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HK40051476B - Trifluoromethyl-substituted sulfonamide as bcl-2-selective inhibitor - Google Patents

Trifluoromethyl-substituted sulfonamide as bcl-2-selective inhibitor Download PDF

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Publication number
HK40051476B
HK40051476B HK62021041230.5A HK62021041230A HK40051476B HK 40051476 B HK40051476 B HK 40051476B HK 62021041230 A HK62021041230 A HK 62021041230A HK 40051476 B HK40051476 B HK 40051476B
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Hong Kong
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compound
preparation
methyl
coch
formula
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HK62021041230.5A
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Chinese (zh)
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HK40051476A (en
Inventor
刘飞
丰巍伟
王斌
徐宏江
汪纪楠
张喜全
王善春
刘彦龙
张健青
姚绎炎
唐旭静
施伟
张洪英
李洋
汤松
朱益忠
刘利民
顾红梅
杨玲
Original Assignee
正大天晴药业集团股份有限公司
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Publication of HK40051476A publication Critical patent/HK40051476A/en
Publication of HK40051476B publication Critical patent/HK40051476B/en

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Description

Trifluoromethyl substituted sulfonamides selective BCL-2 inhibitors
Reference to related applications
The application claims priority and benefit of a chinese patent application No. 201811268572.2 filed on 29 th of the republic of china in 2018, priority and benefit of a chinese patent application No. 201910249783.x filed on 29 th of 2019 on 3 th of the republic of china on 29 th of the republic of china, and priority and benefit of a chinese patent application No. 201910933513.0 filed on 29 th of 2019 on 9 th of the republic of china on 29 th of the republic of china, the entire contents of which are herein incorporated by reference in their entirety.
Technical Field
The present application relates to compounds that selectively inhibit the anti-apoptotic protein BCL-2, methods for their preparation, pharmaceutical compositions containing these compounds, and their use in the treatment of diseases associated with the anti-apoptotic protein BCL-2, such as cancer.
Background
BCL-2 proteins are divided into three families: the BCL-2 family (the family members of which include BCL-2, BCL-XL, etc.), the BAX family and the BH3-only family, wherein the BCL-2 family acts as anti-apoptotic and the members of the latter two families act as pro-apoptotic.
Anti-apoptotic BCL-2 family proteins are implicated in a number of diseases and are being investigated as potential therapeutic drug targets. These targets for interventional therapy include, for example, the BCL-2 family proteins BCL-2 and BCL-XL, among others. Recently, inhibitors of BCL-2 family proteins have been reported in WO2012071374, WO2010138588, WO2010065865. Although inhibitors with high binding to the target protein are taught therein, compound binding affinity is only one of many parameters to be considered. One objective is to produce such compounds: it binds preferentially, i.e. is selective for, one protein over another. To show this selectivity, it is known that compounds show a high binding affinity to a particular protein, and a lower binding affinity to another member.
Disclosed are BCL-2 inhibitors which are less selective than anti-apoptotic BCL-XL proteins and anti-apoptotic BCL-2 proteins and thus produce a greater likelihood of side effects, characterized by inhibiting the anti-apoptotic BCL-XL protein, producing side effects such as thrombocytopenia.
The application comprises a series of compounds, and compared with anti-apoptosis BCL-2 protein and anti-apoptosis BCL-XL protein, the compounds show higher selectivity, and have better performance in the aspect of inhibiting the activity of the anti-apoptosis BCL-2 protein. Meanwhile, the liver microsome has better stability of the liver microsome, optimized pharmacokinetic parameters and better patent medicine prospect.
Detailed Description
In one aspect, the present application relates to compounds of formula I, stereoisomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R 1 selected from halogens;
R 2 is selected from-C 0-6 alkylene-R 3 ；
R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, -COR a 、-SO 2 R b 、-COOC 1-6 Alkyl, or C optionally substituted by halogen 1-6 An alkyl group;
R a or R b Each independently selected from H, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-6 Alkyl radical, said C 1-6 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, or-OC 1-6 Alkyl substitution.
In some embodiments, a structural fragmentIs selected fromIn some embodiments, a structural fragmentIs selected fromIn some embodiments, a structural fragmentIs selected from
In some embodiments, a structural fragmentIs selected fromIn some embodiments, a structural fragmentIs selected from
In some embodiments, R 1 Selected from fluorine or chlorine. In some embodiments, R 1 Selected from chlorine.
In some embodiments, R 2 Is selected from-R 3 or-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 Wherein n is selected from 0, 1, 2,3 or 4; or n is selected from 1, 2 or 3; or n is selected from 1 or 2.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups at the position ofThe N atom of the ring.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, -COR a 、-SO 2 R b Or C optionally substituted by halogen 1-6 An alkyl group.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, -COR a 、-SO 2 R b 、-COOC 1-6 Alkyl, or C optionally substituted by halogen 1-6 An alkyl group.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, -COR a 、-SO 2 R b Or C optionally substituted by halogen 1-6 An alkyl group.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: -COR a 、-SO 2 R b 、-COOC 1-6 Alkyl, or C optionally substituted by halogen 1-6 An alkyl group.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: -COR a 、-SO 2 R b Or C optionally substituted by halogen 1-6 An alkyl group.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with 3-6 membered heterocycloalkyl.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with-COR a And (4) substitution.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 memberedHeterocycloalkyl optionally substituted by-SO 2 R b And (4) substitution.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl being optionally substituted by-COOC 1-6 Alkyl substitution. In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl being optionally substituted by-COOC 1-4 Alkyl substitution.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with C 1-6 Alkyl substitution, said C 1-6 Alkyl optionally substituted with halo; in some embodiments, said C 1-6 Alkyl is optionally substituted with fluorine. In some embodiments, the 5-6 membered heterocycloalkyl is optionally substituted with: methyl, ethyl, methyl substituted by fluorine, or ethyl substituted by fluorine.
In some embodiments, R a Or R b Each independently selected from H, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-4 Alkyl radical) 2 、-NHC 1-4 Alkyl, or-OC 1-4 And (3) alkyl substitution. In some embodiments, R a Selected from H, 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-4 Alkyl radical) 2 or-OC 1-4 Alkyl substitution. In some embodiments, R b Selected from 3-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted with halogen or-CN.
In some embodiments, R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or monooxycyclobutyl, said methyl or ethyl being optionally fluoro, -CN, -OCH 3 or-N (CH) 3 ) 2 And (4) substitution. In some embodiments, R a Selected from H, methyl, isopropyl, tert-butyl, cyclopropyl, or mono-oxetanyl, said methylOptionally substituted by fluorine, -CN, -OCH 3 or-N (CH) 3 ) 2 And (4) substitution. In some embodiments, R b Selected from methyl, ethyl, cyclopropyl, cyclobutyl, or monooxycyclobutyl, said methyl or ethyl being optionally substituted by fluorine.
In some embodiments, R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -CH 2 OCH 3 、-CH 2 CN、-CH 2 N(CH 3 ) 2 Cyclopropyl, cyclobutyl, or monooxycyclobutyl. In some embodiments, R a Selected from H, methyl, isopropyl, tert-butyl, trifluoromethyl, -CH 2 OCH 3 、-CH 2 CN、-CH 2 N(CH 3 ) 2 Cyclopropyl, or monooxycyclobutyl. In some embodiments, R b Selected from methyl, ethyl, trifluoromethyl, pentafluoroethyl, cyclopropyl, cyclobutyl, or monooxycyclobutyl.
In some embodiments, R a Or R b Each independently selected from H, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-4 Alkyl radical) 2 、-NHC 1-4 Alkyl, or-OC 1-4 And (3) alkyl substitution. In some embodiments, R a Selected from H, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-4 Alkyl radical) 2 or-OC 1-4 And (3) alkyl substitution. In some embodiments, R b Is selected from C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted with halogen or-CN.
In some embodiments, R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, or cyclobutyl, said methyl or ethyl being optionally fluoro, -CN, -OCH 3 or-N (CH) 3 ) 2 And (4) substitution. In some embodiments, R a Selected from H, methyl, isopropyl, tert-butylOr cyclopropyl, said methyl being optionally substituted by fluoro, -CN, -OCH 3 or-N (CH) 3 ) 2 And (4) substitution. In some embodiments, R b Selected from methyl, ethyl, cyclopropyl, or cyclobutyl, said methyl group being optionally substituted by fluorine.
In some embodiments, R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, -CH 2 OCH 3 、-CH 2 CN、-CH 2 N(CH 3 ) 2 Cyclopropyl, or cyclobutyl. In some embodiments, R a Selected from H, methyl, isopropyl, tert-butyl, trifluoromethyl, -CH 2 OCH 3 、-CH 2 CN、-CH 2 N(CH 3 ) 2 Or cyclopropyl. In some embodiments, R b Selected from methyl, ethyl, trifluoromethyl, cyclopropyl, or cyclobutyl.
In some embodiments, R a Or R b Each independently selected from optionally substituted-OC 1-4 Alkyl substituted C 1-4 An alkyl group.
In some embodiments, R a Or R b Each independently selected from methyl, isopropyl, or-CH 2 OCH 3 。
In some embodiments, R a Selected from optionally substituted by-OC 1-4 Alkyl substituted C 1-4 An alkyl group.
In some embodiments, R a Selected from methyl, isopropyl, or-CH 2 OCH 3 。
In some embodiments, R b Is selected from C 1-4 An alkyl group.
