CN115340499A - BCL-XL inhibitors and uses thereof - Google Patents
BCL-XL inhibitors and uses thereof Download PDFInfo
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- CN115340499A CN115340499A CN202110524420.XA CN202110524420A CN115340499A CN 115340499 A CN115340499 A CN 115340499A CN 202110524420 A CN202110524420 A CN 202110524420A CN 115340499 A CN115340499 A CN 115340499A
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- alkylene
- alkyl
- membered
- membered aromatic
- aromatic ring
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
The invention provides a BCL-XL inhibitor and application thereof, belonging to the field of chemical medicines. The BCL-XL inhibitor is a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof. Compounds of the inventionThe protein can effectively combine BCL-XL anti-apoptosis protein and inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the protein can be used for preventing or treating diseases related to BCL-XL anti-apoptosis protein, such as cancer, immune diseases, autoimmune diseases and the like. The compound can be used for preparing BCL-XL inhibitors or preparing medicaments and pharmaceutical compositions for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability, high possibility of drug formation, simple preparation, high yield, low cost, high feasibility and good application prospect.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a BCL-XL inhibitor and application thereof.
Background
The occurrence of tumor is related to apoptosis and is caused by imbalance of cell proliferation and apoptosis. BCL-2 family protein plays an important role in the process of apoptosis and becomes a popular target for the research of anti-tumor drugs in recent years. The BCL-XL anti-apoptotic protein is a member of the BCL-2 family of proteins, which, as anti-apoptotic proteins, are overexpressed in a variety of cancer cells.
Patents WO2005/049593 and WO2005/024636 and the like disclose that BCL-XL anti-apoptotic proteins are associated with bladder cancer, brain cancer, breast cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, hepatocellular cancer, lymphoblastic (lymphoblastic) leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer and the like.
In the treatment of cancer, BCL-XL anti-apoptotic proteins can be used by cancer cells to inhibit the therapeutic effects of traditional chemotherapy, affecting the therapeutic effect. It is also because cancer cells can use BCL-XL anti-apoptotic proteins to inhibit the therapeutic effects of traditional chemotherapy that clinicians have to increase the dose of chemotherapeutic drugs, which can lead to side effects such as nausea, hair loss, etc.
With the intensive research, BCL-XL anti-apoptosis protein is found to be an anti-tumor therapeutic target with definite effect. BCL-XL inhibitors can inhibit overexpression of BCL-XL anti-apoptotic proteins in a variety of cancer cells, thereby treating cancer.
Besides being a target for antitumor therapy, BCL-XL anti-apoptotic proteins are also implicated in immune system diseases, described in Current Allergy & Asthma Reports 2003,3,378-38; british Journal of Haematology 2000,110 (3), 584-90; blood 2000,95 (4), 1283-9 and New England Journal of Medicine 2004,351 (14), 1409-1418 disclose that BCL-XL anti-apoptotic protein overexpression is associated with immune and autoimmune diseases. Therefore, BCL-XL inhibitors can treat not only cancer, but also immune and autoimmune diseases.
Therefore, the research on the BCL-XL inhibitor with excellent effect is of great significance.
Disclosure of Invention
The invention aims to provide a BCL-XL inhibitor and application thereof. The BCL-XL inhibitor can inhibit the activity of BCL-XL anti-apoptotic proteins, thereby treating diseases associated with the BCL-XL anti-apoptotic proteins.
The invention provides a compound shown as a formula I, or a salt, a stereoisomer, a hydrate, a solvate, a prodrug or an oxynitride thereof:
wherein the content of the first and second substances,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and aromatic heterocycle are substituted by 0 to 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
Further, the compound is represented by formula II:
wherein the content of the first and second substances,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is substituted by 0 to 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle), - (5-to 10-membered aromatic ring)) -C (O) - (5-10 membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
Further, the compound is represented by formula III:
wherein the content of the first and second substances,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is substituted by 0 to 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C) 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); orTwo R on the same carbon atom 13 Composition = O.
