CN115124517B - Aromatic compound, preparation method, pharmaceutical composition and application thereof - Google Patents
Aromatic compound, preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- CN115124517B CN115124517B CN202210119129.9A CN202210119129A CN115124517B CN 115124517 B CN115124517 B CN 115124517B CN 202210119129 A CN202210119129 A CN 202210119129A CN 115124517 B CN115124517 B CN 115124517B
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- Prior art keywords
- alkyl
- butyl
- methyl
- independently
- formula
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 170
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- -1 ester compound Chemical class 0.000 claims description 59
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- 150000001875 compounds Chemical class 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 36
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 33
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- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- JOVOSQBPPZZESK-UHFFFAOYSA-N phenylhydrazine hydrochloride Chemical class Cl.NNC1=CC=CC=C1 JOVOSQBPPZZESK-UHFFFAOYSA-N 0.000 description 1
- 229940038531 phenylhydrazine hydrochloride Drugs 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012910 preclinical development Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Abstract
The invention discloses an aromatic compound, a preparation method, a pharmaceutical composition and application thereof. The invention provides an application of an aromatic compound shown in a formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof in preparation of an inhibitor, wherein the inhibitor is ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitor. The aromatic compound shown in the formula I can effectively inhibit key ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction in the autophagy process at a molecular level, and has a certain proliferation inhibition effect on human breast cancer cells MCF-7 and human colon cancer cells HCT-116.
Description
Technical Field
The invention relates to aromatic compounds, a preparation method, a pharmaceutical composition and application thereof.
Background
Autophagy is a highly conserved process of cellular self-digestion-the transport of cellular contents to lysosomes for degradation. Autophagy serves as a normal cellular stress response and a fine control mechanism to regulate cell survival under stress conditions, providing some energy and metabolic preconditions, clearing damaged proteins and organelles. In recent years, there has been increasing research evidence that defects or abnormalities in autophagy play an important role in the development, progression and treatment of cancer, and thus regulating autophagy has considerable potential as a cancer treatment method. Although autophagy has a tumor-inhibiting effect in the early stages of cancer development, it favors survival of the formed tumor. This is mainly because autophagy is advantageous for tumor cells to resist extreme environments such as nutritional deficiencies and hypoxia in tumor tissue. This situation is more pronounced in the central part of solid tumors, with autophagy levels significantly higher than surrounding. In some tumors, autophagy provides an energy source for cancer cells, thereby allowing cancer cells to survive in hostile environments that lack nutrition, hypoxia, and acidic environments. Autophagy is thought to provide energy to cancer cells under such adverse conditions, thereby having a pro-cancerous effect. In addition, autophagy plays an important role in early metastasis. Therefore, the autophagy inhibitor can be used as a powerful supplement to the existing anti-tumor treatment methods.
The existing autophagy inhibitors comprise PI3K inhibitor, cycloheximide, vacuole type H (+) -ATPase inhibitor, lysosomal lumen alkalizing agent, acid protease inhibitor and the like. While most autophagy inhibitors remain in the preclinical development stage. The key protein ATG5 of autophagy downstream pathway is a brand new potential target, and no small molecule inhibitor has been reported at present. Meanwhile, ATG5 is positioned at the downstream of the autophagy pathway, and the ATG5 is used as a target, so that side effects can be reduced, and the ATG has congenital advantages in the aspect of drug safety.
Disclosure of Invention
The invention aims to solve the problem that the prior art lacks a small molecular compound with an inhibiting effect on ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction, and therefore, the invention provides an aromatic compound, a preparation method, a pharmaceutical composition and application thereof, and the compound can effectively inhibit key ATG5-ATG16L and/or ATG5-TECAIR protein interaction in an autophagy process at a molecular level, so that the autophagy process is inhibited. In addition, they show a certain killing effect on breast cancer cells MCF-7 and colon cancer cells HCT-116 cells, and have the potential of preparing novel antitumor drugs.
The invention solves the technical problems through the following technical proposal.
The invention provides an application of an aromatic compound shown in a formula I, pharmaceutically acceptable salt thereof, solvate thereof or solvate of pharmaceutically acceptable salt thereof in preparation of an inhibitor; the inhibitor is ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitor;
Wherein,
M is 0, 1,2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 0, 1,2, 3 or 4;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 groups are independently C 1～C6 alkyl groups.
In one aspect, certain parameters in the application are as follows, and parameters not involved are as described in any other aspect (hereinafter referred to simply as "in one aspect"):
The aromatic compound shown in formula I can be And/or
In one embodiment, when R 1 is C 6～C10 aryl substituted with R 1-1, the C 6～C10 aryl can be phenyl.
In one embodiment, R 1 may beFor example
In one embodiment, in R 2, the C 6～C10 aryl group may be phenyl.
In one embodiment, when R 3 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as cyclopropyl.
In one embodiment, when R 4 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halo, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halogen, the number of halogens may be 1, 2, or 3, for example 1 or 3.
In one embodiment, when R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 isWhen said/>For example/>
In one embodiment, in R 4-2, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-3, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-4, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-5, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 isWhen said/>For example/>
In one aspect of the present invention,Can be
In one embodiment, the aromatic compound represented by formula I is not:
In one embodiment, the aromatic compound represented by formula I may be any one of the following compounds:
In one embodiment, the ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitor is used in or outside of a mammalian organism. When the ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitors are used in vitro, they are mainly used for experimental purposes, for example: as a standard sample or a control sample, or prepared into a kit according to a conventional method in the art, the kit provides rapid detection for the ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibition effect.
The present invention also provides an aromatic compound as shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof as described hereinbefore for use in inhibiting ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions.
The invention also provides an aromatic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate thereof or solvate of pharmaceutically acceptable salt thereof,
Wherein m is 0, 1, 2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 0, 1, 2, 3 or 4;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 is independently C 1～C6 alkyl;
However, the aromatic compounds represented by formula I are not the following compounds:
in one embodiment, certain parameters of the aromatic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof are as follows, and parameters not involved are as described in any other embodiment (hereinafter abbreviated as "in one embodiment"):
The definition of each group in the aromatic compound represented by formula I is as described in any one of schemes 1 to 6 below.