In some embodiments, R b Selected from methyl.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl 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, monooxyoxetane, -SO 2 -cyclopropane, -CO-monooxyoxetane, -SO 2 -monooxyoxetane, -SO 2 -cyclobutane, -COOCH 2 CH 3 or-COOCH 3 . In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with: -COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-SO 2 CH 3 Methyl, ethyl, -CH 2 CH 2 F。
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl 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, monooxyoxetane, -SO 2 -cyclopropane, -CO-monooxyoxetane, -SO 2 -monooxyoxetane, -SO 2 -cyclobutane.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with: -COOCH 2 CH 3 or-COOCH 3 。
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl 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, -SO 2 -cyclobutane.
In some embodiments, R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl 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, -SO 2 -cyclobutane.
In some embodiments, R 3 Selected from tetrahydropyran, piperidine, morpholine or dioxane, 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 Selected from tetrahydropyran, piperidine, morpholine or dioxane, 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 Selected from tetrahydropyran, piperidine, morpholine or dioxane, optionally substituted with: -COOCH 2 CH 3 or-COOCH 3 。
In some embodiments, R 3 Selected from tetrahydropyran or bisAnd (3) an oxygen hexacyclic ring.
In some embodiments, R 3 Selected from dioxane.
In some embodiments, R 3 Selected from piperidine or morpholine, 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 Selected from piperidine or morpholine 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 Selected from piperidine or morpholine, optionally substituted with: -COOCH 2 CH 3 or-COOCH 3 。
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected fromIn some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, R 3 Is selected from
In some embodiments, the heteroatoms in the 5-6 membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is selected from 1 or 2.
In some embodiments, the 5-6 membered heterocycloalkyl is selected from dioxane, morpholinyl, tetrahydropyranyl, piperidinyl, or tetrahydrofuranyl.
In some embodiments, the 5-6 membered heterocycloalkyl is selected from 6 membered heterocycloalkyl.
In some embodiments, the 5-6 membered heterocycloalkyl is selected from dioxane, morpholinyl, tetrahydropyranyl, or piperidinyl.
In some embodiments, the 5-6 membered heterocycloalkyl is selected from dioxane.
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 heteroatoms in the 3-6 membered heterocycloalkyl are selected from N or O, and the number of heteroatoms is selected from 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 4-6 membered heterocycloalkyl. In some embodiments, the 3-6 membered heterocycloalkyl is selected from 4 membered heterocycloalkyl or 6 membered heterocycloalkyl.
In some embodiments, the 3-6 membered heterocycloalkyl group is selected from the group consisting of monooxyheterocycloalkyl, tetrahydrofuranyl, tetrahydropyranyl.
In some embodiments, said C 3-6 The cycloalkyl is selected from the group consisting of cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl. In some embodiments, said C 3-6 Cycloalkyl is selected from C 3-4 A cycloalkyl group.
In another aspect, the present application relates to a compound of formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein R is 2 Are as defined for compounds of formula I.
The present application relates to compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof,
or a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is independently the following group:
the present application relates to compounds, or pharmaceutically acceptable salts thereof,
or the following compounds or pharmaceutically acceptable salts thereof:
wherein R is independently the following group:
in another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula I, formula II, or a specific compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
In another aspect, the present application describes a method of treating a disease associated with the anti-apoptotic protein BCL-2 in a mammal, comprising administering to a mammal (preferably a human) in need of such treatment a therapeutically effective amount of a compound of formula I, formula II, or a specified compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.
In another aspect, the present application describes the use of a compound of formula I, formula II or a specific compound described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
In another aspect, the present application describes the use of a compound of formula I, formula II or a specific compound described above, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
In another aspect, the present application describes a compound of formula I, formula II or a specific compound described above, 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.
Wherein the disease related to the anti-apoptosis protein BCL-2 is selected from cancer. The cancer is selected from acute lymphocytic leukemia.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e = O), meaning that two hydrogen atoms are substituted, the oxo does not occur on the aryl.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that the ethyl may be unsubstituted (-CH) 2 CH 3 ) Monosubstituted (e.g. -CH) 2 CH 2 F) Polysubstituted (e.g. -CHFCH) 2 F、-CH 2 CHF 2 Etc.) or completely substituted (-CF) 2 CF 3 ). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Herein C m-n It is the moiety that has an integer number of carbon atoms in the given range. E.g. "C 1-6 By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a group of the formula C n H 2n+1 A hydrocarbon group of (1). The alkyl group may be straight or branched. For example, the term "C 1-6 Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl groups of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthioThe moiety (i.e., alkyl) has the same definition as above. By way of further example, the term "C 1-4 Alkyl "means an alkyl group containing 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).
The term "alkylene" refers to a divalent group formed by removing 1 hydrogen from any position of an alkyl group. For example, the term "C 0-6 Non-limiting examples of alkylene "include, but are not limited to, methylene, ethylene, methylmethylene, dimethylmethylene, 1, 3-propylene, and the like. C 0 A key is indicated.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups 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 may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing 1 to 3 (preferably 1 or 2) heteroatoms independently selected from sulphur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazepane, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutanyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thiaxanyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiacycloheptanyl. Monocyclic heterocycloalkyl groups having 5 or 6 ring atoms are preferred.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) Inhibiting the disease or disease state, i.e., arresting its development;
(iii) Alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" means those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not have a significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," should be interpreted in an open, non-exclusive sense, i.e., "including but not limited to.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively 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, and the like.
Certain isotopically-labeled compounds of the present application (e.g., with 3 H and 14 c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation) 3 H) And carbon-14 (i.e. 14 C)Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and 18 f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, with heavier isotopes (such as deuterium (i.e. deuterium) 2 H) Substitution, where deuterium substitution may be partial or complete, partial deuterium substitution refers to substitution of at least one hydrogen with at least one deuterium, may provide some therapeutic advantage resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in some circumstances.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included herein, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets 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 compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula I described herein, the daily dose is from 0.01mg/kg to 200mg/kg body weight, in single or divided doses.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application. The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select a synthesis procedure or a reaction scheme based on the existing embodiments.
An important consideration in the art of synthetic route planning is the selection of suitable 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 (4 th Ed.) Hoboken, new Jersey: john Wiley & Sons, inc.
In some embodiments, the compounds of formula I herein may be prepared by one skilled in the art of organic synthesis by the following route:
route 1:
route 2:
in the above scheme, R 1 、R 2 OrWherein X is selected from a leaving group, preferably selected from fluorine, chlorine, bromine or iodine; r is 4 Is selected from C 1-6 Alkyl or C 1-4 Alkyl, preferably selected from tert-butyl, methyl or ethyl; r is 5 Selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl); r is 6 Selected from amino protecting groups, preferably from silane protecting groups, more preferably from TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilicon) or TMS (trimethylsilane), TES (triethylsilane), TIPS (triisopropylsilane) protecting groups.
The present application also provides a process for preparing a compound of formula a-4 comprising the steps of:
wherein R is 1 OrThe definition of (1) is as above; x is selected from a leaving group, preferably selected from fluorine, chlorine, bromine or iodine; r is 4 Is selected from C 1-6 Alkyl or C 1-4 Alkyl, preferably selected from tert-butyl, methyl or ethyl; r 6 Selected from amino protecting groups, preferably from silane protecting groups, more preferably from TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilicon) or TMS (trimethylsilane), TES (triethylsilane), TIPS (triisopropylsilane) protecting groups.
The present application also provides a process for preparing a compound of formula a-3, comprising the steps of:
wherein R is 1 、Is as defined above, R 5 Selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl).
The present application also provides a process for preparing a compound of formula a-2, comprising the steps of:
wherein R is 1 、Is as defined above, R 5 Selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl).
The present application also provides a process for preparing a compound of formula a-5, comprising the steps of:
wherein R is 1 、Is as defined above, R 4 Is selected from C 1-6 Alkyl or C 1-4 Alkyl, preferably selected from tert-butyl, methyl or ethyl; r is 6 Selected from amino protecting groups, preferably from silane protecting groups, more preferably from TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl) or TMS (trimethylsilyl), TES (triethylsilyl), TIPS (triisopropylsilyl) protecting groups.
The present application also provides a process for preparing a compound of formula I, comprising the steps of:
wherein R is 1 、R 2 OrThe definition of (A) is as above.
The present application also provides the following intermediate compounds or salts thereof:wherein R is 1 、Is as defined above, R 4 Is selected from C 1-6 Alkyl or C 1-4 Alkyl, preferably selected from tert-butyl, methyl or ethyl; r 5 Selected from amino protecting groups, preferably Boc or Cbz (benzyloxycarbonyl); r is 6 Selected from amino protecting groups, preferably from silane protecting groups, more preferably from TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilicon) or TMS (trimethylsilane), TES: (TES:)Triethylsilicon) and TIPS (triisopropylsilicon) protecting groups. Wherein the salt may be selected from hydrochloride salts and the like.
In more specific embodiments, the compounds are each selected from the following compounds or salts thereof:wherein the salt may be selected from hydrochloride salts and the like.
Detailed Description
Abbreviation: DMF represents N, N-dimethylformamide; boc represents tert-butyloxycarbonyl; naOAc represents sodium acetate; tBu represents a tert-butyl group; TBS represents tert-butyldimethylsilyl; THF represents tetrahydrofuran; DMSO represents dimethyl sulfoxide.
