,N-dimethylsulfamoyl)piperazin-1 -yl)phenoxy)methyl)-1 -methyl-1 H-pyrazol-4-yl)-6-chloro-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 138, 450 mg, 94%); M/Z (ES+), [M+H]⁺ = 1 130; ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .03-1 .18 (br, 9H), 1 .90-1 .99 (m, 2H), 2.78 (s, 6H), 2.82-2.89 (m, 4H), 2.91 -3.00 (m, 4H), 3.01 -3.10 (m, 2H), 3.15 (s, 3H), 3.19-3.27 (m, 4H), 3.34 (s, 3H) 3.44-3.81 (m, 5H) 3.81 -3.95 (m, 6H) 4.15-4.32 (m, 4H) 4.55-4.71 (m, 1 H) 4.74-4.90 (m, 1 H) 5.55 (s, 1 H), 6.42-6.48 (m, 2H), 6.67-6.70 (m, 2H), 6.74 (s, 1 H), 7.12 (s, 1 H), 7.25 (d, 1 H), 7.31 -7.50 (m, 2H), 7.61 -7.78 (m, 2H), 8.05 (d, 1 H), 9.98 (s, 1 H).

Intermediate 139: (S_a)-9-te -Butyl 23-methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-

1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-5,6,9, 12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-9,23-dicarboxylate

A solution of (Sa)-methyl 7-(5-(((teri-butoxycarbonyl)((5-(2-(4-hydroxynaphthalen-2- yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)amino)methyl)-3-((4-(4-(N,N-dimethylsulfamoyl) piperazin-1 -yl)phenoxy) methyl)- 1 -methyl-1 H-pyrazol-4-yl)-6-chloro-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 138, 450 mg, 0.40 mmol) in anhydrous acetonitrile (5 mL) was added to a suspension of K₂C0₃ (1 10 mg, 0.80 mmol) in acetonitrile (20 mL) at 90 °C over 16 h under N₂ via a syringe pump. After addition, the stirring was continued at 90 °C overnight. The mixture was cooled to RT and concentrated. Water (20 mL) was added to the residue and extracted with EtOAc (3 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give ( S_a) -9- ieri-buty I 23-methyl 17-chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-5,6,9,12, 13,22-hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²^0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-9,23-dicarboxylate (Intermediate 139, 330 mg, 72%); M/Z (ES+), [M+H]⁺ = 1034. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 1 .41 (s, 9H), 2.06-2.19 (m, 1 H), 2.33-2.48 (m, 1 H), 2.66-2.78 (m, 2H), 2.83 (s, 6H), 2.89-3.13 (m, 6H), 3.15-3.54 (m, 14H), 3.59-3.94 (m, 5H), 3.96-4.06 (m, 4H), 4.20-4.32 (m, 1 H), 4.77 (AB b, 1 H), 4.87 (AB b, 1 H), 5.08 (s, 1 H), 5.76 (s, 1 H), 6.54 - 6.80 (m, 5H), 7.16 (s, 1 H), 7.38-7.52 (m, 3H), 7.6 -7.77 (m, 1 H), 8.22-8.38 (m, 1 H).

Intermediate 140: (S_a)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

MeOH (2 mL) was added to (S_a)-9-te/t-butyl 23-methyl 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-5,6,9,12,13_^ hexaazaheptacyclo[27 .1 .1⁴'^{7 11} '¹^0^ ^

18,20,23,29,31 , 33,35-tridecaene-9,23-dicarboxylate (Intermediate 139, 330 mg, 0.29 mmol). 4M HCI in 1 ,4-dioxane (1 .08 mL, 4.31 mmol) was added. After stirring at RT under N₂ for 16 h, the mixture was concentrated to dryness. The residue was re-dissolved in DCM (30 mL), washed with sat. NaHC0₃ solution (2 x 10 mL). The organic phase was dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (S_a)-methyl 17-chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-l -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-5,6,9, 12,13,22- hexaazaheptacyclo [27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35 -tridecaene-23-carboxylate (Intermediate 140, 240 mg, 83%); M/Z (ES+), [M+H]⁺ = 934. ¹ H NMR (300 MHz, CHLOROFORM-c/) δ 2.12- 2.39 (m, 2H), 2.83 (s, 6H), 2.85-3.01 (m, 8H), 3.14-3.23 (m, 1 H), 3.26-3.57 (m, 15H), 3.61 -3.75 (m, 5H), 4.00 (s, 3H), 4.78 (AB d, 1 H), 4.90 (AB d, 1 H), 5.35 (s, 1 H), 6.04 (s, 1 H), 6.56-6.71 (m, 4H), 6.95 (d, 1 H), 7.14 (s, 1 H), 7.39-7.53 (m, 3H), 7.65-7.72 (m, 1 H), 8.23-8.30 (m, 1 H).