Further, the air conditioner is characterized in that,
R 1 selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 alkylene-O- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being substituted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C 1～6 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
Further, the air conditioner is characterized in that,
R 1 is selected from-C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 alkylene-O- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being substituted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), - (3-to 10-membered cycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle);
preferably, the first and second electrodes are formed of a metal,
R 1 selected from phenyl,
The phenyl group,
By 0,1, 2 or 3R 13 Substitution;
each R 13 Is independently selected from-C 1～6 Alkyl, -O (C) 1～6 Alkyl), -O-phenyl.
Further, the air conditioner is provided with a fan,
R 2 is selected from-C 0～2 alkylene-C (O) -R 21 ；
R 21 Is selected from-C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being interrupted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), - (3 to 10 membered cycloalkyl); or two R on the same carbon atom 13 Composition = O;
preferably, the first and second electrodes are formed of a metal,
R 2 selected from-C (O) -R 21 ；
R 21 Is selected from-C 1～6 An alkyl group phenyl group,
The phenyl group,
By 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, -O (C) 1～6 Alkyl groups).
Further, the air conditioner is provided with a fan,
R 1 is selected from
And/or, R 2 Is selected from
Preferably, the compound is of formula IV:
wherein R is 2 Is selected from
Further, the structure of the compound is as follows:
the invention also provides application of the compound or the salt thereof, or the stereoisomer thereof, or the hydrate thereof, or the solvate thereof, or the prodrug thereof, or the nitrogen oxide thereof in preparing BCL-XL inhibitors or medicines for preventing and/or treating diseases related to BCL-XL anti-apoptosis proteins;
preferably, the disease is cancer, an immune disease or an autoimmune disease.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or the salt, the stereoisomer, the hydrate, the solvate, the prodrug or the nitrogen oxide thereof as an active substance and adding pharmaceutically acceptable auxiliary materials or auxiliary components.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 Alkyl "refers to an alkyl group containing 1 to 4 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of carbon atoms. E.g. C 1～6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms, for example 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. An alkyl group may be optionally substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as C 1～6 An alkoxy group.
"cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 10 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:
dicyclohexyl and
a dicyclohexyl group.
"heterocycloalkyl" refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged, and spiro ring systems); wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom.
"aromatic ring" refers to aromatic unsaturation-containing groups having 3 to 10 carbon atoms and no ring heteroatoms and having single or multiple rings (including fused, bridged, and spiro ring systems), such as phenyl.
"heteroaromatic ring" refers to an aromatic unsaturated ring containing at least one heteroatom; including single rings or multiple rings (including fused, bridged, and spiro ring systems); wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom.
"halogen" is fluorine, chlorine, bromine or iodine.
"halogen-substituted alkyl" means that a hydrogen atom in an alkyl group can be substituted with one or more halogen atoms. E.g. halogen substituted C 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms with a hydrogen atom substituted by one or more halogen atoms.
“-C 0～4 Alkylene- (3-to 10-membered cycloalkyl) "means 0 to 4 alkylene groups to which 3-to 10-membered cycloalkyl groups are bonded. Similarly, "-C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl) "means that 0 to 4 alkylene groups are linked to a 3-to 10-membered heterocycloalkyl group; "-C 0～4 Alkylene- (5-to 10-membered aromatic ring) "means that 0 to 4 alkylene groups are bonded to a 5-to 10-membered aromatic ring; "-C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle) "means that 5-to 10-membered aromatic heterocycle is bonded to 0 to 4 alkylene groups.
“-C 0～4 alkylene-O- (5-to 10-membered aromatic ring) "means that after 0 to 4 alkylene groups are bonded to one oxygen atom, the oxygen atom is bonded to a 5-to 10-membered aromatic ring; "-C (O) - (5-to 10-membered aromatic heterocycle)" means that a 5-to 10-membered aromatic heterocycle is attached to a carbonyl group.
“-C(O)-R 21 The structure of
“-O(C 1～10 Alkyl) "means that C is attached to the oxygen atom 1～10 An alkyl group.
“-NH(C 1～10 Alkyl) "means that the nitrogen atom is attached to one hydrogen and one C, respectively 1～10 An alkyl group; "-N (C) 1～10 Alkyl) (C 1～10 Alkyl) "means that the nitrogen atom is attached to two carbons, respectively 1～10 An alkyl group.