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. All reagents used herein were commercially available and used without further purification.
Example 1- (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) Preparation of Compound 1-b
Adding phosphorus oxychloride dropwise into a DMF (173.7 g) and dichloromethane (460 mL) solution at 0 ℃, heating to 20 ℃, stirring for 1h, cooling to 0 ℃, adding 3, 3-dimethylcyclohexanone (1-a) (200 g) dropwise, and heating and refluxing overnight after the dropwise addition. The reaction mixture was added dropwise to a solution containing NaOAc (86.7 g), naCl (80 g), water (1.2L) and dichloromethane (600 mL) with stirring at room temperature for 20min, the mixture was separated, the aqueous phase was extracted with dichloromethane (500 mL), the organic phases were combined, and the mixture was washed with a solution containing K 3 PO 4 (40g) Then, a solution of NaCl (90 g) in water (1L) was washed once more, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-b (249 g).
2) Preparation of Compound 1-c
A mixture of compound 1-b (5.36 g), 4-triphenylphosphine palladium (0.18 g), and K 3 PO 4 (16.5 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 2-chloro-4-trifluoromethylphenylboronic acid (6.96 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate, stirring for 0.5h, filtering, separating, extracting the aqueous phase with ethyl acetate 60 mL. Times.2, combining the organic phases, washing the resulting organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 1-c (2 g).
3) Preparation of Compound 1-e
2- [ (1H-pyrrolo [2,3-b ]]Pyridin-5-yl) oxy]-4-Bromobenzoic acid tert-butyl ester (Compound 1-d) (77.8 g), boc-piperazine (55.8 g), tris (dibenzylideneacetone) dipalladium (9 g), and [ (4- (N, N-dimethylamino) phenyl ] methyl- ] -]Di-tert-butylphosphine (5.2 g), sodium tert-butoxide (96.1 g), toluene (800 mL), tetrahydrofuran (300 mL) were mixed, stirred, and heated to 60 ℃ under nitrogen for 24h. With a mixture containing L-cysteine (100 g) and NaHCO 3 (150g) The reaction mixture was washed with aqueous solution (1.5L) of (3) 2 times (750 mL. Times.2), saturated aqueous NaCl solution, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain the compound 1-e (40 g). ESI-MS: m/z =495.4[ M ] +H]+.
4) Preparation of Compounds 1-f
Compound 1-e (40 g), 800mL tetrahydrofuran, 270mL ethanol, and 15mL water were mixed, stirred, KOH (45.3 g) solid was added, the temperature was raised to 80 ℃ and the mixture was refluxed for 8h to complete the reaction. Adding 500mL of water, stirring, adjusting the pH value to 5-6 with dilute hydrochloric acid, filtering, pulping with water (1L) for 2 times (500 mL. Times.2), and drying to obtain a compound 1-f (35 g).
5) Preparation of Compounds 1-h
Compound 1-f (35 g) and methylene chloride (100 mL) were mixed, stirred at room temperature, and 4-dimethylaminopyridine (38.5 g) and 1-ethyl- (3-dimethyl-pyridine) were addedAminopropyl) carbonyl diimine hydrochloride (65.8 g), dissolved with stirring, and 3-nitro-4- [ [ (tetrahydropyran-4-yl) methyl ] is added]Amino group]Benzenesulfonamide (compound 1-g) (25.2 g), and reacted at room temperature for 3 hours. Washed with 5wt% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution in this order, anhydrous Na 2 SO 4 Drying, filtering, concentrating, adding dichloromethane (200 mL) and stirring at room temperature for 2h, filtering, and drying to obtain compound 1-h (40 g).
6) Preparation of Compound 1-i
Adding the compound 1-h into 500mL of isopropanol, stirring, adding 50mL of concentrated HCl, heating to 65 ℃, stirring for 8h, and completely reacting. Filtering, dissolving the filter cake in 300mL of water, dropwise adding saturated sodium bicarbonate to adjust the pH value to 6-7, filtering, drying, pulping the obtained solid with 200mL of ethyl acetate, filtering and drying to obtain a compound 1-i (27 g).
7) Preparation of Compound 1-1
Compound 1-c (1 g) and compound 1-i (2 g) were dissolved in 20mL of methanol, stirred, added with sodium borohydride (0.24 g), and stirred for 6 hours to complete the reaction. Quenching by adding 10mL of saturated aqueous ammonium chloride solution, extracting twice with 20mL of ethyl acetate, washing with saturated aqueous sodium chloride solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 1-1 (200 mg).
Compound 1-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝936.5[M+H]+.
example 2- (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) Preparation of Compound 2-c
Compound 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 3-trifluoromethyl-4-chlorobenzeneboronic acid (6.72 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate, stirring for 0.5h, filtering, separating, extracting the aqueous phase with ethyl acetate 60 mL. Times.2, combining the organic phases, washing the resulting organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 2-c (1.2 g).
2) Preparation of Compound 2-1
Compound 2-c (1 g) and compound 1-i (2.01 g) were dissolved in 20mL of methanol, stirred, added with sodium borohydride (0.27 g), and stirred for 6 hours to complete the reaction. Quenching by adding 10mL of saturated aqueous ammonium chloride solution, extracting twice with 20mL of ethyl acetate, washing with saturated aqueous sodium chloride solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 2-1 (80 mg).
Compound 2-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝936.5[M+H] + .
example 3- (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) Preparation of Compound 3-c
Compound 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 2-trifluoromethyl-4-chlorobenzeneboronic acid (6.72 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate, stirring for 0.5h, filtering, separating, extracting the aqueous phase with ethyl acetate 60 mL. Times.2, combining the organic phases, washing the resulting organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 3-c (1.6 g).
2) Preparation of Compound 3-1
Compound 3-c (1 g) and compound 1-i (2.01 g) were dissolved in 20mL of methanol, stirred, added with sodium borohydride (0.27 g), and stirred for 6h to complete the reaction. Adding 10mL saturated ammonium chloride aqueous solution for quenching, extracting twice with 20mL ethyl acetate, washing with saturated sodium chloride aqueous solution, and anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 3-1 (110 mg).
Compound 3-1: 1 H NMR(500MHz，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)，231(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(125MHz，DMSO-d6)，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：m/z＝936.5[M+H] + .
example 4- (4- { [2- (3-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) Preparation of Compound 4-c
Compound 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 3-chloro-4-trifluoromethylphenylboronic acid (6.72 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate, stirring for 0.5h, filtering, separating, extracting the aqueous phase with ethyl acetate 60 mL. Times.2, combining the organic phases, washing the resulting organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 4-c (1.5 g).
2) Preparation of Compound 4-1
Dissolving compound 4-c (1 g) and compound 1-i (2.01 g) in 20mL of methanol, stirring, adding borohydrideSodium (0.27 g) was added and stirred for 6h to complete the reaction. Quenching by adding 10mL of saturated aqueous ammonium chloride solution, extracting twice with 20mL of ethyl acetate, washing with saturated aqueous sodium chloride solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 4-1 (120 mg).
Compound 4-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝936.5[M+H] + .
example 5- (4- { [2- (2-fluoro-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) Preparation of Compound 5-c
A mixture of compound 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), and K 3 PO 4 (12.74 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 2-fluoro-4-trifluoromethylphenylboronic acid (6.24 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate were added to the reaction mixture, stirred for 0.5h, and filteredSeparating, extracting the water phase with ethyl acetate 60mL × 2, combining the organic phases, washing the obtained organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 5-c (1.8 g).
2) Preparation of Compound 5-1
Compound 5-c (1 g) and compound 1-i (2.12 g) were dissolved in 20mL of methanol, stirred, added with sodium borohydride (0.27 g), and stirred for 6h to complete the reaction. Adding 10mL saturated ammonium chloride aqueous solution for quenching, extracting twice with 20mL ethyl acetate, washing with saturated sodium chloride aqueous solution, and anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 5-1 (90 mg).
Compound 5-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝920.6[M+H] + .
example 6- (4- { [2- (3-fluoro-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) Preparation of Compound 6-c
Compound 1-b (5.16 g), 4-triphenylphosphine palladium (0.17 g), K 3 PO 4 (12.74 g), DMF (60 mL), and water (60 mL) were mixed and stirred for 10min, and 3-fluoro-4-trifluoromethylphenylboronic acid (6.24 g), N 2 And (4) protecting, and reacting for 6h at 100 ℃ until the reaction is complete. 30mL (containing 5wt% NaHCO) 3 +2wt% of L-cysteine) and 50mL of ethyl acetate, stirring for 0.5h, filtering, separating, extracting the aqueous phase with ethyl acetate 60 mL. Times.2, combining the organic phases, washing the resulting organic phase with saturated aqueous NaCl solution, and removing anhydrous Na 2 SO 4 Drying, filtering, concentrating, and performing column chromatography to obtain compound 6-c (1.6 g).
2) Preparation of Compound 6-1
Compound 6-c (1 g) and compound 1-i (2.12 g) were dissolved in 20mL of methanol, stirred, added with sodium borohydride (0.27 g), and stirred for 6h to complete the reaction. Adding 10mL saturated ammonium chloride aqueous solution for quenching, extracting twice with 20mL ethyl acetate, washing with saturated sodium chloride aqueous solution, and anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate, and performing column chromatography to obtain compound 6-1 (150 mg).