Intermediate 141 : (S_a)-Methyl 6-chloro-7-(5-(iodomethyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 - methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

(Sa)-Methyl 6-chloro-7-(5-(hydroxymethyl)-1 ,3-dimethyM H-pyrazol-4-yl)-3-(3- hydroxypropyl)-1 -methyl- 1 H-indole-2-carboxylate (Intermediate 74, 5.16 g, 12.7 mmol) was dissolved in anhydrous THF (125 mL) and DIPEA (8.88 mL, 50.8 mmol) was added. The solution was cooled to 0 °C. Methanesulfonic anhydride (6.64 g, 38.1 mmol) was added and the ice bath was removed. After stirring at RT for 1 h, the mixture was cooled to 0 °C and sodium iodide (9.53 g, 63.6 mmol) was added. The resulting suspension was stirred at 0 °C for 3 h. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (100 mL) and water (200 mL). The layers were separated, the aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic phases were washed with 1 N aqueous HCI (2 x 25 mL), brine, dried over Na₂S04, filtered and concentrated to dryness to give (S_a)-methyl 6-chloro-7-(5- (iodomethyl)-l ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H- indole-2-carboxylate, which was taken on without purification (Intermediate 141 , 8.10 g, 100%); M/Z (ES+), [M+H]⁺ = 594.¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.05 (s, 3H), 2.10-2.23 (m, 2H), 3.02 (s, 3H), 3.19 (t, 2H), 3.58 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.10-4.18 (m, 2H), 4.31 (t, 2H), 7.24 (d, 1 H), 7.64 (d, 1 H).

Intermediate 142: (S_a)-Methyl 6-chloro-7-(5-((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate

(Sa)-Methyl 6-chloro-7-(5-(iodomethyl)-1 ,3-dimethyl-l H-pyrazol-4-yl)-1 -methyl-3-(3- ((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 141 , 6.96 g, 10.9 mmol) was dissolved in anhydrous methanol (120 mL) and cooled to 0 °C. 3-(2-(3-((Acetylthio)methyl)- 1 -methyl-1 H-pyrazol-5-yl)ethyl)naphthalen-1 -yl acetate (Intermediate 46, 4.00 g, 10.5 mmol) was added, the mixture was degassed and re-filled with N₂ and triphenylphosphine (0.06 g, 0.22 mmol) and potassium carbonate (4.37 g, 31 .6 mmol) were added. The resulting

suspension was degassed and re-filled with N₂ three times. After stirring at 0 °C for 30 min under N₂, the mixture was concentrated to dryness. The residue was acidified with 1 N HCI solution to pH=4, the aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic phases were dried over Na₂S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (S_a)-methyl 6-chloro-7-(5-((((5-(2- (4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl-1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3-dimethyl-1 H- pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 142, 7.35 g, 88%); M/Z (ES+), [M+H]⁺ = 764. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.06- 2.20 (m, 5H), 2.79-2.96 (m, 4H), 3.01 (s, 3H), 3.15 (t, 2H), 3.44 (s, 3H), 3.49-3.61 (m, 7H), 3.88 (s, 3H), 3.93 (s, 3H), 4.29 (t, 2H), 5.60 (s, 1 H), 6.51 (d, 1 H), 7.21 (d, 2H), 7.38-7.53 (m, 2H), 7.60 (d, 1 H), 7.67-7.81 (m, 1 H), 8.14-8.28 (m, 1 H).

Intermediate 143: (S_a)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate

K2CO3 (1 .50 g, 10.8 mmol) was added to MeCN (400 mL). The resulting suspension was degassed, re-filled with N₂ and heated to 80 to 85 °C in an oil bath. (S_a)-Methyl 6-chloro-7-(5- ((((5-(2-(4-hydroxynaphthalen-2-yl)ethyl)-1 -methyl- 1 H-pyrazol-3-yl)methyl)thio)methyl)-1 ,3- dimethyl-1 H-pyrazol-4-yl)-1 -methyl-3-(3-((methylsulfonyl)oxy)propyl)-1 H-indole-2-carboxylate (Intermediate 142, 4.12 g, 5.40 mmol) was dissolved in acetonitrile (20 mL), degassed and refilled with N₂. This solution was slowly added to the K2CO3 suspension over 10 h under N₂ via a syringe pump. After addition, stirring was continued at 80 °C overnight. The mixture was cooled to RT and filtered to remove inorganic salts. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (hexanes/EtOAc) to give (Sa)-methyl 17- chloro-5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0^{11 15}.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 143, 2.66 g, 74%); M/Z (ES+), [M+H]⁺ = 668. ¹ H NMR (300 MHz, CHLOROFORM-of) δ 2.07 (s, 3H), 2.13-2.28 (m, 1 H), 2.33-2.52 (m, 1 H), 2.71 -2.86 (m, 3H), 2.90-3.08 (m, 2H), 3.09-3.21 (m, 1 H), 3.22-3.37 (m, 4H), 3.39-3.60 (m, 4H), 3.65 (s, 3H), 3.67-3.76 (m, 1 H), 3.84 (s, 3H), 3.89 (s, 3H), 5.1 1 (s, 1 H), 5.82 (d, 1 H), 6.90 (d, 1 H), 7.18 (s, 1 H), 7.46-7.55 (m, 3H), 7.70-7.81 (m, 1 H), 8.28-8.43 (m, 1 H).

