RU2815486C2 - Trifluoromethyl-substituted sulphonamide as selective inhibitor of bcl-2 - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I

where R¹ is selected from Cl or F; R² is selected from -C_0-3alkylene-R³; R³ is selected from 5-6-membered heterocycloalkyl, wherein heteroatom in 5-6-membered heterocycloalkyl is selected from the group consisting of N and O, and the number of heteroatoms is selected from 1–2, where 5-6-membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 4-6 membered heterocycloalkyl, -COR^a, -SO₂R^b, -COOC_1-6alkyl and C_1-6alkyl, optionally substituted with a halogen atom, where heteroatom in 4-6 membered heterocycloalkyl is selected from O, and the number of heteroatoms is selected from 1; and each of R^a or R^b is independently selected from the group consisting of H, 4-member heterocycloalkyl, C_3-4cycloalkyl and C_1-6alkyl, where C_1-6alkyl is optionally substituted with a halogen atom, -CN, -N(C_1-6alkyl)₂, -NHC_1-6alkyl or -OC_1-6alkyl, wherein the structural fragment is selected from the group, consisting of and , which are selective inhibitors of BCL-2, a pharmaceutical composition and use for treating diseases associated with anti-apoptotic BCL-2, such as cancer.

EFFECT: novel compounds are obtained, which are selective inhibitors of BCL-2.

22 cl, 88 ex, 8 tbl

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit and priority of Chinese Patent Application No. 201811268572.2 filed with the National Intellectual Property Administration of the People's Republic of China on October 29, 2018, Chinese Patent Application No. 201910249783.X filed with the National Intellectual Property Administration of the People's Republic of China on March 29, 2019, and to Chinese Patent No. 201910933513.0, filed with the National Intellectual Property Administration of the People's Republic of China on September 29, 2019, the contents of each of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present application relates to compounds that selectively inhibit the anti-apoptotic protein BCL-2, a method for their preparation, a pharmaceutical composition containing them and their use in the treatment of a disease associated with the anti-apoptotic protein BCL-2, for example, cancer.

BACKGROUND OF THE INVENTION

BCL-2 proteins are divided into three families: the BCL-2 family (including members such as BCL-2 and BCL-XL), the BAX family, and the BH3-only family. Among them, the BCL-2 family plays an anti-apoptotic role, while members of the other two families play a pro-apoptotic role.

Antiapoptotic proteins of the BCL-2 family are associated with many diseases and are being studied as potential therapeutic drug targets. Such targets for invasive therapy include, for example, the BCL-2 and BCL-XL proteins of the BCL-2 family and etc. Recently, inhibitors of BCL-2 family proteins have been reported in WO2012071374, WO2010138588 and WO2010065865. Although they provide inhibitors that bind to the target protein with high affinity, the binding affinity of the compounds is only one of many parameters that must be considered. One goal is to produce a compound that binds preferentially to one protein over another, i.e. characterized by selectivity in its relation. To demonstrate this selectivity, it is widely known that a compound exhibits high binding affinity for a particular protein and low binding affinity for another.

The disclosed BCL-2 inhibitors are less selective for the anti-apoptotic proteins BCL-XL and BCL-2 and are thus more likely to cause side effects. They are characterized by inhibiting the anti-apoptotic protein BCL-XL and causing side effects such as thrombocytopenia.

The present application includes a number of compounds that exhibit higher selectivity for the anti-apoptotic proteins BCL-2 and BCL-XL, and are also characterized by better efficacy in inhibiting the activity of the anti-apoptotic protein BCL-2. At the same time, such compounds are characterized by better stability against liver microsomes and optimized pharmacokinetic parameters, demonstrating better prospects for pharmaceutical properties.

SHORT DESCRIPTION

In one aspect, the present application provides a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

,

Where

R ¹ is selected from a halogen atom;

R ² is selected from -C _0-6 alkylene-R ³ ;

R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b , -COOC _1-6 alkyl and C _1-6 alkyl, optionally substituted with a halogen atom; And

each of R ^a or R ^b is independently selected from the group consisting of H, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with a halogen atom, -CN, - N(C _1-6 alkyl) ₂ , -NHC _1-6 alkyl or -OC _1-6 alkyl.

In some embodiments, the structural fragment selected from . In some embodiments, the structural fragment selected from the group consisting of And . In some embodiments, the structural fragment selected from .

In some embodiments, the structural fragment selected from .

In some embodiments, the structural fragment selected from the group consisting of And .

In some embodiments, R ¹ is selected from the group consisting of fluorine and chlorine atoms. In some embodiments, R ¹ is selected from a chlorine atom.

In some embodiments, R ² is selected from the group consisting of -R ³ and -C _1-6 alkylene-R ³ . In some embodiments, R ² is selected from -C _1-4 alkylene-R ³ .

In some embodiments, R ² is selected from -(CH ₂ ) _n -R ³ , where n is 0, 1, 2, 3 or 4; or n is 1, 2 or 3; or n equals 1 or 2.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups at the N atom on the ring.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, -COR ^a , -SO ₂ R ^b and C _1-6 alkyl, optionally substituted with a halogen atom.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, -COR ^a , -SO ₂ R ^b , -COOC _1-6 alkyl and C _1-6 alkyl, optionally substituted with a halogen atom.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 3-6 membered heterocycloalkyl, -COR ^a , -SO ₂ R ^b and C _1-6 alkyl, optionally substituted with a halogen atom.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of -COR ^a , -SO ₂ R ^b , -COOC _1-6 alkyl and C _1-6 alkyl, optionally substituted with a halogen atom.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of -COR ^a , -SO ₂ R ^b and C _1-6 alkyl , optionally substituted with a halogen atom.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with 3-6 membered heterocycloalkyl.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -COR ^a .

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -SO ₂ R ^b .

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -COOC _1-6 alkyl. In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -COOC _1-4 alkyl.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with a halogen atom; in some embodiments, the C _1-6 alkyl is optionally substituted with a fluorine atom. In some embodiments, the 5-6 membered heterocycloalkyl is optionally substituted with methyl, ethyl, methyl substituted with a fluorine atom, or ethyl substituted with a fluorine atom.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, and C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with a halogen atom, -CN, -N(C _1-4 alkyl) ₂ , -NHC _1-4 alkyl or -OC _1-4 alkyl. In some embodiments, R ^a is selected from the group consisting of H, 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with a halogen atom, -CN, -N( C _1-4 alkyl) ₂ or -OC _1-4 alkyl. In some embodiments, R ^b is selected from the group consisting of 3-6 membered heterocycloalkyl, C _3-6 cycloalkyl, and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with a halogen atom or -CN.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, t -butyl, cyclopropyl, cyclobutyl, and monooxacyclobutyl, wherein methyl or ethyl is optionally substituted with a fluorine atom, -CN, -OCH ₃ or -N(CH ₃ ) ₂ . In some embodiments, R ^a is selected from the group consisting of H, methyl, isopropyl, tert -butyl, cyclopropyl, and monooxacyclobutyl, wherein methyl is optionally substituted with a fluorine atom, -CN, -OCH ₃ or -N(CH ₃ ) ₂ . In some embodiments, R ^b is selected from the group consisting of methyl, ethyl, cyclopropyl, cyclobutyl, and monooxacyclobutyl, wherein methyl or ethyl is optionally substituted with a fluorine atom.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, tert -butyl, trifluoromethyl, pentafluoroethyl, -CH ₂ OCH ₃ , -CH ₂ CN, -CH ₂ N( CH ₃ ) ₂ , cyclopropyl, cyclobutyl and monooxacyclobutyl. In some embodiments, R ^a is selected from the group consisting of H, methyl, isopropyl, tert -butyl, trifluoromethyl, -CH ₂ OCH ₃ , -CH ₂ CN, -CH ₂ N(CH ₃ ) ₂ , cyclopropyl, and monooxacyclobutyl. In some embodiments, R ^b is selected from the group consisting of methyl, ethyl, trifluoromethyl, pentafluoroethyl, cyclopropyl, cyclobutyl, and monooxacyclobutyl.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, C _3-6 cycloalkyl and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with a halogen atom, -CN, -N(C _1-4 alkyl) ₂ , -NHC _1-4 alkyl or -OC _1-4 alkyl. In some embodiments, R ^a is selected from the group consisting of H, C _3-6 cycloalkyl and C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with a halogen atom, -CN, -N(C _1-4 alkyl) ₂ or -OC _1-4 alkyl. In some embodiments, R ^b is selected from the group consisting of C _3-6 cycloalkyl and C _1-4 alkyl, wherein the C _1-4 alkyl is optionally substituted with a halogen atom or -CN.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, t -butyl, cyclopropyl, and cyclobutyl, wherein methyl or ethyl is optionally substituted with a fluorine atom, -CN, -OCH ₃ or -N(CH ₃ ) ₂ . In some embodiments, R ^a is selected from the group consisting of H, methyl, isopropyl, tert -butyl and cyclopropyl, wherein methyl is optionally substituted with a fluorine atom, -CN, -OCH ₃ or -N(CH ₃ ) ₂ . In some embodiments, R ^b is selected from the group consisting of methyl, ethyl, cyclopropyl, and cyclobutyl, wherein methyl is optionally substituted with a fluorine atom.

In some embodiments, each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, tert -butyl, trifluoromethyl, -CH ₂ OCH ₃ , -CH ₂ CN, -CH ₂ N(CH ₃ ) ₂ , cyclopropyl and cyclobutyl. In some embodiments, R ^a is selected from the group consisting of H, methyl, isopropyl, tert -butyl, trifluoromethyl, -CH ₂ OCH ₃ , -CH ₂ CN, -CH ₂ N(CH ₃ ) ₂ and cyclopropyl. In some embodiments, R ^b is selected from the group consisting of methyl, ethyl, trifluoromethyl, cyclopropyl, and cyclobutyl.

In some embodiments, R ^a or R ^b is each independently selected from C _1-4 alkyl, optionally substituted with -OC _1-4 alkyl.

In some embodiments, R ^a or R ^b is each independently selected from the group consisting of methyl, isopropyl, and -CH ₂ OCH ₃ .

In some embodiments, R ^a is selected from C _1-4 alkyl, optionally substituted with -OC _1-4 alkyl.

In some embodiments, R ^a is selected from the group consisting of methyl, isopropyl, and -CH ₂ OCH ₃ .

In some embodiments, R ^b is selected from C _1-4 alkyl.

In some embodiments, R ^b is selected from methyl.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -C(O)H, -COCH ₃ , -COCH(CH ₃ ) ₂ , -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ OCH ₃ , -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , methyl, ethyl, -CF ₃ , -CH ₂ CH ₂ F, -C ₂ F ₅ , tetrahydropyran, monooxacyclobutane, -SO ₂ -cyclopropane, -CO-cyclopropane, -CO-monooxacyclobutane, -SO ₂ -monooxacyclobutane , -SO ₂ -cyclobutane, -COOCH ₂ CH ₃ or -COOCH ₃ . In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -COCH ₃ , -COCH(CH ₃ ) ₂ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , methyl, ethyl or -CH ₂ CH ₂ F.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -C(O)H, -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , -CF ₃ , -C ₂ F ₅ , tetrahydropyran, monooxacyclobutane, -SO ₂ -cyclopropane, -CO-cyclopropane, -CO-monooxacyclobutane, -SO ₂ -monooxacyclobutane or -SO ₂ -cyclobutane.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -COOCH ₂ CH ₃ or -COOCH ₃ .

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -C(O)H, -COCH ₃ , -COCH(CH ₃ ) ₂ , -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ OCH ₃ , -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , methyl, ethyl, -CH ₂ CH ₂ F, tetrahydropyran, -SO ₂ -cyclopropane, -CO-cyclopropane or -SO ₂ -cyclobutane.

In some embodiments, R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with -C(O)H, -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , -CF ₃ , -C ₂ F ₅ , tetrahydropyran, -SO ₂ -cyclopropane, -CO -cyclopropane or -SO ₂ -cyclobutane.

In some embodiments, R ³ is selected from the group consisting of tetrahydropyran, piperidine, morpholine, and dioxane, wherein tetrahydropyran, piperidine, morpholine, or dioxane is optionally substituted with -C(O)H, -COCH ₃ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -CO-cyclopropane, -COCH ₂ CN, -COCF ₃ , -COCH ₂ N(CH ₃ ) ₂ or methyl.

In some embodiments, R ³ is selected from the group consisting of tetrahydropyran, piperidine, morpholine, and dioxane, wherein tetrahydropyran, piperidine, morpholine, or dioxane is optionally substituted with -COCH ₃ , -COCH(CH ₃ ) ₂ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , methyl, ethyl or -CH ₂ CH ₂ F.

In some embodiments, R ³ is selected from the group consisting of tetrahydropyran, piperidine, morpholine and dioxane, wherein tetrahydropyran, piperidine, morpholine or dioxane is optionally substituted with -COOCH ₂ CH ₃ or -COOCH ₃ .

In some embodiments, R ³ is selected from the group consisting of tetrahydropyran and dioxane.

In some embodiments, R ³ is selected from dioxane.

In some embodiments, R ³ is selected from the group consisting of piperidine and morpholine, wherein piperidine or morpholine is optionally substituted with -C(O)H, -COCH ₃ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -CO-cyclopropane, -COCH ₂ CN, -COCF ₃ , -COCH ₂ N(CH ₃ ) ₂ or methyl. In some embodiments, R ³ is selected from the group consisting of piperidine and morpholine, wherein piperidine or morpholine is optionally substituted with -COCH ₃ , -COCH(CH ₃ ) ₂ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , methyl, ethyl, or -CH ₂ CH ₂ F.

In some embodiments, R ³ is selected from the group consisting of piperidine and morpholine, wherein piperidine or morpholine is optionally substituted with -COOCH ₂ CH ₃ or -COOCH ₃ .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of , , And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of And .

In some embodiments, R ³ is selected from the group consisting of , , , , , , , And .

In some embodiments, R ³ is selected from the group consisting of , , , , , And .

In some embodiments, the heteroatom in the 5-6 membered heterocycloalkyl is selected from the group consisting of N and O, and the number of heteroatoms is 1 or 2.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from the group consisting of dioxanyl, morpholinyl, tetrahydropyranyl, piperidinyl, and tetrahydrofuranyl.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from the 6-membered heterocycloalkyl.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from the group consisting of dioxanyl, morpholinyl, tetrahydropyranyl, and piperidinyl.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from dioxanyl.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from morpholinyl.

In some embodiments, the 5-6 membered heterocycloalkyl is selected from tetrahydropyranyl.

In some embodiments, the heteroatom in the 3-6 membered heterocycloalkyl is selected from the group consisting of N and O, and the number of heteroatoms is 1 or 2. In some embodiments, the heteroatom in the 3-6 membered heterocycloalkyl is selected from O, and the number of heteroatoms is 1 or 2. In some embodiments, the 3-6 membered heterocycloalkyl is selected from the 4-6 membered heterocycloalkyl. In some embodiments, the 3-6 membered heterocycloalkyl is selected from the group consisting of 4-membered heterocycloalkyl and 6-membered heterocycloalkyl.

In some embodiments, the 3-6 membered heterocycloalkyl is selected from the group consisting of monooxacyclobutyl, tetrahydrofuranyl, and tetrahydropyranyl.

In some embodiments, the C _3-6 cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, and cyclopentyl. In some embodiments, the C _3-6 cycloalkyl is selected from C _3-4 cycloalkyl.

In another aspect, the present application provides a compound of Formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

,

where R ² is defined in the same way as in the compound of formula I.

This application relates to a compound of formula selected from the group consisting of the following formulas, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

;

or a compound of the following formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof

, where R is independently selected from the group consisting of

This application relates to a compound of formula selected from the group consisting of the following formulas, or a pharmaceutically acceptable salt thereof:

;

or a compound of the following formula or a pharmaceutically acceptable salt thereof,

, where R is independently selected from the group consisting of

In another aspect, the present application provides a pharmaceutical composition containing a compound of Formula I, a compound of Formula II, or a specific compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof disclosed herein. In some embodiments, the pharmaceutical composition disclosed herein further comprises a pharmaceutically acceptable excipient.

In another aspect, this application describes a method of treating a disease associated with the anti-apoptotic protein BCL-2 in a mammal, comprising administering to the mammal (preferably a human) in need of such treatment a therapeutically effective amount of a compound of formula I, a compound of formula II, or a particular compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition based thereon.

In another aspect, this application describes the use of a compound of formula I, a compound of formula II, or a particular compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition based thereon in the preparation of a medicament for the prevention or treatment of a disease associated with an anti-apoptotic protein BCL-2.

In another aspect, the present application describes the use of a compound of Formula I, a compound of Formula II, or a particular compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.

In another aspect, this application discloses a compound of formula I, a compound of formula II, or a specific compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2 .

Disease associated with anti-apoptotic protein BCL-2 selected from cancer. The cancer selected was acute lymphocytic leukemia.

Definitions

Unless otherwise specified, the following terms as used in this application will have the following meanings. A specific term, unless specifically stated otherwise, should not be considered vague or unclear, but should be understood in accordance with its generally accepted meaning in the art. Where a trade name is referred to, it refers to its corresponding commercial product or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, provided that the valence of the particular atom is normal and the resulting compound is stable. If the substituent is an oxo group (i.e. =O), then this means that two hydrogen atoms are replaced and the oxo group is not present in the aromatic group.

The terms “optional” or “optional” mean that the event or circumstance described below may or may not occur. The description includes cases in which the event or circumstance occurs and cases in which the event or circumstance does not occur. For example, ethyl is "optionally" substituted with halogen means that ethyl can be unsubstituted (-CH ₂ CH ₃ ), monosubstituted (for example, -CH ₂ CH ₂ F), polysubstituted (for example, -CHFCH ₂ F, -CH ₂ CHF ₂ and etc.) or completely substituted (-CF ₂ CF ₃ ). Those skilled in the art will appreciate that for any group containing one or more substituents, no substitutions or substitution patterns will be made that are sterically impractical and/or synthetically impossible.

C _mn as used herein means that the fragment contains an integer number of carbon atoms in the specified range. For example, "C _1-6 " means that the group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "alkyl" refers to hydrocarbyl with the general formula C_nH_2n+1. Alkyl may be straight or branched. For example, the term "C_1-6alkyl" refers to an alkyl containing 1-6 carbon atoms (e.g. methyl, ethyl,n- propyl, isopropyl,n-butyl, isobutyl,tues-butyl,rubs-butyl,n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl and etc.). Alkyl moieties (i.e. alkyl) alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio have the same definition as above. As another example, the term "C_1-4alkyl" refers to an alkyl containing 1-4 carbon atoms (e.g. methyl, ethyl,n- propyl, isopropyl,n-butyl, isobutyl,tues-butyl,rubs-butyl and etc.).

The term "alkylene" refers to a divalent group formed by the removal of 1 hydrogen atom from any position in the alkyl. For example, non-limiting examples of the term “C _0-6 alkylene” include, without limitation, methylene, ethylidene, methylmethylene, dimethylmethylene, 1,3-propylidene, etc. C ₀ represents a bond.

The term "cycloalkyl" refers to a carbon ring that is fully saturated and can exist as a monocyclic structure, a bridged cyclic structure, or a spiro structure. Unless otherwise specified, the carbon ring is typically a 3-10 membered ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl(bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic structure, a bridged cyclic structure, or a spiro structure. Unless otherwise specified, a heterocyclyl is typically a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 to 2 heteroatoms) independently selected from the group consisting of sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyls include, but are not limited to, oxiranyl, thiiranyl, and aziranyl. Non-limiting examples of 4-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocycloalkyls include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyls include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-oxathianyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyls include, but are not limited to, azacycloheptanyl, oxacycloheptanyl, and thiocycloheptanyl. Preferably, the heterocycloalkyl is a monocyclic heterocycloalkyl containing 5 or 6 ring atoms.

The terms “treat” or “treatment” mean the administration of a compound or composition disclosed herein for the purpose of preventing, alleviating or eliminating symptoms of a disease or one or more symptoms associated with a disease, and includes:

(i) preventing the occurrence of a disease or disease state in a mammal, in particular where such mammal is predisposed to the disease condition but has not yet been diagnosed;

(ii) suppression of a disease or disease state, i.e. stopping its development; And

(iii) alleviation of a disease or painful condition, i.e. inducing remission.

The term “therapeutically effective amount” refers to the amount of a compound disclosed herein for (i) treating or preventing a particular disease, condition or disorder; (ii) mitigating, alleviating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound disclosed herein that is considered a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal being treated, but can generally be determined by those skilled in the art based on from their own knowledge and the disclosure of the present invention.

The term "pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms that, within the scope of careful medical evaluation, are suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with an acceptable benefit/risk ratio.

The pharmaceutically acceptable salt, for example, may be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, and the like.