"stereoisomers" include enantiomers and diastereomers.
Salts are "pharmaceutically acceptable salts" in the context of the present invention.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by mixing the above compound with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
The compound can effectively combine BCL-XL anti-apoptosis protein and inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the protein can be used for preventing or treating diseases related to BCL-XL anti-apoptosis protein, such as cancer, immune diseases, autoimmune diseases and the like. The compound can be used for preparing BCL-XL inhibitors or preparing medicaments and pharmaceutical compositions for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability, high possibility of drug formation, simple preparation, high yield, low cost, high feasibility and good application prospect.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 The units in (ppm) are given. NMR was measured using a (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument using deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used. The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of Futai Huanghai silica gel as a carrier.
Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, chengdulong chemistry, shaoshi chemistry technology, and Bailingwei technology.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution without specific indication. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mol per liter and% is mass%, unless otherwise specified.
DCM: dichloromethane;
HATU:2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate;
DIPEA: n, N-diisopropylethylamine;
TFA: trifluoroacetic acid;
THF: tetrahydrofuran;
EDCI: 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine;
HOBT: 1-hydroxybenzotriazole;
EA: ethyl acetate;
DMF: n, N-dimethylformamide.
Example 1 preparation of Compound A
The synthetic route for the preparation of compound a is as follows:
step 1: preparation of Compound 4
A50 mL reaction vial was charged with Compound 2 (240.00mg, 998.94. Mu. Mol), compound 3 (185.00mg, 998.80. Mu. Mol), compound 1 (300.00mg, 998.80. Mu. Mol) and methanol (2.0 mL) in that order. The reaction was quenched after stirring for 5 hours at ambient temperature (monitored by LC-MS). After the reaction solution was distilled under reduced pressure, a saturated NaCl solution (20.0 mL) was added to the system, followed by extraction with ethyl acetate (3 × 20.0 mL), the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated to dryness, purified by MPLC, and the solvent was removed by concentration under reduced pressure to obtain compound 4 (223.00mg, 544.60 μmol, yield 54.53%).
Characterization of the compound 4 obtained: MS (ESI) M/z =410.2 (M + 1) + 。
Step 2: preparation of Compound 5
A50 mL reaction flask was charged with compound 4 (223.00mg, 544.60. Mu. Mol), ac 2 O (55.60mg, 544.60 mu mol), DIPEA (148.40mg, 1.15mmol) and dichloromethane (2.0 mL) are stirred at normal temperature for reaction for 30 minutes, then the reaction is quenched (monitored by LC-MS), the pH value of the system is adjusted to 6-7 by 1N hydrochloric acid solution, and the reaction solution is concentrated to obtain a compound 5 (245.89 mg, crude product) which is directly used for the next reaction.
Characterization of the compound 5 obtained: MS (ESI) M/z =452.1 (M + 1) + 。
And 3, step 3: preparation of Compound 6
A50 mL reaction flask was charged with Compound 5 (245.89 mg, crude product), lithium hydroxide hydrate (180.00mg, 540.00. Mu. Mol), methanol (2.0 mL) and water (2.0 mL) in this order, stirred at room temperature for 2 hours and quenched (monitored by LC-MS), the pH of the system was adjusted to 6.0-7.0 with 1N hydrochloric acid solution, and the reaction solution was concentrated to give Compound 6 (137.20mg, 313.61. Mu. Mol, 58.08% yield).
Characterization of the compound 6 obtained: MS (ESI) M/z =438.2 (M + 1) + 。
And 4, step 4: preparation of Compound 8
Compound 6 (137.20mg, 313.61. Mu. Mol), DIPEA (222.60mg, 1.72mmol, 0.3mL), HATU (130.00mg, 313.61. Mu. Mol) and DMF (2.0 mL) were sequentially added into a 50mL reaction flask, and after the temperature of the reaction system was lowered to 0 ℃, compound 7 (78.80mg, 285.12. Mu. Mol) was added, and the reaction was stirred under ice bath conditions for 1 hour and then quenched (LC-MS monitoring). After the reaction solution was distilled under reduced pressure, a saturated NaCl solution (20.0 mL) was added to the system, followed by extraction with ethyl acetate (3 × 20.0 mL), the organic phases were combined, the organic phase was dried with anhydrous sodium sulfate, the solvent was evaporated to dryness, and the solvent was removed by concentration under reduced pressure to obtain compound 8 (218.22 mg, crude product).