Example 1 : (S_a)-17-Chloro-5,12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid

(Sa)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12, 13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,35-undecaene-23-carboxylate (Intermediate 68b, 100 mg, 0.15 mmol) was dissolved in MeOH (990 μΙ_) and THF (990 μΙ_). LiOH (62.3 mg, 1 .49 mmol) in water (990 μΙ_) was added. After stirring at 50 °C for 4 h under N₂, the mixture was cooled to 0 °C, acidified with 1 N HCI solution until pH=3 and then diluted with water (4 ml.) and

CHC /isopropanol (5/1 ) (25 ml_). The layers were separated. The aq. layer was extracted CHC /isopropanol (5/1 ) (2 x 20 ml_). The combined organic phases were dried over Na₂S04, filtered and concentrated to give (S_a)-17-chloro-5, 12,14, 22-tetramethyl-28-oxa-9-thia- 5,6,12,13,22,31 -hexaazaheptacyclo [27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid (Example 1 , 95 mg, 97%); M/Z (ES+), [M+H]⁺ = 659. ¹ H NMR (300MHz, METHANOLS) δ 1 .90-2.10 (m, 5H), 2.07- 2.32 (m, 2H), 2.58-2.94 (m, 7H), 3.08-3.20 (m, 2H), 3.33-3.71 (m, 14H), 3.84 (s, 3H), 5.01 (s, 1 H), 5.87 (br s, 1 H), 6.49 (s, 1 H), 7.15 (d, 1 H), 7.70 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IE^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 45:55 EtOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .86 min, >98% e.e.

Example 2: (S_a)-17-Chloro-5,12, 14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid

(Sa)-methyl 17-chloro-5,12, 14,22-tetramethyl-28-oxa-2,9-dithia-5,6, 12,13,22,31 - hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,35-undecaene-23-carboxylate (Intermediate 73b, 400 mg, 0.58 mmol) was dissolved in MeOH (3 mL) and THF (3 mL). LiOH (277 mg, 1 1 .6 mmol) in water (3 mL) was added. After stirring at RT overnight under N₂, the mixture was cooled to 0 °C, acidified with 1 N HCI solution until pH=3 and then diluted with water (10 mL) and

CHC /isopropanol (5/1 ) (100 mL). The layers were separated. The aq. layer was extracted CHC /isopropanol (5/1 ) (2 x 20 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to give (S_a)-17-chloro-5, 12,14, 22-tetramethyl-28-oxa-2, 9-dithia- 5,6,12,13,22,31 -hexaazaheptacyclo [27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid (Example 2, 273 mg, 66%); M/Z (ES+), [M+H]⁺ = 677. ¹ H NMR (300MHz, METHANOL-^) δ 1 .93-2.10 (m, 5H), 2.07- 2.32 (m, 2H), 2.70-2.83 (m, 3H), 3.13-3.26 (m, 2H), 3.33-3.59 (m, 4H), 3.60-3.67 (m, 8H), 3.71 - 3.80 (m, 1 H), 3.85-4.01 (m, 5H), 4.83 (s, 1 H), 5.90 (s, 1 H), 6.78 (s, 1 H), 7.15 (d, 1 H), 7.72 (d, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak IC^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase=40:60 EtOH:C0₂, UV detection at 220 nm, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 1 .63 min, >98% e.e.

Example 3: (S_a)-17-Chloro-5,12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16, 18,20,23,29,35-undecaene-23-carboxylic acid

An aqueous 2M LiOH solution (2 mL, 4.00 mmol) was added to a solution of (S_a)-methyl 17-chloro-5,12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,35- undecaene-23-carboxylate (Intermediate 80, 180 mg, 0.27 mmol) in a mixture of THF (1 .5 mL) and MeOH (1 .5 mL) at RT. The stirring was continued for 5 h, the reaction mixture was slowly acidified with 2M HCI water solution (pH~ 4-5). The aq. phase was extracted with DCM (5 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by reverse phase chromatography (Xbridge C18, 4.6 x 50 mm 5 μιη, water with 0.2% NH₄OH: MeCN with 0.2% NH₄OH, 30-50% B over 5 min) to give (S_a)-17-chloro- 5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

undecaene-23-carboxylic acid (Example 3, 87.0 mg, 50%) ; M/Z (ES+), [M+H]⁺ = 660. ¹ H NMR (400MHz, DMSO-ofe) δ 1 .67-1 .75 (m, 2H), 1 .88 (s, 3H), 2.07-2.19 (m, 2H), 2.52-2.58 (m, 2H), 3.00-3.12 (m, 3H), 3.13-3.23 (m, 3H), 3.44 (s, 3H), 3.47-3.50 (m, 2H), 3.61 (s, 3H), 3.62-3.70 (m, 2H), 3.79 (s, 3H), 3.85 (AB d, 1 H), 3.98 (AB d, 1 H), 4.86 (s, 1 H), 6.29 (s, 1 H), 6.42 (d, 1 H), 7.13 (d, 1 H), 7.74 (d, 1 H).

Example 4: (S_a)-17-Chloro-9-ethyl-5, 12, 14,22-tetramethyl-28-oxa-2-thia-5,6,9, 12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16,18,20,23,29,35-undecaene-23-carboxylic acid

1 M aq. LiOH solution (0.70 mL, 0.70 mmol) was added to a solution of (Sa)-methyl 17- chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaaza- heptacyclo[27.7.1 .1⁴'⁷.0¹¹ '¹^0⁶'^