The term "pharmaceutical composition" refers to a mixture consisting of one or more compounds or pharmaceutically acceptable salts thereof disclosed herein and a pharmaceutically acceptable excipient. The pharmaceutical composition is intended to facilitate the administration of the compound into the body.

The term "pharmaceutically acceptable excipient" refers to those excipients that do not cause significant irritation in the body and do not impair the biological activity and properties of the active compound. Suitable excipients are generally known to those skilled in the art, for example carbohydrate, wax, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oil, solvent or water.

The word “comprise” and its variants such as “contains” or “comprising” will be understood in an open, non-exclusive sense, i.e. "including without limitation".

The compounds and intermediates disclosed herein may also exist in various tautomeric forms, and all such forms are included within the scope of this application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible upon passage through a low-energy barrier. For example, a protic tautomer (also known as a prototropic tautomer) involves proton transfer interconversions such as keto-enol isomerization and imine-enamine isomerization. A specific example of a protic tautomer is the imidazole moiety, where a proton can be transferred between two nitrogen atoms in the ring. A valence tautomer involves interconversion by recombination of some of the bonding electrons.

This application also provides isotopically labeled compounds that are identical to those listed herein, but contain one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be included in the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl.

Certain isotopically labeled compounds disclosed herein (e.g. compounds labeled with³H and¹⁴C), can be used in the analysis of the distribution of compounds and/or substrate in tissues. Tritiated isotopes (i.e. ³H) and carbon-14 isotopes (i.e. ¹⁴C) are particularly preferred because of their ease of preparation and detectability. Positron active isotopes such as¹⁵O,¹³N,^elevenC and¹⁸F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds disclosed herein generally can be prepared by following procedures similar to those disclosed in the diagrams and/or in the examples below while simultaneously replacing the non-isotopically labeled reagent with the isotopically labeled reagent.

Additionally, substitution with heavier isotopes such as deuterium (i.e. ²H), may provide certain therapeutic benefits (e.g. increased half-lifein vivo or reduced dosage requirements) as a result of higher metabolic stability, and therefore may be preferred in some circumstances in which deuterium substitution may be partial or complete, where partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.

A compound disclosed herein may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers, such as enantiomers and diastereoisomers, are included in this application. The compound containing the asymmetric carbon atoms disclosed herein can be isolated in optically pure form or racemic form. The optically pure form can be isolated from a racemic mixture or can be synthesized using a chiral starting material or a chiral reagent.

The pharmaceutical composition disclosed herein can be prepared by combining a compound disclosed herein with a suitable pharmaceutically acceptable excipient and can be formulated, for example, as a solid, semi-solid, liquid or gas composition, such as in in the form of a tablet, pill, capsule, powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, etc.

Typical routes of administration of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof disclosed herein include, without limitation, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous route of administration.

The pharmaceutical composition disclosed herein can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, panning, grinding, emulsifying, lyophilizing, and the like.

In some embodiments, the pharmaceutical composition is in oral form. In the case of oral administration, the pharmaceutical composition can be formulated by mixing the active compounds with a pharmaceutically acceptable excipient well known in the art. Such excipients may enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

The solid composition for oral administration can be prepared by conventional mixing, filling or tableting. For example, it can be prepared by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding additional suitable excipients if required, and then forming the mixture into granules to obtain tablet cores or dragee cores. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical composition may also be suitable for parenteral administration, for example, in the form of sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all routes of administration of a compound of Formula I described herein, the daily dose administered ranges from 0.01 mg/kg to 200 mg/kg body weight, administered in single or divided doses.

The compounds disclosed herein can be prepared by a variety of synthetic routes well known to those skilled in the art, including the specific embodiments listed below, embodiments prepared by combining them with other chemical synthesis routes, and equivalents thereof, known to those skilled in the art. Preferred embodiments include, without limitation, the examples disclosed herein. Chemical reactions according to the embodiments disclosed herein are carried out in a suitable solvent, which must be suitable for the chemical changes in this application, as well as the reagents and materials necessary for this. Sometimes, in order to prepare the compounds of the present invention, it will be necessary for one skilled in the art to modify or select synthetic steps or reaction schemes based on the presented embodiments.

A key aspect when planning a synthetic route in the field is the selection of appropriate protecting groups for reactive functional groups (e.g. hydroxyl groups in this application). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed.) Hoboken, New Jersey: John Wiley & Sons, Inc.

In some embodiments, a compound of Formula I disclosed herein can be prepared by one skilled in the art of organic synthesis through the following routes.

Way 1:

.

Way 2:

;

.

In the above paths R ¹ , R ² or are as defined above; X is selected from the group consisting of leaving groups, preferably fluorine, chlorine, bromine and iodine atoms; R ⁴ is selected from the group consisting of C _1-6 alkyl and C _1-4 alkyl, preferably tert -butyl, methyl and ethyl; R ⁵ is selected from the group consisting of amino protecting groups, preferably Boc and benzyloxycarbonyl (Cbz); and R ⁶ is selected from the group consisting of amino group protecting groups, preferably silane-based protecting groups, and more preferably tert -butyldimethylsilyl (TBS) and tert -butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS), triethylsilyl (TES) protecting groups ) and triisopropylsilyl (TIPS).

This application also provides a process for preparing a compound of formula A-4, comprising:

,

where R ¹ or are as defined above; X is selected from the group consisting of leaving groups, preferably fluorine, chlorine, bromine and iodine atoms; R ⁴ is selected from the group consisting of C _1-6 alkyl and C _1-4 alkyl, preferably tert -butyl, methyl and ethyl; and R ⁶ is selected from the group consisting of amino group protecting groups, preferably silane-based protecting groups, and more preferably tert -butyldimethylsilyl (TBS) and tert -butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS), triethylsilyl (TES) protecting groups ) and triisopropylsilyl (TIPS).

This application also provides a process for preparing a compound of formula A-3, comprising:

,

where R ¹ or are as defined above, and R ⁵ is selected from the group consisting of amino protecting groups, preferably Boc and benzyloxycarbonyl (Cbz).

This application also provides a process for preparing a compound of formula A-2, comprising:

,

where R ¹ or are as defined above, and R ⁵ is selected from the group consisting of amino protecting groups, preferably Boc and benzyloxycarbonyl (Cbz).

This application also provides a process for preparing a compound of Formula A-5, comprising:

,

where R ¹ or are as defined above; R ⁴ is selected from the group consisting of C _1-6 alkyl and C _1-4 alkyl, preferably tert -butyl, methyl and ethyl; and R ⁶ is selected from the group consisting of amino group protecting groups, preferably silane-based protecting groups, and more preferably tert -butyldimethylsilyl (TBS) and tert -butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS), triethylsilyl (TES) protecting groups ) and triisopropylsilyl (TIPS).

This application also provides a process for preparing a compound of formula I, comprising:

,

where R ¹ , R ² or are as defined above.

This application also provides intermediates of the compounds of the following formulas or salts thereof, , , or , where R ¹ or are as defined above; R ⁴ is selected from the group consisting of C _1-6 alkyl and C _1-4 alkyl, preferably tert -butyl, methyl and ethyl; R ⁵ is selected from the group consisting of amino protecting groups, preferably Boc and benzyloxycarbonyl (Cbz); and R ⁶ is selected from the group consisting of amino group protecting groups, preferably silane-based protecting groups, and more preferably tert -butyldimethylsilyl (TBS) and tert -butyldiphenylsilyl (TBDPS) or trimethylsilyl (TMS), triethylsilyl (TES) protecting groups ) and triisopropylsilyl (TIPS). The salt may be selected from the group consisting of hydrochloride salts and the like.

In more specific embodiments, each of the compounds is selected from the group consisting of compounds of the following formulas or salts thereof: , , or . The salt may be selected from the group consisting of hydrochloride salts and the like.

DETAILED DESCRIPTION

Abbreviations: DMF is N , N -dimethylformamide; Boc is tert -butyloxycarbonyl; NaOAc is sodium acetate; tBu is tert -butyl; TBS is tert -butyldimethylsilyl; THF is tetrahydrofuran; and DMSO is dimethyl sulfoxide.

For a better understanding, the following examples are further described in this application, but are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification.

Example 1. 4-(4-{[2-(2-Chloro-4-trifluoromethylphenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({3-nitro- 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 1-b

Phosphorus oxychloride was added dropwise to a solution of DMF (173.7 g) in dichloromethane (460 ml) at 0°C. After addition, the mixture was heated to 20°C and stirred for 1 hour, then cooled to 0°C and 3,3-dimethylcyclohexanone ( 1-a ) (200 g) was added dropwise. After addition, the mixture was refluxed overnight. The reaction solution was added dropwise to a solution containing NaOAc (86.7 g), NaCl (80 g), water (1.2 L) and dichloromethane (600 ml) with stirring. The resulting mixture was stirred at room temperature for 20 minutes. followed by separation of liquids. The aqueous phase was extracted with dichloromethane (500 ml). The organic phases were combined, washed once with a solution of K ₃ PO ₄ (40 g) and NaCl (90 g) in water (1 L), dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1-b (249 g).

2) Receiving connection 1-c

Compound 1-b (5.36 g), tetrakis(triphenylphosphine) palladium (0.18 g), K ₃ PO ₄ (16.5 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 2-chloro-4-trifluoromethylphenylboronic acid (6.96 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 1-c (2 g).

3) Receiving connection 1-e

Mixed tert -butyl-2-[( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d ) (77.8 g), Boc-piperazine (55 .8 g), tris(dibenzylideneacetone)dipalladium (9 g), [(4-( N , N -dimethylamino)phenyl]di- tert -butylphosphine (5.2 g), sodium tert -butoxide (96.1 g) , toluene (800 ml) and tetrahydrofuran (300 ml) and the mixture was stirred, heated to 60°C and allowed to react for 24 hours under nitrogen atmosphere.The reaction solution was washed successively with a solution of L -cysteine (100 g) and NaHCO ₃ ( 150 g) in water (1.5 L) (750 ml x 2), and then washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain compound 1-e (40 g). ESI-MS: mass/charge = 495.4 [M+H]+.

4) Receiving connection 1-f

Compound 1-e (40 g), tetrahydrofuran (800 ml), ethanol (270 ml) and water (15 ml) were mixed and the mixture was stirred. KOH (45.3 g) was then added and the mixture was heated to 80°C and stirred under reflux for 8 hours until the reaction was complete. Water (500 ml) was added to the reaction solution, stirred, pH was adjusted to 5-6 with dilute hydrochloric acid, filtered, suspended with water (1 L) (500 ml x 2) and dried to give compound 1-f (35 G).

5) Getting connection 1-h

Compound 1-f (35 g) and dichloromethane (100 ml) were mixed and the mixture was stirred at room temperature. Then 4-dimethylaminopyridine (38.5 g) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (65.8 g) were added and dissolved by stirring, and 3-nitro-4-[[(tetrahydropyran-4 -yl)methyl]amino]benzenesulfonamide (compound 1-h ) (25.2 g) and allowed to react at room temperature for 3 hours. The reaction solution was washed successively with 5 wt% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. Dichloromethane (200 ml) was added to the concentrate, stirred at room temperature for 2 hours, filtered and dried to give compound 1-h (40 g).

6) Receiving connection 1-i

Compound 1-h was added to isopropanol (500 ml) and the mixture was stirred. Concentrated HCl (50 ml) was then added and the mixture was heated to 65°C and stirred for 8 hours until the reaction was complete. The reaction mixture was filtered and the filter cake was dissolved in water (300 ml), saturated sodium bicarbonate was added dropwise to adjust the pH to 6-7, filtered and dried. The resulting solid was suspended with ethyl acetate (200 ml), filtered and dried to give compound 1-i (27 g).

7) Getting connection 1-1

Compound 1-c (1 g) and compound 1-i (2 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.24 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 1-1 (200 mg).

Compound 1-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.68 (s, 1H), 8.62 (m, 1H), 8.58 (d, 1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.81 (dd, 1H), 7.70 (d, 1H), 7.54 (m, 3H) , 7.40 (d, 1H), 7.12 (d, 1H), 6.74 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.87 ( m, 4H), 3.55 (d, 2H), 3.37 (d, 2H), 3.32 (m, 4H), 2.27 (d, 1H), 2.19 (m, 1H), 2.09 (s, 1H), 1.96 (s, 2H), 1.89 (m, 1H), 1.63 (d, 2H), 1.50 (m, 2H), 1.28 (m , 4H), 0.98 (d, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.8, 153.9, 147.9, 142.9, 132.5, 130.1, 128.3, 125.6 , 124.7, 120.3, 118.4, 115.5, 114.1, 109.6, 103.4, 100.4, 67.0, 58.3, 50.9, 48.4, 46 ,9, 44.1, 34.6, 30.6, 29.1, 25.2. ESI-MS: mass/charge = 936.5 [M+H]+.

Example 2. 4-(4-{[2-(3-Trifluoromethyl-4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({3-nitro- 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 2-c

Compound 1-b (5.16 g), tetrakis(triphenylphosphine) palladium (0.17 g), K ₃ PO ₄ (12.74 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 3-trifluoromethyl-4-chlorobenzeneboronic acid (6.72 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 2-c (1.2 g).

2) Receiving connection 2-1

Compound 2-c (1 g) and compound 1-i (2.01 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.27 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 2-1 (80 mg).

Compound 2-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.66 (s, 1H), 8.61 (m, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H), 7.67 (d, 1H), 7.54 (m, 4H), 7.40 (d, 1H) , 7.12 (d, 1H), 6.74 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.87 (m, 4H), 3.55 ( d, 2H), 3.32 (m, 6H), 3.01 (s, 2H), 2.21 (d, 2H), 1.98 (m, 2H), 1.87 (m, 1H), 1.60 (d, 2H), 1.45 (m, 2H), 1.28 (m, 4H), 0.98 (d, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.7, 158.4, 158.2, 153.9, 147.9, 146.8, 145.9, 141.5 , 135.6, 134.3, 134.2, 132.5, 132.4, 130.1, 130.0, 129.8, 128.3, 127.6, 127.4, 124.7, 122 ,1, 120.2, 118.4, 115.5, 114.0, 109.5, 103.4, 100.4, 67.0, 58.3, 50.8, 48.4, 46.7 , 44.3, 34.6, 34.3, 30.6, 29.2, 28.3, 25.2, 14.4. ESI-MS: mass/charge = 936.5 [M+H] ⁺ .

Example 3 4-(4-{[2-(4-Chloro-2-trifluoromethylphenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({3-nitro- 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 3-c

Compound 1-b (5.16 g), tetrakis(triphenylphosphine) palladium (0.17 g), K ₃ PO ₄ (12.74 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 2-trifluoromethyl-4-chlorobenzeneboronic acid (6.72 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 3-c (1.6 g).

2) Receiving connection 3-1

Compound 3-c (1 g) and compound 1-i (2.01 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.27 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 3-1 (110 mg).

Compound 3-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.73 (s, 1H), 11.67 (s, 1H), 8.61 (m, 1H), 8.58 (d, 1H), 8.05 (d, 1H), 7.79 (m, 2H), 7.71 (d, 1H), 7.52 (m, 3H), 7.29 (d, 1H) , 7.13 (d, 1H), 6.74 (d, 1H), 6.41 (s, 1H), 6.26 (s, 1H), 3.84 (d, 2H), 3.61 ( d, 2H), 3.18 (m, 4H), 3.05 (s, 3H), 2.31 (d, 1H), 1.89 (m, 5H), 1.61 (d, 2H), 1.51 (m, 1H), 1.41 (m, 1H), 1.24 (d, 6H), 0.91 (m, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.8, 158.5, 158.2, 153.9, 147.9, 146.7,145.9, 139.1, 135 ,6, 134.3, 133.4, 133.1, 133.0, 132.6, 130.0, 128.3, 126.7, 124.7, 120.3, 118.5, 115.5 , 114.1, 109.6, 103.3, 100.4, 67.0, 58.7, 48.4, 46.8, 44.3, 34.5, 34.3, 30.6, 29 ,4, 29.0, 28.9, 27.5, 27.0, 24.6, 22.5. ESI-MS: mass/charge = 936.5 [M+H] ⁺ .

Example 4 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 4-c

Compound 1-b (5.16 g), tetrakis(triphenylphosphine) palladium (0.17 g), K ₃ PO ₄ (12.74 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 3-chloro-4-trifluoromethylphenylboronic acid (6.72 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 4-c (1.5 g).

2) Receiving connection 4-1

Compound 4-c (1 g) and compound 1-i (2.01 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.27 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 4-1 (120 mg).

Compound 4-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 1H), 11.62 (s, 1H), 8.61 (m, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.79 (m, 2H), 7.50 (m, 3H), 7.43 (s, 1H), 7.23 (d, 1H) , 7.12 (d, 1H), 6.71 (dd, 1H), 6.39 (m, 1H), 6.25 (d, 1H), 3.84 (dd, 2H), 3.29 ( m, 4H), 3.24 (m, 2H), 2.21 (d, 3H), 2.03 (d, 3H), 1.88 (m, 1H), 1.60 (m, 2H), 1.43 (m, 3H), 1.22 (m, 4H), 0.94 (d, 9H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.8, 158.6, 158.3, 154.1, 147.9, 146.8, 145.9, 135.7 , 134.7, 134.3, 132.5, 131.4, 130.0, 128.3, 127.8, 125.7, 124.7, 124.5, 120.2, 118.4, 115 .5, 114.0, 109.5, 103.3, 100.4, 67.0, 64.6, 51.0, 48.4, 46.4, 45.2, 44.6, 34.6 , 34.3, 30.6, 29.3, 29.1, 28.2, 28.1, 25.2, 24.8. ESI-MS: mass/charge = 936.5 [M+H] ⁺ .

Example 5 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 5-c

Compound 1-b (5.16 g), tetrakis(triphenylphosphine) palladium (0.17 g), K ₃ PO ₄ (12.74 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 2-fluoro-4-trifluoromethylphenylboronic acid (6.24 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 5-c (1.8 g).

2) Receiving connection 5-1

Compound 5-c (1 g) and compound 1-i (2.12 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.27 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 5-1 (90 mg).

Compound 5-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 2H), 8.61 (m, 1H), 8.57 (d, 1H), 8.03 (d, 1H), 7.80 (dd, 1H), 7.66 (d, 1H), 7.56 (d, 1H), 7.51 (dd, 3H), 7.35 (m, 1H) , 7.12 (d, 1H), 6.73 (dd, 1H), 6.39 (m, 1H), 6.29 (d, 1H), 3.84 (m, 3H), 3.55 ( d, 5H), 3.24 (d, 6H), 2.25 (s, 2H), 1.98 (m, 2H), 1.88 (m, 1H), 1.60 (d, 2H), 1.47 (m, 2H), 1.24 (m, 4H), 0.95 (d, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 159.6, 158.7, 158.5, 158.1, 157.7, 154.0, 147.9, 146.9 , 145.9, 135.6, 134.3, 133.2, 132.5, 132.1, 130.0, 128.3, 124.9, 124.7, 122.7, 122.1, 120 ,2, 118.2, 115.5, 114.1, 109.6, 103.5, 100.4, 67.0, 58.6, 50.8, 48.4, 45.7, 44.3 , 34.5, 34.3, 30.6, 29.1, 28.6, 27.6, 25.1. ESI-MS: mass/charge = 920.6 [M+H] ⁺ .

Example 6 4-[(tetrahydro- 2H- pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 6-c

Compound 1-b (5.16 g), tetrakis(triphenylphosphine) palladium (0.17 g), K ₃ PO ₄ (12.74 g), DMF (60 ml) and water (60 ml) were mixed and the mixture was stirred in for 10 minutes. Then, 3-fluoro-4-trifluoromethylphenylboronic acid (6.24 g) was added and the mixture was allowed to react at 100° C. for 6 hours under N ₂ atmosphere until the reaction was completed. A solution of 5 wt% NaHCO ₃ and 2 wt% L -cysteine in water (30 ml) and ethyl acetate (50 ml) was added to the reaction solution, stirred for 0.5 h and filtered, followed by separation of the liquids. The aqueous phase was extracted with ethyl acetate (60 ml x 2). The organic phases were combined, washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and subjected to column chromatography to give compound 6-c (1.6 g).

2) Getting connection 6-1

Compound 6-c (1 g) and compound 1-i (2.12 g) were dissolved in methanol (20 ml) and the solution was stirred. Sodium borohydride (0.27 g) was then added and the mixture was stirred for 6 hours until the reaction was complete. Saturated aqueous ammonium chloride (10 ml) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 ml×2), washed with saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated and subjected to column chromatography to obtain compound 6-1 (150 mg).