Characterization of the compound 8 obtained: MS (ESI) M/z =696.3 (M + 1) + 。
And 5: preparation of Compound A
Compound 8 (218.22 mg, crude) was dissolved in a mixed solution of 6N HCl and ethyl acetate (5.0 mL) in a 50mL reaction flask, the reaction was stirred at room temperature for 0.5 hour, and the solvent was removed by concentration under reduced pressure to give Compound A (20.80mg, 31.95. Mu. Mol, 10.17% yield).
Characterization of the compound a obtained: MS (ESI) M/z =596.4 (M + 1) + 。
1 H NMR(400MHz,CD 3 OD)δ7.56-7.48(m,2H),7.46-7.42(m,2H),7.40-7.34(m,5H),7.29-7.25(m,3H),7.23-7.21(m,2H),7.17-7.09(m,2H),7.04-6.94(m,6H),5.00-4.93(m,2H),4.66-4.49(m,1H),3.39-3.16(m,1H),3.13-3.04(m,2H),3.01-2.96(m,2H),2.94-2.90(m,1H),2.79-2.38(m,2H),2.37-1.91(m,3H).
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 detection of BCL-XL inhibitory Activity
1. Experimental apparatus and reagents:
2. the experimental method comprises the following steps:
the dry compound powder was dissolved in DMSO to a 10.00mM solution, and the compound was diluted in a gradient using an instrument ECHO and added to a 384-well reaction plate to give a final DMSO concentration of less than 0.5% in the whole reaction system (12.0. Mu.L).
BCL-XL and Tag2-BAK were diluted 4-fold to the desired final concentration using a Diluent buffer in the BCL-XL/BAK Binding Assay Kit, 3.0. Mu.L of BCL-XL and Tag2-BAK solutions, respectively, were pipetted into the 384-well reaction plate containing the compound, centrifuged at 1000rpm for 1 minute, and then placed in a microplate thermostat at 25 ℃ and 280rpm for 15 minutes of pre-incubation. Then detecting buffer (Lot 10A) in BCL-XL/BAK Binding Assay Kit is used to put Anti-tag1-Eu of 100X 3+ (Lot 06A) and Anti-tag2-XL665 (Lot 104A) are respectively diluted to 1x, and Anti-tag1-Eu is prepared according to the proportion of 1 3+ The Anti-tag2-XL665 mixed solution was pipetted 6.0. Mu.L of the antibody mixed solution and added to a 384-well reaction plate, centrifuged at 1000rpm for 1 minute, and then placed on a microplate thermostat shaker at 25 ℃ and 280rpm, and incubated for 2 hours. After the reaction, the microplate reader reads the fluorescence signal value (Flu) in the 384-well reaction plate (Ex =320nm, em = 665/620nm.
Positive controls (positive controls containing DMSO only, BCL-XL solution, tag2-BAK solution before incubation) and negative controls (negative controls containing DMSO only and Tag2-BAK solution before incubation) were set.
3. Data analysis
The percentage of remaining activity at each concentration was calculated as follows:
remaining activity (%) =100% × (Flu) Group of compounds -Flu Negative control )/(Flu Positive control -Flu Negative control )
IC was then calculated using GraphPad 5.0 Fit Effect Curve 50 The value is obtained.
The BCL-XL inhibitory activity of the compound prepared in example and the compound ABT-263 was measured in accordance with the above-described method, and the results of the test are shown in Table 1.
TABLE 1 inhibitory Activity of the Compounds on BCL-XL
The test shows that: the compounds of the invention have inhibitory activity against BCL-XL proteins.