29,35-undecaene-23-carboxylate (Intermediate 821 , 28.0 mg, 0.04 mmol) in THF (0.5 mL) at RT under N₂. The stirring was continued for 20 h under N₂. The mixture was acidified with 2M HCI water solution to pH = 3 and extracted with DCM (3 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by reverse phase chromatography (Xbridge C18, 4.6 x 50 mm 5 μπι, water (0.2% NH₄OH): MeCN (0.2% NH₄OH), 30-50% B over 10 min) to give (S_a)-17-chloro-9-ethyl-5,12,14,22-tetramethyl-28-oxa-2-thia- 5,6,9,12, 13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37), 4(38),6,1 1 (15), 13,16,18,20,23,29,35-undecaene-23-carboxylic acid (Example 4, 15.0 mg, 50%); M/Z (ES+), [M+H]⁺ = 688. ¹ H NMR (500MHz, DMSO-ofe) δ 0.50 (t, 3H), 1 .63-1 .70 (m, 2H), 1 .84- 1 .94 (m, 4H), 1 .96 - 2.19 (m, 3H), 2.97-3.06 (m, 1 H), 3.07-3.22 (m, 5H), 3.24-3.45 (m, 7H), 3.64 (s, 3H), 3.67-3.73 (m, 1 H), 3.76-3.88 (m, 5H), 3.97 (AB d, 1 H), 4.62 (s, 1 H), 4.95 (br s, 1 H), 6.29 (s, 1 H), 6.40 (s, 1 H), 7.1 1 (d, 1 H), 7.74 (d, 1 H), 13.32 (br s, 1 H).

Example 5: (S_a)-17-Chloro-5,9,12,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,35-undecaene-23-carboxylic acid

1 M aq. LiOH (2 mL, 2.00 mmol) was added to a solution of (S_a)-methyl 17-chloro- 5,9,12,14,22-pentamethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaaza

heptacyclo[27.7.1 .1⁴'⁷.0¹¹ '¹^0¹⁶^

29,35-undecaene-23-carboxylate (Intermediate 84, 230 mg, 0.33 mmol) in THF (2 mL) at RT under N₂. The stirring was continued for 20 h under N₂. The mixture was acidified with 2M HCI water solution to pH = 3 and extracted with DCM (3 x 30 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel chromatography (DCM to 10% MeOH in DCM) to give 17-chloro-5,9,12,14,22-pentamethyl-28- oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]

octatriaconta-1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid (Example 5, 158 mg, 64%); M/Z (ES+), [M+H]⁺ = 674. ¹ H NMR (500MHz, DMSO-ofe) δ 1 .59-1 .75 (m, 2H), 1 .82 (s, 3H), 1 .92 (s, 3H), 1 .99-2.10 (m, 1 H), 2.20-2.30 (m, 1 H), 2.91 -3.03 (m, 3H), 3.07- 3.18 (m, 3H), 3.28-3.68 (m, 8H), 3.66 (s, 3H), 3.81 (s, 3H), 3.96 (s, 3H), 4.40 (s, 1 H), 5.00 (s, 1 H), 6.30 (s, 1 H), 6.44 (s, 1 H), 7.17 (d, 1 H), 7.85 (d, 1 H), 13.28 (br s, 1 H).

Example 6: (S_a)-17-Chloro-5,12,14,22-tetramethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid

Lithium hydroxide monohydrate (46.0 mg, 1 .09 mmol) was added to a mixture of (S_a)- methyl 17-chloro-5,12,14,22-tetramethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²\0²⁰'^¾ 0³⁰'³⁵^^

35-tridecaene-23-carboxylate HCI salt (Intermediate 91 , 30.0 mg, 0.04 mmol) in THF (0.50 mL), MeOH (0.50 mL) and water (0.50 mL). The mixture was stirred at RT for 6 h, acidified to pH=1 by addition of 1 N aq. HCI and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to give (S_a)-17-chloro-5, 12, 14,22- tetramethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid as the HCI salt. (Example 6, 27.0 mg, 92%) ; M/Z (ES+), [M+H]⁺ = 637. ¹ H NMR (300MHz, CHLOROFORM-of) δ 2.10 (s, 3H), 2.16-2.43 (m, 2H), 2.61 -2.79 (m, 2H), 2.90-3.01 (m, 5H), 3.10-3.30 (m, 3H), 3.46- 3.96 (m, 7H), 4.08-4.18 (m, 2H), 4.22-4.38 (m, 2H), 5.42-5.80 (m, 2H), 6.91 (d, 1 H), 7.18 (s, 1 H), 7.42-7.58 (m, 3H), 7.67-7.73 (m, 1 H), 8.26-8.48 (m, 1 H).

Example 7: (S_a)-17-Chloro-5,9,12,14,22-pentamethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³⁵]octatriaconta-1 (37),4(38),6,1 1 (15),13, 16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid

Lithium hydroxide monohydrate (59.0 mg, 1 .41 mmol) was added to a mixture of (S_a)- methyl 17-chloro-5,9,12,14,22-pentamethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'² 0²⁰'²^0³⁰'³⁵]octatriaconta-1 (37),4(38),6

35-tridecaene-23-carboxylate (Intermediate 92, 47.0 mg, 0.07 mmol) in THF (0.50 mL), MeOH (0.50 mL) and water (0.50 mL). The mixture was stirred at RT for 6 h, acidified to pH=1 by addition of 1 N aq. HCI and extracted with EtOAc (3 x 15 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated to give (S_a)-17-chloro-5,9, 12, 14,22- pentamethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid as the HCI salt (Example 7, 50.0 mg, 96%) ; M/Z (ES+), [M+H]⁺ = 651 . ¹ H NMR (300MHz, CHLOROFORM-of) δ 2.04 (s, 3H), 2.15 (s, 3H), 2.20-2.60 (m, 4H), 2.65-3.50 (m, 10H), 3.60-3.85 (m, 5H), 4.08-4.38 (m, 4H), 5.42-5.80 (m, 2H), 6.89-6.95 (m, 1 H), 7.10-7.18 (m, 1 H), 7.44-7.58 (m, 3H), 7.67-7.73 (m, 1 H), 8.26-8.48 (m, 1 H).