Compound 6-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝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) Preparation of Compound 7-d
Compound 1-c (198.6 g), 1-Boc-piperazine (175.5 g) was dissolved in acetonitrile (800 mL), stirred, cooled to 0 deg.C, sodium triacetoxyborohydride (532.6 g) was added slowly and stirred at room temperature for 5h. After the reaction was completed, water (1L) and ethyl acetate (300 mL) were added for extraction, and the organic phase was collected and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain the compound 7-d (269.8 g).
2) Preparation of Compound 7-e
Compound 7-d (269.8 g), isopropanol (800 mL), and hydrochloric acid (36-38 wt% in concentration, 169 mL) were mixed, heated to 65 ℃ and reacted for 3h. The solid was precipitated by cooling, filtered and dried to obtain compound 7-e (151.2 g).
Compounds 7-e: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝387.1[M+H] + .
3) Preparation of Compound 7-g
Dissolving NaH (21.1 g) in THF (100 mL), cooling to-20 deg.C, stirring for 10min, and adding 2- [ (1H-pyrrolo [2,3-b ] to the solution]Pyridin-5-yl) oxy]-4-bromobenzoic acid tert-butyl ester (compound 1-d,128.3 g) was dissolved in 200mL of THF, slowly added dropwise to the reaction solution while controlling the internal temperature below 0 ℃ in the dropwise addition, stirred for 30min after the dropwise addition was completed, TBSCl (64.7 g) in THF (200 mL) was added dropwise to the reaction solution while controlling the internal temperature at about-10 ℃ in the dropwise addition, and after the dropwise addition was completedReacting for 30min, adding 500mL saturated sodium bicarbonate and ethyl acetate for extraction after the reaction is completed, collecting an organic phase, and adding anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by column chromatography to obtain compound 7-f (150 g). ESI-MS: m/z =503.1[ m ] +H] + 。
Mixing compound 7-e (151.2 g), 2- [ (1-tert-butyldimethylsilylpyrrolo [2,3-b ]]Pyridin-5-yl) oxy]-4-Bromobenzoic acid tert-butyl ester (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) were mixed, stirred under nitrogen and heated to 100 ℃ for reaction for 24h. After the reaction, water (1L) and ethyl acetate (300 mL) were added for extraction, and the organic phase was collected and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain 7-g (181.9 g) of the compound.
Compound 7-g: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，δ：164.4156.8，155.1，150.3，149.8，146.2，133.6，133.4，133.2，132.0，131.9，131.5，129.5，129.0，128.8，126.4，126.1，124.4，122.8，114.4，113.8，110.2，106.8，103.3，80.1，60.6，52.6，47.1，44.7，35.2，29.4，27.9，27.2，26.7，25.4，19.0.ESI-MS：m/z＝809.4[M+H] +
4) Preparation of Compound 7-h
A mixture of 7-g (181.9 g) of compound, toluene (1.8L), trifluoroacetic acid (107 mL) was heated to 45 ℃ and reacted for 5h. The reaction solution was concentrated, and 1.5L of ethyl acetate and saturated NaHCO were added 3 Washing the aqueous solution with saturated sodium chloride aqueous solution, drying with anhydrous sodium sulfate, filtering, concentrating, adding 1L of toluene and 200mL of ethyl acetate, heating to dissolve, cooling to precipitate solid, filtering, and drying to obtain compound 7-h (83.4 g).
Compounds 7-h: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝639.2[M+H] + .
5) Preparation of Compound 7-k
3-Nitro-4-chlorobenzenesulfonamide (0.64 g), (R) - (1, 4-dioxane) -2-methanamine hydrochloride (0.5 g) and N, N-diisopropylethylamine (1.58 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6.5h, cooled at room temperature, left overnight, and filtered to give compound 7-k (0.65 g). ESI-MS: m/z =316.2[ M-H ]] - .
6) Preparation of Compound 7-1
Compound 7-h (1 g) was mixed with methylene chloride (10 mL), stirred at room temperature, added with 4-dimethylaminopyridine (0.28 g) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.44 g), dissolved with stirring, and added with compound 7-k (0.5 g) and triethylamine (0.44 g) and reacted at room temperature for 3h. Washing with 5wt% hydrochloric acid, saturated sodium bicarbonate water solution, and saturated sodium chloride water solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by column chromatography to obtain compound 7-1 (0.8 g).
Compound 7-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝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) Preparation of Compound 8-k
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), heated to 85 ℃ for 5h, cooled at room temperature, left to stand overnight, and filtered to give compound 8-k (4.70 g). ESI-MS: m/z =316.1[ m-H ] -.
2) Preparation of Compound 8-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 8-k to give compound 8-1.
Compound 8-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝939.4[M+H] + .
example 9- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-acetylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 9-k
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), heated to 85 deg.C, reacted for 5h, cooled at room temperature, allowed to stand overnight, and filtered to give compound 9-k (1.2 g). ESI-MS: m/z =359.0[ m ] +H] + .
2) Preparation of Compound 9-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 9-k to give compound 9-1.
Compound 9-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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：m/z＝979.3[M+H] + .
example 10- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-isobutyrylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 10-k
3-nitro-4-fluorobenzenesulfonamide (1.48 g) and [ (4-isobutyrylmorpholin-2-yl) methyl]Amine (1.5 g) and N, N-diisopropylethylamine (2.2 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 5h, cooled at room temperature, allowed to stand overnight, and filtered with suction to give compound 10-k (1.8 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 10-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 10-k to give compound 10-1.
Compound 10-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1007.3[M+H] + .
example 11- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (R) - (4-methoxyacetyl-morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 11-k
3-nitro-4-fluorobenzenesulfonamide (0.36 g), (R) -2- (aminomethyl) -4-methoxyacetyl morpholine hydrochloride (0.45 g) and N, N-diisopropylethylamine (0.97 g) were dissolved in acetonitrile (20 mL), heated to 85 ℃ and reacted for 5h, cooled at room temperature, allowed to stand overnight, and filtered with suction to give compound 11-k (0.39 g). ESI-MS: m/z =387.1[ m-H ]] - 。
2) Preparation of Compound 11-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 11-k to give compound 11-1.
Compound 11-1: 1 H NMR(500MHz，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：m/z＝1010.4[M+H] + .
example 12- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-methanesulfonylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 12-k
3-nitro-4-fluorobenzenesulfonamide (0.66 g), [ (4-methanesulfonylmorpholin-2-yl) methyl]Amine (0.7 g) and N, N-diisopropylethylamine (0.97 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 5h, cooled at room temperature, left to stand overnight, and filtered under suction to give compound 12-k (1.2 g). ESI-MS: m/z =395.0[ M ] +H] + .
2) Preparation of Compound 12-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 12-k to give compound 12-1.
Compound 12-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1015.3[M+H] + .
example 13- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydro-2H-pyran-3-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 13-k
3-Nitro-4-chlorobenzenesulfonamide (1.0 g), 3-aminomethyl tetrahydropyran hydrochloride (0.77 g) and N, N-diisopropylethylamine (2.18 g) were dissolved in acetonitrile (20 mL), heated to 85 ℃ and reacted for 5 hours, cooled at room temperature, allowed to stand overnight, and suction-filtered to give compound 13-k (1.3 g). ESI-MS: m/z =314.1[ m-H ]] - 。
2) Preparation of Compound 13-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 13-k to give compound 13-1.
Compound 13-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝937.4[M+H] + .
example 14- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-tetrahydro-2H-pyran-2-ylmethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 14-k
3-nitro-4-chlorobenzenesulfonamide (1.2 g), 2-aminomethyl tetrahydropyran (0.7 g) and N, N-diisopropylethylamine (1.64 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ for reaction for 8h, cooled at room temperature, left to stand overnight, and filtered under suction to give 14-k (1.92 g). ESI-MS: m/z =316.0[ M ] +H] + .
2) Preparation of Compound 14-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 14-k to give compound 14-1.
Compound 14-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝936.4[M+H] + .
example 15- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (methylsulfonyl) piperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6 hours, cooled at room temperature, left overnight and filtered with suction to give 15-k (2.40 g). ESI-MS: m/z =393.1[ m ] +H] + .
2) Preparation of Compound 15-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 15-k to give compound 15-1.
Compound 15-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1013.3[M+H] + .
example 16- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (4-acetylmorpholin-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 16-k
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), heated to 85 ℃ for reaction for 6h, cooled at room temperature, left to stand overnight, and filtered to give 16-k (3.40 g). ESI-MS: m/z =373.1[ m ] +H] + .
2) Preparation of Compound 16-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 16-k to give compound 16-1.
Compound 16-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝993.3[M+H] + .
example 17- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (1-methylpiperidin-4-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6 hours, cooled at room temperature, left overnight and filtered with suction to obtain 17-k (3.56 g). ESI-MS: m/z =357.2[ m ] +H] + .
2) Preparation of Compound 17-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 17-k to obtain compound 17-1.
Compound 17-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝977.6[M+H] + .
example 18- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (1-methylpiperidin-4-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 18-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, left overnight and filtered to give 18-k (3.68 g) as a compound. ESI-MS: m/z =343.1[ M ] +H] + .
2) Preparation of Compound 18-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 18-k to give compound 18-1.
Compound 18-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝963.8[M+H] + .
example 19- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (1-ethylpiperidin-4-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, and filtered under suction to give 19-k (3.35 g). ESI-MS: m/z =357.2[ m ] +H] + .