Test example 2 detection of BCL-XL Surface Plasmon Resonance (SPR) binding assay
1. Laboratory instruments and reagents:
2. SPR test method
Preparing a running buffer solution: the protein fixation buffer and the running buffer A have the same components, wherein the NaH 2 PO 4 The concentration was 10mM, na 2 HPO 4 The concentration is 40mM, the NaCl concentration is 150mM, the content of Twenn 20 is 0.03%, and the pH is adjusted to 7.4; naH in running buffer B 2 OP 4 The concentration was 10mM, na 2 HOP 4 The concentration was 40mM, naCl concentration 150mM, tween20 content 0.03%, DMSO content 5.00%, and pH was adjusted to 7.4. The running buffer was prepared and filtered through a 0.22 μm filter.
BCL-XL protein immobilization: BCL-XL was immobilized on NTA chip by His capture and amino coupling using protein immobilization buffer. The surface of the NTA chip is respectively washed by 50mM NaOH and 350mM EDTA, the flow rate is 60.0 mu L/min, and each time lasts for 60 seconds; then with 10mM NiCl 2 Activation was carried out for 1100 seconds, followed by 650 seconds of a mixture of EDC (75.00 mg/mL) and NHS (11.50 mg/mL) in a volume ratio of 1, at an activation flow rate of 10.0. Mu.L/min; then BCL-XL (0.04 mg/mL) was injected at 4.0. Mu.L/min for 850 seconds. After the end of the BCL-XL injection, a mixture of EDC (75.00 mg/mL) and NHS (11.50 mg/mL) in a volume ratio of 1. The final fixed amount of BCL-XL was 4690.00RU.
Compound dilution: diluting the test compound with 100% DMSO to 100 times the desired final concentration, mixing, pipetting 4.0. Mu.L, adding to 396. Mu.L running buffer A, and centrifuging at 15000rpm for 5 minutes, to obtain a 1X compound solution containing 1% DMSO for subsequent dilution. Compound a was serially diluted 2-fold for 9 concentrations starting at 50 μ M (200 μ L compound solution was added to 200 μ L running buffer B for 2-fold dilution for a total of 10 concentration gradients, including 1 concentration of 0 (using running buffer B instead), starting at 50 μ M). The diluted compounds were transferred to 96-well plates for sample injection.
And (3) running a program: the experiment was run at 25 ℃ using running buffer B at a flow rate of 30.0. Mu.L/min. After running buffer B injection 8 times to complete equilibration, compounds were injected sequentially from lowest to highest concentration with binding and dissociation times of 120 seconds, and the injection needles were washed with 50% dmso after each injection. DMSO induced solvent differences were corrected for by 0.50%,0.75%,1.00%,1.25% and 1.50% DMSO.
3. Data analysis
The response of compounds to BCL-XL binding was analyzed after subtraction of the reference channel and 0 concentration, and affinity Kd was fitted by Biacore T200 Evaluation Software using a slow state affinity model (1.
The prepared compounds were subjected to SPR assay as described above and the results are shown in Table 2.
TABLE 2 binding response values of compounds to BCL-XL
The test shows that: the compounds of the invention have binding activity to BCL-XL protein.
In conclusion, the compound can effectively combine BCL-XL anti-apoptosis protein and inhibit the activity of the BCL-XL anti-apoptosis protein; therefore, the BCL-XL anti-apoptotic protein can be used for preventing or treating diseases related to BCL-XL anti-apoptotic proteins, such as cancer, immune diseases, autoimmune diseases and the like. The compound can be used for preparing BCL-XL inhibitors or preparing medicaments and pharmaceutical compositions for preventing or treating diseases related to BCL-XL anti-apoptosis proteins. In addition, the compound has good pharmacological characteristics, good stability, high possibility of drug formation, simple preparation, high yield, low cost, high feasibility and good application prospect.