Example 8: (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

Intermediate 103 (200 mg, 0.21 mmol) was subjected to chiral SFC (Chiralpak OJ^® column, 21 x 250 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 30:70 MeOH with 0.2% NH₄OH:C0₂, UV detection @ 254 nm, loading= 30 mg/inj, cone = 40 mg/mL, flow rate = 75 mL/min, Outlet Pressure = 100 bar) to give two enantiomers: (f?_a)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (S_a)-17-Chloro- 14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Example 8).

(Sa)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22- trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazahepta^

octatriaconta-1 (37),4(38),6, 1 1 (15), 13, 16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylic acid (Example 8) was the first-eluting enantiomer (63 mg, 31 %, >98% e.e.): m/z (ES+), [M+H]⁺ = 955. ¹ H NMR (300 MHz, DMSO-ofe) 5 2.18-2.36 (m, 2H), 2.77 (s, 6H), 2.91 -3.10 (m, 7H), 3.10- 3.26 (m, 4H), 3.43-3.59 (m, 6H), 3.68 (s, 3H), 3.82 (s, 3H), 3.89-4.01 (m, 2H), 4.1 1 (AB d, 1 H), 4.36 (AB d, 1 H), 4.60 (AB d, 1 H), 4.71 (AB d, 1 H), 4.92 (s, 1 H), 6.57 (d, 2H), 6.63-6.76 (m, 3H), 6.87 (d, 1 H), 7.36 (s, 1 H), 7.40-7.61 (m, 3H), 7.66-7.82 (m, 1 H), 8.06-8.20 (m, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak OJ^® column, 4.6 x 100 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 35:65 MeOH with 0.2% NH₄OH:C0₂, UV detection at 254 nm, Diluent: MeOH, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 2.27 min, >98% e.e.

Example 9: (/¾)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,13,22-trimethyl-28-oxa-2,9-dithia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carbox lic acid

Intermediate 110 (140 mg, 0.15 mmol) was subjected to chiral SFC (Chiralpak ID^® column, 21 x 250 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 50:50 EtOH with 0.2% NH₄OH:C0₂, UV detection @ 254 nm, loading= 10 mg/inj, cone = 20 mg/mL in MeOH with 0.2% NH4OH, flow rate = 75 mL/min, Outlet Pressure = 100 bar) to give two enantiomers: (S_a)-17- Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa- 2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.^

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid and (R_a)-17-Chloro- 14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 , 33,35-tridecaene-23-carboxylic acid (Example 9).

(f?a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,13,22- trimethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazahepta^

octatriaconta- 1 (37) ,4(38) ,6, 1 1 , 14, 16, 18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid

(Example 9) was the enantiomer that eluted first (20 mg, 14%, >98% e.e.); m/z (ES+), [M+H]⁺ = 955. ¹ H NMR (300 MHz, METHANOL- ₄) δ 2.12-2.32 (m, 1 H), 2.34-2.47 (m, 1 H), 2.73 (d, 1 H), 2.85 (s, 6H), 2.97-3.35 (m, 12H), 3.45 (s, 3H), 3.53-3.64 (m, 1 H), 3.75 (s, 3H), 3.79-4.16 (m, 7H), 4.77-4.93 (m, 3H), 6.44 (s, 1 H), 6.60 (d, 2H), 6.72 (d, 2H), 6.94 (d, 1 H), 7.38 (s, 1 H), 7.41 - 7.52 (m, 2H), 7.57-7.77 (m, 2H), 8.15-8.28 (m, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak ID^® column, 2.0 x 30 mm, 3 μιη, Temperature = 40 °C, Mobile phase = 45:55 EtOH with 0.2% NH₄OH:C0₂, UV detection at 254 nm, Diluent: MeOH, flow rate = 5.0 mL/min, Outlet Pressure =100 bar. Retention time of 2.43 min, >98% e.e. Example 10: (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)^

Intermediate 114 (770 mg, 0.82 mmol) was subjected to chiral SFC (Chiralpak ID^® column, 21 x 250 mm, 5 μιη, Temperature = 40 °C, Mobile phase = 55:45 MeOH with 0.1 % TFA:C0₂, UV detection @ 254 nm, loading= 20 mg/inj, cone = 20 mg/mL in MeOH/DCM, flow rate = 70 mL/min, Outlet Pressure = 100 bar) to give two enantiomers: (f?_a)-17-Chloro-14-({4-[4- (dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid and (S_a)-17- Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-9- thia-5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Example 10).