2) Preparation of Compound 19-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 19-k to give compound 19-1.
Compound 19-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝977.7[M+H] + .
EXAMPLE 20 4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (1- (2-fluoroethyl) piperidin-4-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 20-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, and filtered to give compound 20-k (3.29 g). ESI-MS: m/z =375.1[ m ] +H] + .
2) Preparation of Compound 20-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 20-k to give compound 20-1.
Compound 20-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝995.4[M+H] + .
example 21- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (4- (methylsulfonyl) morpholin-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 21-k (3.52 g). ESI-MS: m/z =409.1[ m ] +H] + .
2) Preparation of Compound 21-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 21-k to give compound 21-1.
Compound 21-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1029.4[M+H] + .
example 22- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (4-isobutyrylmorpholin-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 22-k (3.42 g). ESI-MS: m/z =401.1[ m ] +H] + .
2) Preparation of Compound 22-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 22-k to give compound 22-1.
Compound 22-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1021.4[M+H] + .
example 23- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1-isobutyrylpiperidin-4-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6 hours, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 23-k (3.24 g). ESI-MS: m/z =385.2[ m ] +H] + .
2) Preparation of Compound 23-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 23-k to give compound 23-1.
Compound 23-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1005.4[M+H] + .
example 24- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-ethylmorpholin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 24-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, left overnight, concentrated and dried to give compound 24-k (3.51 g). ESI-MS: m/z =345.1[ m ] +H] + .
2) Preparation of Compound 24-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 24-k to give compound 24-1.
Compound 24-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝965.4[M+H] + .
example 25- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6 hours, cooled at room temperature, left overnight, concentrated and dried to give compound 25-k (2.91 g). ESI-MS: m/z =385.2[ m ] +H] + .
2) Preparation of Compound 25-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 25-k to give compound 25-1.
Compound 25-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1005.4[M+H] + .
example 26- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4- (3-oxetan) -morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 26-k
Referring to example 25, step 1) preparation of compound 25-k, compound 26-k was prepared by substituting 4- (3-oxetane) -2-aminomethyl morpholine for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine.
2) Preparation of Compound 26-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 26-k to give compound 26-1.
Example 27 4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4- (tetrahydropyran-4-yl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 27-k
Referring to the procedure for the preparation of compound 25-k in step 1) of example 25, compound 27-k was prepared by substituting 4- (tetrahydropyran-4-yl) -2-aminomethylmorpholine for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine.
2) Preparation of Compound 27-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 27-k to give compound 27-1.
Example 28- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4-cyclopropylsulfonylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 28-k
Referring to the procedure for the preparation of compound 25-k of example 25, step 1), compound 28-k (1.01 g) was prepared by substituting 4-cyclopropylsulfonyl-2-aminomethylmorpholine for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine.
2) Preparation of Compound 28-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 28-k to give compound 28-1.
Compound 28-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，δ：164.0，158.9，158.6，158.2，154.0，147.9，146.9，145.9，144.2，139.0，135.6，134.3，132.8，132.6，131.7，130.3，128.3，128.2，125.2，124.9，124.4，120.3，118.4，117.4，115.8，115.1，114.1，109.7，103.5，100.4，73.8，66.1，58.5，48.3，45.8，45.1，44.9，44.3，34.6，29.3，29.1，27.2，25.1，24.8，4.4，4.3.
example 29- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4-cyclopropylformylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 29-k
Referring to the procedure for the preparation of compound 25-k in step 1) of example 25, compound 29-k (0.85 g) was prepared by substituting 4-cyclopropylformyl-2-aminomethylmorpholine for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine.
2) Preparation of Compound 29-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 29-k to give compound 29-1.
Compound 29-1: 1 H NMR(500MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4- (oxetan-3-yl) formylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 30-k
Referring to the procedure for the preparation of compound 25-k in step 1) of example 25, compound 30-k (0.85 g) was prepared by substituting 4- (oxetan-3-yl) formyl-2-aminomethyl morpholine for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine.
2) Preparation of Compound 30-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 30-k to give compound 30-1.
Example 31- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4-cyclobutylsulfonylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 31-k
Referring to example 25, step 1) preparation of compound 25-k, 4-cyclobutylsulfonyl-2-aminomethylmorpholine was used in place of 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to give compound 31-k (0.98 g).
2) Preparation of Compound 31-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 31-k to give compound 31-1.
Compound 31-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4- (oxetan-3-yl) sulfonylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 32-k
Referring to example 25, step 1) preparation of compound 25-k, 4- (oxetan-3-yl) sulfonyl-2-aminomethylmorpholine was used in place of 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to give compound 32-k (1.01 g).
2) Preparation of Compound 32-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 32-k to give compound 32-1.
Example 33 (S) -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) Preparation of Compound 33-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (S) -4-aminotetrahydrofuran hydrochloride to give compound 33-k (1.72 g).
2) Preparation of Compound 33-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 33-k to obtain compound 33-1.
Compound 33-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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) Preparation of Compound 34-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (R) -4-aminotetrahydrofuran hydrochloride to give compound 34-k (1.65 g).
2) Preparation of Compound 34-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 34-k to give compound 34-1.
Compound 34-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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 (R) -4- (4- { {2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydrofuran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 35-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (3R) -tetrahydrofuran-3-methylamine to give compound 35-k (1.10 g).
2) Preparation of Compound 35-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 35-k to give compound 35-1.
Compound 35-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydrofuran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 36-k
Referring to example 25, step 1) a preparation method of compound 25-k, (3S) -tetrahydrofuran-3-methylamine (0.64 g) was substituted for 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine to give compound 36-k (1.39 g).
2) Preparation of Compound 36-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 36-k to give compound 36-1.
Compound 36-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydrofuran-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 37-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (S) -2-tetrahydrofurfuryl amine to give compound 37-k (1.35 g).
2) Preparation of Compound 37-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 37-k to give compound 37-1.
Compound 37-1: 1 H NMR(500MHz，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(125MHz，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 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydrofuran-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 38-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (R) -2-tetrahydrofurfuryl amine to give compound 38-k (1.38 g).
2) Preparation of Compound 38-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 38-k to give compound 38-1.
Compound 38-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydropyran-4-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 39-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 4-aminotetrahydropyran to give compound 39-k (1.70 g).
2) Preparation of Compound 39-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 39-k to give compound 39-1.
Compound 39-1: 1 H NMR(500MHz，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(125MHz，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 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydropyran-3-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 40-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (S) -3-aminotetrahydropyran hydrochloride to give compound 40-k (1.08 g).
2) Preparation of Compound 40-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 40-k to give compound 40-1.
Compound 40-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，δ：164.0，158.9，158.6，158.2，154.0，146.9，145.9，144.2，135.6，134.6，132.8，131.8，130.2，130.0，128.4，127.0，125.3，124.9，124.4，120.3，118.3，117.6，115.7，115.3，114.2，109.7，103.5，100.4，70.1，67.8，58.5，48.1，45.2，44.3，34.6，29.3，29.1，27.7，27.1，24.8，23.0，1.6.
example 41 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (tetrahydropyran-3-yl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 41-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (R) -3-aminotetrahydropyran hydrochloride to give compound 41-k (0.95 g).
2) Preparation of Compound 41-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 41-k to give compound 41-1.
Compound 41-1: 1 H NMR(500MHz，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(125MHz，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 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydropyran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 42-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (R) -3-aminomethyl tetrahydropyran hydrochloride to give compound 42-k (0.36 g).
2) Preparation of Compound 42-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 42-k to give compound 42-1.
Compound 42-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((tetrahydropyran-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 43-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with (S) -3-aminomethyltetrahydropyran hydrochloride, to give compound 43-k (0.39 g).
2) Preparation of Compound 43-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 43-k to give compound 43-1.
Compound 43-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (tetrahydropyran-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 44-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2- (tetrahydro-2H-pyran-2-yl) ethylamine hydrochloride to give compound 44-k (1.18 g).
2) Preparation of Compound 44-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 44-k to give compound 44-1.
Compound 44-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (tetrahydropyran-3-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 45-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2- (tetrahydro-2H-pyran-3-yl) ethylamine to give compound 45-k (1.06 g).
2) Preparation of Compound 45-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 45-k to give compound 45-1.
Compound 45-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (N-ethylmorpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 46-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with N-ethyl-2-propylaminomorph hydrochloride to give compound 46-k (2.03 g).
2) Preparation of Compound 46-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 46-k to give compound 46-1.
Example 47 4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (N- (2-fluoroethyl) morpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 47-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with N- (2-fluoroethyl) -2-propylaminomorpholine hydrochloride to give compound 47-k (2.03 g).
2) Preparation of Compound 47-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 47-1 was obtained by replacing compound 7-k with compound 47-k.
Example 48- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((N-formylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 48-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with N-formyl-2-aminomethylmorpholine hydrochloride to give compound 48-k (0.50 g).
2) Preparation of Compound 48-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 48-k to give compound 48-1.
Compound 48-1: 1 H NMR(500MHz，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(125MHz，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- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((N-methanesulfonylmorpholin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 49-k
Referring to example 25, step 1) A preparation method of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with N-methanesulfonyl-3-aminomethylmorpholine to give compound 49-k (0.63 g).
2) Preparation of Compound 49-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 49-k to give compound 49-1.