Scheme 1:
Wherein m is 0,1, 2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 1,2, 3 or 4;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 is independently C 1～C6 alkyl;
Scheme 2:
Wherein m is 0 or 1; x is O; y is CR 2; z is CH; n is 1,2, 3 or 4; r 1 is carboxy or C 6～C10 aryl substituted with R 1-1; r 2 is C 6～C10 aryl; r 3 is hydrogen; r 4 is nitro, The R 1-1 groups are independently carboxyl groups; the R 4-1 is C 1～C6 alkyl or/>The R 4-2 and R 4-3 are independently C 1～C6 alkyl;
Scheme 3:
wherein m is 1; z is CH; y is CR 2 or N; n is 0;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 is C 1～C6 alkyl or
R 4-2 is C 1～C6 alkyl;
r 4-3 is C 1～C6 alkyl;
R 4-4 is C 1～C6 alkyl;
r 4-5 is C 1～C6 alkyl;
Scheme 4:
Wherein m is 1; y is N; z is CH; n is 0; r 1 is C 6～C10 aryl substituted with R 1-1; r 3 is C 1～C6 alkyl; r 4 is nitro; the R 1-1 groups are independently carboxyl groups;
scheme 5:
m is 0, 1,2 or 3; z is CH; y is CR 2 or N; n is 0;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
R 3 is hydrogen or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 is independently C 1～C6 alkyl;
scheme 6:
Wherein m is 3, Y is N; z is CH; n is 0; r 1 is C 6～C10 aryl substituted with R 1-1; r 3 is C 3～C6 cycloalkyl; r 4 is independently C 1～C6 alkyl or nitro; the R 1-1 groups are independently carboxyl groups.
In one embodiment, the aromatic compound of formula I may beAnd/or/>
In one embodiment, when R 1 is C 6～C10 aryl substituted with R 1-1, the C 6～C10 aryl can be phenyl.
In one embodiment, R 1 may beFor example
In one embodiment, in R 2, the C 6～C10 aryl group may be phenyl.
In one embodiment, when R 3 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as cyclopropyl.
In one embodiment, when R 4 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halo, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 is C 1～C6 alkyl substituted with halogen, the number of halogens may be 1, 2, or 3, for example 1 or 3.
In one embodiment, when R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 isWhen said/>For example/>
In one embodiment, in R 4-2, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-3, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-4, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, in R 4-5, the C 1～C6 alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl, such as methyl.
In one embodiment, when R 4 isWhen said/>For example/>In one aspect of the present invention,Can be/>/>
In one embodiment, the aromatic compound represented by formula I may be any one of the following compounds:
The invention also provides application of the aromatic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate thereof or solvate of the pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing diseases related to ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction. The disease associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions may be colon cancer or breast cancer.
The invention also provides an aromatic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as described above, for use in the treatment and/or prevention of diseases associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions. The disease associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions may be colon cancer or breast cancer.
The present invention also provides a method of treating a disease associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions, comprising administering to a patient a therapeutically effective amount of an aromatic compound as set forth in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as described previously. The disease associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions may be colon cancer or breast cancer.
The invention also provides a pharmaceutical composition, which comprises the aromatic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate thereof or solvate of pharmaceutically acceptable salt thereof, and a substance X, wherein the substance X is a pharmaceutical auxiliary material and/or Olaparib.
The invention also provides a pharmaceutical composition, which comprises a compound 1 and a substance X, wherein the substance X is a pharmaceutical adjuvant and/or Olaparib,
The invention also provides application of the aromatic compound shown in the formula I, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparation of medicines for treating and/or preventing colon cancer or breast cancer.
The invention also provides an aromatic compound shown as the formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above, which are used for treating and/or preventing colon cancer or breast cancer.
The present invention also provides a method of treating colon or breast cancer comprising administering to a patient a therapeutically effective amount of an aromatic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition as described above.
The mass percentage of the aromatic compound shown in the formula I, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof in the pharmaceutical composition is 0.1-99.9%, the mass percentage refers to the percentage of the aromatic compound shown in the formula I, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof in the total mass of the pharmaceutical composition. The sum of the mass fraction of the aromatic compound shown in the formula I, the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof and the pharmaceutical excipients can be 100 percent. The choice of the pharmaceutical excipients varies depending on the route of administration and the nature of the action, and is generally a filler, diluent, binder, wetting agent, disintegrant, lubricant, emulsifier or suspending agent.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The invention also provides a preparation method of the aromatic compound shown in the formula I, which is any scheme,
Scheme 1: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the ester compound shown in the formula A to obtain the aromatic compound shown in the formula I,
Wherein R 5 isOr is/>Substituted C 6～C10 aryl, R 5-1 is C 1～C6 alkyl, m, X, Z, Y, n, R 1、R3 and R 4 are as defined above;
Scheme 2: in a solvent, reacting a compound shown as a formula B with a compound shown as a formula C in the presence of alkali to obtain an aromatic compound shown as a formula I,
Wherein m, Z, Y, n, R 1、R3 and R 4 are as defined above.
In the preparation method, in the scheme 1, the solvent may be conventional in the art, for example, pyridine.
In the preparation method, in the scheme 1, the kind of the base may be conventional in the art, for example, lithium iodide.
In the preparation method, in the scheme 1, the molar ratio of the ester compound represented by formula a to lithium iodide may be conventional in the art, for example, 1:14.
In the preparation method, in the scheme 2, the kind of the solvent may be conventional in the art, for example, absolute ethanol.
In the preparation method, in the scheme 2, the kind of the base may be conventional in the art, for example, diethylamine.
In the preparation method, in the scheme 2, the molar ratio of the compound represented by formula B to the compound represented by formula C may be conventional in the art, for example, 1:1.