Claims (10)
1. A compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof:
wherein, the first and the second end of the pipe are connected with each other,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is substituted by 0 to 3R 13 Substitution;
each R 13 Independent of each otherSelected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C) 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
2. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, wherein: the compound is represented by formula II:
wherein, the first and the second end of the pipe are connected with each other,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
R 3 selected from hydrogen, -C 1～10 Alkyl, halogen, hydroxy, carboxy, amino, cyano;
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is substituted by 0 to 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
3. The compound according to claim 2, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, characterized in that: the compound is represented by formula III:
wherein the content of the first and second substances,
R 1 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 alkylene-O- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～4 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～10 Alkyl, -C 0～4 Alkylene- (3-to 10-membered cycloalkyl), -C 0～4 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (5-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle is substituted by 0 to 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～10 Alkyl, halogen substituted-C 1～10 Alkyl, -OH, -O (C) 1～10 Alkyl), -NH 2 、-NH(C 1～10 Alkyl), -N (C) 1～10 Alkyl) (C 1～10 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
4. The compound according to claim 3, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, characterized in that:
R 1 selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 alkylene-O- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
R 2 selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-C (O) -R 21 ；
R 21 Selected from hydrogen, -C 1～6 Alkyl, -C 0～2 Alkylene radical- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being substituted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C) 1～6 Alkyl), - (3-to 10-membered cycloalkyl), - (3-to 10-membered heterocycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle); or two R on the same carbon atom 13 Composition = O.
5. The compound according to claim 4, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, wherein:
R 1 is selected from-C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 alkylene-O- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle), -C 0～2 alkylene-NH-C (O) - (5-to 10-membered aromatic ring);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being substituted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), -N (C) 1～6 Alkyl) (C 1～6 Alkyl), - (3-to 10-membered cycloalkyl), - (5-to 10-membered aromatic ring), - (5-to 10-membered aromatic heterocycle);
preferably, the first and second liquid crystal display panels are,
R 1 selected from phenyl,
The phenyl group,
By 0,1, 2 or 3R 13 Substitution;
each R 13 Is independently selected from-C 1～6 Alkyl, -O (C) 1～6 Alkyl), -O-phenyl.
6. The compound according to claim 4, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, wherein:
R 2 is selected from-C 0～2 alkylene-C (O) -R 21 ；
R 21 Is selected from-C 1～6 Alkyl, -C 0～2 Alkylene- (3-to 10-membered cycloalkyl), -C 0～2 Alkylene- (3-to 10-membered heterocycloalkyl), -C 0～2 Alkylene- (5-to 10-membered aromatic ring), -C 0～2 Alkylene- (5-to 10-membered aromatic heterocycle);
the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring being substituted by 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, cyano, nitro, -C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OH, -O (C) 1～6 Alkyl), -NH 2 、-NH(C 1～6 Alkyl), - (3 to 10 membered cycloalkyl); or two R on the same carbon atom 13 Composition = O;
preferably, the first and second electrodes are formed of a metal,
R 2 selected from-C (O) -R 21 ；
R 21 Is selected from-C 1～6 An alkyl group phenyl group,
The phenyl group,
By 0,1, 2 or 3R 13 Substitution;
each R 13 Independently selected from halogen, -C 1～6 Alkyl, -O (C) 1～6 Alkyl groups).
7. The compound according to claim 4, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, wherein:
R 1 is selected from
And/or, R 2 Is selected from
Preferably, the compound is of formula IV:
wherein R is 2 Is selected from
8. The compound according to any one of claims 1 to 7, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, characterized in that: the structure of the compound is as follows:
9. use of a compound according to any one of claims 1 to 8, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, or a solvate thereof, or a prodrug thereof, or a nitrogen oxide thereof, for the manufacture of a BCL-XL inhibitor, or for the manufacture of a medicament for the prevention and/or treatment of a disease associated with a BCL-XL anti-apoptotic protein;
preferably, the disease is cancer, an immune disease or an autoimmune disease.
10. A pharmaceutical composition characterized by: the compound is a preparation prepared by taking the compound, or the salt, the stereoisomer, the hydrate, the solvate, the prodrug or the nitrogen oxide thereof of any one of claims 1 to 8 as an active substance and adding pharmaceutically acceptable auxiliary materials or auxiliary components.
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| BRUNCKO, MILAN等: "Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, no. 4, pages 641 - 662 * |
| HEISEY, DANIEL A. R.等: "The ewing family of tumors relies on BCL-2 and BCL-XL to escape PARP inhibitor toxicity", CLINICAL CANCER RESEARCH, vol. 25, no. 5, pages 1664 - 1675 * |
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