The first eluting enantiomer was re-dissolved in 10% MeOH in DCM (20 mL) and water (5 mL) was added. The mixture was basified with sat. NaHC0₃ solution to pH 6-7. The biphase was separated. The aq. phase was extracted with DCM (3 x 5 mL). The combined organic phases were dried over Na₂S04, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes/EtOAc to 10% MeOH in EtOAc) to give (S_a)-17-chloro-14- ({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa-9-thia- 5,6, 12,13,22-pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16, 18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Example 10: 1 10 mg, 14%, >98% e.e.) ; m/z (ES+), [M+H]⁺ = 937. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.10-2.22 (m, 1 H), 2.29-2.42 (m, 1 H), 2.73-2.83 (m, 9H), 2.92 - 3.09 (m, 7H), 3.13-3.17 (m, 1 H), 3.20-3.26 (m, 4H), 3.32-3.69 (m, 10H), 3.73-3.86 (m, 4H), 4.62 (AB d, 1 H), 4.76 (AB d, 1 H), 4.88 (s, 1 H), 6.07 (s, 1 H), 6.53 (d, 2H), 6.71 (d, 2H), 6.86 (d, 1 H), 7.21 (s, 1 H), 7.40-7.52 (m, 2H), 7.57 (d, 1 H), 7.72-7.74 (m, 1 H), 8.1 1 -8.19 (m, 1 H), 13.21 (s, 1 H).

Post Purification ee purity check:

Chiral analysis method: SFC: Chiralpak ID^® column, 4.6 x 30 mm, 3 μιη, Temperature = 40 °C, Mobile phase = 50:50 MeOH with 0.1 %TFA:CO₂, UV detection at 254 nm, flow rate = 4.0 mL/min, Diluent: MeOH, Outlet Pressure =100 bar. Retention time of 2.92 min, >98% e.e.

Example 11 : (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carbox lic acid

(Sa)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)- 5,12,22-trimethyl-28-oxa-2-thia-5,6,9,12,13,22,31 -heptaazaheptacyclo

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

undecaene-23-carboxylate (Intermediate 127a, 63.0 mg, 0.07 mmol) was dissolved in MeOH (0.50 mL), water (0.50 mL) and THF (0.50 mL). LiOH (12.6 mg, 0.53 mmol) was added. After stirring at 60 °C for 1 .5 h under N₂, the mixture was cooled at RT, acidified with 1 N HCI solution until pH=6-7 and concentrated. The residue was purified by silica gel chromatography

(hexanes/DCM to 10% MeOH in DCM) to give the desired product which was re-purified by reverse phase HPLC (Xbridge C18, 4.6 x 50 mm 5 μιη, water with 0.1 % TFA: MeCN with 0.1 % TFA, 0-70% B over 15 min) to give (S_a)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,12, 22-trimethyl-28-oxa-2-thia-5, 6, 9, 12, 13, 22, 31 -heptaazaheptacyclo

[27.7.1 . I ^.O^^ O¹⁶-²^^{20 2}^

undecaene-23-carboxylic acid (TFA salt) (Example 11 , 15 mg, 20%): M/Z (ES+), [M+H]⁺ = 943. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .69-1 .80 (m, 2H), 2.05-2.16 (m, 2H), 2.77 (s, 6H), 2.85-3.08 (m, 5H), 3.10-3.40 (m, 12H), 3.45-3.55 (m, 5H), 3.65 (s, 3H), 3.69-3.85 (m, 1 H), 3.88-4.01 (m, 4H), 4.10-4.19 (m, 1 H), 4.69-4.76 (m, 1 H), 4.79-4.87 (m, 1 H), 5.16 (s, 1 H), 6.04 (s, 1 H), 6.55- 6.62 (m, 3H), 6.70-6.77 (m, 2H), 7.20 (d, 1 H), 7.84 (d, 1 H).

Example 12: (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-

5,9, 12,22-tetramethyl-28-oxa-2-thia-5,6,9,12, 13,22,31 - heptaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 (15),13,16,18,20,23,29,35-undecaene-23-carboxylic acid

[27.7.1 .1⁴'⁷.0¹¹'¹^0¹⁶'²^0²⁰'²⁴.0³⁰'³^

undecaene-23-carboxylate (Intermediate 130a, 75.0 mg, 0.08 mmol) was dissolved in MeOH (0.50 mL), water (0.50 mL) and THF (0.50 mL). LiOH (1 1 .1 mg, 0.46 mmol) was added. After stirring at 60 °C for 3 h under N₂, the mixture was cooled at RT, acidified with 1 N aq. HCI (0.46 mL) to pH=6-7 and concentrated. Water (5 mL) was added to the residue to give a suspension. The solids were collected by filtration and washed with water (5 mL), then Et∑0 (5 mL). The filter cake was purified by silica gel chromatography (DCM to 10% MeOH in DCM) to give (S_a)-17- chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,9,12,22-tetramethyl-28- oxa-2-thia-5,6,9, 12, 13,22,31 -heptaazaheptacyclo

[27.7.1 .1^4J 0^{11 J}^0¹⁶-²\0²^

undecaene-23-carboxylic acid (Example 12, 45.0 mg, 61 %); m/z (ES+), [M+H]⁺ = 957. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .65-1 .75 (m, 2H), 1 .93 (s, 3H), 2.05-2.13 (m, 1 H), 2.18-2.24 (m, 1 H), 2.77 (s, 6H) 2.93-3.08 (m, 8H), 3.09-3.25 (m, 9H), 3.36-3.50 (m, 4H), 3.62-3.69 (m, 4H), 3.86- 3.99 (m, 6H), 4.46 (s, 1 H), 4.49-4.64 (m, 1 H), 4.68-4.80 (m, 1 H), 4.99 (br s, 1 H), 6.31 (s, 6.43 (s, 1 H), 6.53 (d, 2H), 6.72 (d, 2H), 7.14 (d, 1 H), 7.79 (d, 1 H).