Unless otherwise specified, all technical and scientific terms used herein have the standard meanings that claim the art of ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitors. In case there are multiple definitions for a term, the definitions herein control.
The term "pharmaceutically acceptable salt" refers to a salt of a compound that is reacted with a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, the base addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, magnesium, bismuth, ammonium salts, and the like. When the compound contains a relatively basic functional group, the acid addition salt may be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, sulfate, mesylate, and the like. See in particular Handbook of Pharmaceutical Salts Properties, selection, and Use (P.Heinrich Stahl, 2002).
The term "solvate" refers to a material formed upon crystallization of a compound with a solvent (including, but not limited to, water, methanol, ethanol, etc.). The solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
The term "solvate of a pharmaceutically acceptable salt" refers to a compound formed by combining a pharmaceutically acceptable (relatively non-toxic, safe, suitable for patient use) acid or base, a solvent (including but not limited to: water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt is as defined above for the term "pharmaceutically acceptable salt" and the solvent is stoichiometric or non-stoichiometric. Solvates of the pharmaceutically acceptable salts include, but are not limited to, hydrochloride monohydrate.
The term "treatment" refers to any of the following conditions: (1) alleviating one or more biological manifestations of a disease; (2) Interfere with one or more points in the biological cascade that trigger the disease; (3) Slowing the progression of one or more biological manifestations of the disease.
The term "preventing" refers to reducing the risk of developing a disease.
The term "therapeutically effective amount" refers to an amount of a compound administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by one skilled in the art.
The term "patient" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the invention provides an aromatic compound, a preparation method, a pharmaceutical composition and application thereof, in particular to an aromatic compound shown in a formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, which can effectively inhibit key ATG5-ATG16L and/or ATG5-TECAIR protein interaction in an autophagy process at a molecular level and has a certain proliferation inhibition effect on human breast cancer cells MCF-7 and human colon cancer cells HCT-116.
Drawings
FIG. 1 is a 1H-1 H NOESY spectrum of compound 2 in example 1.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Unless otherwise specifically indicated, all references to room temperature in the examples below refer to 20℃to 30 ℃.
EXAMPLE 1 Synthesis of Compounds 1-16
The synthesis of compounds 1-16 was performed using the following reaction steps:
A1000 mL three-necked flask was charged with 20.7g (0.15 mol) of p-nitroaniline, 500mL of HCl (aq, 4N) was added, and the mixture was dissolved by mechanical stirring. 30% sodium nitrite (36 mL) is slowly dripped into the ice salt bath under the conditions of mechanical stirring, and the temperature is controlled to be 0-5 ℃. After the dripping, stirring for 30min. 12.6mL (density 1.16,1.1 eq) of furaldehyde which is steamed again in the dark under the condition of ice salt bath and dark is slowly dripped into the solution, and 3g (22.5 mmol) of copper chloride and 45mL of acetone are added. Stirred overnight and reacted for 2h at 22℃the next day. Filtering and washing to obtain a brown yellow solid. Drying and beating 3 times with diethyl ether to obtain brown yellow solid 5- (4-nitrophenyl) furan-2-formaldehyde 26.1g with a yield of 80.18%.
To a 100mL eggplant-shaped bottle was added 4g (22.5 mmol) of 3-benzoylpropionic acid, and 20mL of acetic anhydride. 3 drops of concentrated sulfuric acid are dripped under stirring to react for 15min. Pouring the reaction solution into ice water under stirring, continuously stirring for 30min, generating yellow precipitate, filtering, washing with water, drying, and recrystallizing with absolute ethanol to obtain pink crystal 2.58g with a yield of 71.67%.
C.500mL three-necked flask was charged with 6.28g (28.9 mmol) of 5- (4-nitrophenyl) furan-2-carbaldehyde, 250mL of ethanol, heated to 50deg.C, monitored by TLC with 29.0mmol of diethylamine, and reacted for 4 hours, wherein the reaction liquid turned from yellow to red and had a red precipitate formed. Suction filtration, water washing and drying are carried out to obtain red solid (E) -3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -5-phenyl-1, 3-dihydro-2H-pyrrole-2-ketone 7.78g, and crude product yield is 75.03%.
10ML of N, N-dimethylformamide and 1.5g (25 mmol) of acetic acid were added to a 250mL eggplant-shaped bottle, 7.92mL (50 mmol) of 25% ammonia water was added dropwise with stirring, 7.78g (21.7 mmol) of (E) -3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -5-phenyl-1, 3-dihydro-2H-pyrrol-2-one was further added, 70mL of N, N-dimethylformamide was added, and the mixture was reacted at 100℃for 4 hours, whereby the reaction mixture became black from red. Cooling to room temperature, pouring the reaction liquid into ice water under stirring, filtering, and washing with water. 6.05g of red-black solid is obtained, and the crude product yield is 77.96%.
E. The secondary amine product from step d (3 mmol), 1.1eq substituted bromobenzyl, was taken up in 180mg of NaH in dry DMF (15 mL) in ice-bath, stirred for 10min, reacted at room temperature for 8h, poured into ice-water, extracted with ethyl acetate, dried and isolated by column chromatography (PE: EA=5:1).
F. the secondary amine product from step d (3 mmol), 1.1eq of the substituted carboxylate and 2.5eq of cesium carbonate were reacted in dry DMF (15 mL) under nitrogen protection at 80℃for 8h, poured into ice water, extracted with ethyl acetate, dried and separated by column chromatography (PE: EA=5:1).
G. the ester product from step e or f (0.5 mmol), anhydrous LiI (14 eq), was reacted in anhydrous pyridine under nitrogen at 110 ℃ for 36h, poured into 1N HCl (aq), pH adjusted to 2, and suction filtered to prepare a thin layer plate separation (first with DCM: meoh=20:1 followed by DCM: meoh=40:1 (containing one thousandth of acetic acid).
Compound 1: (E) -4- (3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) benzoic acid
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 28H18N2O6: 478.1165. Actual measurement ：478.1169;1HNMR(400MHz,DMSO-d6)δ13.05(s,1H),8.36–8.27(m,2H),8.14–8.05(m,2H),7.94–7.85(m,2H),7.62–7.54(s,1H),7.44–7.38(s,1H),7.33(m,5H),7.20(m,3H),6.91–6.82(s,1H).