Compound 6-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.67 (s, 1H), 8.61 (m, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.81 (dd, 1H), 7.72 (m, 1H), 7.52 (dd, 3H), 7.24 (d, 1H) , 7.09 (m, 2H), 6.72 (dd, 1H), 6.39 (m, 1H), 6.27 (d, 1H), 3.87 (m, 4H), 3.55 ( d, 2H), 3.37 (d, 2H), 3.32 (m, 4H), 2.27 (d, 1H), 2.19 (m, 2H), 2.09 (s, 1H), 1.96 (s, 2H), 1.89 (m, 1H), 1.63 (d, 2H), 1.50 (m, 2H), 1.28 (m, 4H), 0.98 (d , 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.8, 158.5, 158.2, 154.0, 149.2, 147.9, 146.8, 145.9 , 135.6, 134.3, 132.5, 132.4, 130.1, 130.0, 128.3, 128.1, 125.1, 120.3, 118.4, 117.6, 117 ,2, 117.1, 115.5, 115.3, 109.6, 103.4, 100.4, 67.0, 58.3, 50.9, 48.4, 46.4, 44.3 , 34.5, 34.3, 31.7, 30.6, 29.0, 28.2, 25.5, 25.1. ESI-MS: mass/charge = 920.6 [M+H] ⁺ .

Example 7. ( R )-4-(4-{[2-(2-Chloro-4-trifluoromethylphenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({ 3-nitro-4-[(1,4-dioxan-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 7-d

Compound 1-c (198.6 g) and 1-Boc-piperazine (175.5 g) were dissolved in acetonitrile (800 ml) and the solution was stirred and cooled to 0°C. Sodium triacetoxyborohydride (532.6 g) was then slowly added and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was extracted with water (1 L) and ethyl acetate (300 ml). The organic phase was collected, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 7-d (269.8 g).

1) Receiving connection 7-e

Compound 7-d (269.8 g), isopropanol (800 ml) and hydrochloric acid (36-38 wt%, 169 ml) were mixed, and the mixture was heated to 65°C and allowed to react for 3 hours. Reaction solution cooled to precipitate a solid, filtered and dried to give compound 7-e (151.2 g).

Compound 7-e : ^1H NMR (500 MHz, DMSO- d6 ), δ: 7.82 (s, 1H), 7.68 (d, 1H), 7.36 (d, 1H), 7.10 (dd, 1H), 2.98 (s, 4H), 2.63 (d, 2H), 2.23 (m, 6H), 1.89 (m, 2H), 1.43 (s, 2H) , 0.94 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 133.1, 132.6, 131.9, 130.9, 129.3, 128.6, 126.5, 125.7, 124.9 , 124.6, 122.7, 60.2, 49.4, 44.7, 35.2, 29.4, 28.4, 27.1, 25.2, 21.4. ESI-MS: mass/charge = 387.1 [M+H] ⁺ .

2) Obtaining compound 7-g

NaH (21.1 g) was dissolved in THF (100 ml) and the solution was cooled to -20°C and stirred for 10 minutes. Tert -butyl-2-[( 1H -pyrrolo[2,3- b ]pyridin-5-yl)oxy]-4-bromobenzoate (compound 1-d , 128.3 g) was dissolved in THF (200 ml), and then slowly added dropwise to the reaction solution while maintaining the internal temperature below 0°C. After addition, the mixture was stirred for 30 minutes. A solution of TBSCl (64.7 g) in THF (200 ml) was added dropwise to the reaction solution, while the internal temperature was maintained at about -10°C, and after the addition, the reaction was allowed to proceed for 30 minutes. After completion of the reaction, the reaction solution was extracted with 500 ml of saturated sodium bicarbonate and ethyl acetate. The organic phase was collected, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography to give compound 7-f (150 g). ESI-MS: mass/charge = 503.1 [M+H] ⁺ .

Mix compound 7-e (151.2 g), tert -butyl-2-[(1- tert -butyldimethylsilylpyrrolo[2,3- b ]pyridin-5-yl)oxy]-4-bromobenzoate (compound 7-f , 197.1 g), tris(dibenzylideneacetone)dipalladium (2.7 g), [(4-( N , N -dimethylamino)phenyl]di- tert -butylphosphine (1.6 g), sodium tert -butoxide (187, 4 g) and toluene (800 ml) and the mixture was stirred, heated to 100°C and allowed to react for 24 hours under nitrogen atmosphere.After completion of the reaction, the reaction solution was extracted with water (1 L) and ethyl acetate (300 ml) The organic phase was collected, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give compound 7-g (181.9 g).

Compound 7-g : ^1H NMR (500 MHz, DMSO- d6 ), δ: 7.95 (s, 1H), 7.82 (s, 1H), 7.65 (t, 2H), 7.37 (m, 4H), 6.76 (d, 1H), 6.47 (s, 1H), 3.14 (s, 2H), 2.64 (d, 1H), 2.55 (d, 1H) , 2.19 (m, 5H), 1.92 (m, 2H), 1.42 (t, 2H), 1.31 (t, 2H), 1.22 (m, 9H), 0.95 ( d, 6H), 0.84 (s, 10H), 0.60 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.4 156.8, 155.1, 150.3, 149.8, 146.2, 133.6, 133.4, 133.2, 132.0, 131.9, 131.5, 129.5, 129.0, 128.8, 126.4, 126.1, 124.4, 122.8, 114.4, 113.8, 110, 2, 106.8, 103.3, 80.1, 60.6, 52.6, 47.1, 44.7, 35.2, 29.4, 27.9, 27.2, 26.7, 25.4, 19.0. ESI-MS: mass/charge = 809.4 [M+H] ⁺

3) Obtaining connection 7-h

A mixture of compound 7-g (181.9 g), toluene (1.8 L) and trifluoroacetic acid (107 ml) was heated to 45°C and allowed to react for 5 hours. The reaction solution was concentrated, ethyl acetate (1.5 l), washed with saturated aqueous NaHCO ₃ and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. Toluene (1 L) and ethyl acetate (200 ml) were added to the concentrate, heated until dissolution was confirmed, cooled to precipitate a solid, filtered and dried to give compound 7-h (83.4 g).

Compound 7-h : ^1H NMR (500 MHz, DMSO- d6 ), δ: 7.98 (s, 1H), 7.82 (s, 1H), 7.73 (d, 1H), 7.64 (d, 1H), 7.46 (s, 1H), 7.40 (s, 1H), 7.32 (d, 1H), 6.73 (d, 1H), 6.36 (d, 1H) , 6.34 (s, 1H), 3.09 (s, 4H), 2.64 (d, 1H), 2.55 (d, 1H), 2.19 (m, 6H), 1.88 ( m, 2H), 1.42 (m, 2H), 1.25 (m, 2H), 0.95 (m, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 166.3, 158.9, 155.1, 148.9, 146.2, 145.3, 135.0, 133.8, 133.2 , 132.0, 131.9, 131.4, 129.5, 129.2, 127.8, 126.4, 124.9, 124.4, 122.7, 120.2, 116.6, 112 ,0, 109.5, 105.3, 100.2, 60.5, 55.3, 52.7, 47.0, 44.7, 35.2, 29.4, 27.2, 25.4 . ESI-MS: mass/charge = 639.2 [M+H] ⁺ .

4) Getting connection 7-k

3-nitro-4-chlorobenzenesulfonamide (0.64 g), ( R )-(1,4-dioxane)-2-methylamine hydrochloride (0.5 g) and N , N -diisopropylethylamine (1.58 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C and allowed to react for 6.5 hours. The reaction solution was cooled at room temperature, left overnight and filtered to give compound 7-k (0.65 G). ESI-MS: mass/charge = 316.2 [MH] ^- .

5) Receiving connection 7-1

Compound 7-h (1 g) and dichloromethane (10 ml) were mixed and the mixture was stirred at room temperature. 4-Dimethylaminopyridine (0.28 g) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.44 g) were then added and dissolved by stirring. Compound 7-k (0.5 g) and triethylamine (0.44 g) were added to the resulting mixture, and the reaction was allowed to proceed at room temperature for 3 hours. The reaction solution was washed successively with 5 wt% hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and purified by column chromatography to give compound 7-1 (0.8 g).

Compound 7-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.66 (s, 1H), 11.37 (s, 1H), 8.59 (t, 1H), 8.57 ( d, 1H), 8.05 (d, 1H), 7.88 (d, 1H), 7.83 (dd, 1H), 7.70 (d, 1H), 7.53 (d, 1H), 7.52 (m, 2H), 7.40 (m, 1H), 7.12 (d, 1H), 6.75 (dd, 1H), 6.40 (dd, 1H), 6.30 (d , 1H), 3.80 (m, 3H), 3.62 (m, 2H), 3.51 (m, 2H), 3.42 (m, 2H), 3.03 (m, 4H), 2 .67 (d, 1H), 2.54 (d, 1H), 2.17 (m, 6H), 1.88 (dd, 2H), 1.42 (t, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 159.2, 159.0, 158.7, 158.4, 158.2, 154.0, 147.8, 146.9 , 145.8, 144.2, 139.0, 135.5, 134.3, 132.8, 132.6, 131.7, 130.1, 130.0, 128.3, 128.2, 127 ,0, 125.1, 124.9, 124.4, 122.75, 120.3, 118.3, 117.5, 115.7, 115.2, 114.2, 122.8, 109.7 , 103.6, 100.4, 58.5, 45.2, 44.3, 43.8, 34.6, 29.2, 29.1, 27.1, 24.8. ESI-MS: mass/charge = 938.5 [M+H] ⁺ .

Example 8. ( S )-4-(4-{[2-(2-Chloro-4-trifluoromethylphenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({ 3-nitro-4-[(1,4-dioxan-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting an 8-k connection

3-Nitro-4-fluorobenzenesulfonamide (3.58 g), ( S )-2-(aminomethyl)-1,4-dioxane hydrochloride (3.0 g) and N , N -diisopropylethylamine (9.47 g) were dissolved in acetonitrile (50 ml) and the solution was heated to 85°C and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to give compound 8-k (4.70 G). ESI-MS: mass/charge = 316.1 [MH] ^- .

2) Getting connection 8-1

Compound 8-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 8-k .

Compound 8-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.66 (s, 1H), 11.37 (s, 1H), 8.59 (t, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.84 (dd, 1H), 7.70 (d, 1H), 7.54 (d, 1H) , 7.52 (m, 2H), 7.40 (m, 1H), 7.11 (d, 1H), 6.75 (dd, 1H), 6.40 (dd, 1H), 6.29 ( d, 1H), 3.79 (m, 3H), 3.65 (m, 2H), 3.51 (m, 2H), 3.42 (m, 2H), 3.03 (m, 4H), 2.67 (d, 1H), 2.54 (d, 1H), 2.17 (m, 6H), 1.88 (dd, 2H), 1.42 (t, 2H), 0.96 (s , 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 158.2, 154.0, 147.9, 146.9, 145.9, 144.3, 135.6, 134.3 , 132.9, 132.6, 131.8, 130.2, 130.0, 128.3, 128.2, 127.0, 125.2, 125.0, 122.8, 120.3, 118 ,3, 115.7, 114.1, 109.7, 103.6, 100.4, 73.4, 68.5, 66.4, 66.2, 58.6, 45.1, 44.4 , 43.9, 34.6, 29.3, 29.1, 27.2, 24.8. ESI-MS: mass/charge = 939.4 [M+H] ⁺ .

Example 9 4-[((4-acetylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving 9-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.56 g), [(4-acetylmorpholin-2-yl)methyl]amine (0.48 g) and N , N -diisopropylethylamine (0.65 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C, and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 9-k (1.2 g). ESI-MS: mass/charge = 359.0 [M+H] ⁺ .

2) Receiving connection 9-1

Compound 9-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 9-k .

Compound 9-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 2H), 8.63 (t, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.84 (dd, 1H), 7.70 (d, 1H), 7.53 (d, 3H), 7.39 (m, 1H) , 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.87 (m, 3H), 3.68 ( m, 2H), 3.60 (m, 3H), 3.48 (m, 2H), 3.40 (m, 2H), 3.30 (m, 2H), 3.18 (m, 1H), 3.02 (m, 2H), 2.29 (m, 1H), 2.19 (m, 1H), 1.96 (d, 2H), 1.49 (t, 2H), 1.24 (m , 1H), 0.97 (s, 9H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 169.1, 164.0, 158.9, 158.6, 158.2, 154.0, 147.9, 146.9, 145.9 , 144.2, 135.5, 134.3, 132.8, 132.6, 131.7, 130.2, 128.3, 128.2, 127.0, 125.2, 124.9, 122 ,8, 120.3, 118.3, 117.4, 115.8, 115.1, 114.2, 109.7, 103.6, 100.4, 73.8, 66.4, 58.5 , 48.5, 46.0, 45.1, 44.9, 44.3, 43.8, 34.6, 29.3, 29.1, 27.2, 24.8, 21.6, 21 ,6. ESI-MS: mass/charge = 979.3 [M+H] ⁺ .

Example 10 4-[((4-isobutyrylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 10-k connection

3-Nitro-4-fluorobenzenesulfonamide (1.48 g), [(4-isobutyrylmorpholin-2-yl)methyl]amine (1.5 g) and N , N -diisopropylethylamine (2.2 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 10-k (1.8 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Receiving connection 10-1

Compound 10-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 10-k .

Compound 10-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.64 (t, 1H), 8.58 (s, 1H), 8.04 ( d, 1H), 7.89 (s, 1H), 7.84 (t, 1H), 7.70 (d, 1H), 7.53 (d, 3H), 7.40 (d, 1H), 7.16 (t, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 4.36 (m, 1H), 3.86 (m , 2H), 3.58 (m, 4H), 3.47 (t, 2H), 3.39 (m, 2H), 3.19 (m, 1H), 3.02 (m, 2H), 2 .87 (m, 2H), 2.71 (m, 1H), 2.57 (m, 1H), 2.29 (m, 1H), 2.20 (m, 1H), 1.96 (s, 2H), 1.49 (m, 2H), 1.24 (m, 1H), 0.97 (s, 12H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 175.2, 164.0, 158.8, 158.6, 158.2, 154.0, 147.9, 146.9, 145.9, 144.2, 135.6, 134.3, 132.8, 132.6, 131.8, 130.2, 130.0, 128.3, 128.2, 127.0, 125.2, 124, 9, 122.8, 120.3, 118.3, 117.9, 115.8, 115.6, 114.1, 109.7, 103.6, 100.4, 74.2, 74.0, 66.6, 58.5, 47.8, 45.2, 45.1, 44.3, 44.1, 34.6, 29.5, 29.3, 29.1, 27.2, 24, 8, 20.0, 19.5. ESI-MS: mass/charge = 1007.3 [M+H] ⁺ .

Example 11 4-[( R )-(4-methoxyacetylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving an 11-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.36 g), ( R )-2-(aminomethyl)-4-methoxyacetylmorpholine hydrochloride (0.45 g) and N , N -diisopropylethylamine (0.97 g) were dissolved in acetonitrile ( 20 ml), and the solution was heated to 85°C and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 11-k (0.39 g) . ESI-MS: mass/charge = 387.1 [MH] ^- .

2) Receiving connection 11-1

Compound 11-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 11-k .

Compound 11-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.64 (m, 1H), 8.57 (d, 1H), 8.04 ( d, 1H), 7.89 (d, 1H), 7.84 (dd, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.52 (m, 2H), 7.38 (m, 1H), 7.21 (d, 1H), 6.75 (dd, 1H), 6.38 (dd, 1H), 6.29 (d, 1H), 3.47 (m , 3H), 3.42 (m, 1H), 3.27 (m, 5H), 2.27 (m, 3H), 2.21 (m, 1H), 2.01 (m, 2H), 1 .98 (d, 2H), 1.48 (t, 3H), 1.24 (m, 7H), 0.97 (s, 9H).

ESI-MS: mass/charge = 1010.4 [M+H] ⁺ .

Example 12 4-[((4-methylsulfonylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 12-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.66 g), [(4-methylsulfonylmorpholin-2-yl)methyl]amine (0.7 g) and N , N -diisopropylethylamine (0.97 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 12-k (1.2 g). ESI-MS: mass/charge = 395.0 [M+H] ⁺ .

2) Receiving connection 12-1

Compound 12-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 12-k .

Compound 12-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.64 (t, 1H), 8.58 (d, 1H), 8.05 ( d, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.54 (d, 3H), 7.39 (d, 1H), 7.17 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.99 (d, 1H), 3.79 (d , 2H), 3.63 (m, 5H), 3.50 (m, 1H), 3.38 (m, 3H), 2.92 (s, 3H), 2.86 (m, 2H), 2 .70 (m, 2H), 2.29 (m, 1H), 2.19 (m, 1H), 1.96 (s, 3H), 1.50 (m, 2H), 1.24 (m, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 158.6, 158.3, 154.0, 147.8, 146.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.8, 130.3, 128.3, 128.2, 127.0, 125.2, 124.4, 122, 8, 120.3, 118.3, 117.6, 115.8, 115.2, 114.1, 109.7, 103.6, 100.4, 73.7, 66.0, 58.5, 47.8, 45.4, 45.2, 45.0, 44.3, 34.6, 34.3, 29.3, 29.3, 29.1, 27.2, 24.8.

ESI-MS: mass/charge = 1015.3 [M+H] ⁺ .

Example 13 4-[(tetrahydro- 2H- pyran-3-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 13-k

3-Nitro-4-chlorobenzenesulfonamide (1.0 g), 3-aminomethyltetrahydropyran hydrochloride (0.77 g) and N , N -diisopropylethylamine (2.18 g) were dissolved in acetonitrile (20 ml), and the solution was heated to 85° C, and allowed to react for 5 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to give compound 13-k (1.3 g). ESI-MS: mass/charge = 314.1 [MH] ^- .

2) Obtaining connection 13-1

Compound 13-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 13-k .

Compound 13-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 1H), 11.69 (s, 1H), 8.59 (t, 1H), 8.57 ( d, 1H), 8.05 (d, 1H), 7.88 (d, 1H), 7.82 (dd, 1H), 7.70 (d, 1H), 7.55 (d, 1H), 7.52 (m, 2H), 7.39 (m, 1H), 7.10 (d, 1H), 6.75 (dd, 1H), 6.40 (dd, 1H), 6.30 (d , 1H), 3.79 (m, 1H), 3.72 (m, 2H), 3.59 (m, 1H), 3.33 (m, 5H), 3.18 (m, 2H), 3 .05 (m, 4H), 2.28 (m, 1H), 2.20 (m, 1H), 2.08 (m, 1H), 1.96 (d, 3H), 1.62 (m, 1H), 1.49 (t, 3H), 1.24 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 158.2, 154.0, 147.8, 146.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.7, 130.2, 130.1, 130.0, 128.3, 127.0, 124.9, 124.8, 124.4, 122.8, 120, 3, 118.3, 117.6, 115.5, 115.3, 114.2, 109.7, 103.6, 100.4, 70.5, 68.0, 58.5, 45.1, 44.9, 44.3, 35.3, 34.6, 29.3, 29.1, 27.2, 27.1, 25.0, 24.8.

ESI-MS: mass/charge = 937.4 [M+H] ⁺ .

Example 14 4-[(4-tetrahydro- 2H- pyran-2-ylmethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 14-k

3-Nitro-4-chlorobenzenesulfonamide (1.2 g), 2-aminomethyltetrahydropyran (0.7 g) and N , N -diisopropylethylamine (1.64 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85 °C , and allowed to react for 8 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to give compound 14-k (1.92 g). ESI-MS: mass/charge = 316.0 [M+H] ⁺ .

2) Obtaining connection 14-1

Compound 14-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 14-k .

Compound 14-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.62 (t, 1H), 8.57 (d, 1H), 8.05 ( d, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.54 (d, 3H), 7.39 (d, 1H), 7.11 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.92 (d, 1H), 3.56 (t , 2H), 3.48 (m, 1H), 3.37 (m, 5H), 2.85 (m, 4H), 2.23 (m, 1H), 2.20 (m, 1H), 1 .96 (s, 2H), 1.80 (m, 1H), 1.65 (d, 1H), 1.50 (m, 5H), 1.28 (m, 2H), 0.97 (d, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 158.6, 158.2, 154.0, 147.9, 146.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.8, 130.2, 130.0, 128.3, 128.2, 127.0, 125.0, 124, 4, 122.8, 120.3, 118.3, 115.8, 114.2, 109.7, 103.6, 100.4, 75.6, 68.0, 58.5, 47.9, 45.2, 44.3, 34.6, 29.3, 29.2, 29.1, 27.2, 26.0, 24.8, 22.9.

ESI-MS: mass/charge = 936.4 [M+H] ⁺ .

Example 15 4-[(1-(methylsulfonyl)piperidin-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 15-k

3-Nitro-4-fluorobenzenesulfonamide (1.57 g), 3-aminomethyl-1-methylsulfonylpiperidine (1.65 g) and N , N -diisopropylethylamine (2.31 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 15-k (2.40 g). ESI-MS: mass/charge = 393.1 [M+H] ⁺ .