Example 13: (S_a)-17-Chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl) 5,12,22-trimethyl-28-oxa-5,6,9,12,13,22- hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

(Sa)-Methyl 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]ph

5,12,22-trimethyl-28-oxa-5,6,9,12,13,22-hexaazaheptacyclo[27 _^

(Intermediate 140, 224 mg, 0.24 mmol) was dissolved in MeOH (2 mL), THF (2 mL) and water (2 mL). LiOH (43.0 mg, 1 .78 mmol) was added. The mixture was stirred at 60-80 °C for 4 h, then cooled to RT, acidified with 1 M HCI solution to pH=6-7 and concentrated to dryness. Water (2 mL) was added to the residue and it was extracted with DCM (3 x 5 mL). The combined organic phases were dried over Na₂S04 filtered and concentrated. The residue was re-dissolved in MeOH (10 mL) and sonicated for 10 min to result in a white suspension. The solids were collected by filtration, washed with MeOH (5 mL) and dried under vacuum to give (S_a)-17-chloro- 14-({4-[4-(dimethylsulfamoyl)piperazin-1 -yl]phenoxy}methyl)-5,12,22-trimethyl-28-oxa- 5,6,9, 12,13,22-hexaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37),4(38),6,1 1 (15),13,16,18, 20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Example 13, 0.160 g, 73%); m/z (ES+), [M+H]⁺ = 920. ¹ H NMR (300 MHz, DMSO-ofe) δ 2.1 1 -2.35 (m, 2H), 2.77 (s, 6H), 2.86-3.25 (m, 15H), 3.36-3.50 (m, 6H), 3.55 (s, 3H), 3.79-3.97 (m, 5H), 4.60 (AB d, 1 H) 4.76 (AB d, 1 H), 4.90 (s, 1 H), 6.42 (s, 1 H), 6.52 (d, 2H), 6.72 (d, 2H), 6.97 (d, 1 H), 7.15 (s, 1 H), 7.33-7.50 (m, 2H), 7.62-7.75 (m, 2H) 8.05-8.08 (m, 1 H). Example 14: (S_a)-17-Chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12, 13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

(Sa)-Methyl 17-chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6, 12, 13,22- pentaazaheptacyclo[27.7.1 .1⁴·⁷.0¹¹ ·¹⁵.0¹⁶·²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta- 1 (37) ,4(38) ,6, 1 1 ( 15) , 13, 16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylate (Intermediate 143, 5.26 g, 7.88 mmol) was dissolved in MeOH (26.3 ml_), THF (26.3 ml.) and water (26.3 ml_). LiOH (1 .13 g, 47.3 mmol) was added. After stirring at 60 °C for 3 h, the mixture was cooled to RT, concentrated to half volume and acidified with 2N HCI solution to pH=5-6. The aqueous phase was extracted with DCM (5 X 50 ml_). The combined organic phases were was dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography

(hexanes/EtOAc to 10% MeOH in DCM) to give the product. The product was re-dissolved in MeOH (30 ml.) and sonicated for 10 min to result in a white suspension. The solids were collected by filtration, washed with MeOH (10 ml.) and dried under vacuum to give (S_a)-17- chloro-5, 12,14,22-tetramethyl-28-oxa-9-thia-5,6,12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵] octatriaconta-

1 (37),4(38),6,1 1 (15), 13,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid (Example 14, 4.73 g, 92%); M/Z (ES+), [M+H]⁺ = 654. ¹ H NMR (300 MHz, DMSO-ofe) δ 1 .88 (s, 3H), 2.10-2.19 (m, 1 H), 2.25-2.35 (m, 1 H), 2.71 -2.88 (m, 3H), 2.92-3.1 1 (m, 3H), 3.1 1 -3.17 (m, 1 H), 3.36-3.44 (m, 5H), 3.47-3.54 (m, 4H), 3.60-3.71 (m, 1 H), 3.73-3.78 (m, 4H), 4.90 (s, 1 H), 6.07 (s, 1 H), 6.92 (d, 1 H), 7.21 (s, 1 H), 7.45-7.50 (m, 2H), 7.61 (d, 1 H), 7.68-7.83 (m, 1 H), 7.99-8.24 (m, 1 H), 13.25 (s, 1 H). Example15: In vitro binding potency of Examples 1 -14

Biochemical binding TR-FRET assay for measuring protein complex disruption

TR-FRET assay was used to assess the ability of compounds to disrupt the interaction between recombinant human Mcl-1 with a labeled BIM peptide probe. The assay was constructed such that GST tagged Mcl-1 protein, was incubated with a Europium-labeled anti- GST antibody and a HyLite Fluor 647-labeled peptide corresponding to the BH3 domain of BIM. Compound IC₅o values were assessed following a 10-point, half-log dilution schema starting at 100 uM or 10 μΜ compound concentration. Specifically, human Mcl-1 enzyme from Mcl-1 (E171 -G327) was cloned into an overexpression vector, expressed as an /V-terminal GST- tagged fusion protein in E coli. and subsequently purified via Glutathione Sepharose-affinity and size-exclusion chromatography. The assay was performed in 384-Well LV plates (Greiner cat #784075) and run in the presence and absence of the compound of interest. Each well of 12 μΙ_ assay mixture contained 10 mM Tris (pH 7.4), 1 .0 mM DTT, 0.005% Tween-20, 150 mM NaCI, 10% DMSO, and 1 .5 nM GST_Mcl-1 , 0.5 nM LanthaScreen Eu tagged GST antibody (Invitrogen Catalog # PV5594), 4.0 nM HyLite Fluor 647-labeled BIM peptide [C(Hilyte647 C2 Maleimide)- WIAQELRRIGDEFN] (SEQ ID NO:1 ). Reactions were incubated at 24 °C for 90 min before reading on a Tecan M1000 spectrfluorometer with excitation at 340 nm and emission at 612nm & 665 nm. Subsequently, ratio of fluorescent emission intensity at 665 nm to 612 nm was calculated for each reaction, and the dose-response of the ratio to testing compound

