CN112661751A

CN112661751A - Heterocyclic compounds as BCL-2 inhibitors

Info

Publication number: CN112661751A
Application number: CN201910983464.1A
Authority: CN
Inventors: 孔祥龙; 周超; 郑之祥
Original assignee: Nanjing Innocare Pharma Tech Co ltd
Current assignee: Nanjing Innocare Pharma Tech Co ltd
Priority date: 2019-10-16
Filing date: 2019-10-16
Publication date: 2021-04-16

Abstract

The present invention relates to compounds, pharmaceutical compositions containing them, and methods for their preparation and use as B-cell lymphoma-2 (BCL-2) inhibitors. The compound is a compound shown in a formula I, or an isomer, a prodrug, a solvate, a stable isotope derivative or a pharmaceutically acceptable salt thereof. The invention also relates to the use of said compounds or compositions containing them for the treatment or prevention of related diseases mediated by BCL-2, such as tumours.

Description

Heterocyclic compounds as BCL-2 inhibitors

Technical Field

The present invention relates to compounds, pharmaceutical compositions containing them and their use as B-cell lymphoma-2 (BCL-2) inhibitors. More particularly, the present invention provides novel compounds that are inhibitors of BCL-2, pharmaceutical compositions containing such compounds, and the use of such compounds to treat or prevent diseases and disorders associated with BCL-2 mediated disorders, such as tumors. The invention also relates to a method for preparing said compounds.

Background

The BCL-2 protein family is one of the core regulatory mechanisms of apoptosis (also called programmed cell death), can receive and transmit Intrinsic intracellular signals or external environmental stress signals, such as nutritional or hypoxic stress, DNA damage, oncogene over-activation, endoplasmic reticulum stress, etc., and mainly plays a leading role in the Intrinsic pathway of apoptosis (Intrinsic pathway). BCL-2 (B-cell lymphoma-2) protein was first discovered in 1986 and expressed by the BCL-2 gene. The BCL-2 gene is a protooncogene, and the protein expressed therefrom is called a BCL-2 family protein. A total of 27 BCL-2 family proteins are present in humans and can be divided into 3 subclasses according to functional and sequence analysis, the first subclass being apoptosis-antagonistic, including BCL-X_LBCL-2, BCL-W, MCL-1 and BFL-1, which are mainly positioned on mitochondria to protect mitochondria from adversity damage; the other two subclasses are those that promote apoptosis, one of which is the ultimate performer of mitochondrial damage, including BAX and BAK. The rest of the genes are classified in BH3 subclass, and can directly sense various cell adversity stress signals. The dynamic balance of interactions between proteins that antagonize and promote apoptosis determines the life and death of a cell. BCL-2 protein for antagonizing apoptosis is closely related to tumors, and abnormal over-expression of BCL-2 family protein exists in about 50 percent of tumors (such as leukemia, rectal cancer, prostate cancer and the like), wherein abnormal BCL-2 activity exists widely in blood tumors. Multiple signaling pathways such as JAK-STAT, NFkB, UPP (ubiquitin-protesome) and the like can cause over-expression of BCL-2 protein which antagonizes apoptosis.

The high expression of BCL-2 family antagonistic apoptosis protein is related to drug resistance of various tumors, for example, the overexpression of BCL-2 antagonistic apoptosis protein can make tumor cells escape apoptosis caused by antitumor drugs, thereby causing drug resistance. It has been shown that inhibition of BCL-2 family proteins inhibits tumor neovascularization and thus tumor metastasis: (Benjamin, D. ; Isaac, J. et al.J. Clin. Oncol.2008, 26(25), 4180). Therefore, the target inhibition of the BCL-2 family anti-apoptosis protein can inhibit the occurrence, development and drug resistance of tumors.

Although more than 20 small molecule inhibitors targeting the BCL-2 family have been reported, with little clinical experience, only 1 of 26 treated Chronic Lymphocytic Leukemia (CLL) cases of the orboclax from terrawa obtained partial responses and had strong neurotoxicity, terminating development in 2013; navitoclax (ABT-263) developed by Erberella does show a good response rate of 50% in phase I dose ramp-up experiments of patients with relapsed or refractory lymphoid malignancies, but also shows a very strong BCL-X_LTargeted toxicity of (3): such as platelet depletion and severe anemia. Venetocalax (ABT-199), developed by Erbery in combination with Roche, is a highly selective inhibitor of BCL-2 (Andrew, J.; Joel, D).et al. Nature Medicine2013, 19(2), 202), in the treatment of relapsed/refractory Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Multiple Myeloma (MM) and the like, both Objective Remission Rate (ORR) and complete remission rate (CR) were greatly improved by combined administration with Ibrutinib and the like (Valentin, r.; grablob, s.Blood2018, 132(12),1248), but still has toxic and side effects of leukopenia and thrombopenia, anemia, diarrhea, dizziness, fatigue, susceptibility to infection and the like, and serious toxic and side effects also comprise pneumonia, anemia, high fever and the like. Therefore, the development of a BCL-2 selective inhibitor with high activity and low toxic and side effects is needed.

Disclosure of Invention

The present invention relates to compounds of formula I, isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts thereof:

wherein:

X⁰is a 3-8 membered heterocyclylene group containing 1 or 2 heteroatoms selected from N, O, S; preferably containsA 5 or 6 membered heterocyclylene having 1 or 2 heteroatoms selected from N, O, S; most preferably

Or

Wherein said

Through the carbon atom connecting end and the structure of the formula I containing X¹Linked to the 6-membered aromatic ring;

X¹is CR⁴Or N; preferably CH or N;

X²is-C (R)⁵R⁶)-、-S(O)_m-, -S-, -O-or-N (R)⁷) -; preferably-O-or-N (R)⁷) -; most preferably-O-or-N (H) -;

X³is optionally substituted C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C3-C8 cycloalkylene, or 3-8 membered heterocyclylene, wherein the optional substituents are halogen, cyano, amino; preferably C1-C6 alkylene, C2-C6 alkenylene, C3-C8 cycloalkylene or 3-8 membered heterocyclylene; further preferred is C1-C4 alkylene or C3-C6 cycloalkylene; most preferably-CH₂-or

X⁴Is an optionally substituted 3-8 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein the optional substituent is a 3-8 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C8 alkyl, halogen, cyano, hydroxy, -SO₂(C1-C8) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C8 alkyl optionally substituted by C1-C8 alkoxy, mono-or di- (C1-C8) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy, halogen, cyano or nitro, or 3-8 membered cycloalkyl; preferably, X⁴Is an optionally substituted 5-or 6-membered saturated heterocyclic radical containing 1 or 2 heteroatoms from the group N, O, SWherein the optional substituents are 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; still further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; still further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C4 alkyl optionally substituted with C1-C4 alkoxy, mono-or di- (C1-C4) alkylamino, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; most preferably, X⁴Is composed of

One or more R⁰Each independently selected from halogen, cyano, nitro, perfluoro C1-C6 alkyl sulfone; preferably, R⁰Mono-substituted at the 3-position of the phenyl ring or di-substituted at the 3-and 5-positions of the phenyl ring, and each is independently selected from halogen, cyano, nitro, perfluoro C1-C4 alkylsulfonyl; most preferably, R⁰Mono-substituted at the 3-position of the benzene ring or di-substituted at the 3-position and the 5-position of the benzene ring, wherein nitro is at the 3-position, and fluorine is at the 5-position;

R¹and R²Each independently selected from hydrogen, linear or branched C1-C8 alkyl, C3-C8 cycloalkyl, 5-6 membered aryl or heteroaryl; preferably selected from hydrogen, linear or branched C1-C6 alkyl, C3-C6 cycloalkyl; most preferably selected from hydrogen, linear or branched C1-C5 alkyl;

R³is an optionally substituted 5-6 membered aryl or heteroaryl group, said optional substituents being C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino; preferably an optionally substituted 5-6 membered aryl group, said optional substituent being C1-C4 alkyl, halogen, hydroxy, cyano or C1-C4 alkoxy; further preferred is a halogen-substituted phenyl group; most preferably 4-chlorophenyl;

R⁴is hydrogen, halogen or C1-C6 alkyl; preferably hydrogen, halogen or C1-C4 alkyl; most preferably hydrogen;

R⁵、R⁶each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl;

R⁷is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; superior foodIs selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl; further preferably hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl; most preferably hydrogen;

R⁸is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

m is 1 or 2;

n is 1,2,3 or 4; preferably 1 or 2.

Further, the present invention relates to a compound of formula I as described hereinbefore, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof,

wherein:

X⁰is a 5 or 6 membered heterocyclylene containing 1 or 2 heteroatoms selected from N, O, S;

X¹is CR⁴Or N;

X²is-C (R)⁵R⁶)-、-S(O)_m-, -S-, -O-or-N (R)⁷)-；

X³Is C1-C6 alkylene, C2-C6 alkenylene, C3-C8 cycloalkylene or 3-8 membered heterocyclylene;

X⁴is an optionally substituted 5-or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, the optional substituent is a 3-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O) R^x(ii) a Wherein said R^xIs optionally saturated with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-to 8-membered ring containing 1 or 2 heteroatoms selected from N, O, SHeterocyclyl, hydroxy or halogen substituted C1-C6 alkyl, or 3-6 membered cycloalkyl;

one or more R⁰Each independently selected from halogen, cyano, nitro, perfluoro C1-C6 alkyl sulfone;

R¹and R²Each independently selected from hydrogen, linear or branched C1-C8 alkyl, C3-C8 cycloalkyl, 5-6 membered aryl or heteroaryl;

R³is an optionally substituted 5-6 membered aryl or heteroaryl group, said optional substituents being C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino;

R⁴is hydrogen, halogen or C1-C4 alkyl;

R⁵、R⁶each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl;

R⁷is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl;

m is 1 or 2;

n is 1,2,3 or 4.

Still further, the present application relates to a compound of formula I as described hereinbefore, isomers, prodrugs, solvates, stable isotopic derivatives thereof, or a pharmaceutically acceptable salt thereof,

wherein:

X¹is CH or N;

X²is-O-or-N (R)⁷)-；

X⁴is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or C (O) R^x(ii) a Wherein said R^xIs optionally substituted by C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, containing 1 or 2 substituents selected from N, O, SHeteroatom 3-8 membered saturated heterocyclyl, hydroxy or halogen substituted C1-C6 alkyl, or 3-6 membered cycloalkyl;

R⁷is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl;

n is 1 or 2.

Still further, the present invention relates to a compound of formula I as described hereinbefore, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is C1-C4 alkylene or C3-C6 cycloalkylene;

X⁴is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl and-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

n is 1 or 2.

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is C1-C4 alkylene or C3-C6 cycloalkylene;

X⁴is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C(O)R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R⁰mono-substituted at the 3-position of the phenyl ring or di-substituted at the 3-and 5-positions of the phenyl ring, and each is independently selected from halogen, cyano, nitro, perfluoro C1-C4 alkylsulfonyl;

R¹and R²Each independently selected from hydrogen, linear or branched C1-C6 alkyl, C3-C6 cycloalkyl;

R³is an optionally substituted 5-6 membered aryl group, the optional substituent being C1-C4 alkyl, halogen, hydroxy, cyano or C1-C4 alkoxy;

n is 1 or 2.

Still further, the present invention relates to a compound of formula I as defined in claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optionalThe substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C4 alkyl optionally substituted with C1-C4 alkoxy, mono-or di- (C1-C4) alkylamino, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R³is phenyl optionally substituted by halogen;

n is 1 or 2.

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁴Is composed of

R⁰Mono-substituted at the 3-position of the benzene ring or di-substituted at the 3-position and the 5-position of the benzene ring, wherein nitro is at the 3-position, and fluorine is at the 5-position;

R¹and R²Each independently selected from hydrogen, linear or branched C1-C5 alkyl;

R³is 4-chlorophenyl;

R⁸is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

n is 1 or 2.

Still further, the present invention relates to a compound of formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof as described hereinbefore, wherein the compound is:

the present invention also relates to the use of a compound of formula I, an isomer, a prodrug, a solvate, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the present invention in the manufacture of a medicament for use as a BCL-2 inhibitor.

The present invention also relates to the use of a compound of formula I as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease associated with BCL-2 mediated disorders, such as a tumour selected from the group consisting of hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma, especially acute lymphatic leukemia.

The present invention further relates to a pharmaceutical composition comprising a compound of formula I as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients.

The invention also relates to the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of a related disease mediated by BCL-2, such as a tumor selected from the group consisting of hematological malignancies, particularly acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma.

The present invention also relates to a method of treating or preventing a related disorder mediated by BCL-2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the present invention or its isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to the invention, said related disease, such as a tumor, selected from hematological malignancies, in particular acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma.

Another aspect of the present invention relates to a compound according to any one of the embodiments of the present invention, or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease associated with BCL-2 mediated, such as a tumor selected from the group consisting of hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma, particularly acute lymphatic leukemia.

Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients for use in the treatment or prevention of a BCL-2 mediated related disorder, such as a tumor selected from the group consisting of hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma, particularly acute lymphatic leukemia.

Another aspect of the present invention relates to a compound of formula I as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment and/or prevention of a related disease mediated by BCL-2. Such BCL-2 mediated associated diseases are for example tumours selected from the group consisting of hematological malignancies, in particular acute lymphatic leukaemia, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain gliomas.

Typical compounds of the invention include, but are not limited to:

and isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof.

According to the present invention, the drug may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.

The pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.

The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants using all methods known in the pharmaceutical art.

Preparation process

The invention also provides a method for preparing the compound.

Scheme 1

R¹、R²Each independently selected from hydrogen, linear or branched C1-C5 alkyl;

the first step is as follows:

under the inert gas atmosphere (such as nitrogen or argon), (I), (II) and 1, 2-dimethyl-1HImidazole in a solvent (e.g., methylene chloride, etc.) at room temperature or under heating in an oil bath (20 to 50 ℃ C.) for 10 to 30 minutes, and titanium tetrachloride and an alkali (e.g., tripropylamine) are added dropwise at low temperature (-50 to-20 ℃ C.) while maintainingReacting at low temperature (-50-20 ℃) to obtain a compound (III);

the second step is that:

adding a compound (III) and a base (such as sodium bis (trimethylsilyl) amide) into an ether solvent (such as tert-butyl methyl ether) under an inert gas (such as nitrogen or argon), stirring at room temperature for 2-10 hours, adding p-toluenesulfonic anhydride, and stirring at room temperature for 5-20 hours to obtain a compound (IV);

the third step:

dissolving a starting material (IV) and 4-chlorobenzene boric acid in a solvent (dioxane and water) under the atmosphere of inert gas (such as nitrogen or argon), using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, using sodium carbonate or potassium carbonate as an alkali, heating in an oil bath under the protection of nitrogen or argon, and stirring for 8-20 hours at the temperature of 70-100 ℃ to obtain a compound (V);

the fourth step:

adding the compound (V) into an anhydrous solvent (such as tetrahydrofuran, and the like), adding lithium aluminum hydride in batches at a low temperature of (-30 to-10 ℃), naturally recovering the room temperature and continuing the reaction to obtain a compound (VI);

the fifth step:

compound (VI) and a chlorinated reagent (e.g., thionyl chloride) are added to an anhydrous solvent (e.g., methylene chloride, etc.) to react at room temperature to give compound (VII).

Scheme 2

the first step is as follows:

under inert gas (such as nitrogen or argon) atmosphere in anhydrous solvent (such asN,NDimethylformamide and tetrahydrofuran), the compound (III), 1,1, 1-trifluoro-N-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide and a base (e.g. potassium carbonate) in an oil bath heated under an inert gas (e.g. nitrogen or argon) blanket at a temperature of 40 to ℃Stirring for 10-20 hours at 60 ℃ to obtain a compound (VIII);

the second step is that:

dissolving a starting material (VIII), 4-chlorobenzene boric acid in a solvent (1, 2-dichloroethane and methanol) under the atmosphere of inert gas (such as nitrogen or argon), adding cesium fluoride by using a palladium complex such as tetrakis (triphenylphosphine) palladium as a catalyst, heating in an oil bath under the protection of nitrogen or argon, and stirring at the temperature of 60-90 ℃ for 1-5 hours to obtain a compound (V);

the third step:

the fourth step:

adding the compound (VI) and a base (such as triethylamine) into an anhydrous solvent (such as tetrahydrofuran, and the like), adding ethylsulfonyl chloride under the protection of nitrogen or argon, and reacting at room temperature to obtain a compound (IX).

Scheme 3

X¹Is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C4 alkyl optionally substituted with C1-C4 alkoxy, mono-or di- (C1-C4) alkylamino, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; preferably, X⁴Is composed of

Wherein R is⁸Is C1-C4 alkyl, cyclopropyl,

X⁵Selected from halogens;

R⁹is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

n is 1 or 2;

the first step is as follows:

compound (X) with 1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridine-5-ols in solvents (e.g. ethylene glycol dimethyl ether orN,N-Dimethylformamide, etc.), adding a base (e.g., potassium carbonate or potassium phosphate, etc.), and reacting for 10 to 20 hours under oil bath heating (80 to 120 ℃), to obtain a compound (XI);

the second step is that:

mixing the compound (XI) and piperazine in a solvent (such as dimethyl sulfoxide), and reacting for 10-20 hours under oil bath heating (40-80 ℃) to obtain a compound (XII);

the third step:

dissolving the starting material (XII) and the compound (VII) in a solvent (such as anhydrous acetonitrile) under an inert gas (such as nitrogen or argon), adding a base (such as triethylamine or diisopropylethylamine, and the like), heating in an oil bath under the protection of nitrogen or argon, and stirring at the temperature of 40-80 ℃ for 8-20 hours to obtain a compound (XIII);

the fourth step:

adding compound (XIII) into a solvent (such as ethanol and water), adding a base (such as lithium hydroxide or sodium hydroxide), and heating at room temperature or in an oil bath (40-80 ℃) to obtain compound (XIV);

the fifth step:

compound (XIV), compound (XV), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine are mixed and stirred in a solvent (such as dichloromethane) and reacted at room temperature for 8 to 20 hours to obtain compound (XVI).

Scheme 4

X¹is CH or N;

X⁵selected from halogens;

the first step is as follows:

compound (IX) is reacted with a base (e.g., triethylamine or diisopropylethylamine, etc.) in a solvent selected from (e.g., tetrahydrofuran, etc.), tert-butyl piperazine-1-carboxylate is added, and at room temperature for 1 to 5 hours to give compound (XVII);

the second step is that:

dissolving compound (XVII) in solvent (such as dichloromethane), adding trifluoroacetic acid or hydrogen chloride dioxane solution under the protection of inert gas (such as nitrogen or argon), and stirring at room temperature to obtain compound (XVIII);

the third step:

dissolving the compound (XVIII) and the compound (XI) in a solvent (such as dimethyl sulfoxide), adding potassium dihydrogen phosphate under the protection of inert gas (such as nitrogen or argon), heating in an oil bath, and stirring at the temperature of 120-150 ℃ for 8-20 hours to obtain the compound (XIII).

Scheme 5

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁵Is selected from bromine;

wherein R is⁸Is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

n is 1 or 2;

the first step is as follows:

dissolving the starting materials (XI), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester in a solvent (such as dioxane) under an inert gas (such as nitrogen or argon), using a palladium complex such as 1,1' -bis diphenylphosphine ferrocene dichloropalladium as a catalyst, adding a base such as sodium carbonate, heating in an oil bath under the protection of an inert gas (such as nitrogen or argon), and stirring at 90-120 ℃ for 10-20 hours to obtain a compound (XIX);

the second step is that:

dissolving compound (XIX) in solvent (such as ethyl acetate), adding trifluoroacetic acid or ethyl acetate solution of hydrogen chloride under the protection of inert gas (such as nitrogen or argon), and stirring at room temperature to obtain compound (XX);

the third step:

dissolving the starting material (XX) and the compound (VII) in a solvent (such as anhydrous acetonitrile) under an inert gas (such as nitrogen or argon), adding a base (such as triethylamine or diisopropylethylamine, and the like), heating in an oil bath under the protection of nitrogen or argon, and stirring at the temperature of 40-80 ℃ for 8-20 hours to obtain a compound (XXI);

the fourth step:

adding the compound (XXI) to a solvent (e.g., ethanol and water), adding a base (e.g., lithium hydroxide or sodium hydroxide), and heating at room temperature or in an oil bath (40 to 80 ℃) to obtain a compound (XXII);

the fifth step:

compound (XXII), compound (XV), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine are mixed and stirred in a solvent (e.g., dichloromethane) and reacted at room temperature for 8 to 20 hours to obtain compound (XXIII).

Scheme 6

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁵Is selected from bromine;

wherein R is⁸Is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

R⁰in the benzene ringIs monosubstituted at the 3-position or disubstituted at the 3-position and the 5-position of the benzene ring, and is nitro at the 3-position and is fluorine at the 5-position;

n is 1 or 2;

the first step is as follows:

adding compound (XI) to a solvent (such as dioxane and water), adding a base (such as lithium hydroxide, sodium hydroxide or potassium hydroxide) and heating at room temperature or in an oil bath (40-80 ℃) to obtain compound (XXIV);

the second step is that:

mixing and stirring compound (XXIV), compound (XV), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 4-dimethylaminopyridine in a solvent (such as dichloromethane) and reacting at room temperature for 8-20 hours to obtain compound (XXV);

the third step:

dissolving the starting materials (XXV), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester in a solvent (such as dioxane) under an inert gas (such as nitrogen or argon) atmosphere, using a palladium complex such as tetratriphenylphosphine palladium as a catalyst, adding a base such as sodium carbonate, heating in an oil bath under the protection of an inert gas (such as nitrogen or argon), and stirring at 80-120 ℃ for 10-20 hours to obtain a compound (XXVI);

the fourth step:

dissolving compound (XXVI) in a solvent (such as dichloromethane), adding trifluoroacetic acid under the protection of inert gas (such as nitrogen or argon), and stirring at room temperature to obtain compound (XXVII);

the fifth step:

the starting material (XXVII), the compound (VII) is dissolved in a solvent (e.g., nitrogen or argon) under an inert gas atmosphereN, N-Dimethylformamide), heated in an oil bath under protection of an inert gas (e.g., nitrogen or argon), and stirred at 40 to 80 ℃ for 3 to 10 hours to obtain compound (XXIII).

Scheme 7

X¹As defined above; x⁵Selected from halogens;

the first step is as follows:

compound (XXVIII) with 1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridine-5-ols in solvents (e.g. ethylene glycol dimethyl ether orN,N-Dimethylformamide, etc.), adding a base (e.g., potassium carbonate or potassium phosphate, etc.), and reacting for 10 to 20 hours under oil bath heating (80 to 120 ℃) to obtain a compound (XXIX);

the second step is that:

dissolving the compound (XXIX) in a solvent (such as methanol and water), adding a base (such as sodium hydroxide), reacting for 10-20 hours under the heating of an oil bath (70-100 ℃), and acidifying with hydrochloric acid to obtain a compound (XXX);

the third step:

compound (XXX) is dissolved in methanol, sulfoxide chloride is added dropwise at room temperature, and the mixture is heated in an oil bath (60-80 ℃) to react for 1-5 hours, so that compound (XI) is obtained.

Scheme 8

R⁰And n is as defined above;

the first step is as follows:

dissolving a compound (XXXI) in chlorosulfonic acid, reacting for 10-20 hours under oil bath heating (120-150 ℃), cooling to room temperature, quenching with ice water, extracting with ethyl acetate, drying and concentrating an organic phase to obtain a crude product, dissolving the crude product in anhydrous tetrahydrofuran, dropwise adding ammonia water at low temperature (-80 to-60 ℃), continuously stirring for 1-5 hours, and acidifying with hydrochloric acid to obtain a compound (XXXII);

the second step is that:

when X is present²is-NH-: dissolving the compound (XXXII) and the corresponding amine in a solvent (e.g. acetonitrile), adding a base (e.g. triethylamine or diisopropylethylamine, etc.), and reacting at room temperature for 10-20 hours under the protection of an inert gas (e.g. nitrogen or argon), thereby obtaining the compound (XXXII)Compound (XV);

when X is present²is-O-: dissolving the corresponding alcohol in a solvent (such as tetrahydrofuran), adding a base (such as sodium hydride and the like), reacting at room temperature for 10-40 minutes under the protection of an inert gas (such as nitrogen or argon), adding the compound (XXXII), and continuing to react at room temperature for 10-20 hours to obtain the compound (XV).