Example 50- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-pivaloylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 50-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4-pivaloylmorpholine to give compound 50-k (1.71 g).
2) Preparation of Compound 50-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 50-k to give compound 50-1.
Compound 50-1: 1 H NMR(500MHz，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(125MHz，DMSO-d6)，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (2-cyanoacetyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 51-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- (2-cyanoacetyl) morpholine to give compound 51-k (1.61 g).
2) Preparation of Compound 51-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 51-k to give compound 51-1.
Compound 51-1: 1 H NMR(500MHz，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(125MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (2, 2-trifluoroacetyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 52-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- (2, 2-trifluoroacetyl) morpholine to give compound 52-k (1.75 g).
2) Preparation of Compound 52-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 52-k to give compound 52-1.
Compound 52-1: 1 H NMR(500MHz，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(125MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (trifluoromethyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 53-k
Referring to example 25, step 1) A preparation method of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- (trifluoromethyl) morpholine to give compound 53-k (1.64 g).
2) Preparation of Compound 53-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 53-k to give compound 53-1.
Example 54- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (perfluoroethyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 54-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- (perfluoroethyl) morpholine to give compound 54-k (1.93 g).
2) Preparation of Compound 54-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 54-k to give compound 54-1.
Example 55- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- ((perfluoroethyl) sulfonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 55-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- ((perfluoroethyl) sulfonyl) morpholine to give compound 55-k (2.05 g).
2) Preparation of Compound 55-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 55-k to obtain compound 55-1.
Example 56- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- ((trifluoromethyl) sulfonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 56-k
Referring to example 25, step 1) preparation of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- ((perfluoroethyl) sulfonyl) morpholine to give compound 56-k (1.75 g).
2) Preparation of Compound 56-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 56-k to give compound 56-1.
Compound 56-1: 1 H NMR(500MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (ethylsulfonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 57-k
Referring to example 25, step 1) a preparation method of compound 25-k, 4-aminomethyl-1- (tetrahydro-2H-pyran) piperidine was replaced with 2-aminomethyl-4- (ethylsulfonyl) morpholine to give compound 57-k.
2) Preparation of Compound 57-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 57-k to give compound 57-1.
Compound 57-1: 1 H NMR(500MHz，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(125MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (2-methoxyacetyl) piperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperatureThen, the mixture was allowed to stand overnight, concentrated and dried to obtain 58-k (1.51 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 58-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 58-k to give compound 58-1.
Compound 58-1: 1 H NMR(500MHz，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：m/z＝1007.4[M+H] + .
example 59- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (methylglycyl) piperidin-4-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 59-k
3-Nitro-4-fluorobenzenesulfonamide (0.91 g), 4-aminomethyl-1- (methylglycidyl) piperidine (0.99 g) and N, N-diisopropylethylamine (1.34 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 59-k (1.62 g). ESI-MS: m/z =400.1[ M ] +H] + .
2) Preparation of Compound 59-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 59-k to give compound 59-1.
ESI-MS：m/z＝1020.4[M+H] + .
Compound 59-1: 1 H NMR(500MHz，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(125MHz，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- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (1- (methylglycyl) piperidin-3-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 60-k
3-nitro-4-fluorobenzenesulfonamide (0.90 g), 3-aminomethyl-1- (methylglycidyl) piperidine (0.98 g) and N, N-diisopropylethylamine (1.32 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 60-k (1.58 g). ESI-MS: m/z =400.0[ M ] +H] + .
2) Preparation of Compound 60-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 60-k to give compound 60-1.
Compound 60-1: 1 H NMR(500MHz，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：m/z＝1020.4[M+H] + .
example 61 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-acetylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 61-k (0.89 g). ESI-MS: m/z =359.0[ m ] +H] + .
2) Preparation of Compound 61-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 61-k to give compound 61-1.
Compound 61-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝979.4[M+H] + .
example 62 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-isobutyrylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 62-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 62-k (0.87 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 62-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 62-k to give compound 62-1.
Compound 62-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1007.4[M+H] + .
example 63 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (methylsulfonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 63-k (0.68 g). ESI-MS: m/z =395.0[ m ] +H] + .
2) Preparation of Compound 63-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 63-k to give compound 63-1.
Compound 63-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1015.3[M+H] + .
example 64 (S) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (2-methoxyacetyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 64-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, left overnight, concentrated and dried to give compound 64-k (0.68 g). ESI-MS: m/z =389.0[ m ] +H] + .
2) Preparation of Compound 64-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 64-k to give compound 64-1.
Compound 64-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1009.4[M+H] + .
example 65 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ ((4-acetylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give 65-k (0.89 g). ESI-MS: m/z =359.0[ m ] +H] + .
2) Preparation of Compound 65-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 65-k to give compound 65-1.
Compound 65-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝979.4[M+H] + .
example 66 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4-isobutyrylmorpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 66-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 66-k (0.87 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 66-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 66-k to give compound 66-1.
Compound 66-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1007.4[M+H] + .
example 67 (R) -4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (methylsulfonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 67-k (0.68 g). ESI-MS: m/z =395.0[ M ] +H] + .
2) Preparation of Compound 67-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 67-k to give compound 67-1.
Compound 67-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1015.3[M+H] + .
example 68- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (4-acetylmorpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 68-k
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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 68-k (1.67 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 68-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 68-k to give compound 68-1.
Compound 68-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1007.4[M+H] + .
example 69 4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (4-isobutyrylmorpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give 69-k (1.69 g). ESI-MS: m/z =415.1[ m ] +H] + .
2) Preparation of Compound 69-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 69-1 was obtained by replacing compound 7-k with compound 69-k.
Compound 69-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1035.3[M+H] + .
example 70- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (4- (2-methoxyacetyl) morpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 70-k
Dissolving 3-nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminopropyl-3- (4- (2-methoxyacetyl) morpholine (1.42 g) and N, N-diisopropylethylamine (4.59 g) in acetonitrile (10 mL), heating to 85 ℃, reacting for 6h, cooling at room temperature, standing overnight, concentrating and drying to obtain a compound 70-k (1.71 g), ESI-MS: m/z =417.1[ M + H ]] + .
2) Preparation of Compound 70-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 70-k to give compound 70-1.
Compound 70-1: 1 H NMR(500MHz，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：m/z＝1037.2[M+H] + .
example 71- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (3- (4- (2-methylsulfonyl) morpholin-2-yl) propyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 71-k
Reacting 3-nitro-4-fluorobenzenesulfonamide (b)1.13 g), 2-aminopropyl-3- (4- (2-methanesulfonyl) morpholine (1.36 g) and N, N-diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 71-k (1.51 g). ESI-MS: m/z =423.0[ m ] +H] + .
2) Preparation of Compound 71-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 71-k to give compound 71-1.
Compound 71-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1043.2[M+H] + .
example 72- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (2- (4- (2-methoxyacetyl) morpholin-2-yl) ethyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 72-k
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 addedThe reaction was carried out for 6 hours while heating to 85 ℃ and then cooling at room temperature, followed by standing overnight, concentration and drying to obtain 72-k (1.56 g). ESI-MS: m/z =403.0[ m ] +H] + .
2) Preparation of Compound 72-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 72-k to give compound 72-1.
Compound 72-1: 1 H NMR(500MHz，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：m/z＝1023.3[M+H] + .
example 73 4- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [1- (2-methoxyacetyl) piperidin-4-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide
1) Preparation of Compound 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), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 73-k (2.58 g). ESI-MS: m/z =387.0[ m ] +H] + .
2) Preparation of Compound 73-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k was changed to compound 73-k to give compound 73-1.
Compound 73-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1007.3[M+H] + .
example 74- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (ethoxyformyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide (Compound 74-1)
1) Preparation of Compound 74-k
3-nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminomethyl-4- (ethoxycarbonyl) morpholine (1.23 g) and N, N-diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6h, cooled at room temperature, allowed to stand overnight, concentrated and dried to give compound 74-k (1.80 g). ESI-MS: m/z =387.1[ M-H ]] - .
2) Preparation of Compound 74-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 74-k to obtain compound 74-1.
Compound 74-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝1009.3[M+H] + .
example 75- (4- { [2- (2-chloro-4-trifluoromethylphenyl) -4, 4-dimethylcyclohex-1-enyl ] methyl } -piperazin-1-yl) -N- ({ 3-nitro-4- [ (4- (methoxycarbonyl) morpholin-2-yl) methyl) amino ] phenyl } sulfonyl) -2- (1H-pyrrolo [2,3-b ] pyridin-5-yloxy) -benzamide (Compound 75-1)
1) Preparation of Compound 75-k
3-nitro-4-fluorobenzenesulfonamide (1.20 g), 2-aminomethyl-4- (methoxycarbonyl) morpholine (1.14 g) and N, N-diisopropylethylamine (4.59 g) were dissolved in acetonitrile (10 mL), heated to 85 ℃ and reacted for 6h, cooled at room temperature, left overnight, concentrated and dried to give compound 75-k (1.73 g). ESI-MS: m/z =373.1[ M-H ]] - .
2) Preparation of Compound 75-1
Referring to the preparation method of compound 7-1 in step 6) of example 7, compound 7-k therein was changed to compound 75-k to give compound 75-1.