2) Obtaining connection 15-1

Compound 15-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 15-k .

Compound 15-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (d, 2H), 8.64 (t, 1H), 8.58 (s, 1H), 8.05 ( s, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.54 (t, 3H), 7.39 (d, 1H), 7.15 (d, 1H), 6.75 (d, 1H), 6.41 (s, 1H), 6.29 (s, 1H), 3.54 (d, 2H), 3.36 (m , 6H), 2.85 (s, 4H), 2.76 (t, 2H), 2.59 (t, 1H), 2.29 (m, 1H), 2.19 (m, 1H), 1 .96 (s, 4H), 1.79 (m, 2H), 1.49 (m, 4H), 1.24 (m, 3H), 0.97 (d, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.8, 158.2, 154.0, 147.8, 146.9, 145.9, 144.2, 135.6, 134.4, 132.8, 132.6, 131.8, 130.2, 128.3, 127.0, 125.0, 122.8, 120.3, 118.3, 115.6, 114, 1, 109.7, 103.5, 100.4, 58.5, 49.3, 46.4, 45.7, 45.2, 44.4, 35.0, 34.6, 34.5, 29.3, 29.1, 27.4, 27.2, 24.8, 24.1.

ESI-MS: mass/charge = 1013.3 [M+H] ⁺ .

Example 16 4-[(2-(4-acetylmorpholin-2-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 16-k connection

3-Nitro-4-fluorobenzenesulfonamide (2.13 g), 2-aminoethyl-4-acetylmorpholine (2 g) and N , N -diisopropylethylamine (3.13 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85 °C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 16-k (3.40 g). ESI-MS: mass/charge = 373.1 [M+H] ⁺ .

2) Obtaining connection 16-1

Compound 16-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 16-k .

Compound 16-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.70 (s, 2H), 8.78 (s, 1H), 8.57 (s, 1H), 8.04 ( s, 1H), 7.82 (m, 2H), 7.69 (d, 1H), 7.52 (s, 1H), 7.44 (m, 2H), 7.38 (d, 1H), 7.23 (m, 1H), 6.75 (d, 1H), 6.39 (s, 1H), 6.29 (s, 1H), 4.87 (m, 2H), 3.89 (d , 2H), 3.43 (m, 8H), 3.03 (m, 4H), 2.90 (m, 2H), 2.67 (m, 2H), 2.20 (m, 4H), 1 .96 (m, 3H), 1.47 (m, 2H), 1.24 (m, 1H), 0.96 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 168.9, 163.9, 163.5, 153.9, 147.6, 145.9, 135.5, 134.4, 133.2, 132.8, 131.7, 130.1, 129.6, 128.3, 127.5, 124.9, 120.2, 115.2, 109.3, 100.4, 74.3, 66, 6, 66.4, 58.5, 49.8, 50.4, 45.7, 45.3, 44.2, 41.2, 34.6, 31.6, 31.4, 29.3, 29.1, 27.2, 24.8, 21.6. ESI-MS: mass/charge = 993.3 [M+H] ⁺ .

Example 17 4-[(3-(1-methylpiperidin-4-yl)propyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 17-k

3-Nitro-4-fluorobenzenesulfonamide (2.34 g), 4-aminopropyl-1-methylpiperidine (2 g) and N , N -diisopropylethylamine (3.56 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85 °C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to give compound 17-k (3.56 g). ESI-MS: mass/charge = 357.2 [M+H] ⁺ .

2) Obtaining connection 17-1

Compound 17-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 17-k .

Compound 17-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.54 (s, 2H), 8.43 (s, 1H), 8.30 (t, 1H), 8.19 ( s, 1H), 7.94 (s, 1H), 7.82 (s, 1H), 7.67 (t, 2H), 7.58 (d, 1H), 7.33 (m, 2H), 6.82 (d, 1H), 6.63 (d, 1H), 6.31 (s, 1H), 6.24 (s, 1H), 3.34 (m, 3H), 2.98 (m , 6H), 2.75 (t, 2H), 2.65 (d, 1H), 2.54 (s, 1H), 2.20 (m, 6H), 1.90 (t, 4H), 1 .56 (s, 3H), 1.35 (m, 4H), 1.23 (s, 1H), 1.17 (t, 3H), 0.96 (d, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 169.2, 164.0, 156.9, 153.4, 149.3, 146.2, 145.2, 135.3, 135.1, 133.2, 132.5, 132.0, 131.5, 129.8, 129.5, 129.2, 127.5, 126.5, 126.2, 125.0, 124.4, 122, 8, 121.5, 120.1, 116.6, 114.1, 109.7, 105.8, 100.1, 60.6, 52.8, 51.4, 51.3, 47.7, 44.7, 35.3, 34.3, 31.3, 29.4, 29.3, 27.3, 25.4, 9.8.

ESI-MS: mass/charge = 977.6 [M+H] ⁺ .

Example 18 4-[(2-(1-methylpiperidin-4-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving 18-k connection

3-Nitro-4-fluorobenzenesulfonamide (2.58 g), 4-aminoethyl-1-methylpiperidine (2 g) and N , N -diisopropylethylamine (3.78 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85 °C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 18-k (3.68 g). ESI-MS: mass/charge = 343.1 [M+H] ⁺ .

2) Obtaining connection 18-1

Compound 18-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 18-k .

Compound 18-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (d, 2H), 8.58 (s, 2H), 8.04 (s, 1H), 7.88 ( s, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.53 (m, 3H), 7.40 (d, 1H), 7.08 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.56 (d, 1H), 3.42 (m, 6H), 3.10 (m , 1H), 2.91 (m, 3H), 2.77 (m, 4H), 2.21 (m, 2H), 1.94 (d, 4H), 1.53 (m, 4H), 1 .36 (m, 2H), 1.24 (m, 2H), 0.97 (d, 9H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 158.6, 158.2, 154.0, 147.6, 146.9, 145.9, 144.3, 135.6, 134.4, 132.9, 132.5, 131.8, 130.1, 128.3, 125.0, 124.8, 120.3, 118.3, 115.6, 115, 4, 114.2, 109.7, 103.6, 100.4, 58.5, 53.9, 45.2, 44.3, 43.1, 34.6, 34.3, 30.8, 29.4, 29.3, 29.1, 28.0, 24.8. ESI-MS: mass/charge = 963.8 [M+H] ⁺ .

Example 19 4-[(2-(1-ethylpiperidin-4-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 19-k

3-Nitro-4-fluorobenzenesulfonamide (2.34 g), 4-aminoethyl-1-ethylpiperidine (2 g) and N , N -diisopropylethylamine (3.43 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85 °C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to obtain compound 19-k (3.35 g). ESI-MS: mass/charge = 357.2 [M+H] ⁺ .

2) Receiving connection 19-1

Compound 19-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 19-k .

Compound 19-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.61 (s, 1H), 11.57 (s, 1H), 8.45 (s, 1H), 8.37 ( t, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 6.64 (d, 1H), 6.33 (s , 1H), 6.23 (s, 1H), 3.31 (m, 3H), 3.01 (s, 6H), 2.81 (t, 1H), 2.66 (m, 3H), 2 .54 (s, 1H), 2.15 (m, 5H), 1.90 (d, 2H), 1.81 (d, 2H), 1.59 (m, 1H), 1.43 (m, 2H), 1.27 (m, 8H), 0.95 (d, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 168.1, 157.2, 153.8, 148.7, 146.6, 146.2, 145.3, 135.4, 135.0, 133.2, 132.5, 132.0, 131.5, 129.7, 129.5, 127.7, 126.6, 126.5, 125.0, 124.7, 124.5, 122, 8, 120.1, 117.0, 114.3, 109.6, 105.1, 100.2, 53.8, 52.8, 47.6, 44.7, 43.1, 42.8, 35.3, 32.6, 31.8, 31.6, 30.3, 29.4, 29.2, 27.3, 25.7, 25.4, 22.6, 14.4. ESI-MS: mass/charge = 977.7 [M+H] ⁺ .

Example 20 4-[(2-(1-(2-fluoroethyl)piperidin-4-yl)ethyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Receiving a 20-k connection

3-Nitro-4-fluorobenzenesulfonamide (2.11 g), 4-aminoethyl-1-(2-fluoroethyl)piperidine (2 g) and N , N -diisopropylethylamine (3.09 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight and filtered under vacuum to give compound 20-k (3.29 g). ESI-MS: mass/charge = 375.1 [M+H] ⁺ .

2) Obtaining connection 20-1

Compound 20-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 20-k .

Compound 20-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.62 (s, 2H), 8.51 (s, 1H), 8.43 (t, 1H), 8.16 ( s, 1H), 8.00 (s, 1H), 7.82 (s, 1H), 7.76 (d, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.47 (s, 1H), 7.33 (d, 1H), 6.95 (d, 1H), 6.66 (d, 1H), 6.36 (s, 1H), 6.21 (s , 1H), 4.69 (s, 1H), 4.60 (s, 1H), 3.39 (m, 2H), 3.12 (d, 2H), 3.03 (s, 3H), 2 .98 (s, 1H), 2.92 (s, 1H), 2.64 (d, 1H), 2.54 (s, 1H), 2.42 (t, 2H), 2.15 (m, 6H), 1.89 (d, 2H), 1.78 (d, 2H), 1.56 (m, 2H), 1.43 (m, 3H), 1.29 (m, 3H), 0. 96 (d, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 163.6, 157.7, 154.4, 148.0, 147.0, 146.2, 145.6, 135.6, 134.8, 133.2, 132.5, 132.0, 131.4, 129.9, 129.5, 129.3, 128.2, 127.9, 127.3, 126.5, 124.9, 124, 4, 122.8, 120.2, 117.6, 116.7, 114.7, 109.4, 104.1, 100.3, 81.6, 80.2, 60.5, 57.4, 57.3, 53.3, 52.7, 47.3, 44.7, 35.3, 34.7, 32.2, 30.7, 29.4, 25.4. ESI-MS: mass/charge = 995.4 [M+H] ⁺ .

Example 21 4-[(2-(4-(methylsulfonyl)morpholin-2-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 21-k

3-Nitro-4-fluorobenzenesulfonamide (2.2 g), 2-aminoethyl-4-methylsulfonylmorpholine (2.52 g) and N , N -diisopropylethylamine (3.26 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 21-k (3.52 g). ESI-MS: mass/charge = 409.1 [M+H] ⁺ .

2) Obtaining connection 21-1

Compound 21-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 21-k .

Compound 21-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.59 (d, 1H), 8.18 (d, 1H), 8.04 ( d, 1H), 7.89 (m, 2H), 7.69 (dd, 1H), 7.56 (d, 1H), 7.52 (m, 2H), 7.40 (m, 1H), 7.27 (m, 1H), 6.75 (d, 1H), 6.40 (m, 1H), 6.30 (m, 1H), 4.00 (m, 3H), 3.67 (m , 1H), 3.59 (m, 3H), 3.46 (m, 1H), 3.35 (m, 5H), 3.15 (m, 3H), 2.28 (m, 3H), 2 .05 (m, 5H), 1.84 (m, 1H), 1.71 (m, 1H), 1.60 (m, 1H), 1.49 (m, 2H), 1.24 (m, 1H), 0.96 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.2, 154.0, 146.9, 146.6, 145.9, 144.2, 139.0, 135.6, 134.5, 132.9, 132.5, 131.8, 130.6, 130.0, 128.3, 128.2, 127.0, 125.7, 124.9, 124.5, 122, 8, 120.3, 118.3, 115.6, 114.2, 109.7, 103.6, 100.5, 66.0, 62.1, 58.5, 58.5, 48.0, 47.9, 45.2, 44.3, 34.6, 29.3, 29.2, 29.1, 27.9, 27.5, 27.1, 24.8.ESI-MS: wt/ charge = 1029.4 [M+H] ⁺ .

Example 22 4-[(2-(4-isobutyrylmorpholin-2-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 22-k

3-Nitro-4-fluorobenzenesulfonamide (2.2 g), 2-aminoethyl-4-isobutyrylmorpholine (2.42 g) and N , N -diisopropylethylamine (3.26 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 22-k (3.42 g). ESI-MS: mass/charge = 401.1 [M+H] ⁺ .

2) Obtaining connection 22-1

Compound 22-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 22-k .

Compound 22-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.69 (s, 2H), 8.79 (s, 1H), 8.58 (s, 1H), 8.05 ( s, 1H), 7.82 (m, 2H), 7.65 (d, 1H), 7.55 (s, 1H), 7.50 (m, 2H), 7.33 (d, 1H), 7.06 (m, 1H), 6.69 (d, 1H), 6.39 (s, 1H), 6.20 (s, 1H), 3.89 (d, 2H), 3.42 (m , 8H), 3.17 (m, 4H), 2.88 (m, 2H), 2.66 (m, 2H), 2.22 (m, 4H), 1.92 (m, 3H), 1 .42 (m, 2H), 1.23 (m, 1H), 0.96 (s, 12H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 174.9, 163.9, 163.5, 158.3, 155.0, 147.6, 146.9, 145.9, 135.7, 134.4, 133.2, 132.6, 131.9, 130.1, 129.6, 129.3, 128.2, 126.5, 124.9, 124.5, 122.8, 120, 2, 118.3, 115.2, 112.8, 109.3, 102.8, 100.4, 74.5, 74.4, 66.6, 66.4, 60.3, 52.4, 49.8, 46.7, 46.0, 45.3, 44.8, 41.5, 35.2, 31.6, 31.4, 29.4, 29.2, 27.3, 25, 3, 20.1, 19.5. ESI-MS: mass/charge = 1021.4 [M+H] ⁺ .

Example 23 4-[(1-isobutyrylpiperidin-4-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 23-k

3-Nitro-4-fluorobenzenesulfonamide (1.99 g), 4-aminomethyl-1-isobutyrylpiperidine (2.0 g) and N , N -diisopropylethylamine (2.91 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 23-k (3.24 g). ESI-MS: mass/charge = 385.2 [M+H] ⁺ .

2) Obtaining connection 23-1

Compound 23-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 23-k .

Compound 23-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.73 (s, 1H), 11.68 (s, 1H), 8.64 (t, 1H), 8.58 ( s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (d, 1H), 7.14 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 4.42 (d , 1H), 3.96 (d, 2H), 3.74 (m, 1H), 3.58 (d, 1H), 3.40 (d, 1H), 3.32 (t, 4H), 2 .98 (t, 3H), 2.86 (m, 2H), 2.47 (s, 1H), 2.29 (m, 1H), 2.20 (m, 1H), 1.93 (m, 4H), 1.74 (m, 2H), 1.49 (m, 2H), 1.24 (m, 1H), 1.14 (m, 1H), 0.97 (s, 12H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 174.5, 164.0, 159.2, 158.9, 158.6, 154.0, 147.9, 146.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.7, 130.2, 130.1, 130.0, 128.3, 127.0, 124, 8, 124.4, 122.8, 120.3, 118.4, 117.5, 115.6, 115.2, 114.2, 109.7, 103.5, 100.4, 58.5, 48.0, 45.2, 45.0, 44.3, 41.4, 35.5, 34.6, 30.7, 29.7, 29.5, 29.3, 29.1, 27, 2, 24.8, 20.0, 19.9. ESI-MS: mass/charge = 1005.4 [M+H] ⁺ .

Example 24 4-[((4-ethylmorpholin-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 24-k connection

3-Nitro-4-fluorobenzenesulfonamide (2.54 g), 3-aminomethyl-4-ethylmorpholine (2.0 g) and N , N -diisopropylethylamine (3.72 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C, and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 24-k (3.51 g). ESI-MS: mass/charge = 345.1 [M+H] ⁺ .

2) Receiving connection 24-1

Compound 24-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 24-k .

Compound 24-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.73 (s, 2H), 8.68 (t, 1H), 8.61 (s, 1H), 8.05 ( s, 1H), 7.92 (d, 1H), 7.88 (s, 1H), 7.70 (d, 1H), 7.58 (s, 1H), 7.53 (m, 2H), 7.40 (d, 1H), 6.75 (d, 2H), 6.41 (s, 1H), 6.29 (s, 1H), 4.05 (d, 3H), 3.61 (m , 8H), 3.35 (m, 6H), 3.12 (m, 3H), 2.25 (m, 2H), 2.00 (s, 2H), 1.49 (m, 2H), 1 .23 (m, 4H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 159.0, 158.7, 158.4, 158.3, 154.0, 146.8, 145.9, 144.2, 139.0, 135.6, 134.6, 132.8, 132.6, 131.8, 131.3, 130.2, 128.4, 128.1, 127.0, 125.9, 125.0, 124, 4, 122.8, 120.3, 118.5, 117.5, 115.4, 115.2, 114.0, 109.6, 103.5, 100.5, 58.5, 47.9, 45.2, 44.3, 34.6, 29.5, 29.3, 29.1, 27.1, 24.8.

ESI-MS: mass/charge = 965.4 [M+H] ⁺ .

Example 25 4-[(1-(tetrahydro- 2H -pyran-4-yl)piperidin-4-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy )-benzamide

1) Receiving connection 25-k

3-Nitro-4-fluorobenzenesulfonamide (1.67 g), 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine (2.0 g) and N , N -diisopropylethylamine (2.91 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 25-k (2.91 g ). ESI-MS: mass/charge = 385.2 [M+H] ⁺ .

2) Obtaining compound 25-1

Compound 25-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 25-k .

Compound 25-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.62 (s, 1H), 11.58 (s, 1H), 8.66 (s, 1H), 8.50 ( s, 1H), 7.99 (s, 1H), 7.82 (s, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.52 (d, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.34 (d, 1H), 6.95 (d, 1H), 6.66 (d, 1H), 6.35 (s , 1H), 6.22 (s, 1H), 3.97 (d, 1H), 3.61 (t, 1H), 3.50 (m, 4H), 3.36 (d, 1H), 3 .03 (s, 4H), 3.90 (s, 2H), 2.83 (t, 1H), 2.61 (m, 2H), 2.54 (s, 1H), 2.16 (m, 6H), 1.90 (m, 4H), 1.74 (m, 1H), 1.42 (t, 2H), 1.24 (m, 4H), 0.96 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 146.2, 145.6, 135.5, 134.7, 133.2, 132.5, 132.1, 132.0, 131.4, 130.1, 130.0, 127.9, 126.5, 125.0, 124.5, 122.8, 120.2, 109.4, 100.3, 74.0, 65.9, 60, 5, 52.7, 49.8, 47.3, 45.4, 44.7, 35.6, 35.3, 34.2, 31.5, 29.5, 29.4, 29.2, 29.0, 27.3, 25.4, 22.6, 14.4. ESI-MS: mass/charge = 1005.4 [M+H] ⁺ .

Example 26 4-[((4-(3-oxetanyl)-morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 26-k

Compound 26-k was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-(3-oxetanyl)-2 -aminomethylmorpholine.

2) Obtaining connection 26-1

Compound 26-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 26-k .

Example 27 4-[((4-(tetrahydropyran-4-yl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Receiving connection 27-k

Compound 27-k was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-(tetrahydropyran-4-yl) -2-aminomethylmorpholine.

2) Obtaining connection 27-1

Compound 27-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 27-k .

Example 28 4-[((4-cyclopropylsulfonylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 28-k

Compound 28-k (1.01 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-cyclopropylsulfonyl -2-aminomethylmorpholine.

2) Obtaining connection 28-1

Compound 28-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 28-k .

Compound 28-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 1H), 11.67 (s, 1H), 8.64 (m, 1H), 8.58 (s, 1H), 8.05 (d, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H) , 7.38 (d, 1H), 7.17 (d, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.55 ( m, 7H), 3.42 (m, 4H), 2.99 (m, 4H), 2.83 (m, 2H), 2.65 (m, 1H), 2.27 (m, 2H), 1.96 (m, 2H), 1.50 (s, 2H), 1.24 (s, 1H), 0.98 (m, 10H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 158.9, 158.6, 158.2, 154.0, 147.9, 146.9, 145.9, 144.2 , 139.0, 135.6, 134.3, 132.8, 132.6, 131.7, 130.3, 128.3, 128.2, 125.2, 124.9, 124.4, 120 ,3, 118.4, 117.4, 115.8, 115.1, 114.1, 109.7, 103.5, 100.4, 73.8, 66.1, 58.5, 48.3 , 45.8, 45.1, 44.9, 44.3, 34.6, 29.3, 29.1, 27.2, 25.1, 24.8, 4.4, 4.3.

Example 29 4-[((4-cyclopropanoylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 29-k

Compound 29-k (0.85 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-cyclopropanoyl -2-aminomethylmorpholine.

2) Obtaining connection 29-1

Compound 29-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 29-k .