Scheme 9

X¹、X²、R⁰、n、R¹、R²、R⁸And R⁹As defined above;

R¹¹is H or F;

when in use

When it is a double bond, E¹Is a C atom;

when in use

When it is a single bond, E¹Is an N atom;

the first step is as follows:

dissolving compound (XXXIII) in solvent (such as methanol), under the protection of inert gas (such as nitrogen or argon), mixing with trifluoroacetic acid or hydrogen chloride dioxane solution, and stirring at room temperature to obtain compound (XXXIV);

the second step is that:

dissolving compound (XXXIV) and corresponding aldehyde (e.g., paraformaldehyde, acetaldehyde, etc.) or ketone (e.g., 3-oxetanone, 4-oxacyclohexanone, etc.) in a solvent (e.g., dichloroethane or methanol), adding sodium triacetoxyborohydride or sodium cyanoborohydride, and stirring at room temperature to obtain compound (XXXV);

the third step:

reacting compound (XXXIV) with the corresponding carboxylic acid R⁸COOH in a solvent (e.g., dichloromethane) with a condensing agent such as 2- (7-benzotriazole oxide)N,N,N',N'Tetramethylurea hexafluorophosphate, addition of a base (e.g., triethylamine or diisopropylethylamine, etc.), and stirring at room temperature, gives compound (XXXVI).

Scheme 10

E¹、X¹、X²、R⁰、n、R¹、R²、R⁸、R⁹And R¹¹As defined above;

the first step is as follows:

dissolving compound (XXXVII) in solvent (such as methanol), under the protection of inert gas (such as nitrogen or argon), mixing with trifluoroacetic acid or hydrogen chloride dioxane solution, and stirring at room temperature to obtain compound (XXXVIII);

the second step is that:

dissolving compound (XXXVIII) and corresponding aldehyde (e.g. paraformaldehyde, acetaldehyde, etc.) or ketone (e.g. 3-oxetanone, 4-oxacyclohexanone, etc.) in a solvent (e.g. dichloroethane or methanol), adding sodium triacetoxyborohydride or sodium cyanoborohydride, and stirring at room temperature to obtain compound (XXXIX);

the third step:

reacting compound (XXXVIII) with the corresponding carboxylic acid R⁸COOH in a solvent (e.g., dichloromethane), and a condensing agent such as 2- (7-benzotriazole oxide) -N,N,N',N'Tetramethylurea hexafluorophosphate, addition of a base (e.g., triethylamine or diisopropylethylamine, etc.), and stirring at room temperature, gives compound (XXXX).

Detailed Description

Definition of

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. Groups not specifically defined in the present invention have meanings commonly represented in the art, which are well known to those skilled in the art.

The expression "Cx-Cy" as used in the present invention denotes the range of the number of carbon atoms, wherein x and y are both integers, e.g. C3-C8 cycloalkyl denotes cycloalkyl having 3-8 carbon atoms, -C0-C2 alkyl denotes alkyl having 0-2 carbon atoms, wherein-C0 alkyl denotes a single chemical bond.

In the present invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof, and the like. Alkyl groups may be optionally substituted or unsubstituted.

In the present invention, the term "alkylene" refers to a substituted or unsubstituted alkyl group having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the alkyl group has the meaning as described hereinbefore. Non-limiting examples of "alkylene" include methylene, ethylene, propylene, butylene, and the like. The alkylene group may be optionally substituted or unsubstituted.

In the present invention, the term "alkenyl" refers to straight-chain, branched-chain hydrocarbon groups containing at least 1 carbon-carbon double bond, which may include 2 to 20 carbon atoms, for example, straight-chain and branched-chain groups of 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. The term "C2-C4 alkenyl" refers to alkenyl groups having 2-4 carbon atoms. Including ethenyl, propenyl, butenyl, buten-2-yl, 2-methylbutenyl. The alkenyl group may be optionally substituted or unsubstituted.

In the present invention, the term "alkenylene" refers to a substituted or unsubstituted alkenyl group having a core of two terminal monovalent groups, which is generated by removing one hydrogen atom from each of two terminal atoms; the alkenyl group has the meaning as described hereinbefore. Non-limiting examples of "alkenylene" include ethenylene, propenylene, butenylene, and the like. Alkenylene groups may be optionally substituted or unsubstituted.

In the present invention, the term "alkynyl" refers to a straight, branched hydrocarbon group containing at least 1 carbon-carbon triple bond, which may include 2 to 20 carbon atoms, for example, straight and branched groups of 2 to 18 carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Wherein 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond, may be present. The term "C2-C4 alkynyl" refers to alkynyl groups having 2-4 carbon atoms. Non-limiting examples include ethynyl, propynyl, butynyl, and butyn-2-yl, 3-methylbutynyl. The alkynyl group may be optionally substituted or unsubstituted.

In the present invention, the term "alkynylene" refers to a substituted or unsubstituted alkynyl group having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the alkynyl group has the meaning as described hereinbefore. Non-limiting examples of "alkynylene" include ethynylene, propynyl, butynyl, and the like. Alkynylene groups may be optionally substituted or unsubstituted.

In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, or may be a 3,4, 5, 6-membered ring. Non-limiting examples of monocyclic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.

In the present invention, the term "cycloalkylene" refers to a substituted or unsubstituted cycloalkyl group having a core of two terminal monovalent groups, which results from the removal of one hydrogen atom from each of the two terminal atoms; the cycloalkyl radicals have the meanings indicated above. Non-limiting examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, 1, 4-cyclohexylene, and the like. Cycloalkylene groups may be optionally substituted or unsubstituted.

In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) m (wherein m is an integer from 0 to 2), but not including the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms of which 1 to 4 are heteroatoms, more preferably a heterocyclyl ring comprising 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably a 5-or 6-membered ring of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, 4-piperidinyl, piperazinyl, morpholinyl, 2-morpholinyl, 4-morpholinyl, thiomorpholinyl, pyranyl, tetrahydropyranyl, 4-tetrahydropyranyl, homopiperazinyl, dioxanyl, 2-dioxanyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted.

In the present invention, the term "heterocyclylene" refers to a substituted or unsubstituted heterocyclic group having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the heterocyclyl group has the meaning as described hereinbefore. Non-limiting examples of "heterocyclylene" include pyrrolidinylene, piperidinyl, piperazinyl, morpholinyl, or

And the like.

In the present invention, the term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 5 to 10 membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cyclyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

the aryl group may be substituted or unsubstituted.

In the present invention, the term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. Preferably 5 to 10 membered. More preferably heteroaryl is 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, and the like, which heteroaryl ring may be fused to an aryl, heterocyclyl, or cyclic ring wherein the ring linked together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

。

heteroaryl groups may be optionally substituted or unsubstituted.

In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.

In the present invention, the term "cyano" refers to "-CN".

In the present invention, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. The alkyl, heterocycloalkyl and cycloalkyl radicals have the meanings indicated above.

In the present invention, the term "amino" refers to "-NH₂”。

In the present invention, the term "alkylamino" refers to an amino group in which a hydrogen on the amino group is substituted with an alkyl group, and includes monoalkylamino and dialkylamino groups. The alkyl group has the meaning as described hereinbefore.

In the present invention, the term "nitro" refers to "-NO₂”。

In the present invention, the term "alkylsulfonyl" refers to a sulfonyl group substituted with an alkyl group. Wherein the alkyl group has the meaning as described hereinbefore. When the hydrogens of the Cx-Cy alkyl groups are all replaced with fluorine, they are referred to as "perfluorinated Cx-Cy alkylsulfone groups".

In the present invention, "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

In the present invention, "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

Such substituents include, but are not limited to, the various groups described previously.

The compounds claimed in the present invention include not only the compounds themselves, but also isomers, prodrugs, solvates, stable isotopic derivatives of the compounds or pharmaceutically acceptable salts thereof.

The term "pharmaceutical composition" as used herein means a mixture containing one or more of the isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, of the compounds of the present invention and other chemical components. Other components such as pharmaceutically acceptable carriers, diluents and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

The term "comprising" as used in the specification includes "consisting of ….

The "room temperature" of the invention means 15-30 ℃.

The "stable isotope derivative" of the present invention includes: an isotopically substituted derivative in which any hydrogen atom in formula I is substituted with 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in formula I is substituted with 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in formula I is substituted with 1 to 3 oxygen 18 atoms.

The "Pharmaceutically acceptable salts" of the present invention are discussed in Berge, et al, "pharmaceutical acceptable salts", j. pharm. sci, 66, 1-19(1977) and are apparent to the pharmaceutical chemist, are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized by a general chemical method.

In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric amount or an excess of the acid (inorganic or organic) or base in a suitable solvent or solvent composition.

By "prodrug" as used herein is meant a compound that is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic properties.

The "isomer" of the present invention means a tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, etc. of the compound of the formula (I) of the present invention. All such isomers, including stereoisomers, geometric isomers, are included in the present invention. The geometric isomers include cis-trans isomers.

As used herein, "solvate" refers to the association of one or more solvent molecules with a compound of the present invention or a salt thereof. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate, acetic acid, and the like.

The present invention includes any polymorph as well as any hydrate or other solvate of the compound or salt thereof.

In the present invention, the term "patient" generally refers to a mammal, especially a human.

In the present invention, the term "tumor" includes benign tumors and malignant tumors, such as cancers.

In the present invention, the term "cancer" encompasses various tumors mediated by BCL-2, including but not limited to hematological malignancies, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma, among others acute lymphoid leukemia.

In the present invention, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention that is effective in treating or preventing the associated diseases mediated by BCL-2.

Examples

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The structures of all compounds of the invention can be determined by nuclear magnetic resonance¹H NMR) and/or mass spectrometric detection (MS).

¹H NMR chemical shifts (. delta.) are reported as PPM (parts per million). NMR was performed by a Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), deuterated dimethyl sulfoxide (DMSO-d ₆) Etc., tetramethylsilane as an internal standard (TMS).

Low resolution Mass Spectrometry (MS) was determined by an Agilent 1260 HPLC/6120 mass spectrometer using an Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm.

Gradient elution conditions one: 0: 95% solvent A1 and 5% solvent B1,1-2:5% solvent A1 and 95% solvent B1; 2.01-2.50, 95% solvent A1 and 5% solvent B1. The percentages are volume percentages of a solvent based on the total solvent volume. Solvent a 1: 0.01% aqueous formic acid; solvent B1: 0.01% formic acid in acetonitrile; the percentages are the volume percent of solute in solution.

The thin-layer silica gel plate is a tobacco stage yellow sea HSGF254 or Qingdao GF254 silica gel plate. The column chromatography generally uses 100-200 or 200-300 mesh silica gel of the yellow sea of the tobacco pipe as a carrier.

Preparative liquid chromatography (prep-HPLC) using Waters SQD2 mass spectrometry directed to a high pressure liquid chromatography separator, XBridge-C18; 30X 150 mm preparation column, 5 μm;

the method comprises the following steps: acetonitrile-water (0.2% formic acid), flow rate 25 mL/min; the second method comprises the following steps: acetonitrile-water (0.8% ammonium bicarbonate) flow rate 25 mL/min;

known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Shanghai Bidi medicine, Shanghai Aladdin chemistry, Shanghai Michelle chemistry, Bailingwei chemistry, Annai and chemistry.

In the examples, unless otherwise specified, all solvents used in the reaction were anhydrous solvents, wherein the anhydrous tetrahydrofuran was commercially available tetrahydrofuran, sodium block was used as a water scavenger, benzophenone was used as an indicator, the solution was refluxed to bluish purple under argon protection, collected by distillation, stored at room temperature under argon protection, and other anhydrous solvents were purchased from ann nai and chemistry and carbofuran chemistry, and all the transfer and use of the anhydrous solvents were performed under argon protection unless otherwise specified.

In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction temperature was room temperature and the temperature range was 15 ℃ to 30 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.

Example 1

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

First step of

2, 5-dimethyl-3-carbonylhexanoic acid methyl ester

Methyl propionate (66.00 g, 0.75 mol), 3-methylbutyryl chloride 1d-1 (90.00 g, 0.75 mol), 1, 2-dimethyl-1HImidazole (90.00 g, 0.94 mol) and dichloromethane (1.5L). Under the protection of argon, the temperature was lowered to-45 ℃ in an ethyl acetate dry ice bath and stirred for 10 minutes, and titanium tetrachloride (540.00 g, 2.86 mol) and tripropylamine (420.00 g, 2.94 mol) were added dropwise and stirred at-45 ℃ for 30 minutes. The mixture was quenched with 1L of water, the organic phase separated and the aqueous phase extracted with dichloromethane (500 mL. times.2). The combined organic phases were washed with saturated brine (500 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. Silica gel column purification (petroleum ether/ethyl acetate = 20: 1) gave the desired product methyl 2, 5-dimethyl-3-carbonylhexanoate 1d-2 (72.00 g, yellow liquid). Yield: 82%;

¹H NMR (400 MHz, CDCl₃) δ 3.73 (s, 3H), 3.54-3.48 (m, 1H), 2.48-2.39 (m, 2H), 2.20-2.14 (m, 1H), 1.33 (d, J = 7.6 Hz, 3H), 0.93-0.90 (m, 6H)

second step of

(Z) -2, 5-dimethyl-3- (p-toluenesulfonyloxy) hex-2-enoic acid methyl ester

Compound 2, 5-dimethyl-3-carbonylhexanoic acid methyl ester 1d-2 (72.00 g, 0.42 mol), sodium bis (trimethylsilyl) amide (2M in tetrahydrofuran, 0.83 mol, 415M L) and methyl tert-butyl ether (1.5L) were mixed and stirred at room temperature for 5 hours under argon-protected conditions. Then p-toluenesulfonic anhydride (177.00 g, 0.54 mol) was added and the reaction was carried out at room temperature for 15 hours under the protection of argon. The mixture was quenched with 1.5L of water, the organic phase separated, the aqueous phase extracted with methyl tert-butyl ether (500 mL. times.2), and the combined organic phases washed with saturated brine (1.5L. times.2). Drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by reverse phase chromatography (water/acetonitrile = 60: 40) to give the desired product ((r): acetonitrile = 60: 40)Z) -methyl 2, 5-dimethyl-3- (p-toluenesulfonyloxy) hex-2-enoate 1d-3 (37.00 g, yellow liquid). Yield: 25 percent of

¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.61 (s, 3H), 2.20 (d, J = 7.2 Hz, 2H), 2.01 (s, 3H), 1.88 (s, 3H), 1.86-1.83 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H)

The third step

(Z) -3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoic acid methyl ester

A compound (, (ii) aZ) Methyl-2, 5-dimethyl-3- (tosyloxy) hex-2-enoate 1d-3 (35.00 g, 0.11 mol), 4-chlorobenzeneboronic acid (23.40 g, 0.15 mol), 1, 4-dioxane (500 mL), water (100 mL) were mixed, and tetrakis (triphenylphosphine) palladium (12.00 g, 10.38 mmol), sodium carbonate (32.00 g, 0.30 mol), and reacted at 80 ℃ for 15 hours under argon protection. The mixture was quenched with 500 mL of water and 500 mL of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (500 mL. times.2). The organic phases were combined with a saturated common salt solution (1.5 L.times.2). Dried over anhydrous sodium sulfate and filtered to remove the drying agent. Removing solvent under reduced pressure to obtain crude product, and purifying with silica gel column (petroleum ether/ethyl acetate = 20: 1) to obtain target product: (Z) -methyl 3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoate 1d-4 (25.00 g, yellow liquid). Yield: 94 percent of

MS m/z (ESI)：267 & 269 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 7.27 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.41 (s, 3H), 2.34 (d, J = 7.2 Hz, 2H), 2.03 (s, 3H), 1.53-1.47 (m, 1H), 0.86 (d, J = 6.8 Hz, 6H)

The fourth step

(Z) -3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol

A compound of (A), (B), (CZ) -3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoic acid methyl ester 1d-4 (1.50 g, 5.62 mmol) and tetrahydrofuran (40 mL) were mixed, the ice salt bath was cooled to-15 deg.C, lithium aluminum hydride (0.32 g, 8.43 mmol) was added slowly in portions, after the addition was complete, the temperature was naturally raised to room temperature, and stirring was carried out for 3 hours. Quench with hydrochloric acid (1M, 20 mL). It was extracted with dichloromethane (50 mL. times.3), the combined organic phases were dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. Decompression desolventizing to obtain the target product (Z) -3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol 1d-5 (1.31 g, light yellow liquid), yield: 98 percent;

MS m/z (ESI): 221 & 223 [M - 17];

the fifth step

(Z) -1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene

A compound of (A), (B), (CZ) -3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol 1d-5 (1.31 g, 5.95 mmol), thionyl chloride (1.5 mL) and dichloromethane (30 mL) were mixed and stirred at room temperature for 1 hour. Decompression desolventizing to obtain the target product (Z) -1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (1.41 g, light yellow liquid), crude;

the sixth step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester

The compound methyl 2, 4-difluorobenzoate 1a (17.20 g, 0.10 mol), 1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridine-5-phenol (synthesized according to Bioconjugate Chemistry, 25(11), 2081-2085; 2014), (28.00 g, 0.10 mol), potassium phosphate (31.80 g, 0.15 mol) and diethylene glycol dimethyl ether (80 mL) were mixed and stirred at 110 ℃ for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with water (50 mL. times.5) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. Purifying the residue by flash column chromatography (petroleum ether/ethyl acetate = 100: 0-70: 30) to obtain the target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester 1b (14.00 g, white solid), yield: 51 percent;

MS m/z (ESI): 287 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.57 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.07-7.88 (m, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.50-7.35 (m, 1H), 6.89-6.75 (m, 1H), 6.58-6.42 (m, 2H), 3.91 (s, 3H)

seventh step

(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4-piperazin-1-yl) benzoic acid methyl ester

2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester 1b (14.00 g, 0.05 mol), piperazine (33.50 g, 0.39 mol) and dimethyl sulfoxide (80 mL) were mixed and stirred at 50 ℃ for 16 hours. The mixture was diluted with ethyl acetate (250 mL), washed with water (150 mL. times.3) and saturated brine (150 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and the drying agent was removed by filtration. Decompression desolventizing to obtain a target product (2- ((1)H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4-piperazin-1-yl) benzoic acid methyl ester 1c (17.00 g, white solid), yield: 99 percent

MS m/z (ESI): 353 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 11.31 (s, 1H), 8.20 (d, J = 2.4 Hz, 1H), 8.00-7.82 (m, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.44-7.34 (m, 1H), 6.74-6.56 (m, 1H), 6.47-6.38 (m, 1H), 6.37-6.22 (m, 1H), 3.80 (s, 3H), 3.28-3.07 (m, 4H), 2.99-2.81 (m, 4H)

Eighth step

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester

Will (2- ((1)H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4-piperazin-1-yl) benzoic acid methyl ester 1c (1.65 g, 4.69 mmol), (b), (c) and (d)Z) 1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (1.43 g, 5.56 mmol),N,Ndiisopropylethylamine (1.82 g, 14.11 mmol) and dry acetonitrile (30 mL) were mixed and stirred at 55 ℃ for 16 h. Performing decompression and desolventizing, and purifying the residue by flash column chromatography (petroleum ether/ethyl acetate = 100: 0-60: 40) to obtain a target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 1e (1.60 g, white solid), yield: 60 percent of

MS m/z (ESI): 573 & 575 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.53 (s, 1H), 8.31-8.04 (m, 1H), 7.94-7.82 (m, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.43-7.32 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.65-6.53 (m, 1H), 6.47-6.38 (m, 1H), 6.28 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H), 3.21-3.00 (m, 4H), 2.73 (s, 2H), 2.36-2.22 (m, 4H), 2.21 (d, J = 7.2 Hz, 2H), 1.82 (s, 3H), 1.56-1.38 (m, 1H), 0.83 (d, J = 6.6 Hz, 6H)

The ninth step

(Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid

Will (a) toZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 1e (1.60 g, 2.79 mmol), sodium hydroxide (0.50 g, 12.50 mmol), ethanol (15 mL) and water (8 mL) were mixedThen, the mixture was stirred at 80 ℃ for 1 hour. The solution was desolventized under reduced pressure, and water (30 mL) and hydrochloric acid (1M, 15 mL) were added to the residue. Extraction was carried out with dichloromethane (30 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. Decompression desolventizing to obtain the target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 1f (1.51 g, white solid), yield: 97 percent;

MS m/z (ESI): 559 & 561 [M + 1];

the tenth step

(Z)-4-((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester

Will (a) toZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 1f (0.50 g, 0.89 mmol), tert-butyl 4-fluoro-4- ((2-nitro-4-sulfamoylphenoxy) methyl) piperidine-1-carboxylate (synthesized according to WO 2017132474) (0.40 g, 0.92 mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (0.34 g, 1.77 mmol), 4-dimethylaminopyridine (0.16 g, 1.31 mmol) and dichloromethane (20 mL) were mixed and stirred at room temperature for 16 h. Performing desolventizing under reduced pressure to obtain a crude product, and purifying the residue by flash column chromatography (dichloromethane/methanol 100: 0-97: 3) to obtain a target product (Z)-4-((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 1g (0.79 g, light yellow solid), yield: 91%;

MS m/z (ESI): 974 & 976 [M + 1];

the eleventh step

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluoropiperidin-4-yl) methoxy)-3-nitrophenyl) sulfonyl) benzamide

Will (a) toZ)-4-((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 1g (0.79 g, 0.81 mmol), hydrogen chloride dioxane solution (4M, 20 mL) and methanol (5 mL) were mixed and stirred at room temperature for 30 minutes. The crude product was desolventized under reduced pressure and the residue was taken up in saturated sodium bicarbonate solution (50 mL) and dichloromethane (50 mL). Extraction was carried out with dichloromethane (50 mL. times.4), the organic phase was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. Decompression desolventizing to obtain the target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 1 (0.60 g, white solid), yield: 85 percent;

MS m/z (ESI): 874 & 876 [M + 1];

¹H NMR (400 MHz, DMSO-d ₆) δ 11.50 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.82-7.77 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.43-7.39 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.26-7.23 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.65-6.58 (m, 1H), 6.31-6.22 (m, 2H), 4.31-4.26 (m, 2H), 3.14-3.10 (m, 2H), 3.06-2.87 (m, 8H), 2.68 (s, 2H), 2.27-2.14 (m, 6H), 2.05-1.96 (m, 2H), 1.80 (s, 3H), 1.43-1.39 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H)。

example 2

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Will (a) toZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 1 (0.20 g, 0.23 mmol), 3-oxetanone (50 mg, 0.69 mmol), sodium cyanoborohydride (44 mg, 0.70 mmol) and methanol (20 mL) were mixed and stirred at room temperature for 24 hours. Quenching with 50 mL of water, extracting with dichloromethane (50 mL. times.4), drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and desolventizing under reduced pressure to obtain the crude product. The crude product is purified from the preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 2 (42 mg, white solid), yield: 20 percent of

MS m/z (ESI): 930 & 932 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.18 (s, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.37 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.24-7.08 (m, 3H), 6.94-6.81 (m, 2H), 6.61-6.45 (m, 2H), 5.98 (s, 1H), 4.80-4.54 (m, 4H), 4.26-4.07 (m, 2H), 3.61-3.44 (m, 1H), 3.18-2.99 (m, 4H), 2.81-2.56 (m, 4H), 2.33-2.13 (m, 8H), 2.12-2.01 (m, 2H), 2.00-1.84 (m, 2H), 1.80 (s, 3H), 1.46-1.38 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 3

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (tetrahydro-2))H-pyran-4-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Example 3 was synthesized according to the procedure of example 2, using tetrahydro-4HThe pyran-4-one replaces 3-oxetanone to obtain a target product (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (tetrahydro-2))H-pyran-4-yl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 3.