Compound 75-1: 1 H NMR(500MHz，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(125MHz，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：m/z＝995.3[M+H] + .
example 76 example 82
Referring to the procedure of example 7, the following compound was obtained:
test example 1 in vitro protein binding inhibitory Activity
1.1 BCL-2/BAK binding inhibition Activity screening
500nM of Tag1-BCL-2 protein stock was diluted to 5nM with dilution buffer in a kit (model: BCL-2/BAK (BH 3) BINDINGASSAYKITS, from cisbio), while 20. Mu.M of Tag2-BAK protein stock was diluted to 120nM, and 5. Mu.L of Tag1-BCL was added to each well-2 protein dilutions, then adding different compounds dissolved in DMSO to the wells with a nanoliter loading apparatus to give a final concentration of compounds of 200nM-0.0488nm, 4-fold gradient of 7 concentrations, while setting blank control wells (no enzyme) and negative control wells (containing enzyme, vehicle DMSO), setting 2 duplicate wells, finally adding 5 μ L of Tag2-BAK protein dilutions per well, mixing by centrifugation, and incubating for 15min at 25 ℃. Using detection buffer solution in the kit to mix 100 times of anti-Tag1-Eu 3+ The diluted concentration is 1X, and 100X anti-Tag2-XL665 is diluted to 1X. anti-Tag1-Eu 3+ Mixing with anti-Tag2-XL665 at a ratio of 1: 1, adding 5. Mu.L of the mixed solution into each well, and reacting at 25 ℃ for 2h or more. Reading the plate (excitation is 620nm and emission is 665 nm) by using a PE Envision multifunctional microplate reader, and calculating IC (integrated Circuit) by adopting four-parameter fitting 50 (shown in Table 1).
1.2 BCL-XL/BAK binding inhibitory Activity screening
300nM of Tag1-BCL-XL protein stock solution was diluted to 2nM with a dilution buffer in a kit (model: BCL-XL/BAK (BH 3) BINDING ASSAYKITS, from cisbio), 10. Mu.M of Tag2-BAK protein stock solution was diluted to 80nM, 5. Mu.L of Tag1-BCL-XL protein diluent was added to each well, then DMSO-dissolved different compounds were added to the wells with a nanoliter loading apparatus to give a final compound concentration of 2000nM-0.488nM, 4-fold gradient for 7 concentrations, a blank control well (containing no enzyme) and a negative control well (containing enzyme, DMSO-vehicle) were incubated, 2 replicate wells were set, and finally 5. Mu.L of Tag2-BAK protein diluent was added to each well, centrifuged and mixed for 15min at 25 ℃. 100x of anti-Tag1-Eu is mixed with detection buffer in the kit 3+ The diluted solution is diluted to 1 × using concentration, and meanwhile, 100 × anti-Tag2-XL665 is diluted to 1 × using concentration. anti-Tag1-Eu 3+ Mixing with anti-Tag2-XL665 at a ratio of 1: 1, adding 5. Mu.L of the mixed solution into each well, and reacting at 25 ℃ for 2h or more. Reading the plate (excitation is 620nm and emission is 665 nm) by using a PE Envision multifunctional microplate reader, and calculating IC (integrated Circuit) by adopting four-parameter fitting 50 (shown in Table 1).
TABLE 1 Compounds inhibit BCL-2/BAK and BCL-XL/BAK binding Activity
Test example 2 compound vs RS4;11 cell proliferation inhibitory Effect
Taking RS4 in an exponential growth phase with good state; 11 cells (from beijing baibo), collect cells to centrifuge tube, low speed table centrifuge, 1500 rpm, centrifuge for 3min, discard supernatant, pipette 5mL complete medium (RPMI basal medium +10wt% Fetal Bovine Serum (FBS)) for cell resuspension. Counting with a cell counter, diluting with complete medium, and adjusting cell density to 2 × 10 5 each/mL, the serum concentration was adjusted to 5% by adding an equal amount of RPMI basal medium, and the cell density was 1X 10 5 seed/mL plate. Inoculating on a 96-well plate using a row gun at 100. Mu.L/well, at 37 ℃ with 5% CO 2 Culturing in a cell culture box with saturated humidity. After 24h of incubation, compound loading was performed using a nanoliter loading apparatus, 2 duplicate wells were set for each concentration, cells without compound were used as negative control, CCK-8 reagent was added after 72h, 10 μ L/well, absorbance was measured at 450nm with an Envision microplate reader after 4h, inhibition was calculated, inhibition (%) = (negative control mean-experimental mean)/(negative control mean-blank mean) × 100%, compound log concentration was plotted as abscissa, inhibition was plotted as ordinate, four parameter analysis, dose-effect curve was fitted, and IC50 was calculated (see table 2).
Compound of table 2 vs RS4;11 cell proliferation inhibitory Effect
Test example 3 evaluation of in vitro hepatic microsomal stability
300 μ L of the final incubated system contained 30 μ L of liver microsomes (protein concentration: 5 mg/mL), 30 μ L of ADADPPH + MgCl 2 mu.L of test compound (in acetonitrile), 237. Mu.L of PBS buffer (pH 7.4). Wherein the proportion of the organic solvent (acetonitrile) is 1 percent (volume ratio). Each species (mouse, rat, human) was made in 2 aliquots of 0.3mL each. Preparing a substrate and enzyme mixing solution with a total volume of 270 mu L for each tube, pre-incubating NADPH at 37 ℃ for 5min, and adding 30 mu L of NADPH + MgCl 2 After mixing, 50. Mu.L of glacial acetonitrile containing an internal standard was added at 0, 15, 30 and 60min to terminate the reaction with 300. Mu.L of glacial acetonitrile containing an internal standard.
50 μ L of the incubated sample was precipitated by adding 300 μ L of glacial acetonitrile containing an internal standard (diazepam 20 ng/mL), vortexed for 5min, and centrifuged (13000rpm, 20 ℃) for 10min. And (4) sucking 70 mu L of supernatant, adding 70 mu L of ultrapure water for dilution and mixing uniformly, and carrying out sample injection analysis by 1 mu L. The parameters for the elimination of compounds in human, rat and mouse liver microsomes are shown in table 3.
TABLE 3 Compound in vitro hepatic microsomal metabolic stability (1. Mu.M)
Test example 4 evaluation of pharmacokinetics in vivo
4.1 evaluation of pharmacokinetics in rats
SD rats weighing 180-220 g are adapted for 3-5 days, and then are randomly grouped, 3 rats in each group are intragastrically administered with the compounds 1-1 and 8-1 according to the dose of 5 mg/kg.
The test animals (SD rats) were fasted for 12h before administration and food for 4h after administration, and water was freely drunk before and after the experiment and during the experiment.
After the intragastric administration, 0.2mL of blood is taken from the orbit for 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 24h, after EDTA-K2 anticoagulation, the blood plasma is transferred to 4 ℃ within 30min, 4000rpm and 10min for centrifugal separation. All plasma was collected and immediately stored at-20 ℃ for testing.
Absorbing 50 mu L of a plasma sample to be detected, adding 300 mu L of acetonitrile solution containing an internal standard (diazepam 20 mg/mL), oscillating and uniformly mixing for 5min, centrifuging at 13000rpm for 10min, taking 75 mu L of supernatant, adding 75 mu L of ultrapure water for dilution, uniformly mixing, absorbing 2 mu L of the diluted solution for LC/MS/MS determination, and recording a chromatogram.
Oral exposure of the compounds of the invention was assessed by in vivo pharmacokinetic experiments in rats. The pharmacokinetic parameters of the compounds were fitted using das3.2.5 software as shown in the table below.
The drug substitution data of the compounds 1-1 and 8-1 are shown in the following Table 4-1.
TABLE 4 pharmacokinetic parameters of the Compounds
4.2 evaluation of Biggee in vivo pharmacokinetics
After 3 male beagle dogs with weight of 9-12 kg are adapted for a period of time, the test compounds are separately gavaged at a dose of 2.5 mg/kg.
The test animals (male beagle dogs) were fasted for 12h before administration and food for 4h after administration, and had free access to water both before and after and during the experiment.
After the administration by gavage, about 0.5mL of blood was collected from the forelimb vein at 0.25h (15 min), 0.5h (30 min), 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, 48h, and 72h, and placed in an EDTA-K2 anticoagulation vacuum blood collection tube, and the plasma was transferred to 4 ℃ within 30min, 4000rpm, and 10min for centrifugal separation. All plasma was collected and immediately stored at-20 ℃ for testing.
Absorbing 50 mu L of a plasma sample to be detected, adding 300 mu L of acetonitrile solution containing an internal standard (diazepam 20 ng/mL), oscillating and uniformly mixing for 5min, centrifuging at 13000rpm for 10min, taking 75 mu L of supernatant, adding 75 mu L of ultrapure water for dilution, uniformly mixing, absorbing 1 mu L of the diluted solution for LC/MS/MS determination, and recording a chromatogram.
Oral exposure of the compounds of the invention was evaluated by a beagle in vivo pharmacokinetic experiment. The pharmacokinetic parameters of the compounds were fitted using DAS3.2.5 software as shown in Table 4-2 below.
In vivo pharmacokinetic parameters of beagle dogs for Compounds of Table 4-2
Test example 5 the test substance was identified in RS4;11 pharmacodynamic evaluation in human B-cell leukemia subcutaneous transplantation model
NOD/SCID mice, female, 9-10 weeks (week old mice when tumor cells were inoculated), weight 16.3-22.0g. Purchased from Ankai Yibo Biotechnology Ltd, producing license number: SCXK (jing) 2017-0006, animal certification No.: 11402400013155. a breeding environment: SPF grade. Mice right anterior dorsal subcutaneous inoculation of 1X 10 7 RS4;11 cells. The day of inoculation was defined as day 0. Average volume of tumor to be detected is 240mm 3 Time, groups were randomized according to tumor size. The following table 5 was used for administration.