Compound 29-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.70 (s, 1H), 8.62 (m, 2H), 8.05 (s, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.39 (d, 1H) , 7.16 (d, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.95 (d, 2H), 3.62 ( m, 4H), 3.49 (m, 3H), 3.39 (m, 3H), 2.91 (m, 2H), 2.75 (m, 2H), 2.33 (m, 6H), 2.02 (m, 1H), 1.50 (s, 2H), 1.24 (s, 1H), 0.97 (s, 6H), 0.78 (d, 4H).

Example 30 4-[((4-(oxetan-3-yl)formylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Getting connection 30-k

Compound 30-k (0.85 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-( oxetan-3-yl)formyl-2-aminomethylmorpholine.

2) Obtaining compound 30-1

Compound 30-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 30-k .

Example 31 4-[((4-cyclobutylsulfonylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 31-k

Compound 31-k (0.98 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-cyclobutylsulfonyl -2-aminomethylmorpholine.

2) Obtaining connection 31-1

Compound 31-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 31-k .

Compound 31-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 1H), 11.69 (s, 1H), 8.61 (m, 2H), 8.05 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.71 (d, 1H), 7.54 (m, 3H), 7.39 (d, 1H) , 7.17 (d, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.95 (d, 2H), 3.62 ( m, 6H), 3.49 (m, 3H), 3.39 (m, 3H), 2.91 (m, 2H), 2.75 (m, 2H), 2.33 (m, 6H), 2.02 (m, 4H), 1.50 (s, 2H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.2, 154.0, 147.8, 146.9, 145.9, 144.2, 135.6, 134.3 , 132.8, 132.6, 131.8, 130.3, 128.3, 128.2, 127.0, 125.2, 124.9, 122.8, 120.3, 118.3, 115 ,8, 114.1, 109.7, 103.5, 100.4, 74.0, 66.3, 58.5, 50.9, 48.0, 45.6, 45.1, 44.9 , 44.3, 34.6, 29.3, 29.1, 27.2, 24.8.

Example 32 4-[((4-(oxetan-3-yl)sulfonylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Receiving connection 32-k

Compound 32-k (1.01 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-( oxetan-3-yl)sulfonyl-2-aminomethylmorpholine.

2) Obtaining connection 32-1

Compound 32-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 32-k .

Example 33 ​ 3-nitro-4-[(tetrahydrofuran-3-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 33-k

Compound 33-k (1.72 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( S ) -4-aminotetrahydrofuran hydrochloride.

2) Obtaining compound 33-1

Compound 33-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 33-k .

Compound 33-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.70 (s, 1H), 11.68 (s, 1H), 8.57 (s, 1H), 8.32 (d, 1H), 8.03 (s, 1H), 7.87 (t, 2H), 7.70 (d, 1H), 7.54 (d, 3H), 7.40 (d, 1H) , 7.13 (d 1H), 6.76 (d, 1H), 6.39 (s, 1H), 6.31 (s, 1H), 3.93 (m, 3H), 3.78 (m ,2H), 3.73 (d, 2H), 3.58 (d, 1H), 3.41 (d, 1H), 3.04 (m, 3H), 2.78 (s, 1H), 2 .34 (m, 2H), 2.28 (m, 1H), 2.08 (s, 1H), 1.96 (s, 2H), 1.90 (m, 1H), 1.49 (m, 2H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 159.1, 158.9, 158.6, 158.3, 158.1, 154.0, 147.0, 146.9 , 145.9, 144.2, 135.5, 134.5, 132.8, 132.5, 131.8, 130.5, 128.3, 128.1, 127.0, 125.6, 125 ,0, 122.8, 120.2, 118.1, 115.8, 114.3, 109.7, 103.7, 100.4, 72.7, 66.9, 58.5, 53.7 , 45.2, 44.3, 34.6, 33.0, 29.3, 29.1, 27.1, 24.8.

Example 34 ( R )-4-(4-{[2-(2-Chloro-4-trifluoromethylphenyl)-4,4-dimethylcyclohex-1-enyl]methyl}-piperazin-1-yl) -N -({ 3-nitro-4-[(tetrahydrofuran-3-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 34-k connection

Compound 34-k (1.65 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( R ) -4-aminotetrahydrofuran hydrochloride.

2) Obtaining connection 34-1

Compound 34-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 34-k .

Compound 34-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 1H), 11.68 (s, 1H), 8.57 (s, 1H), 8.32 (d, 1H), 8.03 (s, 1H), 7.87 (t, 2H), 7.71 (d, 1H), 7.54 (d, 3H), 7.40 (d, 1H) , 7.13 (s, 1H), 6.76 (d, 1H), 6.39 (s, 1H), 6.31 (s, 1H), 3.95 (m, 1H), 3.89 ( m, 1H), 3.79 (m, 2H), 3.73 (d, 2H), 3.60 (d, 1H), 3.42 (d, 1H), 3.29 (m, 2H), 3.05 (m, 3H), 2.78 (m, 1H), 2.33 (m, 2H), 2.21 (m, 1H), 1.96 (s, 2H), 1.91 (m , 1H), 1.49 (m, 2H), 1.23 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 159.2, 158.9, 158.7, 158.4, 158.1, 154.0, 147.0, 146.9, 145.8 , 144.2, 139.0, 135.4, 134.5, 132.8, 132.5, 131.7, 130.5, 128.3, 128.1, 127.1, 125.6, 124 ,9, 124.4, 120.3, 118.1, 117.3, 115.8, 114.9, 114.4, 109.8, 103.7, 100.4, 72.7, 66.9 , 58.5, 53.7, 45.1, 44.3, 34.6, 33.0, 29.2, 29.1, 27.1, 24.8.

Example 35 ​ 3-nitro-4-[((tetrahydrofuran-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 35-k

Compound 35-k (1.10 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( 3R )-tetrahydrofuran-3-methylamine.

2) Obtaining compound 35-1

Compound 35-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 35-k .

Compound 35-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.64 (m, 1H), 8.58 (d, 1H), 8.05 (d, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.54 (d, 3H) , 7.39 (d, 1H), 7.12 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.80 ( m, 2H), 3.71 (m, 2H), 3.63 (m, 2H), 3.52 (m, 2H), 3.40 (m, 4H), 2.58 (m, 1H), 2.28 (m, 2H), 2.08 (s, 2H), 1.98 (m, 4H), 1.67 (m, 1H), 1.50 (m, 2H), 1.24 (m , 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.9, 158.6, 158.2, 154.0, 147.8, 146.9, 145.9, 144.2 , 138.9, 135.6, 134.3, 132.9, 132.5, 131.8, 130.2, 130.1, 128.3, 127.0, 124.9, 124.5, 122 ,8, 120.3, 118.5, 118.3, 117.8, 115.5, 114.2, 109.7, 103.6, 100.4, 70.8, 67.3, 58.5 , 45.8, 45.2, 44.3, 38.1, 34.6, 29.8, 29.3, 29.1, 27.2, 24.8, 1.6.

Example 36 ​ 3-nitro-4-[((tetrahydrofuran-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 36-k

Compound 36-k (1.39 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( 3S )-tetrahydrofuran-3-methylamine (0.64 g).

2) Obtaining compound 36-1

Compound 36-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 36-k .

Compound 36-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.89 (s, 1H), 7.83 (d, 1H), 7.71 (d, 1H), 7.54 (d, 3H) , 7.40 (d, 1H), 7.12 (d, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.81 ( m, 1H), 3.73 (m, 2H), 3.61 (m, 3H), 3.53 (m, 1H), 3.41 (m, 4H), 3.05 (m, 3H), 2.58 (m, 1H), 2.31 (m, 1H), 2.27 (m, 1H), 2.08 (s, 1H), 1.96 (m, 3H), 1.65 (m , 1H), 1.49 (s, 2H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 159.2, 158.9, 158.6, 158.4, 158.1, 154.0, 147.7, 146.9, 145.9 , 144.2, 139.0, 135.5, 134.3, 132.8, 132.5, 131.7, 130.1, 128.3, 128.2, 127.0, 124.9, 124 ,4, 122.7, 120.3, 118.3, 117.5, 115.4, 115.1, 114.2, 109.7, 103.6, 100.4, 70.8, 67.3 , 58.5, 45.8, 45.1, 44.3, 38.1, 34.6, 29.8, 29.3, 29.1, 27.1, 24.8.

Example 37 ​ 3-nitro-4-[((tetrahydrofuran-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 37-k

Compound 37-k (1.35 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( S ) -2-tetrahydrofurfurylamine.

2) Obtaining compound 37-1

Compound 37-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 37-k .

Compound 37-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.62 (s, 1H), 8.58 (m, 1H), 8.04 ( s, 1H), 7.89 (d, 1H), 7.81 (m, 1H), 7.70 (d, 1H), 7.52 (m, 3H), 7.40 (m, 1H), 7.13 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.83 (m, 2H), 3.69 (m , 2H), 3.55 (m, 2H), 3.40 (m, 2H), 3.29 (m, 2H), 3.04 (m, 3H), 2.77 (m, 1H), 2 .27 (m, 1H), 2.21 (m, 1H), 2.00 (m, 1H), 1.96 (m, 2H), 1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 159.2, 158.9, 158.1, 154.0, 148.0, 146.2, 145.9, 144.2, 139.0, 135.5, 134.3, 132.8, 130.2, 130.0, 128.3, 127.0, 125.0, 122.8, 118.3, 117.5, 115, 8, 115.2, 114.2, 109.7, 100.4, 76.9, 67.9, 58.5, 46.9, 45.2, 44.3, 34.6, 29.3, 27.1, 24.8.

Example 38 ​ 3-nitro-4-[((tetrahydrofuran-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 38-k

Compound 38-k (1.38 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( R ) -2-tetrahydrofurfurylamine.

2) Obtaining compound 38-1

Compound 38-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 38-k .

Compound 38-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.61 (m, 2H), 8.04 (d, 1H), 7.88 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (d, 1H) , 7.13 (d, 1H), 6.76 (d, 1H), 6.39 (s, 1H), 6.29 (s, 1H), 3.82 (m, 2H), 3.70 ( m, 2H), 3.56 (m, 2H), 3.41 (m, 2H), 3.38 (m, 1H), 3.04 (m, 3H), 2.79 (m, 1H), 2.31 (m, 2H), 2.18 (s, 1H), 1.98 (m, 3H), 1.89 (m, 2H), 1.65 (m, 1H), 1.49 (m , 2H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 158.9, 158.7, 158.1, 154.0, 147.9, 146.9, 145.9, 144.2 , 139.0, 135.5, 134.3, 132.6, 131.7, 130.0, 128.3, 127.0, 125.0, 124.9, 124.4, 122.7, 120 ,3, 118.3, 117.5, 115.8, 114.2, 109.7, 103.6, 100.4, 76.9, 67.9, 58.5, 46.9, 45.1 , 44.3, 34.6, 29.2, 27.1, 25.7, 24.8.

Example 39 4-[(tetrahydropyran-4-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 39-k

Compound 39-k (1.70 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 4-aminotetrahydropyran .

2) Obtaining connection 39-1

Compound 39-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 39-k .

Compound 39-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.58 (m, 1H), 8.26 (m, 1H), 8.04 ( s, 1H), 7.88 (d, 1H), 7.82 (m, 1H), 7.70 (d, 1H), 7.52 (m, 3H), 7.40 (m, 1H), 7.20 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.88 (m, 3H), 3.58 (m , 2H), 3.47 (m, 2H), 3.39 (m, 2H), 3.30 (m, 2H), 3.04 (m, 3H), 2.77 (m, 1H), 2 .27 (m, 1H), 2.21 (m, 1H), 1.96 (m, 2H), 1.90 (m, 2H), 1.65 (m, 2H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 159.2, 158.9, 158.1, 154.0, 146.9, 146.7, 145.8, 144.2, 139.0, 135.5, 134.4, 132.8, 131.7, 130.1, 128.4, 127.1, 125.1, 122.8, 118.3, 117.3, 115, 7, 115.0, 114.3, 109.7, 103.6, 100.4, 66.0, 58.5, 49.0, 45.1, 44.3, 34.6, 29.3, 27.1, 24.8.

Example 40 ​ 3-nitro-4-[(tetrahydropyran-3-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 40-k

Compound 40-k (1.08 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( S ) -3-aminotetrahydropyran hydrochloride.

2) Obtaining compound 40-1

Compound 40-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 40-k .

Compound 40-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.59 (s, 1H), 8.52 (d, 1H), 8.05 (s, 1H), 7.85 (m, 2H), 7.70 (s, 1H), 7.53 (m, 3H), 7.40 (d, 1H) , 7.16 (d, 1H), 6.74 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.85 (m, 3H), 3.59 ( m, 4H), 3.41 (d, 1H), 3.05 (m, 5H), 2.28 (m, 2H), 2.08 (s, 1H), 1.96 (s, 3H), 1.74 (m, 2H), 1.52 (m, 3H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 164.0, 158.9, 158.6, 158.2, 154.0, 146.9, 145.9, 144.2, 135.6 , 134.6, 132.8, 131.8, 130.2, 130.0, 128.4, 127.0, 125.3, 124.9, 124.4, 120.3, 118.3, 117 ,6, 115.7, 115.3, 114.2, 109.7, 103.5, 100.4, 70.1, 67.8, 58.5, 48.1, 45.2, 44.3 , 34.6, 29.3, 29.1, 27.7, 27.1, 24.8, 23.0, 1.6.

Example 41 ​ 3-nitro-4-[(tetrahydropyran-3-yl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 41-k

Compound 41-k (0.95 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( R ) -3-aminotetrahydropyran hydrochloride.

2) Obtaining connection 41-1

Compound 41-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 41-k .

Compound 41-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.59 (m, 1H), 8.53 (m, 1H), 8.05 ( s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.53 (m, 3H), 7.40 (m, 1H), 7.17 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.85 (m, 3H), 3.59 (m , 2H), 3.47 (m, 2H), 3.39 (m, 2H), 3.30 (m, 2H), 3.04 (m, 2H), 2.27 (m, 1H), 2 .21 (m, 1H), 2.08 (m, 2H), 1.96 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 158.6, 158.2, 154.0, 146.9, 145.9, 144.2, 135.6, 134.6, 132.8, 131.8, 130.2, 128.4, 127.0, 125.3, 125.0, 120.3, 118.5, 118.3, 115.7, 114, 2, 109.7, 103.5, 100.4, 70.1, 67.8, 58.5, 48.2, 45.2, 44.3, 34.6, 29.3, 27.7, 24.8, 23.0.

Example 42 ​ 3-nitro-4-[((tetrahydropyran-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 42-k

Compound 42-k (0.36 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( R ) -3-aminomethyltetrahydropyran hydrochloride.

2) Obtaining connection 42-1

Compound 42-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 42-k .

Compound 42-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.68 (s, 1H), 8.57 (m, 2H), 8.05 (d, 1H), 7.88 (s, 1H), 7.81 (d, 1H), 7.70 (d, 1H), 7.53 (d, 3H), 7.40 (d, 1H) , 7.10 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.78 (m, 3H), 3.59 ( m, 1H), 3.32 (m, 7H), 2.92 (m, 3H), 2.28 (m, 2H), 2.08 (s, 1H), 1.95 (m, 4H), 1.63 (m, 1H), 1.49 (m, 3H), 1.31 (m, 2H), 0.98 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.9, 158.6, 158.2, 154.0, 147.8, 146.9, 145.9, 144.2 , 139.0, 135.6, 134.3, 132.9, 132.6, 131.8, 130.2, 130.0, 128.3, 127.0, 124.9, 124.8, 122 ,8, 120.3, 118.3, 117.7, 115.5, 115.4, 114.2, 109.7, 103.6, 100.4, 70.6, 68.0, 58.5 , 45.2, 44.9, 44.3, 35.3, 34.6, 29.3, 29.1, 27.2, 27.1, 25.0, 24.8, 1.6.

Example 43 ​ 3-nitro-4-[((tetrahydropyran-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Obtaining connection 43-k

Compound 43-k (0.39 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced with ( S ) -3-aminomethyltetrahydropyran hydrochloride.

2) Obtaining connection 43-1

Compound 43-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 43-k .

Compound 43-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 1H), 11.68 (s, 1H), 8.58 (m, 2H), 8.05 (s, 1H), 7.87 (s, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.53 (m, 3H), 7.39 (d, 1H) , 7.11 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.28 (s, 1H), 3.78 (m, 4H), 3.34 ( m, 6H), 3.15 (m, 2H), 2.30 (m, 1H), 2.20 (m, 1H), 2.08 (s, 2H), 1.95 (m, 4H), 1.84 (m, 1H), 1.63 (m, 1H), 1.48 (s, 3H), 1.31 (m, 2H), 0.98 (d, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.7, 158.2, 154.2, 147.8, 146.9, 146.0, 135.7, 134.3 , 132.9, 132.6, 131.8, 130.2, 128.3, 127.0, 124.9, 124.8, 122.8, 120.3, 118.5, 118.3, 115 .5, 109.6, 103.4, 100.4, 70.5, 68.0, 44.9, 35.3, 29.3, 29.2, 27.2, 27.1, 25.0 , 1.6.

Example 44 4-[((2-tetrahydropyran-2-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 44-k connection

Compound 44-k (1.18 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-( tetrahydro- 2H -pyran-2-yl)ethylamine hydrochloride.

2) Obtaining connection 44-1

Compound 44-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 44-k .

Compound 44-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.68 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.83 (d, 1H), 7.71 (m, 1H), 7.54 (m, 3H) , 7.40 (m, 1H), 7.03 (m, 1H), 6.76 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.93 ( m, 1H), 3.78 (m, 1H), 3.59 (d, 1H), 3.41 (m, 7H), 3.05 (m, 4H), 2.55 (s, 2H), 2.31 (m, 1H), 2.21 (m, 1H), 1.96 (s, 2H), 1.76 (m, 3H), 1.59 (d, 1H), 1.49 (m , 4H), 1.29 (m, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.9, 158.6, 158.4, 158.2, 154.0, 147.7, 146.9, 145.9 , 144.2, 139.0, 135.5, 134.4, 132.8, 132.6, 131.7, 130.2, 130.0, 128.3, 127.0, 124.9, 124 ,6, 124.4, 122.8, 120.3, 118.3, 117.5, 115.2, 114.2, 109.7, 103.6, 100.4, 76.3, 67.9 , 58.5, 45.2, 44.3, 34.7, 34.6, 31.8, 29.3, 29.1, 27.1, 26.0, 24.8, 23.4.

Example 45 4-[((2-tetrahydropyran-3-yl)ethyl)amino]phenyl}sulfonyl)-2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 45-k

Compound 45-k (1.06 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-( tetrahydro- 2H- pyran-3-yl)ethylamine.

2) Obtaining compound 45-1

Compound 45-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 45-k .

Compound 45-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.71 (s, 2H), 8.56 (m, 2H), 8.05 (s, 1H), 7.84 (t, 2H), 7.68 (d, 1H), 7.52 (m, 3H), 7.37 (d, 1H), 7.05 (d, 1H), 6.72 (d, 1H) , 6.40 (s, 1H), 6.25 (s, 1H), 3.37 (m, 10H), 3.28 (m, 2H), 3.03 (m, 2H), 2.28 ( d, 1H), 2.17 (d, 1H), 1.93 (s, 2H), 1.85 (d, 1H), 1.51 (m, 8H), 1.23 (m, 2H), 0.96(s,6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 163.9, 158.4, 158.3, 154.5, 147.6, 146.9, 146.0, 135.7, 134.4 , 133.0, 132.5, 131.8, 130.0, 128.3, 128.2, 126.8, 124.9, 124.8, 122.8, 120.3, 118.3, 115 ,4, 109.5, 103.2, 100.4, 72.5, 67.9, 51.6, 45.0, 34.9, 33.9, 31.2, 29.7, 29.3 , 29.2, 27.2, 25.7, 25.1.

Example 46 4-[(3-( N -ethylmorpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 46-k

Compound 46-k (2.03 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by N -ethyl -2-propylaminomorpholine hydrochloride.

2) Obtaining connection 46-1

Compound 46-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 46-k .

Example 47 4-[(3-( N -(2-fluoroethyl)morpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Obtaining connection 47-k

Compound 47-k (2.03 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by N- ( 2-fluoroethyl)-2-propylaminomorpholine hydrochloride.

2) Obtaining compound 47-1

Compound 47-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 47-k .

Example 48 4-[(( N -formylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H -pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 48-k connection

Compound 48-k (0.50 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by N -formyl -2-aminomethylmorpholine hydrochloride.

2) Obtaining connection 48-1

Compound 48-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 48-k .