MS m/z (ESI)：958 & 960 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.66 (s, 1H), 8.56 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.47- 7.43 (m, 1H), 7.23-7.21 (m, 2H), 7.12-7.02 (m, 1H), 6.93-6.88 (m, 2H), 6.60-6.50 (m, 2H), 6.00 (d, J = 4.0 Hz, 1H), 4.08-4.03 (m, 2H), 3.43-3.37 (m, 2H), 3.12-3.02 (m, 8H), 2.75-2.71 (m, 1H), 2.25-2.00 (m, 8H), 2.00-1.95 (m, 4H), 1.89-1.85 (m, 2H), 1.80 (s, 3H), 1.72-1.64 (m, 4H), 1.43-1.38 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 4

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (cyclopropanecarbonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Will (a) toZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 1 (10 mg, 0.01 mmol), cyclopropanecarboxylic acid (1 mg, 0.01 mmol), 2- (7-Oxobenzotriazole)N,N,N',N'-tetramethyluronium hexafluorophosphate (6 mg, 0.02 mmol)，N,NDiisopropylethylamine (5 mg, 0.04 mmol) and dichloromethane (5 mL) were mixed and stirred at room temperature for 1 hour. Diluted with water (30 mL), extracted with dichloromethane (50 mL. times.4), the organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure to give the crude product. The crude product is purified from the preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (cyclopropanecarbonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 4 (4.2 mg, white solid), yield: 39 percent.

MS m/z (ESI): 942 & 944 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 8.02-7.86 (m, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.65-6.47 (m, 2H), 5.98 (s, 1H), 4.65-4.49 (m, 1H), 4.33-4.10 (m, 4H), 3.60-3.41 (m, 1H), 3.23-2.93 (m, 6H), 2.70 (s, 2H), 2.30-2.14 (m, 8H), 1.79 (s, 3H), 1.47-1.40 (m, 1H), 1.36-1.30 (m, 1H), 0.91-0.70 (m, 4H), 0.82 (d, J= 6.4 Hz, 6H)。

Synthetic procedures for examples 5 to 10 reference was made to the procedure of example 4: cyclopropanecarboxylic acid was replaced with a different acid.

Example 5

(Z)-2-((1H-Pyrrole [2,3-b]Pyridin-5-yl) oxy) -N- ((4- ((1-acetyl-4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

MS m/z (ESI): 916 & 918 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.44 (s, 1H), 8.61-8.54 (m, 1H), 8.39-8.30 (m, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.96-7.88 (m, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.50-7.42 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.17-7.10 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.59-6.49 (m, 2H), 5.97 (s, 1H), 4.66-4.51 (m, 1H), 4.28-4.05 (m, 2H), 3.85-3.72 (m, 1H), 3.52-3.40 (m, 1H), 3.15-3.03 (m, 4H), 3.01-2.91 (m, 1H), 2.70 (s, 2H), 2.27-2.15 (m, 8H), 2.14 (s, 3H), 2.07-1.95 (m, 2H), 1.79 (s, 3H), 1.46-1.38 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 6

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (2-methoxyacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 946 & 948 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.95 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.40-8.37 (m, 1H), 8.18 (d, J = 2.4 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.47-7.45 (m, 1H), 7.26-7.24 (m, 1H), 7.18 (d, J = 9.2 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.4 Hz, 2H), 5.97 (d, J = 2.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.28-4.05 (m, 4H), 3.90-3.85 (m, 1H), 3.49 (s, 2H), 3.44 (s, 3H), 3.40-3.37 (m, 1H), 3.21-2.99 (m, 11H), 2.24-2.22 (m, 2H), 2.01 (s, 3H), 1.85-1.80 (m, 2H), 1.46-1.38 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 7

(Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-((1-(N,N-dimethylglycyl) -4-fluoropiperidin-4-yl) Methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 959 & 961 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.42-8.31 (m, 1H), 8.20 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.74-7.60 (m, 1H), 7.52-7.40 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 6.58-6.47 (m, 2H), 6.06-5.92 (m, 1H), 4.64-4.49 (m, 1H), 4.28-4.00 (m, 3H), 3.45-3.33 (m, 1H), 3.31-3.18 (m, 1H), 3.13-2.92 (m, 6H), 2.70 (s, 2H), 2.30 (s, 6H), 2.25-2.16 (m, 6H), 2.15-2.06 (m, 2H), 2.05-1.95 (m, 2H), 1.79 (s, 3H), 1.43-1.37 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 8

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (2-morpholineacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 1001 & 1003 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.39-8.36 (m, 1H), 8.13 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 5.97 (s, 1H), 4.63-4.60 (m, 1H), 4.28-4.12 (m, 2H), 3.98-3.95 (m, 2H), 3.87-3.83 (m, 1H), 3.76-3.68 (m, 8H), 3.5 (s, 2H), 3.14-3.11 (m, 1H), 3.04-2.93 (m, 1H), 2.61-2.56 (m, 4H), 2.30-2.23 (m, 6H), 2.07 (s, 3H), 1.88-1.82 (m, 4H), 1.43-1.36 (m, 1H), 0.84 (d, J = 4.0 Hz, 6H)。

Example 9

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (2- (tetrahydro-2))H-pyran-4-yl) acetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 1000 & 1002 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.39-8.36 (m, 1H), 8.13 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 4.0 Hz, 1H), 7.33-7.31 (m, 2H), 7.19 (d, J = 8.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.63 (s, 1H), 6.58-6.55 (m, 1H), 5.97 (s, 1H), 4.63-4.60 (m, 1H), 4.28-4.12 (m, 2H), 3.98-3.95 (m, 2H), 3.87-3.83 (m, 1H), 3.59-3.36 (m, 8H), 3.14-3.11 (m, 1H), 3.04-2.93 (m, 1H), 2.30-2.23 (m, 4H), 2.20-2.18 (m, 4H), 2.16-2.10 (m, 2H), 2.07 (s, 3H), 2.00-1.95 (m, 2H), 1.71-1.68 (m, 5H), 1.49-1.26 (m, 1H), 0.84 (d, J = 4.0 Hz, 6H)。

Example 10

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (2-hydroxyacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 932 & 934 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.57 (d, J = 4.0 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H), 7.93-7.90 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.26-7.21 (m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.90-6.88 (m, 2H), 6.56-6.53 (m, 2H), 6.00 (s, 1H), 4.59-4.56 (m, 1H), 4.24-4.20 (m, 4H), 3.64-3.60 (m, 1H), 3.46-3.35 (m, 3H), 3.07-3.02 (m, 5H), 2.70 (s, 2H), 2.22-2.18 (m, 6H), 2.08-2.05 (m, 2H), 1.79 (s, 3H), 1.44-1.40 (m, 1H), 0.82 (d, J= 8.0 Hz, 6H)。

Example 11

(Z)-2-((1H-Pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

First step of

4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide

Tert-butyl 4-fluoro-4- ((2-nitro-4-sulfonamidoxyphenoxy) methyl) piperidine-1-carboxylate 11a (synthesized according to WO 2017132474) (0.50 g, 1.15 mmol), hydrogen chloride dioxane solution (4M, 20 mL) and methanol (10 mL) were combined and stirred at room temperature for 1 hour. The solution was then removed under reduced pressure, saturated sodium bicarbonate solution (30 mL) was added to the residue, the mixture was extracted with dichloromethane (15 mL. times.3), the organic phase was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. Desolventizing under reduced pressure gave the desired product 4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide 11b (0.36 g, yellow solid) in yield: 94 percent.

MS m/z (ESI): 334 [M + 1];

Second step of

4- ((1-ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide

4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide 11b (33 mg, 0.10 mmol), a saturated solution of sodium hydrogencarbonate (1 mL) and ethyl acetate (5 mL) were mixed, ethylsulfonyl chloride (38 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to dilute the solution, and the solution was extracted with ethyl acetate (10 mL. times.3). The organic phase was dried over anhydrous sodium sulfate and the drying agent was removed by filtration. Desolventizing under reduced pressure gave the desired product 4- ((1-ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide 11c (35 mg, yellow solid), yield: 84%;

MS m/z (ESI): 426 [M + 1];

the third step

(Z)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Reference example 1 the tenth procedure, wherein tert-butyl 4-fluoro-4- ((2-nitro-4-sulfonamidoxyphenoxy) methyl) piperidine-1-carboxylate was substituted with 4- ((1-ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrobenzenesulfonamide 11c, gave the title product (I) (productZ)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (ethylsulfonyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 11;

MS m/z (ESI): 966 & 968 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.66-8.55 (m, 1H), 8.41-8.33 (m, 1H), 8.19 (s, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 8.1 Hz, 2H), 6.60-6.49 (m, 2H), 5.97 (s, 1H), 4.27-4.13 (m, 2H), 3.87-3.72 (m, 2H), 3.24-3.06 (m, 6H), 3.04-2.95 (m, 2H), 2.74 (s, 2H), 2.31-2.10 (m, 8H), 2.01-1.85 (m, 2H), 1.81 (s, 3H), 1.42-1.36 (m, 4H), 0.82 (d, J = 6.5 Hz, 6H)。

example 12

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorobenzene)Radical) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride

Synthesis of example 12 by reference to the procedure of example 1, wherein the tenth step replaces tert-butyl 4-fluoro-4- ((2-nitro-4-sulfonamidophenyl) methyl) piperidine-1-carboxylate with tert-butyl 4-fluoro-4- ((2-nitro-4-sulfonamidophenyl) amino) methyl) piperidine-1-carboxylate (synthesized according to WO2018041248A 1) to give the desired product: (Z)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride 12.

MS m/z (ESI)：873 & 875 [M + 1]；

¹H NMR (400 MHz, CD₃OD) δ 8.68 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.86-7.84 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.39-7.36 (m, 1H), 7.20-7.16 (m, 3H), 6.83-6.80 (m, 1H), 6.58-6.52 (m, 1H), 6.79 (s, 1H), 3.82-3.60 (m, 8H), 3.49-3.44 (m, 4H), 3.27-3.22 (m, 4H), 2.47-2.43 (m, 2H), 2.21-2.18 (m, 2H), 2.01-1.98 (m, 5H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 13

(Z)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

Example 13 was synthesized by reference to the procedure of example 2, in whichZ)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide (A) is substitutedZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide to give the target product: (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide 13.

MS m/z (ESI): 929 & 931 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 9.03 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.71-8.63 (m, 1H), 8.23-8.08 (m, 2H), 8.00-7.90 (m, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.48-7.42 (m, 1H), 7.25-7.18 (m, 2H), 7.05-6.86 (m, 3H), 6.60-6.48 (m, 2H), 6.01-5.95 (m, 1H), 4.73-4.56 (m, 4H), 3.62-3.49 (m, 4H), 3.09 (s, 2H), 2.71-2.59 (m, 6H), 2.30-2.14 (m, 6H), 2.07-1.98 (m, 4H), 1.91-1.71 (m, 4H), 1.48-1.38 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 14

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -N- ((4- (((1-acetyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

Example 14 was synthesized by reference to the procedure of example 4, in whichZ)-2-((1HPyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 1 to give the target product: (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -N- ((4- (((1-acetyl-4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide 14.

MS m/z (ESI)：915 & 917 [M + 1]；

H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.90 (s, 1H), 8.67-8.64 (m, 1H), 8.18-8.13 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.46-7.42 (m, 1H), 7.22 (d, J = 6.8 Hz, 2H), 6.95 (d, J = 9.2 Hz, 1H), 6.88 (d, J = 6.8 Hz, 2H), 6.56-6.52 (m, 2H), 5.99 (s, 1H), 4.62-4.58 (m, 1H), 3.82-3.78 (m, 1H), 3.57-3.52 (m, 3H), 3.07-3.02 (m, 4H), 2.98-2.95 (m, 1H), 2.71-2.68 (m, 2H), 2.20-2.16 (m, 6H), 2.14 (s, 3H), 2.10-2.05 (m, 2H), 1.86 (s, 3H), 1.78-1.71 (m, 2H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Synthetic procedures for examples 15 to 19 reference was made to the procedure of example 14: acetic acid was replaced with different acids.

Example 15

(Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (2- (tetrahydro-2))H-pyran-4-yl) acetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：999 & 1001 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 1H), 8.90 (s, 1H), 8.65-8.61 (m, 1H), 8.19-8.13 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.44-7.42 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.55-6.52 (m, 2H), 6.00 (s, 1H), 4.62-4.58 (m, 1H), 3.97-3.92 (m, 2H), 3.86-3.82 (m, 1H), 3.55-3.48 (m, 2H), 3.07-3.02 (m, 4H), 2.98-2.95 (m, 1H), 2.71-2.68 (m, 3H), 2.28-2.25 (m, 2H), 2.20-2.16 (m, 8H), 2.06-2.01 (m, 6H), 1.91 (s, 3H), 1.78-1.71 (m, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 16

(Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((1-(N,N-dimethylglycyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：958 & 960 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.87 (s, 1H), 8.67-8.64 (m, 1H), 8.18-8.13 (m, 2H), 7.93 (d, J = 9.6 Hz, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 9.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.56-6.52 (m, 2H), 5.98 (s, 1H), 4.57-4.43 (m, 1H), 4.06-4.02 (m, 1H), 3.57-3.52 (m, 4H), 3.36-3.31 (m, 2H), 3.13-3.09 (m, 6H), 2.71-2.68 (m, 2H), 2.37 (s, 6H), 2.20-2.16 (m, 8H), 1.80 (s, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 17

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (2-morpholineacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：1000 & 1002 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.90 (s, 1H), 8.65-8.61 (m, 1H), 8.19-8.13 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.56-6.52 (m, 2H), 5.99 (s, 1H), 4.55-4.51 (m, 1H), 4.05-4.01 (m, 1H), 3.78-3.72 (m, 4H), 3.58-3.55 (m, 2H), 3.44-3.40 (m, 1H), 3.32-3.28 (m, 1H), 3.20-3.17 (m, 1H), 3.11-3.02 (m, 5H), 2.71 (s, 2H), 2.55-2.50 (m, 6H), 2.28-2.25 (m, 8H), 1.91 (s, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 18

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (2-hydroxyacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：931 & 933 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.90 (s, 1H), 8.65-8.61 (m, 1H), 8.19-8.13 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.56-6.52 (m, 2H), 5.99 (s, 1H), 4.58-4.53 (m, 1H), 3.60-3.30 (m, 5H), 3.11-3.02 (m, 5H), 2.88-2.85 (m, 1H), 2.71 (s, 2H), 2.28-2.25 (m, 6H), 1.91 (s, 3H), 1.88-1.81 (m, 4H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 19

((Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-bisMethylhexan-2-en-1-yl) piperazin-1-yl) -N- ((4- (((1- (2-ethoxyacetyl) -4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：959 & 961 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.90 (s, 1H), 8.64-8.61 (m, 1H), 8.19-8.12 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.45-7.41 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.96-6.88 (m, 3H), 6.55-6.52 (m, 2H), 5.99 (m, 1H), 4.58-4.54 (m, 1H), 4.20-4.12 (m, 2H), 3.98-3.94 (m, 1H), 3.60-3.52 (m, 4H), 3.42-3.38 (m, 1H), 3.07-2.95 (m, 5H), 2.79-2.75 (m, 2H), 2.70 (s, 2H), 2.20-2.15 (m, 6H), 2.08-2.04 (m, 2H), 1.80 (s, 3H), 1.46-1.42 (m, 1H), 1.28-1.22 (m, 3H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 20

(Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide

First step of

(Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-Chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 1f (11 mg, 0.02 mmol), tert-butyl 2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylate (synthesized according to WO 2012058392) (8 mg, 0.02 mmol) and dichloromethane were mixed and reacted under argon protection with 4-dimethylaminopyridine (5 mg, 0.04 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride (6 mg, 0.03 mmol) at room temperature for 15 h under argon protection. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol = 15: 1) to give the desired product (c: (c))Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 20a (13 mg, yellow solid), yield: 71 percent.

MS m/z (ESI)：957 & 959 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.88 (s, 1H), 8.63 (s, 1H), 8.18-8.14 (m, 2H), 7.96 (d, J = 9.6 Hz, 1H), 7.69 (s, 1H), 7.44-7.40 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.92-6.88 (m, 3H), 6.55-6.52 (m, 2H), 5.98 (s, 1H), 4.09-3.70 (m, 6H), 3.64-3.38 (m, 6H), 3.09-2.82 (m, 7H), 2.05-2.01 (m, 2H), 1.79 (s, 3H), 1.58-1.50 (m, 1H), 1.31(s, 9H), 0.86 (d, J = 6.8 Hz, 6H)

Second step of

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide

A compound of (A), (B), (CZ)-2-((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-yl) benzoyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 20a (13 mg, 0.014 mmol) and methanol (1 mL) were mixed and added hydrochloric acid-dioxane solution (4M, 1 mL) under argon protection and reacted at room temperature for 2 hours under argon protection. The mixture was quenched with 25 mL of saturated aqueous sodium bicarbonate and 25 mL of methylene chloride, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol = 15: 1) to give the desired product (c: (c))Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide 20 (5 mg, yellow solid). Yield: 42 percent.

MS m/z (ESI)：857 & 859 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.32 (s, 1H), 8.86 (s, 1H), 8.60 (s, 1H), 8.12-8.08 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.45-7.42 (m, 1H), 7.22 d, J = 8.0 Hz, 2H), 6.90-6.88 (m, 3H), 6.55-6.52 (m, 2H), 6.00 (s, 1H), 4.09-3.70 (m, 6 H), 3.48-3.43 (m, 2H), 3.13-3.08 (m, 6H), 3.09-2.82 (m, 5H), 2.22-2.17 (m, 2H), 1.79 (s, 3H), 1.58-1.50 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 21

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-ethylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

A compound of (A), (B), (CZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylHex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide 20 (4 mg, 0.01 mmol), acetaldehyde (2 mg, 0.05 mmol) and 1, 2-dichloroethane (2 mL) were mixed, and sodium borohydride acetate (10 mg, 0.05 mmol) was added under argon protection, followed by reaction at room temperature for 15 hours under argon protection. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the organic phases were combined and washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol = 15: 1) to give the desired product (c: (c))Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-ethylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide 21 (1.6 mg, yellow solid). Yield: 36 percent.

MS m/z (ESI)：885 & 887 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.08 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.65-8.62 (m, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.90-6.86 (m, 3H), 6.55-6.51 (m, 2H), 5.99 (s, 1H), 3.97-3.90 (m, 2H), 3.74-3.69 (m, 1 H), 3.50-3.45 (m, 3H), 3.05-3.02 (m, 4 H), 2.87-2.82 (m, 2 H), 2.70 (s, 2H), 2.46-2.41 (m, 2H), 2.20-2.16 (m, 7H), 1.87 (s, 3H), 1.46-1.42 (m, 1H), 1.13-1.09 (m, 3H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 22

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

Example 22 was synthesized by reference to the procedure of example 16, wherein (A), (B), (C), (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide 20 substituted (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride 12 to obtain a target product ((4-fluoropiperidin-4-yl) methyl)Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide 22.

MS m/z(ESI)：942 & 944 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.56 (s, 1H), 9.42 (s, 1H), 8.88 (s, 1H), 8.64-8.60 (m, 1H), 8.18-8.15 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.45 (s, 1H), 7.25-7.22 (m, 2H), 6.90-6.88 (m, 3H), 6.56-6.52 (m, 2H), 6.00 (s, 1H), 4.52-4.08 (m, 4H), 3.78-3.72 (m, 10H), 3.69-3.45 (m, 5H), 3.29-3.21 (m, 4H), 2.92-2.87 (m, 2H), 2.72-2.68 (m, 2H), 2.05-1.99 (m, 2H), 1.82 (s, 3H), 1.49-1.47 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 23

(R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide

Example 23 was synthesized by reference to the procedure of example 20, wherein the first step was carried out using (A), (B), (C), (S)-2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester (synthesized according to WO 2012058392) amine substituted 2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester to give the target product: (R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide 23.

MS m/z (ESI): 857 & 859 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.86 (s, 1H), 8.61 (s, 1H), 8.16-8.10 (m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.67 (s, 1H), 7.46-7.44 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.90-6.86 (m, 3H), 6.56-6.53 (m, 2H), 6.00 (s, 1H), 3.97-3.70 (m, 3H), 3.41-3.36 (m, 2H), 3.06-2.91 (m, 6H), 2.75-2.70 (m, 4H), 2.23-2.16 (m, 6H), 1.79 (s, 3H), 1.44-1.37 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H)。

Example 24

(S,Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((4- (3-oxetanyl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide

Synthesis example 24 with reference to the procedure of example 21 to give the desired product (S,Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((4- (3-oxetanyl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide 24.

MS m/z (ESI): 913 & 915 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 9.04 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.17-8.14 (m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.46-7.44 (m, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.90-6.87 (m, 3H), 6.57-6.52 (m, 2H), 5.99 (s, 1H), 4.68-4.60 (m, 3H), 3.99-3.91 (m, 3H), 3.78-3.73 (m, 1H), 3.54-3.39 (m, 3H), 3.10-3.05 (m, 3H), 2.70-2.59 (m, 5H), 2.18-2.10 (m, 8H), 1.79 (s, 3H), 1.46-1.39 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Synthetic procedures for examples 25-30 reference was made to the procedure of example 14.

Example 25

(S,Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -N- ((4- ((4-acetylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

MS m/z (ESI): 899 & 901 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.31 (brs, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.65-8.63 (m, 1H), 8.10-8.09 (m, 2H), 7.92 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.57-6.54 (m, 2H), 5.97 (s, 1H), 4.55-4.42 (m, 2H), 4.01-3.97 (m, 1H), 3.75-3.58 (m, 6H), 3.35-3.31 (m, 2H), 3.12-3.07 (m, 6H), 2.83-2.81 (m, 4H), 2.18 (s, 3H), 1.81 (s, 3H), 1.45-1.43 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 26

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 942 & 944 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 8.65 (s, 1H), 8.12-8.06 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.95-6.89 (m, 3H), 6.57-6.52 (m, 2H), 6.00 (s, 1H), 4.47-4.32 (m, 2H), 4.01-3.97 (m, 1H), 3.74-3.58 (m, 3H), 3.35-3.31 (m, 2H), 3.12-3.07 (m, 7H), 2.81-2.74 (m, 2H), 2.54 (s, 3H), 2.40 (s, 3H), 2.23-2.18 (m, 6H), 1.81 (s, 3H), 1.44-1.38 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H)。

Example 27

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-Nitro-4- (((4- (2- (tetrahydro-2))H-pyran-4-yl) acetyl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide

MS m/z (ESI)：983 & 985 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 0.65H), 9.40 (s, 0.35H), 8.86 (s, 1H), 8.59-8.57 (m, 1H), 8.14-8.02 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.44-7.41 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.90-6.85 (m, 3H), 6.54-6.51 (m, 2H), 6.02-6.00 (m, 1H), 4.62-4.51 (m, 1H), 4.08-4.03 (m, 3H), 3.81-3.76 (m, 2H), 3.60-3.35 (m, 6H), 3.10-3.02 (m, 5H), 2.81-2.62 (m, 5H), 2.31-2.23 (m, 6H), 1.85 (s, 3H), 1.72-1.65 (m, 5H), 1.46-1.42 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 28

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4- (2-hydroxyacetyl) 4)) Morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：915 & 917 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.34 (s, 0.65H), 9.29 (s, 0.35H), 8.89 (s, 1H), 8.63-8.61 (m, 1H), 8.15-8.02 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.69 (s, 1H), 7.45-7.42 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.90-6.86 (m, 3H), 6.58-6.54 (m, 2H), 6.00-5.98 (m, 1H), 4.52-4.41 (m, 1H), 4.21-4.08 (m, 3H), 3.76-3.25 (m, 6H), 3.11-3.00 (m, 5H), 2.88-2.85 (m, 1H), 2.71 (s, 2H), 2.20-2.15 (m, 6H), 1.87 (s, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 29

((S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4- (2-ethoxyacetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：943 & 945 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.48 (s, 0.65H), 9.39 (s, 0.35H), 8.88 (s, 1H), 8.63-8.61 (m, 1H), 8.15-8.02 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.46-7.42 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.90-6.86 (m, 3H), 6.53-6.50 (m, 2H), 6.01 (s, 1H), 4.52-4.41 (m, 1H), 4.21-4.13 (m, 2H), 4.05-3.86 (m, 2H), 3.64-3.31 (m, 7H), 3.11-3.00 (m, 4H), 2.79-2.75 (m, 1H), 2.70 (s, 2H), 2.22-2.15 (m, 6H), 1.85 (s, 3H), 1.46-1.42 (m, 1H), 1.28-1.22 (m, 3H), 0.82 (d, J= 6.8 Hz, 6H)。

Example 30

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4- (2-Morpholineacetyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：984 & 986 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.52 (s, 0.65H), 9.43 (s, 0.35H), 8.87 (s, 1H), 8.62-8.60 (m, 1H), 8.14-8.02 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.67 (s, 1H), 7.45-7.42 (m, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.90-6.85 (m, 3H), 6.56-6.53 (m, 2H), 6.03-6.01 (m, 1H), 4.52-4.41 (m, 1H), 4.21-4.13 (m, 2.35H), 3.78-3.36 (m, 7.65H), 3.30-3.05 (m, 6.65H), 2.88-2.22 (m, 1.35H), 2.71 (s, 2H), 2.58-2.52 (m, 4H), 2.22-2.15 (m, 6H), 1.85 (s, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J= 6.8 Hz, 6H)。

Example 31

(R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- ((4- (3-oxetanyl) morpholin-2-yl) methoxy) phenyl) sulfonyl) benzamide

First step of

(R,Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-nitrophenoxy) methyl) morpholine-4-carboxylic acid tert-butyl ester

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-yl) benzoic acid 1f (25 mg, 0.045 mmol), (b), (c) and (d)R) Tert-butyl (2- ((2-nitro-4-sulfamoylphenoxy) methyl) morpholine-4-carboxylate (synthesized according to WO 2012058392) (21 mg, 0.05 mmol) and dichloromethane (5 mL) were combined, 4-dimethylaminopyridine (9 mg, 0.07 mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (14 mg, 0.07 mmol) were added under argon protection and reacted at room temperature for 15 hours under argon protection. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (dichloromethane/methanol = 20: 1) to give the desired product (aR,Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-nitrophenoxy) methyl) morpholine-4-carboxylic acid tert-butyl ester 31a (27 mg, yellow solid), yield: 61 percent.