Compound 2: (E) -4- ((3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 29H20N2O6: 491.1249. Actual measurement ：491.1156;1HNMR(600MHz,DMSO-d6)δ8.31(d,J＝8.4Hz,2H),8.06(d,J＝8.4Hz,2H),7.78(d,J＝7.9Hz,2H),7.57(d,J＝3.8Hz,1H),7.52–7.42(m,5H),7.36(d,J＝3.8Hz,1H),7.20(s,1H),7.02(d,J＝7.9Hz,2H),6.59(s,1H),4.89(s,2H).
(E) -3- ((3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (3)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 29H20N2O6: 491.1249. Actual measurement ：491.1176;1HNMR(600MHz,DMSO-d6)δ8.30(d,J＝8.9Hz,2H),8.06(d,J＝8.9Hz,2H),7.76(d,J＝7.7Hz,1H),7.60(s,1H),7.56(d,J＝3.8Hz,1H),7.51–7.43(m,5H),7.40–7.35(m,2H),7.22(d,J＝7.8Hz,2H),7.20(s,1H),6.59(s,1H),4.92(s,2H).
(E) -2- (3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) acetic acid (4)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 23H16N2O6: 415.0936. Actual measurement ：415.1030;1HNMR(600MHz,DMSO-d6)δ8.30(d,J＝8.9Hz,2H),8.04(d,J＝8.9Hz,2H),7.60(d,J＝7.1Hz,2H),7.54(d,J＝3.7Hz,1H),7.53–7.45(m,3H),7.31(d,J＝3.8Hz,1H),7.09(s,1H),6.49(s,1H),4.16(s,2H).
(E) -3- (3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) propanoic acid (5)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 23H16N2O6: 429.1092. Actual measurement ：429.1056;1HNMR(600MHz,DMSO-d6)δ8.31(d,J＝8.6Hz,2H),8.04(d,J＝8.6Hz,2H),7.65(d,J＝6.7Hz,2H),7.59–7.52(m,4H),7.32(d,J＝3.8Hz,1H),7.10(s,1H),6.48(s,1H),3.83(t,J＝7.6Hz,2H),2.36(t,J＝7.6Hz,2H).
(E) -4- (3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) butanoic acid (6)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 25H20N2O6: 443.1249. Actual measurement ：443.1256;1HNMR(600MHz,DMSO-d6)δ8.30(d,J＝7.9Hz,1H),8.03(d,J＝7.0Hz,1H),7.64(d,J＝6.8Hz,2H),7.59–7.49(m,4H),7.31(d,J＝3.1Hz,1H),7.10(s,1H),6.48(s,1H),3.66(t,J＝7.2Hz,2H),2.07(t,J＝7.3Hz,2H),1.55(p,J＝7.3Hz,2H).
(E) -5- (3- ((5- (4-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) pentanoic acid (7)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 26H22N2O6: 457.1405. Actual measurement ：457.1403;1HNMR(600MHz,DMSO-d6)δ12.01(s,1H),8.31(d,J＝8.9Hz,2H),8.04(d,J＝8.9Hz,2H),7.67–7.61(m,2H),7.60–7.50(m,4H),7.32(d,J＝3.8Hz,1H),7.11(s,1H),6.49(s,1H),3.64(s,2H),2.08(s,2H),1.31(t,J＝3.5Hz,4H).
(E) -4- ((3- ((5- (4-acetylphenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (8)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 31H23NO5: 488.1503. Actual measurement ：488.1525;1HNMR(400MHz,DMSO-d6)δ8.04(d,J＝8.1Hz,2H),7.95(d,J＝8.2Hz,2H),7.81(d,J＝7.8Hz,2H),7.54 -7.38(m,6H),7.33(d,J＝3.8Hz,1H),7.20(s,1H),7.09(d,J＝7.8Hz,2H),6.59(s,1H),4.91(s,2H),2.58(s,3H).
(E) -4- ((3- ((5- (3-acetylphenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (9)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 31H23NO5: 488.1503. Actual measurement ：488.1520;1HNMR(400MHz,DMSO-d6)δ8.35(t,J＝1.8Hz,1H),8.08(dt,J＝7.8,1.2Hz,1H),7.92(dt,J＝7.8,1.3Hz,1H),7.81(d,J＝8.1Hz,2H),7.63(t,J＝7.8Hz,1H),7.51(dd,J＝6.6,2.9Hz,2H),7.44(q,J＝3.6Hz,3H),7.40(d,J＝3.8Hz,1H),7.31(d,J＝3.8Hz,1H),7.20(s,1H),7.11(d,J＝8.0Hz,2H),6.65(s,1H),4.94(s,2H),2.63(s,3H).
(E) -4- ((3- ((5- (4-acetamidophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (10)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 31H24N2O5: 503.1612. Actual measurement ：503.1627;1HNMR(400MHz,DMSO-d6)δ10.16(s,1H),7.83–7.74(m,5H),7.70(d,J＝8.8Hz,2H),7.52–7.41(m,5H),7.39(s,1H),7.28(d,J＝3.8Hz,1H),7.16(s,1H),7.14(d,J＝3.7Hz,1H),7.05(d,J＝7.7Hz,1H),6.58(s,1H),4.90(s,2H),2.55(s,3H).
(E) -4- ((3- ((5- (3-acetamidophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (11)
Red solid, HRMS (M/z): ESI-HRMS [ M-H ] - (M/z) calcd C 31H24N2O5: 503.1612. Found ：503.1637;1H NMR(600MHz,DMSO-d6)δ10.12(s,1H),8.40(d,J＝1.9Hz,1H),7.88–7.76(m,2H),7.57(dd,J＝6.6,2.9Hz,2H),7.51(dt,J＝7.4,1.6Hz,1H),7.42(dd,J＝6.6,3.1Hz,3H),7.40–7.35(m,2H),7.28(d,J＝3.6Hz,1H),7.21–7.16(m,2H),7.13(d,J＝8.2Hz,2H),6.66(s,1H),4.96(s,2H),2.08(s,3H).