Compound 48-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.65 (s, 1H), 8.57 (m, 1H), 8.04 ( s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.90 (m, 1H), 3.75 (m , 2H), 3.60 (m, 4H), 3.51 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H), 3.06 (m, 2H), 2 .81 (m, 1H), 2.67 (m, 1H), 2.27 (m, 2H), 2.07 (m, 4H), 1.96 (m, 2H), 1.50 (m, 2H), 1.24 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 162.4, 160.1, 157.4, 156.6, 152.4, 146.3, 145.3, 144.2, 142.6, 137.5, 133.9, 132.7, 131.2, 130.2, 130.1, 128.7, 126.8, 123.6, 122.8, 118.8, 116.8, 115, 6, 114.1, 108.1, 98.7, 72.8, 65.4, 56.9, 46.1, 43.6, 42.7, 33.0, 27.5, 23.2.

Example 49 4-[(( N- methylsulfonylmorpholin-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 49-k

Compound 49-k (0.63 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by N -methylsulfonyl -3-aminomethylmorpholine.

2) Obtaining connection 49-1

Compound 49-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 49-k .

Example 50 4-[((4-pivaloylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 50-k connection

Compound 50-k (1.71 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-pivaloylmorpholine.

2) Obtaining connection 50-1

Compound 50-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 50-k .

Compound 50-1 : ^1H NMR (500 MHz, DMSO- d6 ), δ: 11.72 (s, 1H), 11.67 (s, 1H), 8.78 (m, 1H), 8.57 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.83 (t, 1H), 7.70 (d, 1H), 7.52 (d, 3H) , 7.39 (d, 1H), 7.06 (t, 1H), 6.74 (d, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 4.25 ( d, 1H), 4.10 (d, 1H), 3.88 (d, 1H), 3.59 (m, 6H), 3.50 (m, 6H), 3.02 (m, 2H), 2.82 (m, 2H), 2.21 (m, 2H), 1.98 (s, 2H), 1.49 (m, 2H), 1.18 (s, 9H), 0.87 (s , 6H).

¹³ C NMR (125 MHz, DMSO- d 6), δ: 175.8, 163.9, 159.2, 158.9, 158.6, 158.3, 158.2, 154.0, 147.9 , 146.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.8, 130.2, 129.9, 128.3, 128 ,2, 127.0, 125.2, 124.9, 124.5, 122.8, 120.3, 118.4, 117.7, 115.8, 115.4, 114.1, 113.0 , 109.7, 103.5, 100.4, 74.1, 66.5, 58.5, 45.2, 45.0, 44.3, 34.6, 29.3, 29.1.

Example 51 4-[((4-(2-cyanoacetyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 51-k

Compound 51-k (1.61 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-(2-cyanoacetyl)morpholine.

2) Obtaining connection 51-1

Compound 51-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 51-k .

Compound 51-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.05 (s, 1H), 7.87 ( s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.54 (m, 4H), 7.39 (m, 2H), 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.90 (m, 1H), 3.60 (m, 9H), 3.31 (m , 2H), 3.18 (m, 1H), 3.03 (m, 3H), 2.83 (t, 1H), 2.66 (m, 1H), 2.27 (m, 2H), 2 .07 (s, 1H), 1.96 (m, 2H), 1.50 (m, 2H), 1.24 (t, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 163.9, 162.3, 159.0, 154.0, 146.9, 145.8, 139.1, 135.4, 134.3, 132.8, 132.6, 131.7, 130.3, 130.2, 128.2, 127.0, 125.2, 124.9, 124.3, 120.4, 117.1, 109, 7, 103.6, 100.5, 73.7, 66.0, 58.5, 48.2, 45.7, 44.9, 44.5, 34.6, 29.3, 29.1, 27.1, 25.3, 24.8.

Example 52 4-[((4-(2,2,2-trifluoroacetyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy )-benzamide

1) Receiving a 52-k connection

Compound 52-k (1.75 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-(2,2,2-trifluoroacetyl)morpholine.

2) Obtaining connection 52-1

Compound 52-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 52-k .

Compound 52-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.65 (s, 1H), 8.58 (m, 1H), 8.05 ( s, 1H), 7.85 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.17 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.79 (m, 4H), 3.58 (m , 3H), 3.32 (m, 4H), 3.05 (m, 4H), 2.66 (m, 1H), 2.27 (m, 2H), 1.96 (m, 3H), 1 .50 (m, 2H), 1.24 (t, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.6, 154.0, 147.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.8, 130.3, 130.0, 128.3, 127.0, 125.3, 125.0, 120.3, 118.3, 117.5, 115, 8, 109.7, 103.5, 100.4, 73.9, 66.0, 58.5, 51.1, 48.0, 45.5, 44.6, 43.1, 40.3, 34.6, 29.3.

Example 53 4-[((4-(trifluoromethyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 53-k

Compound 53-k (1.64 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-(trifluoromethyl)morpholine.

2) Obtaining connection 53-1

Compound 53-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 53-k .

Example 54 4-[((4-(perfluoroethyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 54-k connection

Compound 54-k (1.93 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-(perfluoroethyl)morpholine.

2) Obtaining connection 54-1

Compound 54-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 54-k .

Example 55 4-[(4-((perfluoroethyl)sulfonyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 55-k

Compound 55-k (2.05 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-((perfluoroethyl)sulfonyl)morpholine.

2) Obtaining connection 55-1

Compound 55-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 55-k .

Example 56 4-[(4-((trifluoromethyl)sulfonyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 56-k

Compound 56-k (1.75 g) was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl -4-((perfluoroethyl)sulfonyl)morpholine.

2) Obtaining connection 56-1

Compound 56-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 56-k .

Compound 56-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.64 (t, 1H), 8.59 (d, 1H), 8.05 ( d, 1H), 7.89 (s, 1H), 7.84 (d, 1H), 7.71 (d, 1H), 7.55 (d, 3H), 7.40 (d, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.29 (s, 1H), 3.80 (d, 2H), 3.64 (m , 5H), 3.52 (m, 1H), 3.38 (m, 3H), 2.91 (s, 3H), 2.86 (m, 2H), 2.72 (m, 2H), 2 .27 (m, 1H), 2.21 (m, 1H), 1.96 (s, 2H), 1.50 (m, 2H), 1.24 (m, 1H), 0.96 (s, 6H).

Example 57 4-[((4-(ethylsulfonyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 57-k

Compound 57-k was prepared based on the preparation method for compound 25-k in step 1) of Example 25, wherein 4-aminomethyl-1-(tetrahydro- 2H- pyran)piperidine was replaced by 2-aminomethyl-4-(ethylsulfonyl) morpholine.

2) Obtaining connection 57-1

Compound 57-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 57-k .

Compound 57-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.64 (s, 1H), 8.58 (m, 1H), 8.05 ( s, 1H), 7.89 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.95 (m, 1H), 3.75 (m , 2H), 3.52 (m, 6H), 3.42 (m, 2H), 3.39 (m, 2H), 3.12 (m, 3H), 2.96 (m, 2H), 2 .77 (m, 1H), 2.28 (m, 2H), 2.08 (m, 1H), 1.96 (m, 2H), 1.50 (m, 2H), 1.24 (t, 4H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 154.0, 147.9, 145.9, 144.2, 139.0, 135.5, 134.3, 132.8, 132.6, 131.7, 130.3, 130.0, 128.3, 127.0, 125.2, 124.9, 120.3, 118.5, 117.3, 115, 8, 109.7, 103.6, 100.5, 73.9, 66.3, 58.5, 47.7, 45.3, 44.9, 42.9, 34.6, 29.3, 27.4, 24.8.

Example 58 4-[((1-(2-methoxyacetyl)piperidin-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 58-k

3-Nitro-4-fluorobenzenesulfonamide (1.03 g), 3-aminomethyl-1-(2-methoxyacetyl)piperidine (1.04 g) and N , N -diisopropylethylamine (1.51 g) were dissolved in acetonitrile (10 ml ), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 58-k (1.51 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Obtaining connection 58-1

Compound 58-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 58-k .

Compound 58-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 1H), 11.68 (s, 1H), 8.64 (m, 1H), 8.58 ( d, 1H), 8.05 (d, 1H), 7.88 (s, 1H), 7.83 (m, 1H), 7.71 (d, 1H), 7.55 (m, 3H), 7.40 (d, 1H), 7.16 (d, 1H), 6.76 (m, 1H), 6.40 (m, 1H), 6.30 (d, 1H), 3.93 (m , 2H), 3.76 (m, 8H), 3.39 (m, 4H), 3.05 (m, 4H), 2.79 (m, 2H), 2.27 (m, 2H), 2 .09 (s, 1H), 1.96 (s, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.37 (m, 2H), 1.24 (s, 1H), 0.97 (s, 6H). ESI-MS: mass/charge = 1007.4 [M+H] ⁺ .

Example 59 4-[((1-(methylglycyl)piperidin-4-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 59-k

3-Nitro-4-fluorobenzenesulfonamide (0.91 g), 4-aminomethyl-1-(methylglycyl)piperidine (0.99 g) and N , N -diisopropylethylamine (1.34 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85° C. and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 59-k (1.62 g). ESI-MS: mass/charge = 400.1 [M+H] ⁺ .

2) Obtaining connection 59-1

Compound 59-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 59-k .

ESI-MS: mass/charge = 1020.4 [M+H] ⁺ .

Compound 59-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.74 (s, 2H), 8.67 (s, 1H), 8.59 (m, 1H), 8.05 ( s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.69 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.61 (m, 4H), 3.38 (m , 5H), 3.02 (m, 4H), 2.81 (m, 7H), 2.67 (m, 2H), 2.28 (m, 2H), 2.02 (m, 3H), 1 .78 (m, 2H), 1.49 (m, 2H), 1.20 (m, 4H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 158.9, 154.0, 147.9, 145.9, 144.2, 139.0, 135.6, 134.3, 132.8, 132.6, 131.8, 130.2, 130.1, 128.3, 127.0, 124.9, 124.5, 120.3, 118.4, 117.6, 115.6, 114, 2, 109.7, 103.5, 100.4, 58.5, 47.7, 45.3, 44.9, 41.7, 34.6, 29.4, 27.1, 24.8.

Example 60 4-[((1-(methylglycyl)piperidin-3-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 60-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.90 g), 3-aminomethyl-1-(methylglycyl)piperidine (0.98 g) and N , N -diisopropylethylamine (1.32 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85° C. and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 60-k (1.58 g). ESI-MS: mass/charge = 400.0 [M+H] ⁺ .

2) Obtaining connection 60-1

Compound 60-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 60-k .

Compound 60-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.63 (m, 1H), 8.59 (d, 1H), 8.04 ( d, 1H), 7.88 (s, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.40 (d, 1H), 7.17 (d, 1H), 6.76 (m, 1H), 6.40 (m, 1H), 6.29 (d, 1H), 3.89 (m, 2H), 3.66 (m , 7H), 3.33 (m, 4H), 3.04 (m, 4H), 2.89 (s, 6H), 2.27 (m, 3H), 2.09 (s, 1H), 1 .96 (s, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.24 (s, 2H), 0.97 (s, 6H). ESI-MS: mass/charge = 1020.4 [M+H] ⁺ .

Example 61 ​ 3-nitro-4-[((4-acetylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 61-k

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( S )-2-aminomethyl-4-acetylmorpholine (0.59 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile (10 ml) , and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 61-k (0.89 g). ESI-MS: mass/charge = 359.0 [M+H] ⁺ .

2) Obtaining connection 61-1

Compound 61-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 61-k .

Compound 61-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.64 (s, 1H), 8.58 (m, 1H), 8.05 ( s, 1H), 7.87 (d, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.91 (m, 1H), 3.67 (m , 2H), 3.60 (m, 4H), 3.47 (m, 2H), 3.42 (m, 2H), 3.30 (m, 2H), 3.17 (m, 1H), 3 .02 (m, 2H), 2.72 (m, 1H), 2.55 (m, 1H), 2.27 (m, 1H), 2.21 (m, 2H), 2.01 (m, 3H), 1.96 (m, 2H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 169.1, 164.0, 158.9, 158.6, 154.0, 147.9, 146.9, 145.9, 144.2, 135.5, 132.8, 131.7, 130.2, 128.3, 128.2, 125.2, 120.3, 118.3, 117.4, 115.8, 114.2, 109, 7, 103.6, 100.4, 73.8, 66.4, 58.5, 48.5, 45.2, 44.3, 41.2, 34.6, 29.3, 27.1, 24.8, 21.6. ESI-MS: mass/charge = 979.4 [M+H] ⁺ .

Example 62 ​ 3-nitro-4-[((4-isobutyrylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting a 62-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( S )-2-aminomethyl-4-isobutyrylmorpholine (0.69 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile (10 ml) , and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 62-k (0.87 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Obtaining connection 62-1

Compound 62-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 62-k .

Compound 62-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.64 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.92 (m , 1H), 3.80 (m, 1H), 3.60 (m, 4H), 3.47 (m, 2H), 3.39 (m, 2H), 3.30 (m, 2H), 3 .19 (m, 1H), 2.86 (m, 5H), 2.72 (m, 1H), 2.57 (m, 1H), 2.27 (m, 2H), 1.96 (m, 2H), 1.50 (m, 2H), 1.00 (s, 6H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 158.9, 154.0, 147.9, 145.6, 144.2, 139.0, 135.5, 134.3, 132.8, 132.6, 131.7, 130.2, 130.0, 128.3, 127.0, 125.2, 125.0, 120.3, 118.4, 117.3, 115.8, 109, 7, 103.6, 100.4, 74.0, 66.6, 58.5, 45.3, 44.3, 42.9, 34.6, 29.3, 27.1, 24.8, 20.0. ESI-MS: mass/charge = 1007.4 [M+H] ⁺ .

Example 63 ​ 3-nitro-4-[(((4-(methylsulfonyl)morpholine)-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy )-benzamide

1) Receiving connection 63-k

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( S )-2-aminomethyl-4-(methylsulfonyl)morpholine (0.72 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile ( 10 ml), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 63-k (0.68 g) . ESI-MS: mass/charge = 395.0 [M+H] ⁺ .

2) Obtaining connection 63-1

Compound 63-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 63-k .

Compound 63-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 1H), 11.69 (s, 1H), 8.65 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.89 (d, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.98 (m , 1H), 3.79 (m, 3H), 3.66 (m, 2H), 3.58 (m, 3H), 3.49 (m, 1H), 3.44 (m, 1H), 3 .35 (m, 2H), 2.92 (m, 4H), 2.85 (m, 2H), 2.69 (m, 2H), 2.27 (m, 1H), 2.21 (m, 1H), 1.96 (m, 3H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 158.6, 154.0, 147.8, 146.9, 145.9, 144.2, 135.6, 132.8, 131.7, 130.3, 128.3, 128.2, 125.2, 120.3, 118.3, 115.8, 115.1, 114.1, 109.7, 103, 6, 100.4, 73.7, 66.0, 58.5, 47.9, 45.4, 44.3, 34.6, 29.3, 27.2, 24.8. ESI-MS: mass/charge = 1015.3 [M+H] ⁺ .

Example 64 ​ 3-nitro-4-[((4-(2-methoxyacetyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy )-benzamide

1) Getting a 64-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( S )-2-aminomethyl-4-(2-methoxyacetyl)morpholine (0.70 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 64-k (0.68 G). ESI-MS: mass/charge = 389.0 [M+H] ⁺ .

2) Receiving connection 64-1

Compound 64-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 64-k .

Compound 64-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.76 (s, 1H), 11.73 (s, 1H), 8.65 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.85 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.40 (m, 1H), 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.67 (m , 5H), 3.36 (m, 7H), 2.99 (m, 5H), 2.78 (m, 1H), 2.28 (m, 3H), 1.96 (m, 3H), 1 .50 (m, 3H), 0.97 (s, 9H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.9, 159.3, 158.9, 158.7, 158.4, 153.0, 147.9, 145.9, 144.2, 139.1, 135.5, 134.3, 132.8, 131.7, 130.2, 128.4, 127.1, 125.0, 124.9, 124.4, 122.8, 120, 5, 119.4, 117.0, 115.1, 114.8, 112.4, 109.6, 100.5, 76.7, 66.6, 58.5, 45.2, 44.7, 40.9, 34.6, 29.3, 29.1, 27.2, 24.9. ESI-MS: mass/charge = 1009.4 [M+H] ⁺ .

Example 65 ​ 3-nitro-4-[((4-acetylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Getting connection 65-k

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( R )-2-aminomethyl-4-acetylmorpholine (0.59 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile (10 ml) , and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 65-k (0.89 g). ESI-MS: mass/charge = 359.0 [M+H] ⁺ .

2) Obtaining compound 65-1

Compound 65-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 65-k .

Compound 65-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 1H), 11.69 (s, 1H), 8.64 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.39 (m, 1H), 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.89 (m , 2H), 3.67 (m, 2H), 3.58 (m, 3H), 3.49 (m, 3H), 3.30 (m, 2H), 3.17 (m, 2H), 3 .02 (m, 2H), 2.72 (m, 1H), 2.56 (m, 1H), 2.27 (m, 2H), 2.21 (m, 1H), 2.02 (m, 3H), 1.96 (m, 2H), 1.50 (m, 2H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 169.1, 164.0, 158.9, 158.6, 158.2, 154.0, 147.8, 146.9, 145.8, 144.2, 139.0, 135.5, 132.8, 131.7, 130.2, 128.3, 128.2, 124.4, 120.3, 118.3, 115.8, 114, 9, 114.1, 109.7, 103.6, 100.4, 73.8, 66.4, 58.5, 48.5, 45.4, 44.3, 41.2, 34.6, 29.3, 29.1, 27.1, 24.8, 21.6. ESI-MS: mass/charge = 979.4 [M+H] ⁺ .

Example 66 ​ 3-nitro-4-[((4-isobutyrylmorpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 66-k connection

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( R )-2-aminomethyl-4-acetylmorpholine (0.69 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile (10 ml) , and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 66-k (0.87 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Obtaining connection 66-1

Compound 66-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 66-k .

Compound 66-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.64 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.56 (m, 3H), 7.40 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.91 (m , 2H), 3.81 (m, 1H), 3.60 (m, 4H), 3.45 (m, 2H), 3.39 (m, 2H), 3.30 (m, 2H), 3 .18 (m, 1H), 3.03 (m, 2H), 2.87 (m, 2H), 2.72 (m, 1H), 2.57 (m, 1H), 2.27 (m, 1H), 2.21 (m, 1H), 1.96 (m, 2H), 1.50 (m, 2H), 1.00 (s, 6H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 175.2, 164.0, 158.2, 154.0, 147.8, 146.9, 145.9, 144.2, 139.0, 135.5, 134.3, 132.8, 132.6, 131.7, 130.2, 128.3, 125.2, 124.4, 120.3, 118.3, 115.8, 114, 1, 109.7, 103.6, 100.4, 74.0, 66.6, 58.5, 56.5, 45.3, 44.3, 41.5, 34.6, 29.4, 29.3, 27.1, 24.3, 20.0. ESI-MS: mass/charge = 1007.4 [M+H] ⁺ .

Example 67 ​ 3-nitro-4-[(((4-(methylsulfonyl)morpholine)-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy )-benzamide

1) Receiving connection 67-k

3-Nitro-4-fluorobenzenesulfonamide (0.68 g), ( R )-2-aminomethyl-4-(methylsulfonyl)morpholine (0.72 g) and N , N -diisopropylethylamine (2.59 g) were dissolved in acetonitrile ( 10 ml), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 67-k (0.68 g) . ESI-MS: mass/charge = 395.0 [M+H] ⁺ .

2) Obtaining compound 67-1

Compound 67-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 67-k .

Compound 67-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 1H), 11.69 (s, 1H), 8.64 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.85 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.16 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.98 (m , 2H), 3.79 (m, 2H), 3.66 (m, 2H), 3.56 (m, 3H), 3.49 (m, 2H), 3.38 (m, 3H), 2 .92 (m, 3H), 2.88 (m, 2H), 2.70 (m, 2H), 2.27 (m, 1H), 2.21 (m, 1H), 1.96 (m, 2H), 1.50 (m, 2H), 1.24 (t, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 159.3, 159.0, 158.7, 158.2, 154.0, 147.8, 146.9, 145.8, 144.2, 139.0, 135.5, 132.8, 131.7, 130.2, 128.3, 128.2, 124.3, 120.4, 118.4, 115.8, 114.8, 114, 1, 109.7, 103.6, 100.5, 73.7, 66.0, 58.5, 47.8, 45.4, 44.3, 34.6, 29.3, 29.1, 27.1, 24.8. ESI-MS: mass/charge = 1015.3 [M+H] ⁺ .

Example 68 4-[(3-(4-acetylmorpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving a 68-k connection

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminopropyl-3-(4-acetyl)morpholine (1.22 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml ), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 68-k (1.67 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Obtaining connection 68-1

Compound 68-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 68-k .