MS m/z (ESI)：958 & 960 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.13 (brs, 1H), 9.47 (s, 1H), 8.55 (s, 1H), 8.35-8.33 (m, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.47-7.45 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.19-7.17 (m, 1H), 6.89 (d, J = 8.0 Hz, 2H), 6.54-6.44 (m, 2H), 5.98 (s, 1H), 4.24-4.20 (m, 2 H), 3.93-3.86 (m, 4H), 3.58-3.50 (m, 3H), 3.13-3.08 (m, 4H), 2.92-2.89 (m, 2H), 2.74-2.70 (m, 2H), 2.20-2.13 (m, 4H), 1.79 (s, 3H), 1.48 (s, 9H), 1.43-1.40 (m, 1H), 0.83 (d, J = 6.4 Hz, 6H)

Second step of

(R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (morpholin-2-ylmethoxy) -3-nitrophenyl) sulfonyl) benzamide

A compound of (A), (B), (CR,Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-nitrophenoxy) methyl) morpholine-4-carboxylic acid tert-butyl ester 31a (27 mg, 0.03 mmol) was mixed with methanol (2 mL), and a hydrochloric acid-dioxane solution (4M, 2 mL) was added under argon protection and reacted at room temperature for 2 hours. The mixture was quenched with 25 mL of saturated aqueous sodium bicarbonate and 25 mL of methylene chloride, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and the drying agent was removed by filtration. Decompression desolventizing to obtain the target product (R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (morpholin-2-ylmethoxy) -3-nitrophenyl) sulfonyl) benzamide 31b (24 mg, yellow solid). Yield: 98 percent.

MS m/z (ESI)：858 & 860 [M + 1]；

The third step

Will (a) toR,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (morpholin-2-ylmethoxy) -3-nitrophenyl) sulfonyl) benzamide 26b (7 mg, 0.01 mmol), 3-oxetanone (2 mg, 0.03 mmol), sodium cyanoborohydride (1 mg, 0.02 mmol) and methanol (2 mL) were mixed and stirred at room temperature for 24 hours. Desolventizing under reduced pressure to obtain crude product, purifying the crude product with preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- ((4-oxoethan-3-yl) morpholin-2-yl) methoxy) phenyl) sulphoneAcyl) benzamide 31 (1.9 mg, white solid), yield: 25 percent.

MS m/z (ESI)：914 & 916 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.10 (brs, 1H), 8.89 (s, 1H), 8.54 (s, 1H), 8.35-8.28 (m, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.68-7.67 (m, 1H), 7.45-7.42 (m, 1H), 7.22 (d, J = 8.8 Hz, 2H), 7.21-7.17 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.55-6.53 (m, 2H), 5.98 (s, 1H), 4.68-4.60 (m, 4H), 4.23-4.16 (m, 4H), 4.03-3.95 (m, 2H), 3.73-3.71 (m, 2H), 3.55-3.52 (m, 1H), 3.13-3.08 (m, 4H), 2.85-2.82 (m, 1H), 2.70 (s, 2H), 2.58-2.53 (m, 2H), 2.20-2.01 (m, 4H), 1.79 (s, 3H), 1.45-1.41 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 32

(R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -N- ((4- ((4-Acetylmorpholin-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

Will (a) toR,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (morpholin-2-ylmethoxy) -3-nitrophenyl) sulfonyl) benzamide 31b (7 mg, 0.01 mmol), acetic acid (1 mg, 0.02 mmol), 2- (7-benzotriazol oxide) -N,N,N',N'Tetramethyluronium hexafluorophosphate (5 mg, 0.01 mmol), triethylamine (2 mg, 0.02 mmol) and dichloromethane (2 mL) were mixed and stirred at room temperature for 1 hour. Desolventizing under reduced pressure to obtain crude product, purifying the crude product with preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (R,Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -N- ((4- ((4-Acetylmorpholin-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl)) Piperazin-1-yl) benzamide 32 (2 mg, white solid), yield: 27 percent.

MS m/z (ESI): 900 & 902 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 0.4H), 9.01 (s, 0.6H), 8.60 (s, 0.6H), 8.59 (s, 0.4H), 8.54-8.53 (m, 1H), 8.20-8.19 (m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.69-7.67 (m, 1H), 7.45-7.44 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.20-7.18 (m, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.56-6.54 (m, 2H), 5.98 (s, 1H), 4.61-4.58 (m, 0.4H), 4.46-4.42 (m, 0.6H), 4.32-4.16 (m, 2H), 3.99-3.79 (m, 4H), 3.61-3.55 (m, 2H), 3.37-3.31 (m, 0.4H), 3.20-3.17 (m, 0.6H), 3.08-3.06 (m, 4H), 2.90-2.84 (m, 1H), 2.70 (s, 2H), 2.20-2.16 (m, 4H), 2.13 (s, 3H), 1.79 (s, 3H), 1.43-1.40 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 33

(R,Z)-2-((1H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4- (2-Morpholineacetyl) morpholin-2-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Synthesis example 33 according to the procedure of example 32, in which 2-morpholineacetic acid was used instead of acetic acid to give the desired product: (R,Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4- (2-morpholinoacetyl) morpholin-2-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 33.

MS m/z (ESI): 985 & 987 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 0.4H), 9.01 (s, 0.6H), 8.59 (s, 0.6H), 8.57 (s, 0.4H), 8.38-8.33 (m, 1H), 8.19-8.17 (m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.68-7.66 (m, 1H), 7.48-7.46 (m, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.23-7.21 (m, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.56-6.55 (m, 2H), 5.98 (s, 1H), 4.54-4.22 (m, 4H), 4.11-3.97 (m, 3H), 3.88-3.67 (m, 8H), 3.60-3.55 (m, 2H), 3.31-3.13 (m, 2H), 3.08-3.06 (m, 4H), 2.88-2.85 (m, 2H), 2.71 (s, 2H), 2.55-2.53 (m, 4H), 1.79 (s, 3H), 1.43-1.40 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 34

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (piperidin-4-ylmethoxy) phenyl) sulfonyl) benzamide

First step of

4- ((2-Nitro-4-aminosulfonylmethylphenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (0.20 g, 0.93 mmol) and tetrahydrofuran (10 mL) were mixed, and sodium hydride (0.09 g, 2.25 mmol, 60% dispersion in mineral oil) was added under ice-water bath and stirred for 30 minutes. The compound 4-fluoro-3-nitrobenzenesulfonamide 34a-1 (0.20 g, 0.91 mmol) was added and stirred at room temperature for 16 hours. After addition of saturated ammonium chloride solution (10 mL), the mixture was quenched, extracted with ethyl acetate (15 mL. times.3), and the organic phase was washed with saturated brine (30 mL). Drying with anhydrous sodium sulfate, filtering to remove desiccant, and removing solvent under reduced pressure. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 100: 0-1: 1) to give the target product tert-butyl 4- ((2-nitro-4-aminosulfonylmethylphenoxy) methyl) piperidine-1-carboxylate 34a (0.23 g, light yellow solid), yield: 61 percent.

MS m/z (ESI): 416 [M + 1];

Second step of

(Z)-4-(((4-(N- (2- ((1H-pyrrole [2, 3-)b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) piperidine-1-carboxylic acidTert-butyl ester

Synthesis of example 34 by reference to the procedure of example 20, wherein tert-butyl 2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylate is substituted with tert-butyl 4- ((2-nitro-4-aminosulfonylmethylphenoxy) methyl) piperidine-1-carboxylate in the first step to give the desired product: (Z)-4-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester 34 b.

MS m/z (ESI): 956 & 958 [M + 1]；

The third step

Example 34 was synthesized by reference to the procedure of example 20, wherein the second step was performed using (A)Z)-4-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester 34b substitution ((R) (B)Z)-2-(((4-(N-(2-((1H-pyrrole [2,3-b]Pyridine-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 20a to give the target product (tert-butyl ester: (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) morpholine-4-carboxylic acidZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (piperidin-4-ylmethoxy) phenyl) sulfonyl) benzamide 34.

MS m/z (ESI): 856 & 858 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 11.85 (s, 1H), 10.30 (s, 1H), 8.56 (s, 1H), 8.40-8.23 (m, 1H), 8.00-7.81 (m, 1H), 7.63 (s, 1H), 7.48 (s, 1H), 7.40-7.30 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.17-7.06 (m, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.63-6.32 (m, 2H), 5.99 (s, 1H), 4.15-4.02 (m, 2H), 3.84-3.67 (m, 8H), 3.57-3.41 (m, 4H), 3.00 (s, 2H), 2.35-2.16 (m, 4H), 2.14-2.04 (m, 2H), 1.88 (s, 3H), 1.58-1.52 (m, 1H), 1.45-1.40 (m, 1H), 0.92-0.73 (m, 6H)。

The synthetic procedures for examples 35 and 36 refer to the experimental procedure of example 31.

Example 35

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- ((1- (3-oxetanyl) piperidin-4-yl) methoxy) phenyl) sulfonyl) benzamide

MS m/z (ESI): 912 & 914 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.58-8.46 (m, 1H), 8.41-8.27 (m, 1H), 8.20 (s, 1H), 7.99-7.86 (m, 1H), 7.68 (s, 1H), 7.43 (s, 1H), 7.22 (d, J= 8.0 Hz, 2H), 7.16-7.08 (m, 1H), 6.90 (d, J = 7.6 Hz, 2H), 6.01-6.47 (m, 2H), 5.97 (s, 1H), 4.75-4.49 (m, 4H), 4.14-3.86 (m, 2H), 3.52-3.33 (m, 2H), 3.15-2.98 (m, 2H), 2.87-2.74 (m, 4H), 2.73-2.60 (m, 2H), 2.34-2.11 (m, 7H), 1.79 (s, 3H), 1.76-1.58 (m, 5H), 1.47-1.39 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

Example 36

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((1- (3-oxetanyl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

MS m/z (ESI): 911 & 913 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.53-8.50 (m, 1H), 8.19-8.18 (m, 1H), 8.15-8.13 (m, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.70-7.69 (m, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.90-6.88 (m, 3H), 6.55-6.53 (m, 2H), 5.98 (s, 1H), 4.68-4.60 (m, 4H), 3.49-3.44 (m, 1H), 3.28-3.25 (m, 2H), 3.06-3.05 (m, 4H), 2.82-2.79 (m, 4H), 2.70 (s, 2H), 2.20-2.19 (m, 6H), 1.87-1.82 (m, 5H), 1.79 (s, 3H), 1.44-1.41 (m, 1H), 0.82 (d, J= 6.6 Hz, 6H)。

The synthetic procedures of examples 37 to 44 refer to the experimental procedure of example 32.

Example 37

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (2-hydroxyacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 914 & 916 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.35 (dd, J = 8.9, 2.2 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.58-6.50 (m, 2H), 5.98 (d, J = 1.9 Hz, 1H), 4.74-4.65 (m, 1H), 4.21-4.15 (m, 2H), 4.09-3.94 (m, 2H), 3.61-3.53 (m, 1H), 3.11-3.00 (m, 5H), 2.81-2.72 (m, 2H), 2.70 (s, 2H), 2.29-2.11 (m, 8H), 2.07-1.87 (m, 2H), 1.79 (s, 3H), 1.47-1.36 (m, 1H), 0.82 (d, J= 6.6 Hz, 6H)。

Example 38

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (2-ethoxyacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 942 & 944 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.18 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.12 (s, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.60-6.47 (m, 2H), 5.99 (s, 1H), 4.73-4.60 (m, 1H), 4.25-4.09 (m, 2H), 4.25-4.09 (m, 4H), 4.07-3.85 (m, 2H), 3.17-2.90 (m, 6H), 2.70 (s, 2H), 2.67-2.58 (m, 2H), 2.26-2.14 (m, 8H), 1.80 (s, 3H), 1.46-1.38 (m, 1H), 1.16-1.07 (m, 3H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 39

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((1- (2-Morpholineacetyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 983 & 985 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.9, 2.3 Hz, 1H), 8.20 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.50-7.43 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.59-6.51 (m, 2H), 5.97 (d, J = 2.2 Hz, 1H), 4.74-4.62 (m, 1H), 4.24-4.15 (m, 1H), 4.12-4.04 (m, 1H), 4.01-3.92 (m, 1H), 3.78-3.67 (m, 4H), 3.33-3.10 (m, 2H), 3.09-2.98 (m, 5H), 2.70 (s, 2H), 2.66-2.58 (m, 1H), 2.56-2.45 (m, 4H), 2.24-2.10 (m, 8H), 1.90-1.82 (m, 3H), 1.79 (s, 3H), 1.47-1.29 (m, 1H), 0.85-0.77 (m, 6H)。

Example 40

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-Nitro-4- (((1- (2- (tetrahydro-2H-pyran-4-yl) acetyl) piperidin-4-yl) methoxy) phenyl) sulfonyl) benzamide

MS m/z (ESI): 982 & 984 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.54 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.70 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 6.59-6.50 (m, 2H), 5.98 (s, 1H), 4.80-4.69 (m, 1H), 4.13-4.02 (m, 1H), 4.01-3.84 (m, 5H), 3.48-3.39 (m, 2H), 3.18-2.92 (m, 6H), 2.70 (s, 2H), 2.64-2.52 (m, 1H), 2.33-2.26 (m, 2H), 2.24-2.08 (m, 8H), 1.89-1.82 (m, 6H), 1.79 (s, 3H), 1.48-1.41 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

EXAMPLE 41

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((1- (2-hydroxyacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 913 & 915 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.53-8.50 (m, 1H), 8.19-8.16 (m, 2H), 7.94 (d, J = 9.1 Hz, 1H), 7.70-7.69 (m, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.91-6.88 (m, 3H), 6.56-6.53 (m, 2H), 5.98-5.97 (m, 1H), 4.70-4.67 (m, 1H), 4.18-4.17 (m, 2H), 3.64 (s, 1H), 3.59-3.56 (m, 1H), 3.31-3.27 (m, 2H), 3.06-2.99 (m, 6H), 2.75-2.70 (m, 3H), 2.20-2.18 (m, 6H), 2.00-1.99 (m, 1H), 1.93-1.90 (m, 2H), 1.79 (s, 3H), 1.45-1.39 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 42

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((1- (2-ethoxyacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 941 & 943 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.53-8.50 (m, 1H), 8.19-8.14 (m, 2H), 7.94 (d, J = 9.1 Hz, 1H), 7.69-7.68 (m, 1H), 7.45-7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.90-6.88 (m, 3H), 6.56-6.53 (m, 2H), 5.99-5.98 (m, 1H), 4.68-4.65 (m, 1H), 4.20-4.10 (m, 2H), 4.06-4.03 (m, 1H), 3.60-3.54 (m, 2H), 3.30-3.25 (m, 2H), 3.07-3.05 (m, 4H), 2.71-2.65 (m, 3H), 2.62-2.59 (m, 1H), 2.20-2.18 (m, 6H), 1.97-1.96 (m, 3H), 1.89-1.85 (m, 2H), 1.79 (s, 3H), 1.46-1.40 (m, 1H), 1.25-1.23 (m, 3H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 43

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-Nitro-4- (((1- (2- (tetrahydro-2H-pyran-4-yl) acetyl) piperidin-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

MS m/z (ESI): 981 & 983 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.53-8.51 (m, 1H), 8.19-8.16 (m, 2H), 7.94 (d, J = 9.1 Hz, 1H), 7.71-7.70 (m, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.91-6.88 (m, 3H), 6.56-6.53 (m, 2H), 5.98-5.97 (m, 1H), 4.75-4.72 (m, 1H), 3.97-3.93 (m, 3H), 3.46-3.40 (m, 2H), 3.31-3.24 (m, 2H), 3.07-3.05 (m, 5H), 2.70 (s, 2H), 2.61-2.54 (m, 1H), 2.28-2.26 (m, 2H), 2.20-2.18 (m, 6H), 2.09-2.07 (m, 1H), 1.96-1.85 (m, 4H), 1.79 (s, 3H), 1.70-1.67 (m, 5H), 1.43-1.42 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Example 44

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((1- (2-morpholinoacetyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI): 982 & 984 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.53-8.50 (m, 1H), 8.20-8.19 (m, 1H), 8.18-8.15 (m, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.70-7.69 (m, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.91-6.88 (m, 3H), 6.55-6.53 (m, 2H), 5.99-5.98 (m, 1H), 4.69-4.66 (m, 1H), 4.19-4.16 (m, 1H), 3.73-3.71 (m, 4H), 3.29-3.27 (m, 2H), 3.15-3.00 (m, 5H), 2.80-2.78 (m, 1H), 8.18-8.15 (m, 1H), 2.70 (s, 2H), 2.63-2.56 (m, 1H), 2.52-2.51 (m, 4H), 2.20-2.18 (m, 6H), 2.02-1.99 (m, 1H), 1.93-1.85 (m, 4H), 1.79 (s, 3H), 1.46-1.40 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。

Synthetic procedures for examples 45 to 52 reference was made to the experimental procedure of the second step of example 34, wherein tert-butyl 4- ((2-nitro-4-sulfonamidomethylphenoxy) methyl) piperidine-1-carboxylate was substituted with a different sulfonamide.

Example 45

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((1-methylpiperidin-4-yl) methyl) amino) 3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：869 & 871 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 1H), 8.80 (s, 1H), 8.47-8.44 (m, 1H), 8.14 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.40 (s, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.75-6.70 (m, 1H), 6.53-6.50 (m, 1H), 6.45 (s, 1H), 6.10 (s, 1H), 5.45 (s, 1H), 3.51-3.45 (m, 4 H), 3.22-3.18 (m, 2H), 3.09-3.02 (m, 6 H), 2.37 (s, 3H), 2.22-2.18 (m, 4H), 2.05-1.98 (m, 3H), 1.84-1.81 (m, 5H), 1.76-1.73 (m, 2H), 1.44-1.40 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 46

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

MS m/z (ESI)：856 & 858 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 8.83 (s, 1H), 8.52-8.48 (m, 1H), 8.18-8.09 (m, 3H), 7.94 (d, J = 9.2 Hz, 1H), 7.62 (s, 1H), 7.32-7.29 (m, 2H), 6.95-6.92 (m, 3H), 6.72-6.68 (m, 1H), 6.59-6.52 (m, 1H), 6.05-5.96 (m, 1H), 4.04-4.01 (m, 4 H), 3.72-3.69 (m, 2 H), 3.61-3.58 (m, 2 H), 3.47-3.4 2(m, 4 H), 3.26-3.22 (m, 2H), 3.20-3.15 (m, 4H), 2.28-2.25 (m, 2H), 2.05-1.98 (m, 4H), 1.80-1.77 (m, 2H), 1.55-1.49 (m, 1H), 0.83-0.78 (m, 6H)。

Example 47

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-Nitro-4- ((tetrahydro-2)H-pyran-4-yl) methoxy) phenyl) sulfonyl) benzamide

MS m/z (ESI)：857 & 859 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 1H), 8.28-8.25 (m, 1H), 8.14-8.12 (m, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.71-7.69 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.18 (m, 2H), 7.15-7.12 (m, 3H), 6.92-6.85 (m, 2H), 6.53-6.49 (m, 2H), 5.98 (s, 1H), 4.08-4.03 (m, 4H), 3.53-3.40 (m, 6H), 3.09-3.02 (m, 4H), 2.73-2.68 (m, 2H), 2.23-2.18 (m, 4H), 1.98 (s, 3H), 1.85-1.80 (m, 3H), 1.43-1.40 (m, 1H), 0.82 ( d, J = 6.8 Hz, 6H)。

Example 48

(S,Z)-N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide trifluoroacetate salt

MS m/z (ESI): 858 & 860 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 11.35 (s, 1H), 9.87 (s, 1H), 8.87 (s, 1H), 8.65-8.62 (m, 1H), 8.16-8.13 (m, 2H), 8.00-7.96 (m, 1H), 7.62-7.58 (m, 1H), 7.35-7.28 (m, 3H), , 6.94-6.80 (m, 3H), 6.72-6.59 (m, 2H), 5.98 (s, 1H), 3.92-3.63 (m, 7H), 3.57-3.48 (m, 4H), 3.40-3.35 (m, 4H), 2.28 (s, 2H), 2.06-2.00 (m, 4H), 1.98 (s, 3H), 1.48-1.44 (m, 1H), 0.83 (d, J = 6.4 Hz, 6H)。

Example 49

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluorotetrahydro-2-yl)H-pyran-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：875 & 877 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.18 (s, 1H), 9.19 (s, 1H), 8.58 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.23-7.17 (m, 3H), 6.89 (d, J = 4.8 Hz, 2H), 6.55-6.52 (m, 2H), 5.98 (s, 1H), 4.37-4.35 (m, 2H), 3.91-3.88 (m, 2H), 3.77-3.67 (m, 4H), 3.08-3.01 (m, 4 H), 2.75-2.70 (m, 2H), 2.09-2.03 (m, 4H), 1.92-1.88 (m, 4H), 1.82 (s, 3H), 1.44-1.38 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 50

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-Fluorotetrahydro-2))H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：874 & 876 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.06 (s, 1H), 9.32 (s, 1H), 8.91 (s, 1H), 8.66-8.63 (m, 1H), 8.19-8.14 (m, 2H), 7.94 (d, J = 9.2 Hz, 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 9.2 Hz, 1H), 6.89 (d, J= 8.4 Hz, 2H), 6.56-6.52 (m, 2H), 5.98 (s, 1H), 3.88-3.84 (m, 2H), 3.77-3.72 (m, 2H), 3.57-3.52 (m, 2H), 3.08-3.04 (m, 4H), 2.87-2.82 (m, 2H), 2.20-2.16 (m, 6H), 1.91-1.85 (m, 4H), 1.80 (s, 3H), 1.46-1.42 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 51

(R,Z)-N- ((4- (((1, 4-dioxan-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

MS m/z (ESI)：858 & 860 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 8.94 (s, 1H), 8.89 (s, 1H), 8.62-8.60 (m, 1H), 8.20-8.16 (m, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.26-7.23 (m, 2H), 6.91-6.88 (m, 3H), 6.52-6.49 (m, 2H), 5.98 (s, 1H), 3.89-3.76 (m, 6H), 3.69-3.66 (m, 1H), 3.48-3.21 (m, 6H), 3.12-3.08 (m, 2H), 2.87-2.84 (m, 2H), 2.72-2.68 (m, 2H), 2.05-1.99 (m, 2H), 1.82 (s, 3H), 1.43-1.40 (m, 1 H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 52

(R,Z)-N- ((4- ((1, 4-dioxan-2-yl) methoxy) -3-nitrophenyl) sulfonyl) -2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

MS m/z (ESI)：859 & 861 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.19 (s, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.31-8.28 (m, 1H), 8.16-8.15 (m, 1H), 7.93-7.91 (m, 1H),7.61 (s, 1H), 7.41 (s, 1H), 7.23-7.21 (m, 2H), 7.14-7.11 (m, 1H), 6.90-6.88 (m, 2H), 6.56-6.54 (m, 2H), 6.50 (s, 1H), 6.03 (s, 1H) , 4.18-3.15 (m, 2H) , 4.05-4.00 (m, 1H), 3.96-3.93 (m, 1H), 3.82-3.68 (m, 4H), 3.66-58 (m, 2H), 3.29-3.23 (m, 1H), 3.07-3.02 (m, 4H), 2.72 (s, 2H), 2.22-2.19 (m, 4H), 1.80 (s, 3H), 1.43-1.40 (m, 1 H), 0.82 (d, J = 6.8 Hz, 6H)。

Example 53

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

First step of

2, 5-dimethyl-3- ((trifluoromethylsulfonyl) oxo) hex-2-enoic acid methyl ester

The compound methyl 2, 5-dimethyl-3-carbonylhexanoate 1d-2 (1.00 g, 5.81 mmol), 1,1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (4.30 g, 12.00 mmol) andN,Ndimethylformamide (20 mL), tetrahydrofuran (20 mL), potassium carbonate (2.80 g, 20.28 mmol) under argon, and 45 ℃ for 15 hours under argon. The mixture is quenched with 50 mL of water and 50 mL of ethyl acetate, the organic phase is separated off and the aqueous phase is quenched with ethyl acetate (50 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (petroleum ether/ethyl acetate = 20: 1) to give the desired product methyl 2, 5-dimethyl-3- (((trifluoromethyl) sulfonyl) oxo) hex-2-enoate 53a (5.10 g, yellow liquid). Yield: and 55 percent.