(E) -4- ((3- ((5- (4-carbamoylphenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (12)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 30H22N2O5: 489.1456. Actual measurement ：489.1475;1HNMR(400MHz,DMSO-d6)δ7.97(d,J＝8.5Hz,2H),7.89(d,J＝8.3Hz,2H),7.80-7.70(br,2H),7.37(d,J＝3.7Hz,1H),7.52-7.41(m,5H),7.39(s,2H),7.31(d,J＝3.8Hz,1H),7.18(s,1H),6.98(d,J＝7.0Hz,2H),6.58(s,1H),4.89(s,2H).
(E) -4- ((3- ((5- (3-carbamoylphenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (13)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 30H22N2O5: 489.1456. Actual measurement ：489.1504;1HNMR(400MHz,DMSO-d6)δ8.32(d,J＝1.8Hz,1H),8.15(s,1H),7.96(d,J＝7.8Hz,1H),7.84(d,J＝7.9Hz,1H),7.78-7.70(br,2H),7.56(t,J＝7.8Hz,1H),7.53-7.38(m,6H),7.32(d,J＝3.8Hz,1H),7.30(d,J＝3.8Hz,1H),7.18(s,1H),6.93(d,J＝6.5Hz,2H),6.63(s,1H),4.88(s,2H).
(E) -4- ((3- ((5- (3-nitrophenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (14)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 29H20N2O6: 491.1249. Actual measurement ：491.1267;1HNMR(600MHz,DMSO-d6)δ8.56(t,J＝2.0Hz,1H),8.25(dt,J＝7.8,1.2Hz,1H),8.17(dd,J＝8.0,2.2Hz,1H),7.82(d,J＝8.3Hz,2H),7.76(t,J＝8.0Hz,1H),7.53(d,J＝3.7Hz,1H),7.52–7.41(m,5H),7.33(d,J＝3.8Hz,1H),7.20(s,1H),7.13(d,J＝8.1Hz,2H),6.62(s,1H),4.93(s,2H).
(E) -4- ((3- ((5-phenyl furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (15)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 29H20N2O6: 446.1398. Actual measurement ：446.1406;1HNMR(400MHz,DMSO-d6)δ7.92–7.73(m,4H),7.53–7.41(m,7H),7.39-7.34(m,1H),7.30(d,J＝3.7Hz,1H),7.26(d,J＝3.7Hz,1H),7.19(s,1H),7.11(d,J＝8.0Hz,2H),6.58(s,1H),4.91(s,2H).
(E) -4- ((3- ((5- (4-methylsulfonylphenyl) furan-2-yl) methylene) -2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-1-yl) methyl) benzoic acid (16)
Red solid, ESI-HRMS [ M-H ] - (M/z) calculated C 30H23NO6 S524.1173. Actual measurement ：524.1175;1HNMR(400MHz,DMSO-d6)δ8.07(d,J＝8.9Hz,2H),8.00(d,J＝8.5Hz,2H),7.82(d,J＝8.3Hz,2H),7.52–7.42(m,6H),7.34(d,J＝3.9,1H),7.20(s,1H),7.12(d,J＝8.1Hz,2H),6.61(s,1H),4.92(s,2H),3.24(s,3H).
The double bond configuration of compounds 1-16 was confirmed to be E-type via 1H-1 H NOESY spectra, using compound 2 as an example, as shown in FIG. 1 for 1H-1 H NOESY spectra of compound 2.
1H-1 H NOESY analysis of compound 2: the 6.5925ppm s peak is H on the double bond outside the ring, and is in the unshielded region of the c ring, but is influenced by the N atom electroconjugation, the chemical shift value is not increased much, and the 7.1977ppm s peak is double bond H of the lactam ring, and the chemical shift value is high. The double bond configuration is E-type, as is known from 1H-1 H NOESY, 6.5925ppm and 7.1977ppm of H have no steric coupling.
EXAMPLE 2 Synthesis of Compounds 17-26
The synthesis of compounds 17-26 was performed using the following reaction steps:
h. Para-substituted phenylhydrazine hydrochloride (5 mmol) was dissolved in acetic acid (5 mL), ethyl acyl acetate (6 mmol) was added, heated to reflux overnight, cooled to room temperature, part of the solvent was removed under reduced pressure, filtered, washed with dichloromethane, and the solid obtained by filtration was purified by column chromatography (MeOH: dcm=1:20) to give a solid product.
I. Bromobenzene analog (1 mmol), 5-formyl-2-furanboronic acid (1.31 mmol) and (Ph 3P)2PdCl2 (35.1 mg,50 μmol) were dissolved in a mixed solvent of DME (3 mL), ethanol (2 mL), 2M Na 2CO3 (3 mL), heated at 50 ℃ for 1-4h, cooled to room temperature, extracted with ethyl acetate (10 ml×3) the combined organic layers were washed with saturated brine, dried over anhydrous NaSO 4, filtered, concentrated under reduced pressure, and purified by column chromatography (PE/ea=7:1) to afford a yellowish green flocculent solid.
J. The aldehyde product (0.3 mmol) obtained in step i is dissolved in absolute ethanol together with the pyrazolone product (0.3 mmol) obtained in step h, diethylamine (21.9 mg,0.3 mmol) is added and heated at 50℃for 2-6h. After cooling the product precipitated and was collected by filtration and purified by column chromatography (MeOH: dcm=1:17) to give a red solid.