Compound 68-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.74 (s, 2H), 8.61 (s, 1H), 8.58 (m, 1H), 8.05 ( s, 1H), 7.88 (d, 1H), 7.85 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.07 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.83 (m, 1H), 3.66 (m , 2H), 3.59 (m, 1H), 3.40 (m, 4H), 3.32 (m, 2H), 3.10 (m, 2H), 3.05 (m, 2H), 2 .83 (m, 1H), 2.63 (m, 1H), 2.27 (m, 2H), 2.21 (m, 1H), 2.00 (m, 3H), 1.71 (m, 3H), 1.96 (m, 2H), 1.50 (m, 4H), 1.24 (t, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 168.8, 164.0, 159.3, 159.0, 158.7, 154.0, 147.7, 145.8, 144.2, 139.0, 135.5, 132.8, 131.7, 130.1, 128.3, 124.4, 120.4, 117.3, 115.4, 114.9, 109.7, 100, 5, 75.1, 66.3, 58.5, 46.1, 45.1, 44.3, 42.8, 41.3, 34.6, 29.3, 29.1, 27.1, 24.8, 21.6. ESI-MS: mass/charge = 1007.4 [M+H] ⁺ .

Example 69 4-[(3-(4-isobutyrylmorpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 69-k

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminopropyl-3-(4-isobutyryl)morpholine (1.40 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml ), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 69-k (1.69 g). ESI-MS: mass/charge = 415.1 [M+H] ⁺ .

2) Obtaining connection 69-1

Compound 69-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 69-k .

Compound 69-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.73 (s, 1H), 11.67 (s, 1H), 8.60 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.07 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.83 (m , 3H), 3.58 (m, 2H), 3.40 (m, 5H), 3.32 (m, 3H), 3.15 (m, 1H), 3.05 (m, 3H), 2 .85 (m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.27 (m, 1H), 2.21 (m, 1H), 1.96 (m, 2H), 1.70 (m, 2H), 1.50 (m, 4H), 1.01 (s, 6H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 174.9, 164.0, 159.0, 158.7, 158.2, 154.0, 147.7, 146.9, 145.8, 144.2, 139.0, 135.5, 132.8, 131.7, 130.0, 128.3, 124.9, 124.4, 120.3, 118.4, 115.4, 109, 7, 100.4, 75.2, 66.6, 58.5, 46.3, 45.2, 44.3, 42.9, 34.6, 29.4, 29.1, 27.1, 24.8, 24.3, 20.6. ESI-MS: mass/charge = 1035.3 [M+H] ⁺ .

Example 70 4-[(3-(4-(2-methoxyacetyl)morpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Getting connection 70-k

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminopropyl-3-(4-(2-methoxyacetyl))morpholine (1.42 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 70-k (1.71 G). ESI-MS: mass/charge = 417.1 [M+H] ⁺ .

2) Obtaining connection 70-1

Compound 70-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 70-k .

Compound 70-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.73 (s, 1H), 11.69 (s, 1H), 8.64 (m, 1H), 8.58 ( d, 1H), 8.05 (d, 1H), 7.89 (s, 1H), 7.83 (m, 1H), 7.71 (d, 1H), 7.54 (m, 3H), 7.40 (d, 1H), 7.18 (d, 1H), 6.76 (m, 1H), 6.39 (m, 1H), 6.30 (d, 1H), 4.26 (m , 2H), 3.64 (m, 6H), 3.54 (m, 2H), 3.49 (m, 2H), 3.39 (m, 4H), 3.05 (m, 4H), 2 .79 (m, 2H), 2.27 (m, 1H), 2.21 (m, 1H), 2.09 (s, 1H), 1.96 (s, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.37 (m, 2H), 1.24 (s, 1H), 0.97 (s, 6H).

ESI-MS: mass/charge = 1037.2 [M+H] ⁺ .

Example 71 4-[(3-(4-(2-methylsulfonyl)morpholin-2-yl)propyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Receiving connection 71-k

3-Nitro-4-fluorobenzenesulfonamide (1.13 g), 2-aminopropyl-3-(4-(2-methylsulfonyl))morpholine (1.36 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 71-k (1.51 G). ESI-MS: mass/charge = 423.0 [M+H] ⁺ .

2) Obtaining connection 71-1

Compound 71-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 71-k .

Compound 71-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.62 (s, 1H), 8.57 (m, 1H), 8.05 ( s, 1H), 7.89 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.07 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 3.92 (m, 1H), 3.78 (m , 2H), 3.53 (m, 4H), 3.35 (m, 7H), 2.89 (m, 7H), 2.55 (m, 1H), 2.21 (m, 2H), 1 .96 (m, 2H), 1.70 (m, 2H), 1.52 (m, 4H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 154.0, 147.7, 145.9, 144.2, 136.0, 134.3, 132.9, 132.6, 131.8, 130.2, 130.0, 128.4, 127.0, 125.0, 124.7, 122.8, 120.3, 118.3, 115.4, 114, 2, 109.7, 103.6, 100.4, 74.7, 65.9, 58.5, 50.1, 45.1, 44.3, 42.8, 34.6, 29.3, 27.2, 24.8. ESI-MS: mass/charge = 1043.2 [M+H] ⁺ .

Example 72 4-[(2-(4-(2-methoxyacetyl)morpholin-2-yl)ethyl)amino]phenyl}sulfonyl)-2-(1 H -pyrrolo[2,3- b ]pyridin-5-yloxy)- benzamide

1) Receiving a 72-k connection

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminoethyl-2-(4-(2-methoxyacetyl))morpholine (1.33 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml) and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 72-k (1.56 G). ESI-MS: mass/charge = 403.0 [M+H] ⁺ .

2) Obtaining connection 72-1

Compound 72-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 72-k .

Compound 72-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.64 (m, 1H), 8.58 (d, 1H), 8.04 ( d, 1H), 7.88 (s, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.39 (d, 1H), 7.16 (d, 1H), 6.76 (m, 1H), 6.39 (m, 1H), 6.29 (d, 1H), 3.89 (m, 2H), 3.70 (m , 6H), 3.55 (m, 2H), 3.51 (m, 2H), 3.40 (m, 4H), 3.04 (m, 4H), 2.79 (m, 2H), 2 .28 (m, 1H), 2.21 (m, 1H), 2.11 (s, 1H), 1.96 (s, 2H), 1.62 (m, 2H), 1.35 (m, 2H), 1.24 (s, 1H), 0.97 (s, 6H). ESI-MS: mass/charge = 1023.3 [M+H] ⁺ .

Example 73 4-[((1-(2-methoxyacetyl)piperidin-4-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide

1) Receiving connection 73-k

3-Nitro-4-fluorobenzenesulfonamide (1.56 g), 4-aminomethyl-1-(2-methoxyacetyl)piperidine (1.59 g) and N , N -diisopropylethylamine (2.30 g) were dissolved in acetonitrile (10 ml ), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 73-k (2.58 g). ESI-MS: mass/charge = 387.0 [M+H] ⁺ .

2) Obtaining connection 73-1

Compound 73-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 73-k .

Compound 73-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.74 (s, 1H), 11.69 (s, 1H), 8.64 (s, 1H), 8.58 ( m, 1H), 8.05 (s, 1H), 7.89 (d, 1H), 7.82 (m, 1H), 7.70 (d, 1H), 7.54 (m, 3H), 7.39 (m, 1H), 7.14 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 4.08 (m , 2H), 3.76 (m, 3H), 3.58 (m, 1H), 3.31 (m, 6H), 2.93 (m, 4H), 2.54 (m, 2H), 2 .27 (m, 2H), 1.96 (m, 4H), 1.74 (m, 2H), 1.50 (m, 2H), 1.24 (m, 4H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 164.0, 158.9, 154.0, 147.9, 146.9, 145.8, 144.2, 139.0, 135.5, 134.3, 132.8, 132.6, 131.7, 130.2, 130.1, 128.3, 127.0, 124.8, 120.4, 118.5, 117.2, 115, 8, 114.9, 109.7, 103.6, 100.5, 71.2, 58.7, 48.0, 45.2, 44.4, 41.3, 35.3, 30.3, 29.6, 27.4. ESI-MS: mass/charge = 1007.3 [M+H] ⁺ .

Example 74 4-[((4-(ethoxyformyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide (compound 74 -1 )

1) Receiving a 74-k connection

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminomethyl-4-(ethoxyformyl)morpholine (1.23 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85° C. and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 74-k (1.80 g). ESI-MS: mass/charge = 387.1 [MH] ^- .

2) Receiving connection 74-1

Compound 74-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 74-k .

Compound 74-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.70 (s, 2H), 8.64 (s, 1H), 8.57 (m, 1H), 8.04 ( s, 1H), 7.88 (d, 1H), 7.83 (m, 1H), 7.70 (d, 1H), 7.53 (m, 3H), 7.39 (m, 1H), 7.15 (d, 1H), 6.75 (d, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 4.08 (m, 2H), 3.89 (m , 3H), 3.65 (m, 2H), 3.51 (m, 7H), 2.96 (m, 3H), 2.79 (m, 2H), 2.21 (m, 2H), 2 .02 (m, 1H), 1.95 (m, 2H), 1.50 (m, 2H), 1.23 (m, 1H), 1.18 (m, 3H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 162.4, 156.0, 153.6, 152.5, 146.3, 145.3, 144.3, 142.8, 134.0, 132.7, 131.3, 131.0, 130.2, 128.6, 126.7, 126.6, 125.4, 123.6, 123.3, 118.7, 116.7, 114, 2, 108.1, 101.9, 98.8, 72.1, 64.5, 59.8, 56.9, 43.5, 42.8, 33.1, 27.5, 25.6, 23.3. ESI-MS: mass/charge = 1009.3 [M+H] ⁺ .

Example 75 4-[((4-(methoxyformyl)morpholin-2-yl)methyl)amino]phenyl}sulfonyl)-2-( 1H- pyrrolo[2,3- b ]pyridin-5-yloxy)-benzamide (compound 75 -1 )

1) Getting connection 75-k

3-Nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminomethyl-4-(methoxyformyl)morpholine (1.14 g) and N , N -diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 ml), and the solution was heated to 85°C and allowed to react for 6 hours. The reaction solution was cooled at room temperature, left overnight, concentrated and dried to give compound 75-k (1.73 g). ESI-MS: mass/charge = 373.1 [MH] ⁺ .

2) Obtaining compound 75-1

Compound 75-1 was prepared based on the preparation method for compound 7-1 in step 6) of Example 7, with compound 7-k replaced by compound 75-k .

Compound 75-1 : ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 1H), 11.68 (s, 1H), 8.64 (m, 1H), 8.58 ( d, 1H), 8.05 (d, 1H), 7.88 (s, 1H), 7.83 (m, 1H), 7.71 (d, 1H), 7.55 (m, 3H), 7.40 (d, 1H), 7.16 (d, 1H), 6.76 (m, 1H), 6.40 (m, 1H), 6.30 (d, 1H), 3.93 (m , 2H), 3.76 (m, 8H), 3.49 (m, 4H), 3.02 (m, 4H), 2.79 (m, 2H), 2.28 (m, 2H), 2 .08 (s, 1H), 1.96 (s, 2H), 1.51 (m, 2H), 1.24 (s, 1H), 0.97 (s, 6H).

¹³ C NMR (125 MHz, DMSO-d6), δ: 162.4, 157.6, 157.3, 157.0, 156.6, 154.0, 152.4, 146.3, 145.3, 144.3, 142.6, 137.4, 133.9, 132.7, 131.2, 131.0, 130.1, 128.6, 126.7, 126.6, 123.6, 123, 4, 122.8, 118.7, 116.7, 115.9, 114.2, 113.6, 112.6, 108.1, 102.0, 98.8, 72.1, 64.5, 56.9, 51.3, 43.6, 43.4, 42.7, 33.0, 27.7, 27.5, 25.5, 23.2.

ESI-MS: mass/charge = 995.3 [M+H] ⁺ .

Example 76 - Example 82

The following compounds were prepared based on the preparation procedure of Example 7:

Number Structure Characteristic 76-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.62 (s, 1H), 11.58 (s, 1H), 8.45 (s, 1H), 8.37 (t, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.55 (d , 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 6.64 (d, 1H), 6.33 (s, 1H), 6 .23 (s, 1H), 3.31 (m, 4H), 3.01 (m, 6H), 2.87 (s, 1H), 2.81 (t, 1H), 2.66 (m, 3H), 2.54 (s, 1H), 1.90 (d, 2H), 1.81 (d, 2H), 1.59 (m, 2H), 1.43 (m, 2H), 1. 27 (m, 8H), 0.97 (s, 6H). ESI-MS: mass/charge = 1027.3 [M+H] ⁺ . 77-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.61 (s, 1H), 11.57 (s, 1H), 8.45 (s, 1H), 8.37 (t, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.54 (d , 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.86 (d, 1H), 6.65 (d, 1H), 6.32 (s, 1H), 6 .23 (s, 1H), 3.31 (m, 3H), 3.01 (m, 6H), 2.81 (t, 1H), 2.66 (m, 3H), 2.54 (s, 1H), 2.10 (s, 3H), 1.90 (d, 2H), 1.81 (d, 2H), 1.59 (m, 2H), 1.43 (m, 2H), 1, 27 (m, 7H), 0.97 (s, 6H). ESI-MS: mass/charge = 991.4 [M+H] ⁺ . 78-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.62 (s, 1H), 11.56 (s, 1H), 8.44 (s, 1H), 8.36 (t, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.71 (d, 1H), 7.67 (d, 1H), 7.55 (d , 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 6.66 (d, 1H), 6.33 (s, 1H), 6 .23 (s, 1H), 3.54 (m, 4H), 3.30 (m, 6H), 2.69 (t, 1H), 2.66 (m, 3H), 2.54 (s, 1H), 1.96 (m, 1H), 1.84 (d, 2H), 1.74 (d, 2H), 1.59 (m, 2H), 1.45 (m, 6H), 1, 27 (m, 2H), 1.10 (s, 6H), 0.97 (s, 6H). ESI-MS: mass/charge = 1019.4 [M+H] ⁺ . 79-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.61 (s, 1H), 11.57 (s, 1H), 8.45 (s, 1H), 8.37 (t, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.71 (d, 1H), 7.66 (d, 1H), 7.54 (d , 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.86 (d, 1H), 6.65 (d, 1H), 6.32 (s, 1H), 6 .23 (s, 1H), 3.40 (m, 2H), 2.86 (m, 4H), 2.81 (t, 1H), 2.66 (m, 4H), 2.54 (s, 1H), 2.10 (s, 3H), 1.90 (d, 2H), 1.81 (d, 2H), 1.59 (m, 3H), 1.43 (m, 3H), 1, 27 (m, 5H), 0.97 (s, 6H). ESI-MS: mass/charge = 977.3 [M+H] ⁺ . 80-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.63 (s, 1H), 11.57 (s, 1H), 8.44 (s, 1H), 8.36 (t, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.67 (d, 1H), 7.55 (d , 1H), 7.36 (s, 1H), 7.33 (d, 1H), 6.87 (d, 1H), 6.66 (d, 1H), 6.33 (s, 1H), 6 .23 (s, 1H), 3.54 (m, 4H), 3.30 (m, 6H), 2.69 (t, 1H), 2.66 (m, 3H), 2.54 (s, 1H), 1.96 (m, 1H), 1.84 (d, 2H), 1.74 (d, 2H), 1.59 (m, 2H), 1.45 (m, 4H), 1, 27 (m, 2H), 1.10 (s, 6H), 0.97 (s, 6H). ESI-MS: mass/charge = 1005.4 [M+H] ⁺ . 81-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.72 (s, 2H), 8.64 (m, 1H), 8.58 (d, 1H), 8.04 (d, 1H), 7.88 (s, 1H), 7.84 (m, 1H), 7.70 (d, 1H), 7.55 (m, 3H), 7.39 (d, 1H), 7.16 (d , 1H), 6.76 (m, 1H), 6.39 (m, 1H), 6.29 (d, 1H), 3.89 (m, 2H), 3.70 (m, 4H), 3 .55 (m, 3H), 3.51 (m, 2H), 3.40 (m, 4H), 3.04 (m, 4H), 2.79 (m, 2H), 2.28 (m, 1H), 2.21 (m, 1H), 1.96 (s, 2H), 1.62 (m, 2H), 1.35 (m, 2H), 1.15 (s, 3H), 0. 97 (s, 6H). ESI-MS: mass/charge = 979.4 [M+H] ⁺ . 82-1 ^1H NMR (500 MHz, DMSO-d6), δ: 11.71 (s, 2H), 8.65 (m, 1H), 8.59 (d, 1H), 8.04 (d, 1H), 7.88 (s, 1H), 7.85 (m, 1H), 7.71 (d, 1H), 7.56 (m, 3H), 7.40 (d, 1H), 7.16 (d , 1H), 6.76 (m, 1H), 6.40 (m, 1H), 6.30 (d, 1H), 3.89 (m, 2H), 3.70 (m, 4H), 3 .57 (m, 3H), 3.51 (m, 2H), 3.38 (m, 4H), 3.04 (m, 2H), 2.32 (s, 3H), 2.27 (m, 1H), 2.20 (m, 1H), 1.96 (s, 2H), 1.62 (m, 2H), 1.35 (m, 2H), 0.97 (s, 6H). ESI-MS: mass/charge = 979.3 [M+H] ⁺ .

Experimental Example 1 Protein Binding Inhibitory Activity in vitro

1.1. Screening for BCL-2/BAK Binding Inhibitory Activity

500 nM Tag1-BCL-2 protein stock solution and 20 µM Tag2-BAK protein stock solution were diluted to 5 nM and 120 nM concentrations, respectively, using the kit dilution buffer (Model: BCL-2/BAK Binding Assay Kits (BH3) from Cisbio). 5 μl of Tag1-BCL-2 protein diluent was added to each well, then the different compounds dissolved with DMSO were added to the wells via a nanoliter pipette, providing final compound concentrations that ranged from 200 nM to 0.0488 nM (4-4 total). multiple gradient for 7 concentrations). Blank control wells (no enzyme) and negative control wells (enzyme plus DMSO vehicle) were prepared in duplicate. Finally, 5 μL of Tag2-BAK protein diluent was added to each well, and the mixture was thoroughly mixed by centrifugation and incubated at 25°C for 15 min. Both 100× anti-Tag1-Eu ³⁺ and 100× anti-Tag2-XL665 were diluted to a working concentration of 1× using detection buffer from the kit. Anti-Tag1-Eu ³⁺ antibody and anti-Tag2-XL665 antibody were mixed thoroughly in a 1:1 ratio, and the mixture was added to the wells in an amount of 5 μl/well and incubated at 25°C for 2 hours or more. The plate was read using a PE Envision multifunctional microplate reader (excitation wave: 620 nm, emission wave: 665 nm) and the IC ₅₀ value was calculated (shown in Table 1) using a four-parameter fit.

1.2. Screening for BCL-XL/BAK Binding Inhibitory Activity

300 nM Tag1-BCL-XL protein stock solution and 10 µM Tag2-BAK protein stock solution were diluted to 2 nM and 80 nM concentrations, respectively, using the kit dilution buffer (Model: BCL-XL/BAK Binding Assay Kits (BH3) from Cisbio). 5 μl of Tag1-BCL-XL protein diluent was added to each well, then the different compounds dissolved with DMSO were added to the wells via a nanoliter pipette, providing a final compound concentration that ranged from 2000 nM to 0.488 nM (a total of 4-fold gradient for 7 concentrations). Blank control wells (no enzyme) and negative control wells (enzyme plus DMSO vehicle) were prepared in duplicate. Finally, 5 μL of Tag2-BAK protein diluent was added to each well, and the mixture was thoroughly mixed by centrifugation and incubated at 25°C for 15 min. Both 100× anti-Tag1-Eu ³⁺ and 100× anti-Tag2-XL665 were diluted to a working concentration of 1× using detection buffer from the kit. Anti-Tag1-Eu ³⁺ antibody and anti-Tag2-XL665 antibody were mixed thoroughly in a 1:1 ratio, and the mixture was added to the wells in an amount of 5 μl/well and incubated at 25°C for 2 hours or more. The plate was read using a PE Envision multifunctional microplate reader (excitation wave: 620 nm, emission wave: 665 nm) and the IC ₅₀ value was calculated (shown in Table 1) using a four-parameter fit.