¹H NMR (400 MHz, CDCl₃) δ 3.79 (s, 3H), 2.69 (d, J = 7.2 Hz, 2H), 2.07 (s, 3H), 2.02-1.93 (m, 1H), 0.94 (d, J = 6.4 Hz, 6H)

Second step of

3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoic acid methyl ester

The compound methyl 2, 5-dimethyl-3- ((trifluoromethylsulfonyl) oxo) hex-2-enoate 53a (0.13 g, 0.43 mmol), 4-chlorobenzeneboronic acid (0.16 g, 1.03 mmol), 1, 2-dichloroethane (2 mL), and methanol (2 mL) were mixed, and tetrakis (triphenylphosphine) palladium (62 mg, 0.05 mmol), cesium fluoride (0.30 g, 2.00 mmol), and reacted at 70 ℃ for 1 hour under argon protection. The mixture was quenched with 25 mL of water and 25 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (petroleum ether/ethyl acetate = 20: 1) to give the desired product methyl 3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoate 53b (0.11 g, yellow liquid). Yield: 91 percent.

MS m/z (ESI)：267 & 269 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 7.32-7.27 (m, 1H), 7.25-7.21 (m, 1H), 7.07-7.03 (m, 2H), 3.79 (s, 1.5H), 3.41 (s, 1.5H), 2.50 (d, J = 7.2 Hz, 1H), 2.34 (d, J= 7.2 Hz, 1H), 2.03 (s, 1.5H), 1.73 (s, 1.5H), 1.53-1.42 (m, 1H), 0.89-0.82 (m, 6H)

The third step

3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol

The compound methyl 3- (4-chlorophenyl) -2, 5-dimethylhex-2-enoate 53b (0.11 g, 0.41 mmol) and tetrahydrofuran (3 mL) were mixed, and lithium aluminum hydride (38 mg, 1.00 mmol) was added under an argon atmosphere, followed by a reaction at room temperature under an argon atmosphere for 1 hour. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, the organic phase is separated off and the aqueous phase is extracted with dichloromethane (25 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and the drying agent was removed by filtration. The target product, 3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol 53c (95 mg, yellow liquid), was obtained by exsolution under reduced pressure.

MS m/z (ESI)：221 & 223 [M - 17]；

¹H NMR (400 MHz, CDCl₃) δ 7.31-7.27 (m, 2H), 7.05-7.02 (m, 2H), 4.31 (s, 1 H), 3.93 (s, 1H), 2.30-2.24 (m, 2H), 1.92 (s, 1.5H), 1.65 (s, 1.5H), 1.49-1.42 (m, 1H), 0.88-0.82 (m, 6H)

The fourth step

3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl ethanesulfonate

The compound, 3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ol 53c (95 mg, 0.40 mmol), triethylamine (0.30 g, 2.97 mmol) and tetrahydrofuran (5.0 mL) were mixed. Ethyl sulfonyl chloride (0.13 g, 1.02 mmol) was added under argon and reacted at room temperature for 1 hour under argon. The mixture was desolventized under reduced pressure to give the desired product 3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-ylethanesulfonate 53d (0.12 g, yellow liquid), crude;

the fifth step

4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-carboxylic acid tert-butyl ester

The compound 3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl ethanesulfonate 53d (0.12 g, 0.36 mmol), triethylamine (0.30 g, 2.97 mmol) and tetrahydrofuran (5 mL) were mixed. Under the protection of argon, piperazine-1-carboxylic acid tert-butyl ester (0.20 g, 1.08 mmol) is added, and the reaction is carried out for 2 hours at room temperature under the protection of argon. The mixture was quenched with 25 mL of water and 25 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase by using anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by preparative silica gel plate (petroleum ether/ethyl acetate = 5: 1) to give the desired product tert-butyl 4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-carboxylate 53e (95 mg, yellow liquid). Yield: 61 percent.

MS m/z (ESI)：407 & 409 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 7.27-7.23 (m, 1H), 7.03-6.99 (m, 2H), 6.94-6.91 (m, 1H), 3.47-3.43 (m, 4H), 3.36-3.31 (m, 2H), 2.39-2.32 (m, 4H), 2.28 (d, J= 7.2 Hz, 1H), 2.22 (d, J = 7.2 Hz, 1H), 1.86 (s, 1.5H), 1.60 (s, 1.5H), 1.49 (s, 9H), 1.45-1.39 (m, 1H), 0.85-0.78 (m, 6H)

The sixth step

1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine trifluoroacetate salt

The compound tert-butyl 4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-carboxylate 53e (95 mg, 0.23 mmol) and dichloromethane (2 mL) were mixed, and trifluoroacetic acid (1 mL) was added under an argon atmosphere, followed by a reaction at room temperature under an argon atmosphere for 2 hours. The mixture was desolventized under reduced pressure to give the desired product 1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine trifluoroacetate 53f (60 mg, yellow liquid), crude.

MS m/z (ESI)：307 & 309 [M + 1]；

Seventh step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester

The compound 1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine trifluoroacetate 53f (60 mg, 0.20 mmol), 2- ((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester (85 mg, 0.30 mmol) and dimethylsulfoxide (2 mL) were mixed, and potassium dihydrogen phosphate (0.20 g, 1.47 mmol) was added under an argon atmosphere, followed by reaction at 130 ℃ for 10 hours under an argon atmosphere. The mixture was taken up in 25 mL of water and 25 mL of ethyl acetate and the organic phase separated. The aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The crude product was purified by preparation of silica gel plate (petroleum ether/ethyl acetate = 1: 1) to give the target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 53g (11 mg, yellow solid). Yield: 10 percent.

MS m/z (ESI)：573 & 575 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H), 8.21-8.18 (m, 1H), 7.91-7.87 (m, 1H), 7.54-7.50 (m, 1H), 7.38-7.32 (m, 1H), 7.21-7.18 (m, 3H), 6.98-6.95 (m, 1H), 6.91-6.88 (m, 1H), 6.41-6.38 (m, 1H), 6.31-6.27 (m, 1H), 3.78 (s, 3H), 3.29-3.27 (m, 4H), 3.18-3.14 (m, 2H), 2.49-2.42 (m, 4H), 2.38 (d, J = 7.2 Hz, 1H), 2.28 (d, J = 7.2 Hz, 1H), 1.89 (s, 1.5H), 1.60 (s, 1.5H), 1.45-1.39 (m, 1H), 0.90-0.82 (m, 6H)

Eighth step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 53g (11 mg, 0.02 mmol), water (1 mL) and 1, 4-dioxane (1 mL) were mixed and potassium hydroxide (56 mg, 1.00 mmol) was added under argon protection and reacted at 60 ℃ for 2 hours under argon protection. The mixture was quenched with 25 mL of dilute hydrochloric acid (1M) and 25 mL of dichloromethane, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain the target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 53h (11 mg, yellow)A colored solid), crude.

MS m/z (ESI)：559 & 561 [M + 1]；

The ninth step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2-yl)H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 53h (11 mg, 0.02 mmol), 3-nitro-4- (((tetrahydro-2-ol)H-pyran-4-yl) methyl) amino) benzenesulfonamide (13 mg, 0.04 mmol) and dichloromethane (3 mL) were mixed, and under an argon atmosphere, 4-dimethylaminopyridine (4 mg, 0.03 mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (8 mg, 0.04 mmol) were added, and under an argon atmosphere, the reaction was carried out at room temperature for 15 hours. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified by preparation of silica gel plates (dichloromethane/methanol = 15: 1) to give the desired product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 53 (4 mg, yellow solid). Yield: 24 percent.

MS m/z (ESI)：856 & 858 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.87 (s, 1H), 8.91-8.87 (m, 1H), 8.55-8.50 (m, 1H), 8.13-8.09 (m, 2H), 7.99-7.93 (m, 1H), 7.75-7.71 (m, 1H), 7.47-7.43 (m, 1H), 7.27-7.24 (m, 2H), 6.96-6.92 (m, 4H), 6.59-6.52 (m, 2H), 6.05-5.96 (m, 1H), 4.04-4.01 (m, 2H), 3.47-3.42 (m, 2H), 3.26-3.22 (m, 2H), 3.20-3.15 (m, 4H), 2.61-2.57 (m, 2H), 2.41-2.38 (m, 2H), 2.28-2.25 (m, 4H), 1.89 (s, 1.5H), 1.80-1.77 (m, 5H), 1.60 (s, 1.5H), 1.45-1.39 (m, 1H), 0.83-0.78 (m, 6H)。

Example 54

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- (((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methyl) amino) -5-nitrophenyl) sulfonyl) benzamide

First step of

3, 4-difluoro-5-nitrobenzenesulfonamide

1, 2-difluoro-3-nitrobenzene 54a-1 (1.00 g, 6.29 mmol) was dissolved in chlorosulfonic acid (1.2 mL) and stirred under reflux overnight. After cooling to room temperature, the reaction mixture was slowly added to ice water. Extraction was performed with ethyl acetate (50 mL. times.3), and the organic phase was washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product of 3, 4-difluoro-5-nitrobenzenesulfonyl chloride. The crude product, 3, 4-difluoro-5-nitrobenzenesulfonyl chloride, was dissolved in anhydrous tetrahydrofuran (20 mL) and ammonia (2 mL, 37%) was slowly added dropwise at-78 ℃ in a dry ice bath of ethanol. After stirring at-78 ℃ for two hours, concentrated hydrochloric acid was added to adjust the pH of the system to about 2. The temperature was raised to room temperature, and the tetrahydrofuran solvent was removed under reduced pressure. The mixture was extracted with ethyl acetate (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by a silica gel column (0 to 1: 2 = ethyl acetate: petroleum ether) to obtain the target product 3, 4-difluoro-5-nitrobenzenesulfonamide 54a-2 (0.14 g, yellow solid). Yield: 9 percent.

¹H NMR (400 MHz, DMSO-d ₆) δ 8.38-8.36 (m, 1H), 8.29-8.26 (m, 1H), 7.84 (s, 2H)

Second step of

4-fluoro-4- (((2-nitro-4-aminosulfonylphenyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester

3, 4-difluoro-5-nitrobenzenesulfonamide 54a-2 (70 mg, 0.29 mmol), tert-butyl 4- (aminomethyl) -4-fluoropiperidine-1-carboxylate (80 mg, 0.34 mmol) was added to acetonitrile (10 mL), and the mixture was addedN,NDiisopropylethylamine (0.14 g, 1.09 mmol), reacted at room temperature under nitrogen overnight. The mixture was quenched with 25 mL of water and 25 mL of ethyl acetate, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure and purified with a silica gel column (ethyl acetate: petroleum ether = 0-1: 1) to give the target product, tert-butyl 4-fluoro-4- (((2-nitro-4-aminosulfonylphenyl) amino) methyl) piperidine-1-carboxylate 54a (0.10 g, yellow solid). Yield: 80 percent.

MS m/z (ESI)：451 [M + 1];

The third step

(Z)-4-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-fluoro-6-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester

Will (a) toZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoic acid 1f (12 mg, 0.02 mmol), tert-butyl 4-fluoro-4- (((2-nitro-4-aminosulfonylphenyl) amino) methyl) piperidine-1-carboxylate 54a (9 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (8 mg, 0.04 mmol), p-dimethylaminopyridine (5 mg, 0.04 mmol) and reacted for 3 hours with stirring at room temperature. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (20 mL. times.2), and the combined organic phases were washed with saturated brine (30 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, desolventized under reduced pressure and purified with a silica gel column (dichloromethane: methanol = 20: 1) to obtain the objective product: (Z)-4-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-fluoro-6-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 54b (10 mg, yellow solid). Yield: 51 percent.

MS m/z (ESI): 991 & 993 [M + 1];

The fourth step

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- (((4-fluoropiperidin-4-yl) methyl) amino) -5-nitrophenyl) sulfonyl) benzamide

Will (a) toZ)-4-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (3-) 4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzoyl) sulfamoyl) -2-fluoro-6-nitrophenyl) amino) methyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester 54b (10 mg, 0.01 mmol) was dissolved in methanol (0.5 mL), dioxane solution (6M, 2.5 mL) was added, and stirring was carried out for 1 hour. The solvent was removed under reduced pressure and the crude product was dissolved in dichloromethane (30 mL) and washed once with saturated sodium bicarbonate (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. Decompression desolventizing to obtain the product (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- (((4-fluoropiperidin-4-yl) methyl) amino) -5-nitrophenyl) sulfonyl) benzamide 54c (10 mg, yellow solid), crude.

MS m/z (ESI): 891 & 893 [M + 1];

The fifth step

Will (a) toZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- (((4-fluoropiperidin-4-yl) methyl) amino) -5-nitrophenyl) sulfonyl) benzamide 54c (10 mg, 0.01 mmol), oxetan-3-one (10 mg, 0.14 mmol) was dissolved in methanol (2.5 mL), and sodium cyanoborohydride (10 mg, 0.16 mol) was added and stirred at room temperature overnight. The solution was removed under reduced pressure, the residue was dissolved in 25 mL of water and 25 mL of methylene chloride, and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified on preparative silica gel plate (20: 1 = dichloromethane: methanol) to give the desired product (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-enecyclobutane-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- (((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methyl) amino) -5-nitrophenyl) sulfonyl) benzamide 54 (2 mg, white solid), yield: 18 percent.

MS m/z (ESI)：947 & 949 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.59 (s, 1H), 8.73 (s , 1H), 8.58-8.56 (m, 1H), 8.14 (s, 1H), 7.98-7.92 (m, 2H), 7.71 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.25-7.22 (m, 1H), 6.9-7.89 (m, 2H), 6.57-6.54 (m, 2H), 5.98 (s, 1H), 4.70-4.66 (m, 4H), 3.87-3.84 (m, 1H), 3.64-3.59 (m, 2H), 3.19-3.10 (m, 4H), 2.67-3.62 (m, 2H), 2.36-2.18 (m, 10H), 2.01 (s, 3H), 1.95-1.62 (m, 4H), 1.43-1.40 (m, 1H), 0.83 (d, J = 6.8 Hz, 6H)。

Example 55

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -5-nitrophenyl) sulfonyl) benzamide

Reference example 54 procedureExample 55, wherein the second step used 4-fluoro-4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester to replace 4- (aminomethyl) -4-fluoropiperidine-1-carboxylic acid tert-butyl ester to obtain the target product: (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-fluoro-4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -5-nitrophenyl) sulfonyl) benzamide 55.

MS m/z (ESI): 948 & 950 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 8.32 (s, 1H), 8.20-8.17 (m, 2H), 7.94 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.46-7.44 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 2H), 6.57-6.54 (m, 2H), 5.97 (s, 1H), 4.70-4.66 (m, 2H), 4.63-4.60 (m, 2H), 4.30 (d, J = 22 Hz, 2H), 3.55-3.52 (m, 1H), 3.08-3.03 (m, 3H), 2.72-2.69 (m, 2H), 2.63-2.60 (m, 2H), 2.24-2.19 (m, 7H), 2.06-2.00 (m, 6H), 1.80 (s, 3H), 1.44-1.39 (m, 1H), 0.82 (d, J = 6.4 Hz, 6H)。

The synthetic procedure of example 56 was followed in the experimental procedure of example 32.

Example 56

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -N- ((4- (((1-acetyl-4-fluoropiperidin-4-yl) methyl) amino) -3-fluoro-5-nitrophenyl) sulfonyl) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) benzamide

MS m/z (ESI): 933 & 935 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 8.69 (s, 1H), 8.53-8.47 (s, 1H), 8.17-8.13 (m, 1H), 7.98-7.90 (m, 2H), 7.66-7.61 (m, 1H), 7.42-7.39 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.93-6.85 (m, 2H), 6.58-6.50 (m, 2H), 6.05-6.00 (m, 1H), 3.89-3.78 (m, 2H), 3.77-3.70 (m, 1H), 3.46-3.37 (m, 1H), 3.30-3.21 (m, 2H), 3.10-2.87 (m, 6H), 2.24-2.17 (m, 8H), 2.12 (s, 3H), 2.04-1.97 (m, 2H), 1.79 (s, 3H), 1.41-1.38 (m, 1H), 0.85-0.79 (m, 6H)。

Example 57

(R,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride

First step of

4-(3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (tert-butoxycarbonyl) phenyl) -3, 6-dihydropyridine-1 (2)H) -tert-butyl formate

2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid tert-butyl ester 57a (synthesized according to Journal of Organic Chemistry, 84(8), 4814-oxazone 4829; 2019) (0.15 g, 0.39 mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl formate (0.14 g, 0.45 mmol), sodium carbonate (0.12 g, 1.11 mmol) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (28 mg, 0.04 mmol) was added to a1, 4-dioxane/water mixture (5/1, 6 mL), the system was replaced with nitrogen 3 times, and the temperature was raised to 90 ℃ for reaction for 2 hours. After cooling to room temperature, the mixture is quenched with 25 mL of water and 25 mL of ethyl acetate and the organic phase is separated off. The aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified by silica gel column separation (50% ethyl acetate/petroleum ether) to give 4- (3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (tert-butoxycarbonyl) phenyl) -3, 6-dihydropir-zinePyridine-1 (2)H) Tert-butyl formate 57b (0.17 g, white solid), yield: 89.5 percent.

MS m/z (ESI): 492 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.86 (s, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.44-7.40 (m, 1H), 7.22 (dd, J= 8.0, 4.0 Hz, 1H), 6.94 (d, J = 4.0 Hz, 1H), 6.52 (d, J = 4.0 Hz, 1H), 6.05 (s, 1H), 4.04 (s, 2H), 3.59 (t, J = 4.0 Hz, 2H), 2.42-2.39 (m, 2H) 1.46 (s, 9H), 1.45 (s, 9H)

Second step of

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid trifluoroacetate salt

Mixing 4- (3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (tert-butoxycarbonyl) phenyl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl formate 57b (0.17 g, 0.35 mmol) was dissolved in a trifluoroacetic acid/dichloromethane mixture (1/3, 4 mL) and stirred at room temperature for 1 hour. Decompression desolventizing to obtain a product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid trifluoroacetate 57c (0.16 g crude, white solid), crude.

MS m/z (ESI): 336 [M + 1];

The third step

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid

Will (a) toZ) -1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (0.33 g, 1.28 mmol), 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid trifluoroacetate 57c (0.16 g, 0.36 mmol) (1/3, 4 mL) andN,Ndiisopropylethylamine (0.39 g, 3.00 mmol) was addedN,NDimethylformamide (2 mL), stirred at room temperature for 1 hour. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2)The combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. The residue was purified by preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)₂O（0.5 % NH₄OH) 25% -40%) to give the product (C: (OH))Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid 57d (83 mg, white solid). Yield: 43.2 percent.

MS m/z (ESI): 556 & 558 [M + 1];

The fourth step

(S,Z)-2-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoyl) sulfonamide) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester

Will (a) toZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoic acid 57d (83.0 mg, 0.15 mmol), (b 1b 2, b 3, c 6-tetrahydropyridin-4-yl) benzoic acidS) Tert-butyl (2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylate (48 mg, 0.12 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.14 g, 0.73 mmol), 4-dimethylaminopyridine (91 mg, 0.75 mmol) were added to dichloromethane (5 mL) and stirred at room temperature overnight. The mixture was quenched with 25 mL of water and the organic phase was separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (25 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. Separating and purifying the residue with a silica gel column (70-100% ethyl acetate/petroleum ether) to obtain a target product (S,Z)-2-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoyl) sulfonamide) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 57e (56 mg, yellow solid). Yield: 39.1 percent.

MS m/z (ESI): 954 & 956 [M + 1];

The fifth step

Will (a) toS,Z)-2-(((4-(N-(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) benzoyl) sulfonamide) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 57e (56 mg, 0.59 mmol) was added to a dioxane solution of hydrogen chloride (4M, 2 mL) and stirred at room temperature for 2 hours. Decompression desolventizing to obtain a product (R,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride 57 (52 mg, yellow solid), yield: 100 percent.

MS m/z (ESI): 854 & 856 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.64 (d, J = 4.0 Hz, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.35-7.24 (m, 3H), 7.19-7.06 (m, 4H), 6.72 (d, J = 4.0 Hz, 1H), 6.08 (s, 1H), 6.01 (s, 1H), 4.15-4.05 (m, 2H), 3.95-3.84 (m, 2H), 3.76-3.71 (m, 2H), 3.69-3.63 (m, 2H), 3.60-3.43 (m, 5H), 3.24-3.16 (m, 1H), 3.12-3.02 (m, 2H), 2.83-2.68 (m, 1H), 2.58-2.34 (m, 2H), 2.05-1.99 (s, 3H), 1.42-1.40 (m, 1H), 0.90-0.84 (m, 6H)。

Example 58

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((4- (3-oxetanyl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) Benzamide derivatives

Will (a) toR,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride 57 (20 mg, 0.02 mmol), triethylamine (10 mg, 010 mmol), 3-oxetanone (10 mg, 0.14 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol) were added methanol (5 mL) and reacted at room temperature overnight. Desolventizing under reduced pressure, and purifying the residue with a liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)₂O（0.5 % NH₄OH) 25% -35%) to obtain the product (A)S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((4- (3-oxetanyl) morpholin-2-yl) methyl) amino) phenyl) sulfonyl) benzamide 58 (3.3 mg, yellow solid), yield: 16.1 percent.

MS m/z (ESI): 910 & 912 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.69–8.60 (m, 1H), 8.19-8.11 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.47-7.41 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.95–6.85 (m, 3H), 6.68 (s, 1H), 6.57-6.51 (m, 1H), 5.92 (s, 1H), 4.76-4.56 (m, 4H), 4.00-3.86 (m, 2H), 3.76 (t, J = 8.0 Hz, 1H), 3.56-3.35 (m, 3H), 2.92-2.81 (m, 3H), 2.70 (d, J = 8.0 Hz, 1H), 2.61 (d, J = 8.0 Hz, 1H), 2.45-2.36 (m, 2H), 2.32-2.07 (m, 5H), 2.01-1.92 (m, 2H), 1.84 (s, 3H), 1.44-1.40 (m, 1H), 0.83 (d, J = 8.0 Hz, 6H)。

Example 59

(S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

Will (a) toR,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride 57 (20 mg, 0.02 mmol),N,NDimethylglycine (4 mg, 0.04 mmol) and 2- (7-benzotriazole oxide) -N,N,N',N' -tetramethyluronium hexafluorophosphate (13 mg, 0.03 mmol) was added to methylene chloride (5 mL), and triethylamine (10 mg, 0.10 mmol) was added dropwise to the mixture, followed by reaction at room temperature for 0.5 hour. Desolventizing under reduced pressure, and purifying the residue with a liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)₂O（0.5 % NH₄OH) 20% -40%) to obtain the product (A)S,Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide 59 (2.3 mg, yellow solid), yield: 10.9 percent.