concentration was fitted to a select fit model that will provide the best fit quality using automatic parameter to derive IC₅o values for each testing compound.

Ratio Calculation =Emission 665nm / Emission 612 * 10000

% inhibition=100 - [(Test Ratio - Min (compound control))/ (Max (DMSO control)- Min

(compound control))]

Table 2. Results from TR-FRET Mcl-1 binding assay

11 <3

12 nt

13 <3

14 <3

^*nt = not tested

Example 16: In vitro activity of Examples 1 -13

Caspase Activity assay

This is a cell assay to measure the induction of apoptosis in MOLP-8 (multiple myeloma), MV4;1 1 (acute myeloid leukemia), and NCI-H23 (non-small cell lung cancer) cells after 6 h treatment with Mcl-1 inhibitors. On the first day, 3000 (MOLP-8, MV4;1 1 ) or 1250 (NCI- H23) cells/well were seeded with 50 μΐ of growth media (IMDM + 10% FBS+2 mM L-Glu for MV4;1 1 and RPMI-1640 + 10% FBS+2 mM L-Glu for all others) in 384-well white microplates, and incubated overnight (37 °C, 5% C0₂, 80% RH). On the second day, the cells were treated with Mcl-1 inhibitors using an ECHO acoustic liquid handler (10 point half-log serial dilution, 31 .5 μΜ top concentration, 0.3% final DMSO concentration). After 6 h incubation (37 °C, 5% C0₂, 80% RH), 25 μΐ of Caspase-Glo 3/7 reagent (Promega) was added into each well, and plates were incubated at room temperature for 30 min protected from light. Luminescence was recorded using an Infinite M200 microplate reader (Tecan) with a 100 ms integration time. EC₅o values were calculated using GeneData analysis software.

Table 3. Results from in vitro Caspase Activity assay

^*nt = not tested

Claims

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

wherein

Wis NH orCH;

^"" is a single bond when W is NH or a double bond when W is CH;

ZisSorCH₂;

Y is selected from S NH, NCH₃ and NCH₂CH₃; and

2. A com ound of Formula (la) or (lb), or a pharmaceuticall acceptable salt thereof:

(lb) wherein Wis NH orCH;

^"""" is a single bond when W is NH or a double bond when W is CH;

ZisSorCH₂;

Y is selected from S NH, NCH₃ and NCH₂CH₃; and

XisCHaor

3. A compound of Formula (II or a pharmaceutically acceptable salt thereof:

wherein

D is NH orCH;

^"" is a single bond when D is NH or a double bond when D is CH;

B is S orCH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

4. A compound of Formula (lla) or (lib), or a pharmaceutically acceptable salt thereof:

(Ma) (lib) wherein

D is NH or CH;

^"" is a single bond when D is NH or a double bond when D is CH;

B is S or CH₂; and

A is selected from S, NH, NCH₃ and NCH₂CH₃.

5. A compound of Formula III), or a pharmaceutically acceptable salt thereof:

in

J is NH or CH;

^"" is a single bond when J is NH or a double bond when J is CH;

G is S or CH₂; and

E is selected from S, NH and NCH₃.

A compound of Formula (Ilia) or (lllb), or a pharmaceutically acceptable salt thereof:

wherein

J is NH or CH;

^"""" is a single bond when J is NH or a double bond when J is CH; G is S or CH₂; and

E is selected from S, NH and NCH₃.

7. A compound which is 17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

8. A compound which is (S_a)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 ,14,16,18,20 23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

9. A compound which is (f?_a)-17-chloro-14-({4-[4-(dimethylsulfamoyl)piperazin-1 - yl]phenoxy}methyl)-5,13,22-trimethyl-28-oxa-2,9-dithia-5,6, 12,13,22- pentaazaheptacyclo[27.7.1 .1⁴'⁷.0¹¹'¹⁵.0¹⁶'²¹.0²⁰'²⁴.0³⁰'³⁵]octatriaconta-

1 (37),4(38),6,1 1 ,14,16,18,20,23,29,31 ,33,35-tridecaene-23-carboxylic acid:

or a pharmaceutically acceptable salt thereof.

10. A compound as shown in Table 1 , or a pharmaceutically acceptable salt thereof.

1 1 . A pharmaceutical composition comprising a compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof and a pharmaceutical excipient, carrier or diluent.

12. A method of treating cancer comprising administering to a subject in need thereof a compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof.

13. A compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, for use in treating cancer.

14. The use of a compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

15. A pharmaceutical composition comprising a compound of any one of claims 1 -10, or a pharmaceutically acceptable salt thereof, for use in treating cancer.