4- (4, 5-Dihydro-3-methyl-4- ((5- (4, 5-dimethyl-2-nitrophenyl) furan-2-yl) methylene) -5-oxapyrazol-1-yl) benzoic acid (17)
Red solid ,1H NMR(400MHz,DMSO-d6):12.79(brs,1H),8.64(d,J＝4.0Hz,1H),8.03(d,J＝8.4Hz,2H),7.97(d,J＝8.8Hz,2H),7.81(s,1H),7.71(s,1H),7.51(s,1H),7.18(d,J＝4.0Hz,1H),2.30(s,3H),2.32(s,3H),2.33(s,3H);13C NMR(100MHz,DMSO-d6):172.73,167.73,160.67,157.38,156.50,150.99,148.49,147.53,146.32,136.39,136.33,136.25,135.26,132.47,132.03,131.05,127.48,125.18,122.86,122.69,119.98,25.08,24.91,18.71;HRMS(m/z):[M+H]+calcd for C24H20N3O6,446.1347,found,446.1342.
4- (4- ((5- (4, 5-Dimethyl-2- (trifluoromethyl) phenyl) furan-2-yl) methylene) -3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (18)
Red solid ,1H NMR(400MHz,DMSO-d6)δ12.83(brs,1H),8.73(d,J＝3.4Hz,1H),8.09(d,J＝8.3Hz,2H),8.02(d,J＝8.4Hz,2H),7.82(s,1H),7.72(s,1H),7.69(s,1H),7.22(d,J＝3.4Hz,1H),2.38(s,6H),2.36(s,3H).13C NMR(100MHz,DMSO-d6)δ166.68,161.83,156.49,151.56,150.20,141.79,141.52,139.35,131.50,130.31(2C),129.75,129.57(q,J＝238.5Hz),127.68,126.54,125.93,124.39,122.89,121.21,116.87(2C),114.59,28.85,18.99,12.72.HRMS(ESI):m/z Calcd for C25H19F3N2O4[M-H]-467.1224,found 467.1246.
4- (4- ((5- (2- (Dimethylphosphoryl) phenyl) furan-2-yl) methylene-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (19)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.65(brs,1H),8.72(d,J＝3.8Hz,1H),8.10(d,J＝8.4Hz,2H),8.02(d,J＝8.4Hz,2H),8.01–7.97(m,1H),7.90–7.85(m,1H),7.78–7.73(m,1H),7.71(s,1H),7.69–7.65(m,1H),7.54(d,J＝3.8Hz,1H),2.36(s,3H),1.70(d,J＝13.3Hz,6H).13C NMR(100MHz,DMSO-d6)δ166.69,161.83,158.86,151.53,150.14,141.53,133.92(d,J＝88.4Hz),132.03(d,J＝16.5Hz),131.55,131.38,130.85(d,J＝5.9Hz),130.32(2C),129.89,129.63(d,J＝10.1Hz),126.82,125.92,120.99,116.87(2C),116.64,115.74,17.74(d,J＝71.7Hz,2C),12.71.HRMS(ESI):m/z Calcd for C24H21N2O5P[M-H]-447.1115,found 447.1151.
4- (4- ((5- (2- (Difluoromethyl) phenyl) furan-2-yl) methylene-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (20)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.75(brs,1H),8.64(d,J＝3.1Hz,1H),8.10(d,J＝8.7Hz,2H),8.05–8.00(m,3H),7.84(d,J＝9.2Hz,2H),7.74–7.69(m,1H),7.71(t,J＝53,4Hz,1H),7.65(t,J＝7.5Hz,1H),7.39(t,J＝7.0Hz,1H),2.37(s,3H).13C NMR(100MHz,DMSO-d6)δ166.66,161.84,157.20,151.55,150.56,141.54,131.20,130.36(t,J＝25.4Hz),130.29(2C),130.05,129.87,128.72,126.95,126.74,125.95,121.12,119.59,116.88(2C),114.44,112.81(t,J＝234.2Hz),12.77.HRMS(ESI):m/z Calcd for C23H16F2N2O4[M-H]-421.1005,found 421.1011.
4- (4- ((5- (4, 5-Dimethyl-2-nitrophenyl) thiophen-2-yl) methylene-3-methyl-5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (21)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.78(s,1H),8.23(s,1H),8.16(d,J＝3.9Hz,1H),8.09(d,J＝8.7Hz,2H),8.02(d,J＝8.8Hz,2H),7.90(s,1H),7.55(s,1H),7.37(d,J＝3.8Hz,1H),2.39(s,3H),2.38(s,6H).13C NMR(100MHz,DMSO-d6)δ166.67,162.20,151.78,150.18,146.03,143.38,142.84,138.36,136.84,132.39,130.21(2C),129.09,128.40,125.93,125.08,124.03,120.76,119.61(2C),116.79,18.96,18.77,12.73.HRMS(ESI):m/zCalcd for C24H19N3O5S[M-H]-460.0973,found 460.0971
4- (3-Cyclopropyl-4- ((5- (4, 5-dimethyl-2-nitrophenyl) thiophen-2-yl) methylene) -3-ethyl-5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (22)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.82(brs,1H),8.69(d,J＝3.8Hz,1H),8.09(d,J＝8.8Hz,2H),8.01(d,J＝8.7,3H),7.85(s,1H),7.77(s,1H),7.61(s,1H),7.22(d,J＝3.9Hz,1H),2.76(q,J＝7.4Hz,2H),2.37(s,3H),2.36(s,3H),1.27(t,J＝7.4Hz,3H).13CNMR(100MHz,DMSO-d6)δ166.71,161.92,155.32,154.66,150.48,144.94,142.57,141.53,140.36,131.34,130.45,130.27,128.96,126.43,125.04,120.71,119.19,116.88,113.98,19.59,19.05,18.89,10.74.HRMS(ESI):m/z Calcd for C25H21N3O6[M-H]-458.1358,found 458.1375.