MS m/z (ESI): 939 & 941 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.90 (s, 1H), 8.70-8.59 (m, 1H), 8.19-8.00 (m, 3H), 7.67 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.95-6.81 (m, 3H), 6.67 (s, 1H), 6.54 (s, 1H), 5.91 (s, 1H), 4.57-4.47 (m, 1H), 4.44-4.31(m, 1H), 4.23-4.14 (m, 1H), 4.03-3.94 (m, 2H), 3.80-3.21 (m, 5H), 3.16-3.05 (m, 2H), 3.03-2.86 (m, 4H), 2.73-2.62 (m, 1H), 2.54-2.42 (m, 2H), 2.32 (s, 6H), 2.22 (d, J = 8.0 Hz, 2H), 1.87 (s, 3H), 1.42-1.40 (m, 1H), 0.83 (d, J = 8.0 Hz, 6H)。

Example 60

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

First step of

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid methyl ester

The compound methyl 4-bromo-2-fluorobenzoate 60a (2.30 g, 9.87 mmol) and 1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridin-5-ol (2.90 g, 10.00 mmol) andN,N-dimethylformamide (20 mL) and potassium carbonate (4.00 g, 28.99 mmol) was added under argon. After stirring at 90 ℃ for 15 hours under argon, the mixture is quenched with 100 mL of water and 100 mL of ethyl acetate and the organic phase is separated off. The aqueous phase was extracted with ethyl acetate (50 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by silica gel column (petroleum ether/ethyl acetate = 1: 1) to give the desired product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid methyl ester 60b (1.60 g, yellow solid). Yield: and 47 percent.

MS m/z (ESI)：347 & 349 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.01 (s, 1H), 8.18 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.40-7.26 (s, 2H), 6.97 (s, 1H), 6.51-6.48 (m, 1H), 3.89 (s, 3H)

Second step of

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid

A compound- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid methyl ester 60b (0.35 g, 1.01 mmol), water (5 mL) and 1, 4-dioxane (5 mL) were combined and potassium hydroxide (0.22 g, 3.93 mmol) was added under argon. After stirring for 2 hours at 50 ℃ under argon, the mixture was quenched with 100 mL of water and 10 mL of dilute hydrochloric acid (1N). White solid precipitated and was filtered. The solid is dried under reduced pressure to obtain a target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid 60c (0.33 g, white solid). And (5) crude product.

MS m/z (ESI)：333 & 335 [M + 1]；

The third step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromo-N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromobenzoic acid 60c (0.33 g, 1.00 mmol), 3-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) benzenesulfonamide (0.32 g, 1.02 mmol) and dichloromethane (50 mL) were mixed, 4-dimethylaminopyridine (0.49 g, 4.02 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.34 g, 1.77 mmol) were added under argon protection, and the mixture was reacted at room temperature for 15 hours under argon protection. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and the drying agent was removed by filtration. Decompression desolventizing to obtain a crude target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromo-N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 60d (0.63 g, yellow solid), yield: 100 percent.

MS m/z (ESI)：630 & 632 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.94-8.91 (m, 2H), 8.57-8.54 (m, 1H), 8.21-8.14 (m, 3H), 8.00 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.48-7.42 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 6.70 (d, J = 8.4 Hz, 1H), 6.59-6.56 (m, 1H), 4.08-4.05 (m, 2H), 3.43-3.40 (m, 2H), 3.30-3.27 (m, 2H), 2.05-1.99 (m, 1H), 1.76-1.73 (m, 2H), 1.47-1.43 (m, 2H)

The fourth step

4-(3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (((3-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) carbamoyl) phenyl) -3, 6-dihydropyridine-1 (2)H) -tert-butyl formate

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-bromo-N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 60d (0.20 g, 0.32 mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl carboxylate (0.31 g, 1.00 mmol), 1, 4-dioxane (10 mL) and water (1 mL) were mixed, and tetrakis (triphenylphosphine) palladium (35 mg, 0.03 mmol), sodium carbonate (0.21 mg, 1.98 mmol) and reacted at 85 ℃ for 15 hours under argon protection. The mixture is quenched with 25 mL of water and 25 mL of dichloromethane, and the organic phase is separated. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression and desolventizing to obtain a crude product. The crude product was purified by silica gel column (dichloromethane/methanol = 20: 1) to give the desired product 4- (3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (((3-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) carbamoyl) phenyl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl formate 60e (0.14 g, yellow solid). Yield: 58 percent.

MS m/z (ESI)：733 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 9.13 (s, 1H), 8.93 (s, 1H), 8.57-8.54 (m, 1H), 8.21-8.14 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.70-7.67 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.70 (s, 1H), 6.59-6.56 (m, 1H), 6.00 (s, 1H), 4.06-4.02 (m, 4H), 3.58-3.52 (m, 2H), 3.43-3.40 (m, 2H), 3.30-3.27 (m, 2H), 2.32-2.28 (m, 2H), 2.05-1.99 (m, 1H), 1.76-1.73 (m, 2H), 1.47-1.43 (m, 2H), 1.40 (s, 9H)

The fifth step

2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzamide trifluoroacetate salt

Compound 4- (3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (((3-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) carbamoyl) phenyl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl formate 60e (60 mg, 0.08 mmol) and dichloromethane (2.0 mL) were mixed, trifluoroacetic acid (1.0 mL) was added under argon atmosphere, and the mixture was reacted at room temperature for 2 hours under argon atmosphere. The mixture is decompressed and desolventized to obtain a target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzamide trifluoroacetate 60f (50 mg, yellow liquid), crude.

MS m/z (ESI)：633 [M + 1]；

The sixth step

Compound 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -4- (1,2,3, 6-tetrahydropyridin-4-yl) benzamide 60f (44 mg, 0.06 mmol), (b), (c) and (d)Z) -1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (38 mg, 0.15 mmol) benzene andN,N-dimethylFormamide (2.0 mL) was mixed and potassium carbonate (40 mg, 0.29 mmol) was added under argon. After stirring at 40 ℃ for 5 hours under argon, the mixture is quenched with 25 mL of water and 25 mL of dichloromethane and the organic phase is separated off. The aqueous phase was extracted with dichloromethane (25 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. Residue preparation silica gel plate purification (dichloromethane/methanol = 15: 1) to yield the desired product (c: (c))Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 60 (6 mg, yellow solid). Yield: 10 percent.

MS m/z (ESI)：853 & 855 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 11.58 (s, 1H), 8.88 (s, 1H), 8.55-8.51 (m, 1H), 8.18-7.98 (m, 4H), 7.57 (s, 1H), 7.32-7.29 (m, 2H), 7.01-6.92 (m, 5H), 6.72-6.68 (m, 1H), 6.59 (s, 1H), 5.81 (m, 1H), 4.04-3.98 (m, 2H), 3.72-3.69 (m, 4H), 3.64-3.60 (m, 2H), 3.54-3.49 (m, 2H), 3.47-3.42 (m, 2H), 3.26-3.22 (m, 2H), 2.05-1.98 (m, 2H), 1.97 (s, 3H), 1.82-1.77 (m, 3H), 1.44-1.40 (m, 1H), 0.83-0.78 (m, 6H)。

Example 61

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamides

First step of

5-bromo-3- ((1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl) oxy) -2-cyanopyridine

Reacting the compound 1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridine-5-phenol 61a (1.50 g, 5.17 mmol) (synthesized according to Bioconjugate Chemistry, 25(11), 2081-2085; 2014), 5-bromo-3-nitrocyanopyridine (1.18 g, 5.18 mmol) and potassium phosphate (1.65 g, 7.78 mmol) were dissolved in 1, 4-dioxane (20 mL) and reacted at 90 ℃ for 12 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (20 mL. times.3). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing vacuum desolventizing to obtain the target product 5-bromo-3- ((1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -2-cyanopyridine 61b (2.20 g, yellow solid), yield: 90 percent.

MS m/z (ESI): 471 & 473 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 3.6 Hz, 1H), 7.35 (d, J = 1.8 Hz, 1H), 6.60 (d, J = 3.6 Hz, 1H), 1.90-1.83 (m, 3H), 1.14 (d, J = 7.6 Hz, 18H)

Second step of

3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid

Compound 5-bromo-3- ((1- (triisopropylsilyl) -1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -2-cyanopyridine 61b (2.20 g, 4.67 mmol) and sodium hydroxide (0.83 g, 20.75 mmol) were dissolved in methanol (30 mL) and water (20 mL) and reacted at 75 ℃ for 12 hours. The reaction solution was adjusted to pH = 5 to 6 with dilute hydrochloric acid (1M) and desolventized under reduced pressure. The residue was dissolved in methanol and filtered. Decompressing and desolventizing the filtrate to obtain 3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid 61c (3.00 g, yellow solid). The crude product was used directly as the next reaction.

MS m/z (ESI): 334 & 336 [M + 1];

The third step

3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid methyl ester

Compound 3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid 61c (3.00 g, crude) was dissolved in methanol (30 mL), thionyl chloride (2 mL) was slowly added dropwise at room temperature, and after completion of the addition, the reaction was carried out at 70 ℃ for 2 hours. The reaction mixture was desolventized under reduced pressure, and the residue was dissolved in methylene chloride (150 mL) and washed with water (30 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and desolventized under reduced pressure. Purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1-3: 1) to obtain the target product 3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid methyl ester 61d (0.45 g, yellow solid) in 25% yield over two steps.

MS m/z (ESI): 348 & 350 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 11.42 (s, 1H), 8.47 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.73 (d, J = 2.2 Hz, 1H), 7.51-7.49 (m, 1H), 7.37 (s, 1H), 6.53 (s, 1H), 4.02 (s, 3H)；

The fourth step

1' - (tert-butyl) -6-methyl-5- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -3',6' -dihydro- [3,4' -bipyridine]-1',6(2'H) Esters of dicarboxylic acids

Compound 3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromomethylpyridinecarboxylic acid methyl ester 61d (0.42 g, 1.21 mmol), 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2)H) Tert-butyl formate (0.56 g, 1.81 mmol) and sodium carbonate (0.38 g, 3.58 mmol) were dissolved in 1, 4-dioxane (20 mL), 1' -bis-diphenylphosphinoferrocene palladium dichloride (87 mg, 0.12 mmol) was added under nitrogen and the mixture was reacted at 100 ℃ for 12 hours. The reaction solution was filtered, and the filtrate was desolventized under reduced pressure. Purifying the residue by silica gel column chromatography (petroleum ether/ethyl acetate = 10: 1-1: 1) to obtain the target product 1' - (tert-butyl) -6-methyl-5- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -3',6' -dihydro- [3,4' -bipyridine]-1',6(2'H) Dicarboxylate 61e (0.20 g, yellow solid) in 37% yield.

MS m/z (ESI): 451 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 11.05 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.16 (s, 1H), 6.51 (s, 1H), 6.10 (s, 1H), 4.05-4.04 (m, 2H), 4.00 (s, 3H), 3.58-3.57 (m, 2H), 2.39-2.37 (m, 2H), 1.45 (s, 9H)

The fifth step

5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-Carboxylic acid methyl ester

The compound 1' - (tert-butyl) -6-methyl-5- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -3',6' -dihydro- [3,4' -bipyridine]-1',6(2'H) The dicarboxylate 61e (0.10 g, 0.22 mmol) was dissolved in ethyl acetate (3 mL), and a solution of ethyl acetate hydrochloride (2M, 3 mL) was added at room temperature, followed by stirring at room temperature for 1 hour. The reaction solution is decompressed and desolventized, the residue is dissolved by dichloromethane/methanol (10: 1), and the pH value is adjusted to about 8-9 by triethylamine. The mixture is decompressed and exsolution is carried out to obtain 5- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]Methyl 6-carboxylate 61f (yellow solid), crude was used directly in the next reaction.

MS m/z (ESI): 351 [M + 1];

The sixth step

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-Carboxylic acid methyl ester

Compound 5- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-Carboxylic acid methyl ester 61f (crude, 0.22 mmol), (b), (c), (d), (Z) -1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (70 mg, 0.27 mmol) andN,Ndiisopropylethylamine (72 mg, 0.56 mmol) was dissolved in acetonitrile (4 mL) and reacted at 40 ℃ for 12 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent,and (4) decompressing and desolventizing. The residue was purified on preparative silica gel plates (dichloromethane/methanol = 20: 1) to give the desired product (aZ)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]61g of methyl 6-carboxylate (15 mg, yellow solid).

MS m/z (ESI): 571 & 573 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.64 (s, 1H), 8.44 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.42-7.39 (m, 1H), 7.25 (s, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 6.50 (s, 1H), 6.06 (s, 1H), 3.98 (s, 3H), 2.92-2.83 (m, 3H), 2.43-2.36 (m, 5H), 2.23 (d, J = 7.2 Hz, 2H), 1.85 (s, 3H), 1.48-1.42 (m, 1H), 0.84 (d, J = 6.6 Hz, 6H)

Seventh step

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carboxylic acid

A compound of (A), (B), (CZ)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]Methyl (61 g, 10 mg, 0.02 mmol) of (E) -6-carboxylate was dissolved in methanol (4 mL) and water (1 mL), and sodium hydroxide (3 mg, 0.08 mmol) was added to stir the reaction at room temperature for 2 hours. The pH of the reaction solution is adjusted to 5-6 by dilute hydrochloric acid (1M). Extraction was performed with methylene chloride/methanol (20: 1, 20 mL), the organic phase was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. Decompression desolventizing to obtain the target product (Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carboxylic acid 61h (crude).

MS m/z (ESI): 557 & 559 [M + 1];

Eighth step

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((3-Nitro)-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamides

A compound of (A), (B), (CZ)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carboxylic acid 61H (crude, 0.01 mmol), 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide (4 mg, 0.01 mol), 4-dimethylaminopyridine (2 mg, 0.02 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3 mg, 0.02 mmol) were dissolved in dichloromethane (1 mL) and reacted at room temperature for 12 hours. The reaction solution is decompressed and desolventized, and the residue is purified by preparative chromatography (Xbridge-C18; 30X 150 mm column, 5 μm, acetonitrile-water, 15% -30%, 0.1% ammonium bicarbonate, 25 mL/min) to obtain the target product (A)Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]6-carboxamide 61 (1 mg, yellow solid).

MS m/z (ESI): 854 & 856 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.77-8.76 (m, 1H), 8.51-8.49 (m, 1H), 8.26 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.10 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.04 (s, 1H), 6.94-6.85 (m, 3H), 6.49 (s, 1H), 6.06 (s, 1H), 4.03-4.00 (m, 2H), 3.43-3.39 (m, 2H), 3.32-3.18 (m, 4H), 2.89 (s, 2H), 2.84-2.82 (m, 2H), 2.39-2.37 (m, 2H), 2.29-2.28 (m, 2H), 2.22 (d, J = 7.2 Hz, 2H), 1.82 (s, 3H), 1.74-1.71 (m, 3H), 1.46-1.41 (m, 1H), 0.84 (d, J = 6.6 Hz, 6H)。

Example 62

(R,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide hydrochloride

First step of

(S,Z)-2-((4-(N-(5-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carbonyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester

With reference to the eighth step of EXAMPLE 61, the procedure was followed, whereinS) 3-nitro-4- (((tetrahydro-2-yl) amino) 2- (((2-nitro-4-aminosulfonylphenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester amineHThe (pyran-4-yl) methyl) amino) phenylmethanesulfonamide is used to obtain a target productS,Z)-2-((4-(N-(5-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carbonyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 62a (8 mg, yellow solid), yield: 8 percent.

MS m/z (ESI): 955 & 957 [M + 1];

Second step of

Will (a) toS,Z)-2-((4-(N-(5-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -1'- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -1',2',3',6 '-tetrahydro- [3,4' -bipyridine]-6-carbonyl) aminosulfonyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 62a (8 mg, 0.01 mmol) was dissolved in methanol (2 mL), dioxane solution (4) was addedM, 2 mL) was reacted at room temperature for 2 hours. Concentrating the reaction solution to obtain a target compound (a)R,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]6-carboxamide hydrochloride 62 (7 mg, yellow solid) in 97.7% yield.

MS m/z (ESI): 855 & 857 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.71 (s, 1H), 8.58 (s, 1H), 8.35-8.31 (m, 1H), 8.13 (d, J = 2.4 Hz, 1H), 7.92 (s, 1H), 7.75-7.70 (m, 2H), 7.33-7.27 (m, 2H), 7.16-7.13 (m, 3H), 6.75 (s, 1H), 6.21 (s, 1H), 4.32-4.29 (m, 2H), 4.18-4.13 (m, 2H), 3.85-3.60 (m, 7H), 3.39-3.32 (m, 1H), 2.95-2.89 (m, 1H), 2.88 (s, 2H), 2.46-2.37 (m, 2H), 2.31-2.20 (m, 2H), 2.01 (s, 3H), 1.42-1.36 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H)。

Example 63

(S,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- (((4-methylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamides

Will (a) toR,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]6-carboxamide hydrochloride 62 (7 mg, 0.01 mmol) was suspended in dichloromethane (15 mL), triethylamine (10 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. After concentration, the mixture was dissolved in methanol (3 mL), and paraformaldehyde (30 mg, 1.00 mmol) and sodium triacetoxyborohydride (21 mg, 0.13 mmol) were added to react at room temperature for 18 hours. The reaction was quenched with saturated ammonium chloride (5 mL) and extracted with dichloromethaneTake (25 mL. times.2) and combine the organic phases. The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and desolventized under reduced pressure. Purifying the residue by high performance liquid chromatography (Xbridge-C18; 30X 150 mm column, 5 μm, acetonitrile-water, 15% -30%, 0.1% ammonium bicarbonate, 25 mL/min) to obtain the target compoundS,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- (((4-methylmorpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]6-carboxamide 63 (1 mg, yellow solid), yield 14.3%.

MS m/z (ESI): 869 & 871 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 8.62 (s, 1H), 8.35-8.29 (m, 1H), 8.28-8.22 (m, 1H), 8.19-8.16 (m, 1H), 7.97 (s, 1H), 7.57-7.54 (m, 2H), 7.35-7.29 (m, 2H), 7.18-7.10 (m, 3H), 6.48 (s, 1H), 6.15 (s, 1H), 4.32-4.29 (m, 2H), 4.21-4.16 (m, 2H), 3.98-3.66 (m, 7H), 3.42-3.34 (m, 1H), 3.02-2.99 (m, 1H), 2.89 (s, 2H), 2.83 (s, 3H), 2.75-2.69 (m, 2H), 2.30-2.22 (m, 2H), 1.85 (s, 3H), 1.42-1.38 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H)。

Example 64

(S,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamides

Will (a) toR,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide hydrochloride 62 (8 mg, 0.01 mmol),N,N-dimethylglycineAcid (2 mg, 0.02 mmol) and 2- (7-benzotriazole oxide) -N,N,N',N' -tetramethyluronium hexafluorophosphate (7 mg, 0.02 mmol) was added to methylene chloride (3 mL), and triethylamine (5 mg, 0.05 mmol) was added dropwise to the mixture, followed by reaction at room temperature for 0.5 hour. Desolventizing under reduced pressure, and purifying the residue with preparative liquid phase (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H₂O（0.5 % NH₄OH) 20% -40%) to give the product (C: (C))S,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide 64 (1.5 mg, yellow solid), yield: 16 percent.

MS m/z (ESI): 940 & 942 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.54 (s, 1H), 8.35-8.31 (m, 1H) , 8.04-8.02 (m, 1H), 7.94 (s, 1H), 7.46-7.38 (m, 2H), 7.26-7.20 (m, 2H), 7.00-6.97 (m, 3H), 6.33 (s, 1H), 6.05 (s, 1H), 4.30-4.26 (m, 2H), 4.08-3.99 (m, 2H), 3.80-3.56 (m, 7H), 3.35-3.32 (m, 1H), 3.03-2.97 (m, 1H), 2.58 (s, 6H), 2.58-2.50 (m, 2H), 2.31-2.20 (m, 4H), 2.19-2.17 (m, 2H), 1.86 (s, 3H), 1.44-1.40 (m, 1H), 0.89 (d, J = 6.4 Hz, 6H)。

Example 65

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide hydrochloride

Synthesis example 65 according to the procedure of example 62, wherein the second step replaces 3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) benzenesulfonamide with tert-butyl 4-fluoro-4-hydroxymethylpiperidine-1-carboxylate to give the desired product (I)Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide hydrochloride 65.

MS m/z (ESI): 872 & 874 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.58-8.56 (m, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 8.26-8.22 (m, 2H), 7.75 (m, 1H), 7.66-7.63 (m, 1H), 7.50-7.48 (m, 1H), 7.32-7.26 (m, 2H), 7.17-7.13 (m, 2H), 6.78 (m, 1H), 6.23 (s, 1H), 4.48-4.43 (m, 2H), 3.95-3.85 (m, 2H), 3.77-3.74 (m, 2H), 3.66-3.58 (m, 2H), 3.40-3.28 (m, 4H), 2.41 (s, 2H), 2.38-2.31 (m, 2H), 2.30-2.28 (m, 2H), 2.19-2.01 (m, 2H), 2.00 (s, 3H), 1.40-1.36 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H)。

Example 66

(Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N-((4-((1-(N,N-dimethylglycyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamides

Example 66 was synthesized by reference to the procedure of example 64, in whichZ)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]-6-carboxamide hydrochloride substitution (R,Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]The 6-formamide hydrochloride 62 obtains a target product (Z)-5-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -1' - (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) -1',2',3',6' -tetrahydro- [3,4' -bipyridine]6-carboxamide 66.

MS m/z (ESI): 957 & 959 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 2.4 Hz, 1H), 8.21 (s, 1H), 8.05-8.02 (m, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.40 (d, J=3.2 Hz, 1H), 7.28-7.26 (m, 2H), 7.16 (s, 1H), 7.10-7.08 (m, 1H), 7.04-7.02 (m, 2H), 6.40 (m, 1H), 6.01 (s, 1H), 4.42-4.39 (m, 2H), 4.19-4.13 (m, 2H), 4.00-3.95 (m, 2H), 3.78-3.74 (m, 2H), 3.38-3.34 (m, 2H), 3.10-3.05 (m, 4H), 2.75 (s, 6H), 2.65-2.62 (m, 2H), 2.38 (s, 2H), 2.30-2.28 (m, 2H), 2.10-2.01 (m, 2H), 1.88 (s, 3H), 1.44-1.35 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H)。

Example 67

(R,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

First step of

5-bromo-3- ((1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridine-2-carboxylic acid methyl ester

Compound 3- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5-bromopyridine-2-carboxylic acid methyl ester 61d (7.00 g, 20.11 mmol) was dissolved in tetrahydrofuran (120 mL), sodium hydrogen (1.20 g, 30.00 mmol, 60% dispersed mineral oil) was slowly added under ice bath, stirred for 30 minutes, and triisopropylchlorosilane (4.06 g,21.15 mmol). After the completion of the dropwise addition, the reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution (300 mL), extracted with ethyl acetate (500 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. Purifying the residue by silica gel column chromatography (ethyl acetate/petroleum ether 1% -4%) to obtain the target product 5-bromo-3- ((1- (triisopropylsilyl) -1%H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridine-2-carboxylic acid methyl ester 67a (4.10 g, white solid), yield: 40 percent.

MS m/z (ESI): 504 & 506 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.40-7.39 (m, 2H), 6.55 (d, J = 3.6 Hz, 1H), 3.99 (s, 3H), 1.93-1.78 (m, 3H), 1.13 (d, J = 7.6 Hz, 18H)

Second step of

4- (6- (methoxycarbonyl) -5- ((1- (triisopropylsilyl) -1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester

Compound 5-bromo-3- ((1- (triisopropylsilyl) -1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridine-2-carboxylic acid methyl ester 67a (4.10 g, 8.13 mmol), piperazine-1-carboxylic acid tert-butyl ester (3.03 g, 16.29 mmol) and cesium carbonate (5.29 g, 16.23 mmol) were dissolved in dioxane (50 mL), tris (dibenzylideneacetone) dipalladium (0.75 g, 0.81 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.94 g, 1.62 mmol) were added under argon and the mixture was reacted at 100 ℃ for 12 hours. The reaction solution was filtered, and the filtrate was desolventized under reduced pressure. Purifying the residue by silica gel column chromatography (ethyl acetate/petroleum ether 10: 1-2: 1) to obtain the target product 4- (6- (methoxycarbonyl) -5- ((1- (triisopropylsilyl) -1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester 67b (1.80 g, yellow solid), yield: 36 percent.