Table 5 human B-cell leukemia RS4;11 routes of administration, dosages and regimens in subcutaneous animal models
Group of n Administration set Dosage (mg/kg) Mode of administration Time of administration
1 6 Vehicle p.o. Single pass
2 6 1-1 25 p.o. Single pass
3 6 1-1 50 p.o. Single pass
4 6 8-1 25 p.o. Single pass
Note: n: the number of animals; the administration volume was 10. Mu.L/g.
Clinical symptoms observed during the experiment were recorded in the raw data. Tumor volume calculation formula: tumor volume (mm) 3 )＝1/2×(a×b 2 ) (wherein a represents a long diameter and b represents a short diameter). studyDirector was used in the experiment TM (version number 3.1.399.19, supplier studio System, inc., s.san Francisco, CA, USA) software data were collected, including measurements of the long and short diameters of tumors and weighing of animal weights. The original data is directly imported into software after being measured by a balance and a vernier caliper, and the data is obtainedAny changes will be recorded in this software. Relative tumor proliferation rate, T/C%, is the percentage value of the relative tumor volume or tumor weight of the treated and control groups at a time point. The calculation formula is as follows:
T/C％＝T RTV /C RTV ×100％(T RTV : mean RTV for treatment groups; c RTV : vehicle control mean RTV; RTV = V t /V 0 ，V 0 Is the tumor volume of the animal in the group, V t Tumor volume in the animal after treatment).
Relative tumor inhibition, TGI (%), calculated as follows: TGI% = (1-T/C) × 100%. (T and C are the Relative Tumor Volume (RTV) or Tumor Weight (TW) at a particular time point for the treated and control groups, respectively).
All experimental results are expressed as mean tumor volume ± SEM (mean standard error). Independent sample T test method is used to compare the relative tumor volume of the treated group with that of the control group. All data were analyzed using SPSS 18.0. p < 0.05 is a significant difference. The results are shown in Table 6.
Table 6 in human B-cell leukemia RS4;11 table for analyzing drug effect of each group in subcutaneous model
Note: 1. data are expressed as "mean ± standard error";
2.T/C％＝T RTV /C RTV ×100％；TGI％＝(1-T/C)×100％。
test example 6 human platelet toxicity test (Caspase 3 Activity assay)
10mL of human whole blood is extracted by using a heparin sodium anticoagulation tube, the whole blood is evenly mixed by turning upside down, 90g of the mixture is centrifuged for 10min, and the supernatant is collected and then 1950g of the supernatant is centrifuged for 10min. Discarding supernatant, resuspending and mixing with 4mL PBS, centrifuging for 5min at 1190g, discarding supernatant, resuspending platelets with PBS and adjusting density to 2-3 × 10 8 One per mL. According to 2-3X 10 7 one/mL of the cells were seeded in a 96-well plate at 100. Mu.L/well,50 μ L of control buffer was added to the negative control wells, 50 μ L of compound was added to each well of the compound wells to give a final concentration of 2.5 μ M,2 μ M,1 μ M or 0.5 μ M, and the wells were incubated at 37 ℃ for 90min in an incubator. The liquids in the 96-well plates were transferred to 1.5mL centrifuge tubes, respectively. Centrifuging at 4 deg.C at 6000g for 5min, discarding supernatant, and placing on ice for use. Diluting 5 × lysate into 1 × lysate with water provided in the kit, and adding protease inhibitor cocktail according to the ratio of 1: 200 to prepare a lysis mixed solution to be used. Adding 40 mu L of lysis mixed solution into each centrifuge tube, resuspending the platelets at the bottom by a pipettor, lysing for 15-20min on ice, centrifuging for 10min at 14000g at 4 ℃, and subpackaging the samples for later use. A reaction mixture was prepared by diluting 10X of the detection solution with water supplied from the kit to 1X of the detection solution and adding substrate Ac-DEVD-AMC at a ratio of 1: 600. Add 5. Mu.L of assay buffer to the blank wells and 40. Mu.L of reaction mix. To the negative control well, 5. Mu.L of control platelet lysate and 40. Mu.L of reaction mixture were added. In the compound group, 5. Mu.L of platelet lysate and 40. Mu.L of reaction mixture were added. Wherein 40 μ L of reaction mixture is added at last, mixed gently, and read by PE Envision multifunctional microplate reader (excitation 360nm, emission 46 nm), and the detection is performed once every 10min for 6 times. Caspase-3 activity was determined based on the intensity of released AMC fluorescence, i.e., the slope of the line fitted to each well represents the Caspase activity (all data were normalized and baseline was ABT-199). The results are shown in tables 7 and 8.
Effect of the Compounds of Table 7 on human platelet Caspase3 Activity
Note: the data is normalized.
Effect of the Compounds of Table 8 on human platelet Caspase3 Activity
Note: the data were normalized.

Claims (23)

1. A compound of formula I, stereoisomers thereof or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
R 1 selected from chlorine;
R 2 is selected from- (CH) 2 ) n -R 3 N is selected from 1, 2 or 3;
R 3 selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, C 3-4 Cycloalkyl, -COR a 、-SO 2 R b 、-COOC 1-6 Alkyl, or C optionally substituted by halogen 1-6 An alkyl group;
R a or R b Each independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-6 Alkyl radical, said C 1-6 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-6 Alkyl radical) 2 、-NHC 1-6 Alkyl, or-OC 1-6 Alkyl substitution;
structural fragmentIs selected from
2. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R 2 Is selected from- (CH) 2 ) n -R 3 Wherein n is selected from 1 or 2.
3. A compound of formula I according to claim 1, its stereoisomers or their pharmaceuticalsA salt acceptable as above, wherein R 2 Is selected from- (CH) 2 ) n -R 3 Wherein n is selected from 1.
4. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups at the ring's N atom.
5. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 3-6 membered heterocycloalkyl, -COR a 、-SO 2 R b 、-COOC 1-4 Alkyl-substituted or optionally halogen-substituted C 1-6 An alkyl group.
6. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R a Or R b Each independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl radical, said C 1-4 Alkyl is optionally substituted by halogen, -CN, -N (C) 1-4 Alkyl radical) 2 、-NHC 1-4 Alkyl, or-OC 1-4 And (3) alkyl substitution.
7. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, or monooxycyclobutyl, said methyl or ethyl being optionally substituted by fluoro, -CN, -OCH 3 or-N (CH) 3 ) 2 And (4) substitution.
8. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in claim 7, wherein R a Or R b Each independently selected from H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, pentafluoroethyl, -CH 2 OCH 3 、-CH 2 CN, or-CH 2 N(CH 3 ) 2 Cyclopropyl, cyclobutyl, or monooxycyclobutyl.
9. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 6, wherein R a Or R b Each independently selected from optionally substituted-OC 1-4 Alkyl substituted C 1-4 An alkyl group.
10. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 9, wherein R a Or R b Each independently selected from methyl, isopropyl, or-CH 2 OCH 3 。
11. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Selected from 5-6 membered heterocycloalkyl, said 5-6 membered heterocycloalkyl 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, monooxyoxetane, -SO 2- Cyclopropane, -CO-monooxyoxetane, -SO 2- Monooxetane, -SO 2- Cyclobutane, -COOCH 2 CH 3 or-COOCH 3 。
12. A compound of formula I according to claim 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereofSalt of, wherein R 3 Selected from tetrahydropyran, piperidine, morpholine or dioxane, 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 。
13. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in claim 12, wherein R 3 Selected from tetrahydropyran, piperidine, morpholine or dioxane, 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 。
14. A compound of formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in claim 13, wherein R 3 Selected from tetrahydropyran, piperidine, morpholine or dioxane, optionally substituted with: -COCH 3 、-COCH(CH 3 ) 2 、-COCH 2 OCH 3 、-SO 2 CH 3 Ethyl group, -COOCH 2 CH 3 or-COOCH 3 。
15. A compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein R 3 Is selected from
16. A compound of formula I as claimed in claim 15, wherein R is a stereoisomer thereof or a pharmaceutically-acceptable salt thereof 3 Is selected from
17. A compound of formula I as claimed in claim 16, wherein R is a stereoisomer thereof or a pharmaceutically-acceptable salt thereof 3 Is selected from
18. The following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof,
；
or the following compounds:
wherein R is independently the following group:
19. a compound which is a compound having a structure represented by formula (I),
or the following compounds:
whereinAnd R is independently the following group:
20. a pharmaceutical composition comprising a compound of any one of claims 1-19, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
21. Use of a compound of any one of claims 1-19, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the prevention or treatment of a disease associated with the anti-apoptotic protein BCL-2.
22. The use of claim 21, wherein the disease associated with the anti-apoptotic protein BCL-2 is selected from the group consisting of cancer.
23. The use of claim 21, wherein the disease associated with the anti-apoptotic protein BCL-2 is selected from acute lymphocytic leukemia.
HK62021041230.5A 2018-10-29 2019-10-29 Trifluoromethyl-substituted sulfonamide as bcl-2-selective inhibitor HK40051476B (en)

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