4- (3-Cyclopropyl-4- ((5- (4, 5-dimethyl-2-nitrophenyl) furan-2-yl) methylene) -5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (23)
Red solid ,1H NMR(400MHz,DMSO-d6)δ12.85(s,1H),8.73(d,J＝3.7Hz,1H),8.06(d,J＝8.8Hz,2H),8.00(d,J＝8.7Hz,2H),7.89(s,1H),7.85(s,1H),7.81(s,1H),7.28(d,J＝3.7Hz,1H),2.38(s,3H),2.37(s,3H),2.31–2.24(m,1H),1.01(d,J＝6.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ166.81,161.92,155.35,154.86,150.62,144.96,142.67,141.49,140.44,130.57,130.25(2C),129.03,126.49,125.09,121.56,119.24,116.90(2C),116.69,114.06,19.06,18.91,7.47,7.24,6.60.HRMS(ESI):m/z Calcd for C26H21N3O6[M-H]-470.1358,found470.1370.
4- (3-Cyclopropyl-4- ((5- (4, 5-dimethyl-2- (trifluoromethyl) phenyl) thiophen-2-yl) methylene) -5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (24)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.82(brs,1H),8.51(s,1H),8.24(d,J＝3.7Hz,1H),8.06(d,J＝8.8Hz,2H),8.00(d,J＝8.8Hz,2H),7.70(s,1H),7.48(s,1H),7.38(d,J＝3.5Hz,1H),2.38(s,3H),2.37(s,3H),1.08–1.02(m,4H),0.87–0.83(m,1H).13C NMR(100MHz,DMSO-d6)δ166.64,162.38,156.73,152.29,143.13,141.52,138.53,138.18,136.68,133.41,130.26(2C),129.02,128.77,127.34,127.32,126.91,124.41(q,J＝177.3Hz),120.71,116.79(2C),18.87,10.72(2C),7.55,6.74.HRMS(ESI):m/z Calcd for C27H21F3N2O3S[M+H]+511.1298,found 511.1289.
4- (3-Methyl-4- ((5- (3-nitrophenyl) thiophen-2-yl) methylene) -5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (25)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.76(brs,1H),8.61(s,1H),8.15(s,1H),8.07(d,J＝8.1Hz,2H),8.04–7.99(m,3H),7.69(s,1H),7.60(s,1H),7.56(s,1H),7.25(d,J＝2.6Hz,1H),2.33(s,3H).13C NMR(100MHz,DMSO-d6)δ166.90,164.48,161.63,153.43,151.37,149.70,144.53,141.38,131.40,129.75(q,J＝176.5Hz),128.02,127.95,126.92,126.46,126.33,121.57,121.48,121.44,120.80,116.80,116.58,114.87,12.66.HRMS(ESI):m/z Calcd for C22H15N3O5S[M+H]+434.0805,found 434.0806.
4- (3-Methyl-4- ((5- (4-nitrophenyl) thiophen-2-yl) methylene) -5-oxo-4, 5-dihydro-1H-pyrazol-1-yl) benzoic acid (26)
Red solid ,1H NMR(600MHz,DMSO-d6)δ12.91(brs,1H),8.34(d,J＝8.9Hz,2H),8.14(d,J＝8.9Hz,2H),8.11(d,J＝8.8Hz,2H),8.05–8.02(m,3H),7.75(d,J＝8.1Hz,1H),7.40(d,J＝8.2Hz,1H),2.38(s,3H).13C NMR(100MHz,DMSO-d6)δ166.64,162.38,156.73,152.29,143.13,141.52,138.53,138.18,136.68,133.41,130.26(2C),129.02,128.77,127.34,127.32,126.91,124.41(q,J＝177.3Hz),120.71,116.79(2C),18.87,10.72(2C),7.55,6.74.HRMS(ESI):m/z Calcd for C22H15N3O5S[M+H]+434.0805,found 434.0808.
Effect example 1 results of Compounds tested for inhibition of the Activity of ATG-ATG16L and ATG5-TECAIR
The Flag-ATG5 and His-ATG16 protein complex, and the Flag-ATG5 and His-TECAIR protein complex were obtained by expression and purification with the use of a co-expression vector pACYCDuet-1 (brand: novagen, cat. No. 71147-3) by Escherichia coli. Inhibitor activity test. The protein complexes were formulated to appropriate concentrations (final concentrations of ATG5-ATG16 and ATG5-TECAIR protein complexes in the system were 10nM and 40nM, respectively) to avoid the hook effect and with appropriate experimental signal to noise ratios, inhibitors were added at different concentrations (final concentrations of 0.14. Mu.M, 0.41. Mu.M, 1.2. Mu.M, 3.7. Mu.M, 11. Mu.M, 33. Mu.M, 100. Mu.M, respectively), followed by donor/acceptor addition, incubation at 25℃for 2h and detection of Em620, em665 on an enzyme-labeled instrument, by calculation to obtain HTRF ratio (Em 665/Em 620. Times.10000). Inhibition curves were fitted using the log (inhibitor) vs response-variable slope algorithm in GRAPHPAD PRISM with inhibitor concentration as x-axis and HTRF ratio as y-axis, and IC 50 values were obtained, which under the present experimental conditions were considered to be inhibitory with IC 50 values below 200 μm. The specific results are shown in Table 1.
TABLE 1
Remarks: in the table, "-means not tested.
Effect example 2 influence of partial Compounds on autophagy flow
The effect of compounds on autophagy was identified using flow cytometry-based autophagy detection methods. At present, this work has tested the autophagy inhibitory effect of the compound on COS-7 cells (purchase unit: china academy of sciences cell bank, catalogue number: SCSP-508) at a concentration of 20. Mu.M. The results are shown in Table 2 using 3-MA, NSC 66389 cell autophagy inhibitor (3-MA, NSC 66389: brand, gene Operation; product number: IPA1009-0010 MG) as positive control, wherein lower autophagy cell ratio indicates higher degree of autophagy inhibition, i.e. better autophagy inhibition effect of the compound on COS-7 cells.