MS m/z (ESI): 610 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.11-8.09 (m, 2H), 7.50 (d, J = 2.8 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 3.92 (s, 3H), 3.60-3.45 (m, 4H), 3.24-3.15 (m, 4H), 1.90-1.77 (m, 3H), 1.45 (s, 9H), 1.12 (d, J = 7.6 Hz, 18H)

The third step

3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (piperazin-1-yl) pyridine-2-carboxylic acid methyl ester hydrochloride

Reacting 4- (6- (methoxycarbonyl) -5- ((1- (triisopropylsilyl) -1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) pyridin-3-yl) piperazine-1-carboxylic acid tert-butyl ester 67b (0.70 g, 1.15 mmol), hydrogen chloride dioxane solution (4M, 20 mL) and methanol (10 mL) were mixed and stirred at room temperature for 1 hour. Decompression desolventizing to obtain a target product 3- ((1)H-pyrrole [2,3-b ]]Pyridin-5-yl) oxy) -5- (piperazin-1-yl) pyridine-2-carboxylic acid methyl ester hydrochloride 67c (0.41 g, white solid), yield: 100 percent.

MS m/z (ESI): 354 [M + 1];

The fourth step

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid methyl ester

Will be 3- ((1)H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (piperazin-1-yl) pyridine-2-carboxylic acid methyl ester hydrochloride 67c (0.41 g, 1.05 mmol), (b), (c) and (d)Z) 1-chloro-4- (1-chloro-2, 5-dimethylhex-2-en-3-yl) benzene 1d (0.35 g, 1.36 mmol),N,Ndiisopropylethylamine (0.75 g, 5.81 mmol) and acetonitrile (15 mL) were mixed and stirred at room temperature for 16 h. The reaction was quenched with water (300 mL), extracted with dichloromethane (100 mL. times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolventized under reduced pressure. Purifying the residue by flash column chromatography (dichloromethane/methanol = 100: 0-96: 4) to obtain a target product (A)Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid methyl ester 67d (0.40 g, white solid), yield: 61 ％。

MS m/z (ESI): 574 & 576 [M + 1];

The fifth step

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid

Will (a) toZ)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid methyl ester 67d (0.40 g, 0.70 mmol), sodium hydroxide (0.30 g, 7.50 mmol), ethanol (10 mL) and water (5 mL) were mixed and stirred at 80 ℃ for 1 hour. The mixture was desolventized under reduced pressure, and the residue was extracted with methylene chloride (30 mL. times.3) by adding water (30 mL) and hydrochloric acid (1M, 15 mL). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and carrying out decompression and desolventizing to obtain a target product: (Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid 67e (0.13 g, white solid), yield: 33 percent.

MS m/z (ESI): 560 & 562 [M + 1];

The sixth step

(S,Z)-2-((4-(N-(3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) picolinoyl) sulfonylcarbamoyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester

Will (a) toZ)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) pyridine-2-carboxylic acid 67e (15 mg, 0.027 mmol), (b), (c) and (d)S) Tert-butyl (2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylate (11 mg, 0.026 mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (8 mg, 0.04 mmol), 4-dimethylaminopyridine (5 mg, 0.04 mmol) and dichloromethane (5 mL) were mixed and stirred at room temperature for 16 h. Desolventizing under reduced pressure to obtain crude product, purifying the crude product with preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (S,Z)-2-((4-(N-(3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) picolinoyl) sulfonylcarbamoyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 67f (8 mg, white solid), yield: 31 percent.

MS m/z (ESI): 958 & 960 [M + 1];

Seventh step

Will (a) toR,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) carbamic acid tert-butyl ester) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

(S,Z)-2-((4-(N-(3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) picolinoyl) sulfonylcarbamoyl) -2-nitrophenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester 67f (8 mg, 0.008 mmol) was dissolved in methanol (2 mL), and dioxane solution (4M, 2 mL) was added to react at room temperature for 2 hours. The reaction mixture was concentrated, suspended in methylene chloride (25 mL), washed with a saturated solution of sodium carbonate (20 mL), and dried over anhydrous sodium sulfate. Filtering and concentrating to obtain the target compound (R,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 67 (7 mg, yellow solid) yield 97.7%.

MS m/z (ESI): 858 & 860 [M + 1];

¹H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 8.61-8.57 (m, 1H), 8.31-8.29 (m, 2H), 8.28-8.25 (m, 1H), 7.85 (s, 1H), 7.55-7.52 (m, 1H), 7.37-7.35 (m, 1H), 7.24-7.22 (m, 2H), 6.91-6.89 (m, 3H), 6.58-6.43 (m, 1H), 6.34 (s, 1H), 4.42-4.40 (m, 2H), 3.85-3.60 (m, 7H), 3.39-3.32 (m, 1H), 3.15-3.11 (m, 4H), 2.98-2.94 (m, 1H), 2.73 (s, 2H), 2.24-2.20 (m, 4H), 2.00 (s, 3H), 1.44-1.40 (m, 1H), 0.83 (d, J = 6.4 Hz, 6H)。

Example 68

(S,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

Will be provided withN,NDimethylglycine (2 mg, 0.02 mmol) dissolved in dichloromethane (5 mL) was addedN,NDiisopropylethylamine (10 mg, 0.08 mmol) and 2- (7-benzotriazole oxide)N,N,N',N' -tetramethylurea hexafluorophosphate (8 mg, 0.02 mmol), was added after stirring at room temperature for 10 minutes (b) ((iii))R,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 67 (6 mg, 0.007 mmol) was reacted at room temperature for 10 hours. The reaction mixture was diluted with methylene chloride (15 mL), washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. Filtering, vacuum desolventizing, and purifying the residue by high performance liquid chromatography (Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm, ACN/H)₂O（0.5 % NH₄OH) 20% -40%) to obtain the target compound (S,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N-((4-(((4-(N,N-dimethylglycyl) morpholin-2-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 68 (0.8 mg, yellow solid) yield 12.1%.

MS m/z (ESI): 943 & 945 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 8.60-8.58 (m, 1H), 8.30-8.27 (m, 2H), 8.27-8.26 (m, 1H), 7.86 (s, 1H), 7.56-7.51 (m, 1H), 7.39-7.34 (m, 1H), 7.25-7.22 (m, 2H), 6.93-6.87 (m, 3H), 6.55-6.48 (m, 1H), 6.30 (s, 1H), 4.40-4.30 (m, 2H), 3.90-3.62 (m, 7H), 3.41-3.36 (m, 1H), 3.38 (s, 2H), 3.19-3.14 (m, 4H), 2.88-2.82(m, 1H), 2.60 (s, 2H), 2.45 (s, 6H), 2.25-2.20 (m, 4H), 2.02 (s, 3H), 1.40-1.36 (m, 1H), 0.84 (d, J = 6.4 Hz, 6H)。

Example 69

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

Synthesis of example 69 by reference to the procedure of example 67, wherein in the sixth step tert-butyl 4-fluoro-4- (hydroxymethyl) piperidine-1-carboxylate is used instead of (S) The (2- (((2-nitro-4-sulfamoylphenyl) amino) methyl) morpholine-4-carboxylic acid tert-butyl ester is obtained as a target productZ)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 69.

MS m/z (ESI): 875 & 877 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J = 2.1 Hz, 1H), 7.95-7.88 (m, 2H), 7.43 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 3.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.07-6.94 (m, 3H), 6.69 (d, J = 2.1 Hz, 1H), 6.36 (d, J = 3.4 Hz, 1H), 6.08 (s, 1H), 4.14-4.06 (m, 2H), 3.78-3.72 (m, 2H), 3.70-3.64 (m, 2H), 3.63-3.55 (m, 2H), 3.16-3.07 (m, 2H), 2.97-2.86 (m, 2H), 2.77 (s, 2H), 2.36-2.24 (m, 4H), 2.06-1.90 (m, 2H), 1.86 (s, 3H), 1.64-1.53 (m, 2H), 1.47-1.41 (m, 1H), 0.95-0.73 (m, 6H)。

Example 70

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperaziOxazin-1-yl) -N-((4-((1-(N,N-dimethylglycyl) -4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

Example 70 was synthesized by reference to the procedure of example 68, whereinZ)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 69 substitution ((4-fluoropiperidin-4-yl) methoxy)R,Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((morpholin-2-ylmethyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 67 gives the target product: (Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide 70.

MS m/z (ESI): 960 & 962 [M + 1];

¹H NMR (400 MHz, CD₃OD) δ 8.37 (s, 1H), 8.01-7.85 (m, 3H), 7.50-7.42 (m, 1H), 7.37 (s, 1H), 7.31-7.21 (m, 1H), 7.08-6.94 (m, 3H), 6.90 (s, 1H), 6.67 (s, 1H), 6.35 (s, 1H), 3.66-3.56 (m, 4H), 3.41-3.23 (m, 6H), 3.14-3.02 (m, 2H), 2.77 (s, 2H), 2.54-2.41 (m, 6H), 2.32-2.23 (m, 4H), 2.05-1.96 (m, 4H), 1.84 (s, 3H), 1.75-1.66 (m, 2H), 1.46-1.37 (m, 1H), 0.87-0.77 (m, 6H)。

Synthetic procedures for examples 71 and 72 referring to the sixth procedure in example 67, substituting (a) with a different sulfonamideS) -tert-butyl 2- (((2-nitro-4-aminoxanthylphenyl) amino) methyl) morpholine-4-carboxylate.

Example 71

(Z)-3-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazine-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) pyridine-2-carboxamide

MS m/z (ESI): 857 & 859 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 8.59-8.56 (m, 1H), 8.23-8.21 (m, 2H), 8.10 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.59-7.57 (m, 1H), 7.38-7.35 (m, 1H), 7.24-7.22 (m, 2H), 6.90-6.88 (m, 3H), 6.50-6.46 (m, 1H), 6.31 (s, 1H), 4.04-4.00 (m, 2H), 3.44-3.38 (m, 2H), 3.29-3.23 (m, 2H), 3.13-3.10 (m, 4H), 2.72 (s, 2H), 2.68-2.64 (m, 4H), 2.29-2.27 (m, 4H), 1.80 (s, 3H), 1.74-1.71 (m, 3H), 1.47-1.43 (m, 1H), 0.83 (d, J = 6.4 Hz, 6H)。

Example 72

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-Fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) pyridine-2-carboxamide

MS m/z (ESI): 875 & 877 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H), 8.92 (s, 1H), 8.71-8.61 (m, 1H), 8.30-8.21 (m, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.02-6.96 (m, 1H), 6.94-6.83 (m, 2H), 6.70 (s, 1H), 6.51-6.45 (m, 1H), 6.29 (s, 1H), 5.57 (s, 1H), 3.94-3.85 (m, 2H), 3.80-3.72 (m, 2H), 3.33 (s, 2H), 3.15-3.06 (m, 4H), 2.88-2.67 (m, 6H), 2.33-2.16 (m, 6H), 1.81 (s, 3H), 1.48-1.44 (m, 1H), 0.83 (d, J = 6.4 Hz, 6H)。

Example 73

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

First step of

(Z) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol

Will (a) toZ) -3- (4-chlorophenyl) -2-methylbut-2-enoic acid ethyl ester 73a (according to Organic)&Biomolecular Chemistry, 13(30), 8205-8210; 2015 Synthesis) (80 mg, 0.34 mmol) was dissolved in dry tetrahydrofuran (3 mL), and a solution of lithium borohydride in tetrahydrofuran (2M, 0.34 mL) was added, followed by reaction at room temperature for 2 hours. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (25 mL. times.2), and washed with saturated brine (15 mL). Drying with anhydrous sodium sulfate, filtering and concentrating to obtain the target compound (Z) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol 73b (60 mg, colorless liquid) in 91% yield.

MS m/z (ESI): 179 & 181 [M - 17]

Second step of

(Z) -4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine-1-carboxylic acid tert-butyl ester

Will (a) toZ) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol 73b (60 mg, 0.31 mmol) was dissolved in tetrahydrofuran (3 mL), and triethylamine (68 mg, 0.67 mmol) and ethylsulfonyl chloride (47 mg, 0.37 mmol) were added and stirred at room temperature for 3 hours. To the reaction mixture were added tert-butyl piperazine-1-carboxylate (76 mg, 0.41 mmol) and triethylamine (68 mg, 0.67 mmol), and the mixture was reacted at room temperature for 18 hours. The reaction mixture was concentrated, diluted with dichloromethane (25 mL) and washed with saturated brine (20 mL). Drying with anhydrous sodium sulfate, filtering and concentratingAnd (4) shrinking. The residue was purified with preparative silica gel plate (petroleum ether: ethyl acetate = 5: 1) to obtain the objective compound (Z) Tert-butyl (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine-1-carboxylate 73c (50 mg, colorless liquid) in 44.9% yield.

MS m/z (ESI): 365 & 367 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, J = 8.4 Hz, 2H), 6.96 (d, J =8.4 Hz, 2H), 3.45-3.41 (m, 4H), 2.75 (s, 2H), 2.16-2.13 (m, 4H), 1.94 (s, 3H), 1.84 (s, 3H), 1.43 (s, 9H)

The third step

(Z) -1- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine hydrochloride

Will (a) toZ) Tert-butyl (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine-1-carboxylate 73c (49 mg, 0.11 mmol) was dissolved in methanol (2 mL), and dioxane solution (4M, 2 mL) was added thereto to react at room temperature for 1 hour. Concentrating the reaction solution to obtain a crude product of the target compound (a)Z) -1- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine hydrochloride 73d (crude, 40 mg) was charged directly to the next step.

MS m/z (ESI): 265 & 267 [M + 1];

The fourth step

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester

Will (a) toZ) -1- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazine hydrochloride 73d (crude, 40 mg, 0.13 mmol) was suspended in dichloromethane (10 mL) and addedN,NDiisopropylethylamine (0.13 g, 1.00 mmol), and after stirring for 5 min concentration was added. The residue was dissolved in dimethyl sulfoxide (2 mL) and 2- ((1) was addedH-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester (37 mg, 0.13 mmol) andN,Ndiisopropylethylamine (0.13 g, 1.00 mmol), heated to 120 ℃ for 16 h. The reaction solution was poured into water (15 mL), extracted with ethyl acetate (15 mL. times.3), and the organic phases were combined. Washing with saturated brine (15 mL. times.3) and dryingDried over sodium sulfate and concentrated. The residue was purified on preparative silica gel plates (ethyl acetate) to give the title compound: (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 73e (18 mg, yellow solid) in 32.2% yield over two steps.

MS m/z (ESI): 531 & 533 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.55 (s, 1H), 8.16 (s, 1H), 7.89-7.87(m, 1H), 7.52-7.51 (m, 1H), 7.33-7.30 (m, 1H), 7.27-7.25 (m, 2H), 6.97-6.94 (m, 2H), 6.55-6.52 (m, 1H), 6.43-6.40 (m, 1H), 6.27 (s, 1H), 3.78 (s, 3H), 3.37-3.33 (m, 4H), 2.75 (s, 2H), 2.26-2.23 (m, 4H), 2.04 (s, 3H), 2.00 (s, 3H)

The fifth step

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid

Will (a) toZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid methyl ester 73e (18 mg, 0.033 mmol) was dissolved in methanol (3 mL) and water (3 mL), added sodium hydroxide (4 mg, 0.10 mmol), and heated to 50 ℃ for reaction at room temperature for 18 hours. The reaction solution was adjusted to pH 4-5 with dilute hydrochloric acid, extracted with ethyl acetate (25 mL. times.2), and the organic phases were combined. Washing with saturated brine (10 mL), drying over anhydrous sodium sulfate, filtering and concentrating to obtain crude target compound (A)Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid 73f (crude, 18 mg) which was directly fed to the next step.

MS m/z (ESI): 517 & 519 [M + 1];

The sixth step

Will (a) toZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) benzoic acid 73f (crude, 0.02 mmol) was dissolved in dichloromethane (1.5 mL) and 3-nitro-4- (((tetrahydro-2-yl) benzoic acid was added in sequenceHPyran-4-yl) methyl) amino) benzenesulfonamide (10 mg, 0.03 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (6 mg, 0.03 mmol), and reacted at room temperature for 16 hours. The reaction mixture was concentrated, diluted with dichloromethane (15 mL) and washed with saturated brine (10 mL). Dried over anhydrous sodium sulfate and concentrated. The residue was purified on a preparative silica gel plate (ethyl acetate) to give the title compound (A)Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))HPyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 73 (3.5 mg, yellow solid), yield 25.2%.

MS m/z (ESI): 814 & 816 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 9.14 (s, 1H), 8.90 (s, 1H), 8.54-8.50 (m, 1H), 8.20-8.13 (m, 2H), 8.00-7.93 (m, 1H), 7.71-7.68 (m, 1H), 7.48-7.45 (m, 1H), 7.25-7.21 (m, 2H), 7.01-6.90 (m, 3H), 6.56-6.55 (m, 2H), 5.97 (s, 1H), 4.04-4.01 (m, 2H), 3.46-3.40 (m, 2H), 3.30-3.25 (m, 2H), 3.15-3.09 (m, 4H), 3.06 (s, 2H), 2.24-2.20 (m, 1H), 1.97 (s, 3H), 1.93 (s, 3H), 1.93-1.89 (m, 4H), 1.79-1.70 (m, 3H), 1.45-1.35 (m, 1H)。

Example 74

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Synthesis example 74 was conducted in accordance with the procedure of example 60 to obtain the desired product (aZ)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (1- (3- (4-chlorophenyl) -2-methylbut-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 74.

MS m/z (ESI)：811 & 813 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.92 (s, 1H), 8.91(s, 1H), 8.57-8.54 (m, 1H), 8.25 (s, 1H), 8.21-8.14 (m, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.95-6.92 (m, 3H), 6.60 (s, 1H), 6.55 (s, 1H), 5.81 (s, 1H), 4.06-4.02 (m, 2H), 3.73-3.71 (m, 2H), 3.70 (s, 2H), 3.68 (s, 2H), 3.43-3.40 (m, 2H), 2.82-2.78 (m, 2H), 2.39-2.32 (m, 2H), 2.06-2.04 (m, 1H), 2.05-1.98 (s, 3H), 1.92 (s, 3H), 1.81-1.78 (m, 3H), 1.53-1.47 (m, 1H)。

Example 75

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (1- (3- (4-chlorophenyl) -2-methyl-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -propionic acidN- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Synthesis example 75 with reference to the procedure of example 73 gave the desired product (a)Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (1- (3- (4-chlorophenyl) -2-methyl-2-en-1-yl) -1,2,3, 6-tetrahydropyridin-4-yl) -propionic acidN- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 75.

MS m/z (ESI): 828 & 830 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.13 (s, 1H), 9.33 (s, 1H), 8.89 (s, 1H), 8.54-8.51 (m, 1H), 8.20-8.16 (m, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.47-7.45 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.93-6.88 (m, 3H), 6.56-6.52 (m, 2H), 5.97 (s, 1H), 4.05-4.01 (m, 2H), 3.45-3.40 (m, 2H), 3.28-3.25 (m, 2H), 3.12-3.06 (m, 4H), 2.71-2.67 (m, 2H), 2.30 (q, J = 7.2 Hz, 2H), 2.23-2.18 (m, 3H), 2.00-1.93 (m, 2H), 1.81 (s, 3H), 1.76-1.72 (m, 3H), 1.49-1.38 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H)。

Example 76

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) allyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Example 76 was synthesized by reference to the procedure of example 73, wherein in the first step: (Z) Ethyl-3- (4-chlorophenyl) acrylate (synthesized according to Organic Letters, 19(2), 316-Z) The target product (3- (4-chlorphenyl) -2-methyl butyl-2-ethyl enoate 73a is obtainedZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) allyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 76.

MS m/z (ESI): 786 & 788 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.54-8.51 (m, 1H), 8.20-8.16 (m, 2H), 7.97 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.46-7.44 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1 H), 6.59-6.54 (m, 3H), 6.01 (s, 1H), 5.78-5.74 (m, 1H), 4.05-4.01 (m, 2H), 3.76-3.73 (m, 2H), 3.45-3.40 (m, 2H), 3.28-3.11 (m, 7H), 2.24-2.20 (m, 1H), 2.02-2.00 (m, 1H), 1.87-1.84 (m, 2H), 1.76-1.73 (m, 3H), 1.45-1.37 (m, 1H)。

Example 77

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-ethylbut-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

First step of

(Z) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol

With reference to example 73, the synthesis was carried out in a first working step usingZ)3- (4-chlorophenyl) -2-ethyl-2-benzoic acid ethyl ester 77a (synthesized according to Organic Letters, 19(2), 316-319; 2017) ((R))Z) The target product (3- (4-chlorphenyl) -2-methyl butyl-2-ethyl enoate 73a is obtainedZ) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol 77 b.

MS m/z (ESI): 193 & 195 [M - 17];

¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 3.86-3.84 (m, 2H), 2.25-2.21 (m, 2H), 1.96 (s, 3H), 1.03-0.98 (m, 3H)

Second step of

(Z) -1-chloro-4- (3- (chloromethyl) pent-2-en-2-yl) benzene

Will (a) toZ) -3- (4-chlorophenyl) -2-methylbut-2-en-1-ol 77b (27 mg, 0.13 mmol) was dissolved in dichloromethane (3 mL), cooled to 0 ℃ in an ice water bath, three drops of thionyl chloride were added, and the reaction was continued at this temperature for 30 minutes. Directly concentrating the reaction solution to obtain crude product of the target compound (Z) -1-chloro-4- (3- (chloromethyl) pent-2-en-2-yl) benzene 77c (27 mg, yellow oil), crude was directly charged to the next step;

the third step

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-ethylbut-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Will (a) toZ) -1-chloro-4- (3- (chloromethyl) pent-2-en-2-yl) benzene 77c (27 mg, 0.12 mmol) and 2- ((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) -4- (piperazin-1-yl) benzamide 77d (synthesized according to Faming Zhuanli Shenqing, 107089981) (16 mg, 0.03 mmol) was dissolved inN,NTo dimethylformamide (2 mL), potassium carbonate (36 mg, 0.26 mmol) was added, and the reaction was allowed to warm to 40 ℃ for 18 hours. Cooling to room temperature, filtering, and subjecting the filtrate to high performance liquid chromatography (Agilent ZORBAX XDB-C18, 4.6 × 50 mm, 3.5 μm, ACN/H)₂O（0.5 % NH₄OH) 20% -40%) to obtain the target compound (Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2-ethylbut-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))HPyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 77 (8 mg, yellow solid), yield 38.4%.

MS m/z (ESI): 828 & 830 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 10.12 (s, 1H), 9.61 (s, 1H), 8.89 (s, 1H), 8.53-8.50 (m, 1H), 8.23-8.17 (m, 2H), 7.96-7.93 (m, 1H), 7.71-7.69 (m, 1H), 7.48-7.46 (m, 1H), 7.25-7.23 (m, 2H), 6.92-6.90 (m, 3H), 6.56-6.55 (m, 2H), 5.97 (s, H), 4.05-4.01 (m, 2H), 3.44-3.42 (m, 2H), 3.28-3.25 (m, 2H), 3.14-3.06 (m, 4H), 2.81 (s, 2H), 2.25-2.23 (m, 6H), 2.01 (s, 3H), 1.95-1.93 (m, 2H), 1.76-1.73 (m, 3H), 1.05-1.01 (m, 3H)。

Example 78

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2,5, 5-trimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide

Reference example 73 procedureSynthesis example 78 to give the desired product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -2,5, 5-trimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 78.