Table 1. Inhibitory activity of compounds regarding BCL-2/BAK and BCL-XL/BAK binding Compound BCL-2/BAK BCL-XL/BAK Compound BCL-2/BAK BCL-XL/BAK IC ₅₀ (nM) IC ₅₀ (nM) 1-1 2.7 133 37-1 1.59 142.1 3-1 0.86 > 2000 38-1 2.81 187 4-1 0.80 > 2000 42-1 2.81 220.3 6-1 5.7 1972 43-1 1.8 121 7-1 3.5 289 45-1 2.18 242.7 8-1 2.8 155 48-1 1.4 118 9-1 1.8 50-1 2.59 211.1 10-1 2.8 194 51-1 1.9 11-1 1.6 140 52-1 3.9 175 12-1 1.4 113 56-1 3.55 381 13-1 3.6 387 57-1 3.4 268 14-1 5.1 338 58-1 2.35 145.2 15-1 3.83 729 59-1 1.1 16-1 3.09 653 60-1 1.1 17-1 2.0 61-1 1.52 18-1 2.7 62-1 2.35 144.9 19-1 2.5 63-1 2.3 217 20-1 2.1 65-1 1.5 134 21-1 2.40 66-1 2.6 273 23-1 5.10 302 67-1 0.6 199 24-1 5.11 556 71-1 0.76 109 28-1 3.7 266 72-1 2.32 121.6 29-1 2.1 73-1 1.6 204 31-1 4.6 485 74-1 1.66 252.3 35-1 1.61 232.5 75-1 3.5 322 36-1 1.78 157.4

Experimental Example 2: Inhibitory effect of compounds on RS4;11 cell proliferation

RS4;11 cells (from Nanjing Cobioer) in logarithmic growth phase and in good cell condition were added to a centrifugation tube and centrifuged at 1500 rpm. within 3 min. in a low speed centrifuge. The supernatant was removed and 5 ml of complete medium (RPMI basal medium + 10 wt % fetal bovine serum (FBS)) was added using a pipette to resuspend the cells. Cells were counted using a cytometer, diluted with complete medium to a cell density of 2 x ¹⁰⁵ cells/ml, and an equivalent amount of RPMI basal medium was added to adjust the serum concentration to 5% and cell density to 1 x ¹⁰⁵ cells/ml for sowing on a tablet. Cells were seeded into a 96-well plate at 100 μl/well using a pipette and incubated in a 37°C, 5% CO ₂ saturated humidity incubator. After incubation for 24 h, compounds were loaded using a nanoliter pipette, wells were prepared in duplicate for each concentration, and cells without compound were used as negative controls. After 72 hours, CCK-8 reagent was added at 10 μL/well for incubation for 4 hours, then the absorbance value was measured at 450 nm using an Envision plate reader and the degree of inhibition was calculated. Inhibition rate (%) = (average of the negative control group - average of the experimental group) / (average of the negative control group - average of the blank group) × 100%. The dose-response curve was fitted by four-parameter analysis, with the logarithm of the compound concentration serving as the abscissa and the degree of inhibition serving as the ordinate, thereby calculating the IC ₅₀ (FIG. 2).

Table 2. Inhibitory effect of compounds on RS4;11 cell proliferation Compound Cages RS4;11 Compound Cages RS4;11 IC ₅₀ (nM) IC ₅₀ (nM) 1-1 2.3 31-1 3.0 6-1 2.4 35-1 9.6 7-1 4.6 38-1 6.6 8-1 2.5 42-1 6.8 9-1 2.7 43-1 1.9 10-1 5.6 48-1 1.4 11-1 2.5 50-1 4.3 12-1 1.7 51-1 1.1 13-1 8.1 52-1 0.9 14-1 8.6 57-1 2.3 15-1 7.2 58-1 5.3 16-1 7.8 59-1 1.0 17-1 2.9 60-1 1.3 18-1 4.3 61-1 3.2 19-1 3.5 62-1 4.1 20-1 3.9 63-1 1.4 21-1 4.1 65-1 1.8 23-1 10 66-1 3.3 28-1 3.0 67-1 0.8 29-1 1.3 71-1 6.1 74-1 6.9 73-1 1.5 75-1 3.9

Experimental Example 3: Stability in vitro in the liver microsome

300 μl of the final incubation system contained 30 μl of liver microsomes (protein concentration: 5 mg/ml), 30 μl of NADPH + MgCl ₂ , 3 μl of test compound (in acetonitrile) and 237 μl of PBS buffer (pH 7.4), where part organic solvent (acetonitrile) was 1% (volume ratio). Samples were obtained in duplicate for each species (mouse, rat and human) and the volume of each sample was 0.3 ml. To each tube, 270 μl of a mixed solution of substrate, enzyme, and NADPH was added after preincubation at 37°C for 5 min. 30 μl of NADPH + MgCl ₂ was added and mixed. Then 50 μl of the mixture was taken after 0 min., 15 min., 30 min. and 60 min. and 300 μl of ice-cold acetonitrile containing internal standard was added to stop the reaction.

To 50 μL of the incubated sample, 300 μL of ice-cold acetonitrile containing internal standard (20 ng/mL diazepam) was added for precipitation and shaken for 5 min. and centrifuged (13000 rpm, 20°C) for 10 min. 70 μL of supernatant was collected and diluted with 70 μL of ultrapure water. After thorough mixing, 1 μl of the resulting sample was added for analysis. The parameters for the destruction of compounds in liver microsomes of humans, rats and mice are presented in Table 3.

Table 3. In vitro metabolic stability of compounds in liver microsomes (1 µM) Connection number Mouse Rat Human Residual content after 60 min. (%) Residual content after 60 min. (%) Residual content after 60 min. (%) 1-1 78.9% 88.4% 70.8% 6-1 65.3% 61.2% 65.9% 8-1 73.9% 90.9% 86.3% 9-1 55.7% 101.7% 69.8% 10-1 30.1% 69.9% 78.0% 11-1 62.9% 66.3% 67.4% 12-1 93.4% 80.2% 91.3%

Experimental Example 4: Pharmacokinetics in vivo

4.1. Pharmacokinetics in rats

SD rats weighing 180-220 g after 3-5 days of adaptive feeding were randomly divided into groups containing 3 rats in each group, and they were intragastrically administered compounds 1-1 and 8-1 at a dose of 5 mg/kg.

Animals to be tested (SD rats) were fasted for 12 hours before administration and fed 4 hours after administration, and water was allowed to drink freely before, after and during the experiment.

Approximately 0.2 ml of blood was collected from the orbit at 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after intragastric administration and after anticoagulation with EDTA-K2, blood samples were transferred to a centrifuge within 30 min. and centrifuged at 4000 rpm. within 10 min. at 4°C with separation of blood plasma. All blood plasma samples were collected and directly stored at -20°C for testing.

To 50 μl of the blood plasma sample to be tested, 300 μl of acetonitrile solution containing internal standard (20 mg/ml diazepam) was added, shaken and mixed thoroughly for 5 min, and centrifuged at 13,000 rpm. within 10 min. 75 μL of supernatant was collected and diluted with 75 μL of ultrapure water. After thorough mixing, 2 μl of the resulting sample was taken for LC/MS/MS determination and the chromatogram was recorded.

Oral exposure to the compounds disclosed herein was assessed through in vivo pharmacokinetic experiments in rats. The pharmacokinetic parameters for the compounds, approximated using DAS3.2.5 software, are presented in the table below.

Pharmacokinetic data for compounds 1-1 and 8-1 are presented in Table 4-1 below.

Table 4-1. Pharmacokinetic parameters for compounds PK parameters 1-1 IG 5 mg/kg 8-1 IG 5 mg/kg _Tmax (h.) 4.00±0.00 4.00±0.00 C _max. (ng/ml) 378±83.5 739±226 AUC(0-24 h) (ng*h/ml) 3705±848 5973±2021 AUC(0-∞) (ng*h/ml) 4456±1335 6558±1805 t _1/2 (h) 8.73±0.31 7.62±2.78 MRT(0-t) (h) 8.95±4.99 7.35±0.45

4.2. Pharmacokinetics in Beagle dogs

Three male Beagle dogs weighing 9-12 kg were administered intragastric test compounds at a dose of 2.5 mg/kg after adaptive feeding over a period of time.

Animals to be tested (male beagle dogs) were fasted for 12 hours before administration and fed 4 hours after administration, and water was allowed to drink freely before, after and during the experiment.

After intragastric administration, approximately 0.5 ml of blood was collected from the vein of the forelimb after 0.25 hours (15 minutes), 0.5 hours (30 minutes), 1 hour, 1.5 hours, 2 hours. , 4 hours, 6 hours, 8 hours, 10 hours, 24 hours, 30 hours, 48 hours and 72 hours and placed in an anticoagulation tube containing EDTA-K2. Blood samples were transferred to a centrifuge within 30 min. and centrifuged at 4000 rpm. within 10 min. at 4°C with separation of blood plasma. All blood plasma samples were collected and directly stored at -20°C for testing.

To 50 μl of the blood plasma sample to be tested, 300 μl of acetonitrile solution containing internal standard (20 ng/ml diazepam) was added, shaken and mixed thoroughly for 5 minutes, and centrifuged at 13,000 rpm. within 10 min. 75 μL of supernatant was collected and diluted with 75 μL of ultrapure water. After thorough mixing, 1 μL of the resulting sample was taken for LC/MS/MS determination and the chromatogram was recorded.

Oral exposure to the compounds disclosed herein was assessed through in vivo pharmacokinetic experiments in Beagle dogs. Pharmacokinetic parameters for the compounds, approximated using DAS3.2.5 software, are presented in Table 4-2 below.

Table 4-2. Pharmacokinetic parameters for compounds in Beagle dogs Test connection 8-1 Dose 2.5 mg/kg T1/2 (h.) 19.47±1.64 _Tmax (h.) 3.33±1.16 C _max. (ng/ml) 1429±769 AUC0-72 h. (h*ng/ml) 26269±13586 AUC0-∞ (h*ng/ml) 27692±14182 MRT _final (h.) 17.2±1.62

Experimental Example 5: Pharmacodynamics of Compounds in a Subcutaneous Xenograft Model of Human RS4;11 B-cell Leukemia

NOD/SCID female mice, 9-10 weeks old (age since tumor cell transplantation) with a body weight of 16.3-22.0 g, were purchased from Beijing AniKeeper Biotech Co.,Ltd.; Product license number: SCXK (Jing) 2017-0006 and animal certification number: 11402400013155 Breeding medium: SPF category. Mice were transplanted subcutaneously on the right anterior dorsal side with 1 × 10 ⁷ RS4;11 cells. The day of transplantation was defined as day 0. When the average tumor volume was 240 mm ³ , mice were randomly divided into groups according to tumor size. Administration was carried out as indicated in Table 5 below.

Table 5. Route of administration, dose, and dosing regimen for the subcutaneous xenograft model of human RS4;11 B-cell leukemia. Group n Introduction group Dose (mg/kg) Route of administration Time of administration 1 6 Carrier medium p.o. One dose 2 6 1-1 25 p.o. One dose 3 6 1-1 50 p.o. One dose 4 6 8-1 25 p.o. One dose

Note: n - number of animals; the injected volume was 10 µl/g.

Clinical symptoms observed during the experiment were recorded as raw data. The formula for calculating tumor volume is: tumor volume (mm ³ ) = 1/2 × (a × b ² ) (where a represents the long axis dimension and b represents the short axis dimension). The experiment collected data using StudyDirector™ software (version no. 3.1.399.19, supplier: Studylog System, Inc., South San Francisco, California, USA), including long- and short-axis tumor diameter measurements and results weighing animals. The raw data obtained from the scales and calipers was entered directly into the software and any changes in the data were recorded. Relative tumor proliferation rate (T/C%) refers to the percentage of relative tumor volume or tumor weight of the treatment group and control groups at specific time points. The formula for calculation was as follows:

T/C% = T _RTV / C _RTV × 100% (T _RTV : mean RTV of the treatment group; C _RTV : mean RTV of the vehicle control group; RTV = V _t / V ₀ , where V ₀ represents is the tumor volume of the animal after grouping, and V _t is the tumor volume of the animal after treatment).

The degree of tumor growth inhibition (TGI%) was calculated according to the following formula: TGI% = (1 - T/C) × 100%. (T and C represent the relative tumor volume (RTV) or tumor weight (TW) at a specific time point for the treatment group and control group, respectively).

All experimental results are expressed as mean tumor volume ± SEM (standard deviation of the mean). The relative tumor volume of the treatment group was compared with the tumor volume of the control group for any significant difference by T test for independent samples. All data p < 0.05, analyzed using SPSS 18.0., were defined as a significant difference. The results are presented in Table 6.

Experimental Example 6: Toxicity Experiment on Human Platelets (Caspase-3 Activity Assay)

10 ml of human whole blood was collected using an anticoagulation tube containing sodium heparin, mixed thoroughly by inversion and centrifuged at 90 g for 10 min. The supernatant was collected and centrifuged at 1950 g for 10 min. The supernatant was removed and the residue was resuspended in 4 ml PBS and centrifuged at 1190 g for 5 min, and the procedure was repeated again. The supernatant was removed and platelets were resuspended in PBS and adjusted to a density of 2-3 x 10 ⁸ cells/ml. Cells were seeded in a 96-well plate at a density of 2-3 x 10 ⁷ cells/ml and at 100 μl/well. Add 50 μL of negative control control buffer to each well, and 50 μL of compound at the appropriate concentration is added to each compound well so that the final compound concentration is 2.5 μM, 2 μM, 1 μM, or 0.5 μM, then incubate in an incubator at 37°C for 90 minutes. The liquids in the 96-well plate were respectively transferred into 1.5 ml centrifuge tubes. The tubes were centrifuged at 4°C and 6000 g for 5 min. and placed on ice after removing the supernatant for further use. The 5× lysis buffer was diluted to 1× lysis buffer with water from the kit, and the protease inhibitor mixture was added at a ratio of 1:200 to obtain a lysis mixture for further use. 40 μl of lysis mixture was added to each centrifuge tube and the platelets at the bottom were resuspended using a pipette. The suspension was lysed on ice for 15-20 minutes. and centrifuged at 4°C and 14000 g for 10 min. The sample was placed in a subbag for later use. Dilute the 10× assay buffer to 1× assay buffer with water from the kit and add Ac-DEVD-AMC substrate at a ratio of 1:600 to form a reaction mixture. Add 5 μl of assay buffer and 40 μl of reaction mixture to each control well with a blank solution. Add 5 μl of control platelet lysate and 40 μl of the reaction mixture to each negative control well. 5 μl of platelet lysate and 40 μl of the reaction mixture were added to each well containing the compound. During this procedure, 40 μl of the reaction mixture was added at the end. The resulting mixture was gently mixed and platelets were read using a PE Envision multifunctional microplate reader (excitation wave: 360 nm, emission wave: 460 nm) 6 times every 10 min. Caspase-3 activity was determined based on the fluorescence intensity released by AMC, which was the slope of the fitted line graph to which each well corresponded and represented caspase activity (all data were normalized and the reference was ABT-199). The results are presented in tables 7-8.

Table 7. Effect of compounds on human platelet caspase-3 activity Compound Incline Compound Incline Compound Concentration
2.5 µM Compound Concentration
1 µM Compound Concentration
2.5 µM Compound Concentration
1 µM Negative control 0.03 0.04 17-1 0.43 0.48 1-1 0.28 0.67 18-1 0.46 0.31 6-1 0.22 0.45 19-1 0.18 0.12 8-1 0.94 0.59 20-1 0.71 0.37 7-1 0.67 0.48 Note: data has been normalized.

Table 8. Effect of compounds on human platelet caspase-3 activity Compound Incline Compound Incline Compound concentration 0.5 µM Compound concentration 2 µM Compound concentration 0.5 µM Compound Concentration
2 µM Negative control 0.15 0.09 43-1 0.19 0.09 11-1 0.42 0.57 57-1 0.08 0.04 12-1 0.27 0.33 65-1 0.44 0.43 28-1 0.04 0.03 Note: data has been normalized

Claims (47)

1. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, , where R ¹ is selected from Cl or F; R ² is selected from -C _0-3 alkylene-R ³ ; R ³ is selected from a 5-6 membered heterocycloalkyl, wherein the heteroatom in the 5-6 membered heterocycloalkyl is selected from the group consisting of N and O, and the number of heteroatoms is selected from 1-2, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 4-6 membered heterocycloalkyl, -COR ^a , -SO ₂ R ^b , -COOC _1-6 alkyl and C _1-6 alkyl, optionally substituted with a halogen atom, where the heteroatom in the 4- 6-membered heterocycloalkyl is selected from O, and the number of heteroatoms is selected from 1; And each of R ^a or R ^b is independently selected from the group consisting of H, 4-membered heterocycloalkyl, C _3-4 cycloalkyl and C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with a halogen atom, -CN, -N( C _1-6 alkyl) ₂ , -NHC _1-6 alkyl or -OC _1-6 alkyl, while the structural fragment selected from the group consisting of And . 2. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ² is selected from -(CH ₂ ) _n -R ³ , where n is 1, 2 or 3. 3. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 2, wherein n is 1 or 2. 4. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 2, wherein n is 1. 5. A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims. 1-4, wherein R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups at the N atom in the ring. 6. A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims. 1-5, where R ³ is selected from 5-6 membered heterocycloalkyl, wherein the 5-6 membered heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of 4-6 membered heterocycloalkyl, -COR ^a , -SO ₂ R ^b , -COOC _1-4 alkyl and C _1-6 alkyl, optionally substituted with a halogen atom. 7. A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims. 1-6, wherein each of R ^a or R ^b is independently selected from the group consisting of H, 4-membered heterocycloalkyl, C _3-4 cycloalkyl and C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with a halogen atom, - CN, -N(C _1-4 alkyl) ₂ , -NHC _1-4 alkyl or -OC _1-4 alkyl. 8. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 7, wherein each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, tert -butyl, cyclopropyl, cyclobutyl and monooxacyclobutyl where methyl or ethyl is optionally substituted with a fluorine atom, -CN, -OCH ₃ or -N(CH ₃ ) ₂ . 9. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 7, wherein each of R ^a or R ^b is independently selected from the group consisting of H, methyl, ethyl, isopropyl, tert -butyl, trifluoromethyl, pentafluoroethyl, - CH ₂ OCH ₃ , -CH ₂ CN and -CH ₂ N(CH ₃ ) ₂ , cyclopropyl, cyclobutyl and monooxacyclobutyl. 10. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 7, wherein each of R ^a or R ^b is independently selected from C _1-4 alkyl, optionally substituted by -OC _1-4 alkyl. 11. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 10, wherein each of R ^a or R ^b is independently selected from the group consisting of methyl, isopropyl and -CH ₂ OCH ₃ . 12. A compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-6, where R ³ is selected from 5-6 membered heterocycloalkyl, where 5-6 membered heterocycloalkyl is optionally substituted with -C(O)H, -COCH ₃ , -COCH(CH ₃ ) ₂ , -COC(CH ₃ ) ₃ , -COCF ₃ , -COCH ₂ CN, -COCH ₂ OCH ₃ , -COCH ₂ N(CH ₃ ) ₂ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -SO ₂ CF ₃ , -SO ₂ C ₂ F ₅ , methyl, ethyl, -CF ₃ , -CH ₂ CH ₂ F, -C ₂ F ₅ , tetrahydropyran, monooxacyclobutane, -SO ₂ -cyclopropane, -CO-cyclopropane, -CO-monooxacyclobutane, -SO ₂ - monooxacyclobutane, -SO ₂ -cyclobutane, -COOCH ₂ CH ₃ or -COOCH ₃ . 13. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 12, wherein R ³ is selected from the group consisting of tetrahydropyran, piperidine, morpholine and dioxane, wherein tetrahydropyran, piperidine, morpholine or dioxane is optionally substituted with -COCH ₃ , - COCH(CH ₃ ) ₂ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , -SO ₂ CH ₂ CH ₃ , -CO-cyclopropane, -COCH ₂ CN, -COCF ₃ , -COCH ₂ N(CH ₃ ) ₂ , methyl, ethyl, -CH ₂ CH ₂ F, -COOCH ₂ CH ₃ or -COOCH ₃ . 14. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 12, wherein R ³ is selected from the group consisting of tetrahydropyran, piperidine, morpholine and dioxane, wherein tetrahydropyran, piperidine, morpholine or dioxane is optionally substituted with -COCH ₃ , - COCH(CH ₃ ) ₂ , -COCH ₂ OCH ₃ , -SO ₂ CH ₃ , methyl, ethyl, -CH ₂ CH ₂ F, -COOCH ₂ CH ₃ or -COOCH ₃ . 15. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 16. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is selected from the group consisting of , , , , , , , , , , , , , , , , , , , , , , , or . 17. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ is selected from the group consisting of , , , , , , , , or . 18. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, selected from a compound of formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, , where R ² is as defined in paragraph 1. 19. A compound of the following formulas, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: ; or a compound of the following formula , where R is independently selected from the group consisting of 20. A compound of the following formulas or a pharmaceutically acceptable salt thereof: ; or a compound of the following formula , where R is independently selected from the group consisting of 21. A pharmaceutical composition for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2, containing a compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-20. 22. Use of a compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-20 or the pharmaceutical composition according to claim 21 in the preparation of a medicinal product intended for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.