MS m/z (ESI): 870 & 872 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 9.44 (s, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.58-8.47 (m, 1H), 8.20 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 9.2, 2.1 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.49-7.43 (m, 1H), 7.20 (d, J= 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 9.3 Hz, 1H), 6.58-6.47 (m, 2H), 5.98 (d, J = 2.0 Hz, 1H), 4.08-3.97 (m, 2H), 3.46-3.38 (m, 2H), 3.31-3.24 (m, 2H), 3.11-2.98 (m, 4H), 2.78 (s, 2H), 2.37 (s, 2H), 2.26-2.15 (m, 4H), 1.82 (s, 3H), 1.78-1.71 (m, 5H), 0.73 (s, 9H)。

Example 79

(Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2,5, 5-trimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) pyridine-2-carboxamide

Synthesis example 79 with reference to the procedure of example 67 was conducted to obtain the desired product (Z)-3-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -5- (4- (3- (4-chlorophenyl) -2,5, 5-trimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) pyridine-2-carboxamide 79.

MS m/z (ESI): 871 & 873 [M + 1];

¹H NMR (400 MHz, CDCl₃) δ 8.91 (d, J = 2.2 Hz, 1H), 8.80 (s, 1H), 8.53-8.49 (m, 2H), 8.27-8.23 (m, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.48-7.43 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.6 Hz, 2H), 6.49 (s, 1H), 6.27 (d, J = 1.8 Hz, 1H), 4.09-3.97 (m, 4H), 3.47-3.36 (m, 4H), 3.29-3.24 (m, 2H), 3.13-3.10 (m, 2H), 2.80 (s, 2H), 2.38 (s, 2H), 2.25-2.22 (m, 2H), 2.02-1.92 (m, 5H), 1.84 (s, 3H), 0.74 (s, 9H)。

Examples 80 and 81

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

(Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide

Will (a) toZ)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Fluoropiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 80a (synthesized according to example 1) (26 mg, 0.03 mmol), 3-oxetanone (14 mg, 0.19 mmol), sodium cyanoborohydride (19 mg, 0.30 mmol) and methanol (5 ml) were mixed and stirred at room temperature for 16 hours. Desolventizing under reduced pressure gave the crude product, which was dissolved in dichloromethane (15 mL) and washed with saturated brine (10 mL). Drying over anhydrous sodium sulfate, concentrating, and purifying the crude product from the preparative liquid phase (ACN/H)₂O20% -45%) to obtain the target product (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1-methylpiperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 80 (2 mg, white)Solid), yield: 8% and (Z)-2-((1H-pyrrole [2,3-b]Pyridin-5-yl) oxy) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methoxy) -3-nitrophenyl) sulfonyl) benzamide 81 (1 mg, white solid), yield: 4 percent.

MS m/z (ESI)：874 & 876 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.63 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.46-7.44 (m, 1H), 7.23-7.19 (m, 6H), 6.62 (d, J = 8.8 Hz, 1H), 6.52-6.48 (m, 1H), 6.05 (s, 1H), 5.71-5.68 (m, 1H), 4.31 (d, J = 21.2 Hz, 2H), 3.58-3.32 (m, 4H), 3.36-3.32 (m, 8H), 3.13-3.09 (m, 2H), 2.87 (s, 3H), 2.35-2.30 (m, 6H), 1.47-1.43 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H)；

MS m/z (ESI)：916 & 918 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 8.32 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.45-7.42 (m, 1H), 7.23-7.19 (m, 6H), 6.62 (d, J = 8.8 Hz, 1H), 6.52-6.48 (m, 1H), 6.02 (s, 1H), 5.71-5.68 (m, 1H), 4.71-4.65 (m, 2H), 4.63-4.60 (m, 2H), 4.20 (d, J = 18.8 Hz, 2H), 3.58-3.54 (m, 4H), 3.41-3.38 (m, 8H), 3.20-3.15 (m, 4H), 2.35-2.23 (m, 5H), 1.46-1.42 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H)。

The synthetic procedures for examples 82 and 83 were followed in the experimental procedure of example 80.

Examples 82 and 83

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1-methylpiperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -5-methylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- (((4-fluoro-1- (3-oxetanyl) piperidin-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide

MS m/z (ESI)：873 & 875 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.70 (s, 1H), 8.48-8.44 (m, 1H), 8.10 (s, 1H), 7.85-7.79 (m, 2H), 7.42-7.38 (m, 1H), 7.23-7.19 (m, 4H), 6.99 (d, J = 8.8 Hz, 2H), 6.72-6.68 (m, 1H), 6.48-6.43 (m, 1H), 6.32-6.29 (m, 1H), 6.15-6.12 (m, 1H), 5.50-5.45 (m, 1H), 3.48-3.44 (m, 2H), 3.10-3.02 (m, 4H), 2.83-2.79 (m, 2H), 2.71-2.68 (m, 2H), 2.34-2.26 (m, 8H), 2.23 (s, 3H), 1.82-1.68 (m, 4H), 1.48-1.43 (m, 1H), 0.81 (d, J = 6.4 Hz, 6H)。

MS m/z (ESI)：915 & 917 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 8.58-8.52 (m, 1H), 8.09 (s, 1H), 7.83-7.79 (m, 1H), 7.72-7.48 (m, 2H), 7.23-7.19 (m, 4H), 6.99 (d, J = 8.8 Hz, 2H), 6.48-6.43 (m, 2H), 6.32-6.12 (m, 2H), 5.50-5.45 (m, 1H), 4.83-4.58 (m, 8H), 3.48-3.44 (m, 3H), 3.10-3.02 (m, 4H), 2.87-2.80 (m, 4H), 2.34-2.26 (m, 4H), 1.98-1.79 (m, 4H), 1.48-1.43 (m, 1H), 0.80 (d, J = 6.4 Hz, 6H)。

Example 84

(Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-Morpholinylcyclohexyl) amino) -3-nitrophenyl) sulfonyl) benzamide

Example 84 was synthesized by reference to the procedure of the second step of example 34, in which 4- ((4-morpholinylcyclohexyl) amino) -3-nitrobenzenesulfonamide (synthesized according to WO 2012058392) was substituted- ((2-nitro-4-sulfamoylphenoxy) methyl) piperidine-1-carboxylic acid tert-butyl ester to give the target product (C: (S) ((R))Z)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (3- (4-chlorophenyl) -2, 5-dimethylhex-2-en-1-yl) piperazin-1-yl) -N- ((4- ((4-morpholinylcyclohexyl) amino) -3-nitrophenyl) sulfonyl) benzamide 84.

MS m/z (ESI)：925 & 927 [M + 1]；

¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 8.89-8.86 (m, 1H), 8.69 (d, J = 8.8 Hz, 0.6H), 8.34 (d, J = 8.8 Hz, 0.4H), 8.20-8.13 (m, 2H), 7.95 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.45-7.42 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.90-6.86 (m, 3H), 6.55-6.52 (m, 2H), 5.98 (s, 1H), 3.85-3.81 (m, 1H), 3.74-3.70 (m, 4H), 3.23-3.19 (m, 1H), 3.07-3.00 (m, 4H), 2.71 (s, 2H), 2.58-2.53 (m, 4H), 2.25-2.21 (m, 6H), 1.87 (s, 3H), 1.88-1.81 (m, 4H), 1.46-1.42 (m, 5H), 0.82 (d, J = 6.4 Hz, 6H)。

Biological experiments

Assay for the inhibition of BCL-2 biological Activity

Evaluation of the Effect of the Compounds of the invention on the biological Activity of BCL-2 Using fluorescence polarization assay

The experimental methods are summarized as follows:

the effect of a compound on the biological activity of BCL-2 was assessed by measuring the effect of the compound on the binding activity of BCL-2 and BIM using an affinity assay method based on the principle of fluorescence polarization. The reaction buffer contained the following components: PBS (pH 7.4, 3mM Na)₂HPO₄、155mM NaCl、1mM KH₂PO₄) 1mM DTT; the human source recombination BCL-2 protein (the cargo number is 10195-H08E) is purchased from Beijing Yiqian Shenzhou biotechnology limited and is diluted to 5nM by reaction buffer; FITC-labeled BIM polypeptide was purchased from Nanjing King-Share Biotech, Inc. and diluted to 5nM in reaction buffer.

Compounds were diluted to 0.1, 1, 10 μ M in 100% DMSO solutions, then serially diluted 4-fold with DMSO to minimum concentrations of 0.0061, 0.061, 0.61nM, and diluted 50-fold with reaction buffer at each concentration point.

Mu.l of the compound solution and 12. mu.l of BCL-2 protein solution were added to a black 384-well assay plate, mixed well and incubated for 15 minutes at room temperature. Then, 15. mu.l of FITC-BIM solution was added, and the reaction mixture was incubated at room temperature for 30 minutes in the absence of light, and then immediately subjected to detection of fluorescence polarization on an Envision multifunctional microplate reader (Perkin Elmer) at 480nm as an excitation wavelength and 535nm as an emission wavelength. In this experiment, the BCL-2 protein was not added as a negative control (100% inhibition), and the BCL-2 protein but no compound was added as a positive control (0% inhibition). The percent inhibition of the affinity of a compound for BCL-2 protein can be calculated using the following formula:

compound IC₅₀Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:

Y = Bottom+(Top-Bottom)/(1+10^((logIC₅₀-X)*slope factor))

wherein Y is the inhibition percentage, X is the logarithm value of the concentration of the compound to be detected, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.

BCL-X_LAssay for inhibition of biological Activity

Evaluation of the Compounds of the invention on BCL-X Using fluorescence polarization experiments_LEffect of biological Activity

The experimental methods are summarized as follows:

affinity assay method using fluorescence polarization principle by detecting compound pair BCL-X_LAnd BIM, thereby evaluating the effect of the compound on BCL-X_LThe effect of biological activity. The reaction buffer contained the following components: PBS (pH 7.4, 3mM Na)₂HPO₄、155mM NaCl、1mM KH₂PO₄) 1mM DTT; human recombinant BCL-X_LProtein (cat # 10455-H08E) was purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd and diluted to 10nM with reaction buffer; FITC-labeled BIM polypeptide was purchased from Nanjing King-Share Biotech, Inc. and diluted to 10nM in reaction buffer.

Compounds were diluted to 1 μ M dissolved in 100% DMSO and then serially diluted 4-fold with DMSO to a minimum concentration of 0.061nM, each concentration point being diluted 50-fold with reaction buffer.

To a black 384-well assay plate, 3. mu.l of compound solution and 12. mu.l of BCL-X were added_LProtein solution, mix well and incubate for 15 minutes at room temperature. Then, 15. mu.l of FITC-BIM solution was added, and the reaction mixture was incubated at room temperature for 30 minutes in the absence of light, and then immediately subjected to detection of fluorescence polarization on an Envision multifunctional microplate reader (Perkin Elmer) at 480nm as an excitation wavelength and 535nm as an emission wavelength. In this experiment, BCL-X was not added_LProteome as negative control (100% inhibition), plus BCL-X_LProtein but no compound added group served as positive control (0% inhibition). Compound pair BCL-X_LThe percent inhibition of protein affinity can be calculated using the following formula:

Y = Bottom+(Top-Bottom)/(1+10^((logIC₅₀-X)*slope factor))

RS4 half the effective inhibitory concentration IC of 11 cells (acute lymphoblastic leukemia cells)₅₀Measurement of (2)

The effect of the compounds of the invention on the proliferation of RS4;11 cells was evaluated using a luminescence cell viability assay.

The experimental methods are summarized as follows:

using the CellTilter-glo (CTG) assay kit, the cell proliferation status of RS4, 11 was detected by detecting ATP, a key indicator of viable cell metabolism, using a unique, highly sensitive and stable luciferase, which generated a luminescent signal proportional to the number of viable cells in the culture medium.

The CellTilter-Glo reagent (Promega, G7572) consists of CellTilter-Glo freeze-dried powder and CellTilter-Glo buffer solution, and the freeze-dried powder is dissolved in the buffer solution when in use.

RS4, 11 cells(ATCC, CRL-1873) culture in RPMI1640 complete Medium (Thermofisiher, 72400-047) containing 10% FBS (GBICO, 10099-141) and 100 units/ml penicillin mixed solution (Thermofisiher, 15140122), when the coverage of the cells in the culture vessel reached 80-90%, they were digested with 0.25% trypsin (containing EDTA) (Thermofisiher, 25200056) and blown off and planted in a white 384-well plate (Thermofisiher, 164610), and then the 384-well plate was placed at 37 ℃ and 5% CO₂Was cultured overnight in an incubator. Compounds were dissolved in 100% DMSO diluted to 5mM and then serially diluted 4-fold in DMSO to a minimum concentration of 0.061 μ M, each concentration point diluted 50-fold with FBS-free RPMI1640 medium. If the compound IC₅₀The values are very low and the initial concentration of the compound can be reduced. After overnight, 3 μ L of the diluted compound was added to each well and mixed by gentle centrifugation, wherein the cell-free group served as negative control (100% inhibition) and the 0.2% DMSO group served as positive control (0% inhibition). The 384-hole plate is placed at 37 ℃ and 5% CO₂The incubation was continued in the incubator, after 48 hours the cells were equilibrated to room temperature, 15. mu.l of CTG reagent was added to each well, the cells were gently shaken on a shaker for 3 minutes to ensure adequate lysis, allowed to stand for 10 minutes to stabilize the luminescence signal, and then the luminescence signal was read with an envision (Perkin Elmer).

The percentage of inhibition of RS4, 11 cell proliferation by the compound can be calculated by the following formula:

percent inhibition =100-_{Compound (I)}-signal_{Negative control})/(signal_{Positive control}-signal_{Negative control})

Y = Bottom + (Top- Bottom)/(1+10^((LogIC₅₀-X) * slope factor))

wherein Y is the percentage of inhibition, Bottom is the Bottom plate of the curve, Top is the Top plate of the curve, and X is the logarithm of the concentration of the compound to be measured.

BCL-2 and BCL-X in vitro as described above_LThe results of the protein activity assay are shown in table 1 below,

the results of the cell experiments are shown in Table 2.

Table 1: BCL-2 and BCL-X_LResults of protein Activity detection

Compound numbering	BCL-2 IC₅₀ (nM)	BCL-2 Ki (nM)	BCL-X_L IC₅₀(nM)	BCL-X_L Ki (nM)
					1	3.11	0.46	199.42	24.51
2	2.47	0.37	>1000	>122.92
					3	2.58	0.38	108.58	13.35
4	10.05	1.48	>1000	>122.92
					5	7.02	1.04	>1000	>122.92
6	1.16	0.17	>1000	>122.92
					7	1.43	0.21	781.37	96.05
8	1.03	0.15	>1000	>122.92
					9	1.51	0.22	>1000	>122.92
10	1.46	0.22	>1000	>122.92
					11	14.5	2.14	>1000	>122.92
12	1.93	0.28	391.24	48.09
					13	3.53	0.52	>1000	>122.92
14	1.18	0.17	>1000	>122.92
					15	2.35	0.35	>1000	>122.92
16	3.19	0.47	>1000	>122.92
					17	1.35	0.2	>1000	>122.92
18	2.79	0.41	>1000	>122.92
					19	1.98	0.29	>1000	>116.13
20	2.86	0.42	353.14	43.41
					21	2.62	0.39	194.59	23.92
22	2.11	0.31	320.62	39.41
					23	1.99	0.29	395.89	48.67
24	1.70	0.25	>1000	>122.92
					25	1.89	0.28	>1000	>122.92
26	1.09	0.16	481.76	59.22
					27	2.98	0.44	>1000	>116.13
28	3.25	0.48	>1000	>116.13
					29	3.02	0.45	>1000	>116.13
30	1.76	0.26	>1000	>116.13
					31	58.82	8.68	>1000	>122.92
32	65.63	9.68	>1000	>122.92
					33	78.67	11.61	>1000	>122.92
34	13.35	1.97	795.13	97.74
					35	6.76	1	>1000	>116.13
36	3.09	0.46	>1000	>116.13
					37	4.78	0.71	>1000	>116.13
38	6.81	1	>1000	>116.13
					39	3.93	0.58	>1000	>116.13
40	20.5	3.03	>1000	>116.13
					41	2.26	0.33	>1000	>116.13
42	2.75	0.41	>1000	>116.13
					43	9.8	1.45	>1000	>116.13
44	2.35	0.35	>1000	>116.13
					45	7.58	1.12	643.23	79.07
46	11.18	1.65	>1000	>122.92
					47	13.84	2.04	>1000	>122.92
48	6.93	1.02	>1000	>122.92
					49	3.16	0.47	>1000	>122.92
50	2.35	0.35	704.27	86.57
					51	21.65	3.19	>1000	>122.92
52	77.94	11.5	>1000	>122.92
					53	13	1.98	>1000	>122.92
54	1.77	0.26	>1000	>122.92
					55	35.83	5.29	>1000	>122.92
56	1.7	0.25	>1000	>116.13
					57	0.82	0.12	447.31	54.98
58	1.35	0.2	>1000	>122.92
					59	0.7	0.1	385.25	47.36
60	21.47	3.17
					61	3.12	0.46	>1000	122.92
62	11.07	1.63	891.8	109.62
					63	4.63	0.68	679.18	83.49
64	1.47	0.22	917.08	112.73
					65	2.09	0.31	312.65	38.43
66	0.45	0.07	344.29	42.32
					67	23.52	3.47	>1000	>122.92
68	3.15	0.47	>1000	>122.92
					69	32.44	4.79	>1000	>122.92
70	6.41	0.95	>1000	>122.92
					71	29.56	4.36	>1000	>122.92
72	15.56	2.30	>1000	>122.92
					73	9.53	1.24	>1000	>122.92
74	18.35	2.71
					75	10.74	1.58
76	153.74	22.69	>1000	>122.92
					77	23.81	3.51
78	21.56	3.18	>1000	>122.92
					79	50.91	7.51	>1000	>122.92
80	43.4	6.4	561.74	69.05
					81	21.23	3.13	>1000	>122.92
82	3.12	0.46
					83	2.2	0.33
84	13.76	2.03

Table 2: RS4, 11 cell activity test results

Compound numbering	RS4;11(nM)	Compound numbering	RS4;11(nM)
				1	151.96	32	975.59
2	123.33	33	1187.39
				3	74.6	45	141.45
4	139.88	46	92.78
				5	116.25	49	111.46
6	151.04	50	93.77
				7	62.02	53	317.68
8	97.71	54	139.05
				9	303	57	360.68
10	265.31	58	142.4
				11	108.36	59	313.95
12	62.98	61	210.8,
				13	154.61	62	1711.66
14	305.28	63	286.27
				15	299.62	64	520.24
16	78.13	65	723.7
				17	304.6	66	477.32
18	148.4	68	357.12
				20	60.47	70	296.85
21	101.46	73	419.78
				23	41.03	75	247.97
24	23.21	82	298.79
				25	226.35	83	197.41
26	39.63	84	175.83
				31	795.42

From the above experimental results, it can be seen that the compounds of the examples of the present invention can effectively and selectively inhibit the activity of BCL-2 on BCL-X_LThe inhibition was weak. Can be used for treating various cancers caused by abnormal over-expression of BCL-2 family protein: especially acute lymphoblastic leukemia, such as malignant hemopathy, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, and brain glioma. And avoid the interference of BCL-X_LInhibiting the toxic and side effects caused by platelet decrease. Part of the compounds can also effectively inhibit RS4 and 11 acute lymphocyte proliferation. Has strong inhibition effect on malignant hematological diseases such as acute lymphatic leukemia and the like.

Claims

1. A compound of formula I, isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts thereof:

wherein:

X⁰is a 3-8 membered heterocyclylene group containing 1 or 2 heteroatoms selected from N, O, S; preferably a 5 or 6 membered heterocyclylene containing 1 or 2 heteroatoms selected from N, O, S; most preferably

Or

Wherein said

X¹is CR⁴Or N; preferably CH or N;

；

X⁴Is an optionally substituted 3-8 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein the optional substituent is a 3-8 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C8 alkyl, halogen, cyano, hydroxy, -SO₂(C1-C8) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C8 alkyl optionally substituted by C1-C8 alkoxy, mono-or di- (C1-C8) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy, halogen, cyano or nitro, or 3-8 membered cycloalkyl; preferably, X⁴Is an optionally substituted 5-or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein the optional substituent is a 3-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O)R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; still further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; still further preferably, X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C4 alkyl optionally substituted with C1-C4 alkoxy, mono-or di- (C1-C4) alkylamino, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl; most preferably, X⁴Is composed of

；

One or more R⁰Each independently selected from halogen, cyano, nitro, perfluoro C1-C6 alkyl sulfone; preferably, R⁰Mono-substituted in the 3-position of the benzene ring or in benzeneRing disubstituted in positions 3 and 5 and each independently selected from halogen, cyano, nitro, perfluoro C1-C4 alkylsulfonyl; most preferably, R⁰Mono-substituted at the 3-position of the benzene ring or di-substituted at the 3-position and the 5-position of the benzene ring, wherein nitro is at the 3-position, and fluorine is at the 5-position;

R⁷is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; preferably hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl; further preferably hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl; most preferably hydrogen;

R⁸is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

m is 1 or 2;

n is 1,2,3 or 4; preferably 1 or 2.

2. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X¹is CR⁴Or N;

X²is-C (R)⁵R⁶)-、-S(O)_m-, -S-, -O-or-N (R)⁷)-；

X⁴is an optionally substituted 5-or 6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, the optional substituent is a 3-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R³is an optionally substituted 5-6 membered aryl or heteroaryl group, said optional substituents being C1-C6 alkyl, halogen, hydroxy, cyano, C1-C6 alkoxy, mono-or di- (C1-C6) alkaneAn amino group;

R⁴is hydrogen, halogen or C1-C4 alkyl;

R⁷is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl;

m is 1 or 2;

n is 1,2,3 or 4.

3. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X¹is CH or N;

X²is-O-or-N (R)⁷)-；

X⁴is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is a 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, C1-C6 alkyl, halogen, -SO₂(C1-C6) alkyl or C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R³is an optionally substituted 5-6 membered aryl or heteroaryl group, the optional substituent being a C1-C6 alkaneHalogen, hydroxy, cyano, C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino;

R⁷is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl;

n is 1 or 2.

4. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is C1-C4 alkylene or C3-C6 cycloalkylene;

R¹and R²Each independently selected from hydrogen, linear chainOr branched C1-C8 alkyl, C3-C8 cycloalkyl, 5-6 membered aryl or heteroaryl;

n is 1 or 2.

5. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is C1-C4 alkylene or C3-C6 cycloalkylene;

X⁴is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C6 alkyl optionally substituted with C1-C6 alkoxy, mono-or di- (C1-C6) alkylamino, 3-8 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R⁰mono-substituted in the 3-position of the phenyl ring or di-substituted in the 3-and 5-positions of the phenyl ring, and each is independently selected from halogen, cyano, nitro, perfluoroC1-C4 alkylsulfonyl;

n is 1 or 2.

6. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁴Is optionally substituted 4-piperidyl, 2-morpholinyl, 4-tetrahydropyranyl or 2-dioxanyl, wherein the optional substituent is 3-6 membered saturated heterocyclic group containing 1 oxygen atom, C1-C4 alkyl, halogen, -SO₂(C1-C4) alkyl or-C (O) R^x(ii) a Wherein said R^xIs C1-C4 alkyl optionally substituted with C1-C4 alkoxy, mono-or di- (C1-C4) alkylamino, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, hydroxy or halogen, or 3-6 membered cycloalkyl;

R³is phenyl optionally substituted by halogen;

n is 1 or 2.

7. A compound of formula I according to claim 1, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,

wherein:

X⁰is composed of

Or

Wherein said

X¹is CH or N;

X²is-O-or-N (H) -;

X³is-CH₂-or

X⁴Is composed of

R³is 4-chlorophenyl;

R⁸is C1-C4 alkyl, cyclopropyl,

R⁹Is hydrogen, C1-C4 alkyl,

R¹⁰Is C1-C4 alkyl;

n is 1 or 2.

8. The compound of claim 1, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the compound is

。

9. Use of a compound according to any one of claims 1-8, an isomer, prodrug, solvate, stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a BCL-2 inhibitor.

10. Use of a compound according to any one of claims 1-8, an isomer, prodrug, solvate, stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a BCL-2 mediated related disease, such as a tumor selected from the group consisting of hematological malignancies, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma, and particularly acute lymphatic leukemia.

11. A pharmaceutical composition comprising a compound according to any one of claims 1-8, an isomer, prodrug, solvate, stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents, and excipients.