TABLE 2
Effect example 3 inhibition of proliferation activity of partial Compounds on several tumor cell lines
Human breast cancer cells MCF-7 and human colon cancer cells HCT-116 to be detected were cultured in DMEM and DMEM/F12 medium containing 10% fetal bovine serum, respectively. Cells were seeded in 96-well plates at a cell concentration of 8000 MCF-7 and HCT-116 per 100. Mu.L, and zeroed with medium alone. The test compound having a mother liquor concentration of 20mM (final concentration of 20. Mu.M, three times in parallel) and the test compound having a concentration of Olaparib +20mM (final concentration of 20. Mu.M, three times in parallel) were added to the 96-well plate, respectively, and then incubated in a CO 2 incubator at 37℃for 48 hours. To each well, 10 μ LCCK-8 solution was added and incubated at 37℃for 2 hours, and the absorbance of each well was measured at a wavelength of 450nm using a microplate reader. Cell viability = (experimental group light absorption value-zeroing group light absorption value)/(control group light absorption value-zeroing group light absorption value) was calculated.
The reagents used were as follows: breast cancer cell MCF-7, procurement unit: cell bank of China academy of sciences, commodity catalog number: SCSP-531;
Colon cancer cell HCT-116, procurement unit: cell bank of China academy of sciences, commodity catalog number: TCHu99 to 99;
10% fetal bovine serum, brand: mesGen, product number: MFB1661;
DMEM, brand: mesGen, product number: MG4905-S;
DMEM/F12 broth, brand: mesGen, product number: MG8645-S;
olaparib, brand: topScience, product number: t3015;
CCK-8 kit, brand: mesGen, product number: MG6432.
The specific results are shown in the following table:
As can be seen from the results in the table, the inhibition activity of the compound on HCT-116 was superior to MCF-7 when administered alone. When used in combination with Olaparib, there was no significant effect on HCT-116, but the inhibitory effect of the compounds on MCF-7 cell lines could be improved.
Claims (22)
1. The application of an aromatic compound shown in a formula I or pharmaceutically acceptable salt thereof in preparing an inhibitor is characterized in that the inhibitor is an ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitor;
Wherein,
M is 0, 1,2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 0, 1,2, 3 or 4;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 groups are independently C 1～C6 alkyl groups.
2. The use according to claim 1, wherein,
The aromatic compound shown in the formula I isAnd/or
And/or, when R 1 is C 6～C10 aryl substituted with R 1-1, the C 6～C10 aryl is phenyl;
And/or, in R 2, the C 6～C10 aryl is phenyl;
And/or, when R 3 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or, when R 4 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the halogen is fluorine, chlorine, bromine or iodine;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the number of halogen is 1,2 or 3;
And/or, when R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-2, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-3, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-4, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-5, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, the aromatic compound shown in the formula I is not the following compound:
and/or, the ATG5-ATG16L and/or ATG5-TECAIR protein-protein interaction inhibitor is used in or outside a mammalian organism.
3. Use according to claim 2, characterized in that it fulfils one or more of the following conditions:
(1) When R 3 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(2) When R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl is cyclopropyl;
(3) When R 4 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(4) When R 4 is C 1～C6 alkyl substituted with halogen, the halogen is fluorine;
(5) When R 4 is C 1～C6 alkyl substituted with halogen, the C 1～C6 alkyl is methyl;
(6) When R 4 is C 1～C6 alkyl substituted by halogen, the number of the halogen is 1 or 3;
(7) When R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(8) In R 4-2, the C 1～C6 alkyl is methyl;
(9) In R 4-3, the C 1～C6 alkyl is methyl;
(10) In R 4-4, the C 1～C6 alkyl is methyl;
(11) In R 4-5, the C 1～C6 alkyl group is methyl.
4. The use according to claim 2, wherein,
R 1 is
And/or when R 4 isWhen said/>For/>
And/or when R 4 isWhen said/>For/>
5. The use according to claim 4, wherein,
R 1 is
6. The use according to claim 4, wherein,
For/>
7. The use according to claim 1, wherein the aromatic compound of formula I is any one of the following compounds:
8. an aromatic compound shown in a formula I or pharmaceutically acceptable salt thereof, which is characterized in that,
M is 0,1,2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 0,1,2,3 or 4; r 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 is independently C 1～C6 alkyl;
however, the aromatic compound shown in the formula I is not the following compound:
/>
9. the aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein each group in the aromatic compound of formula I is defined as in scheme 1:
scheme 1:
Wherein m is 0,1, 2 or 3; x is O or S; z is CH; y is CR 2 or N; n is 1,2, 3 or 4;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 groups are independently C 1～C6 alkyl groups.
10. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein each group in the aromatic compound of formula I is defined as in any one of schemes 2 to 6:
Scheme 2:
Wherein m is 0 or 1; x is O; y is CR 2; z is CH; n is 1,2, 3 or 4; r 1 is carboxy or C 6～C10 aryl substituted with R 1-1; r 2 is C 6～C10 aryl; r 3 is hydrogen; r 4 is nitro, The R 1-1 groups are independently carboxyl groups; the R 4-1 is C 1～C6 alkyl or/>The R 4-2 and R 4-3 are independently C 1～C6 alkyl;
Scheme 3:
wherein m is 1; z is CH; y is CR 2 or N; n is 0;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
r 3 is hydrogen, C 1～C6 alkyl or C 3～C6 cycloalkyl;
R 4 is C 1～C6 alkyl, C 1～C6 alkyl substituted by halogen, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 is C 1～C6 alkyl or
R 4-2 is C 1～C6 alkyl;
r 4-3 is C 1～C6 alkyl;
R 4-4 is C 1～C6 alkyl;
r 4-5 is C 1～C6 alkyl;
Scheme 4:
Wherein m is 1; y is N; z is CH; n is 0; r 1 is C 6～C10 aryl substituted with R 1-1; r 3 is C 1～C6 alkyl; r 4 is nitro; the R 1-1 groups are independently carboxyl groups;
scheme 5:
m is 0, 1,2 or 3; z is CH; y is CR 2 or N; n is 0;
R 1 is carboxy or C 6～C10 aryl substituted with R 1-1;
R 2 is C 6～C10 aryl;
R 3 is hydrogen or C 3～C6 cycloalkyl;
R 4 is independently C 1～C6 alkyl, nitro,
The R 1-1 groups are independently carboxyl groups;
The R 4-1 groups are independently C 1～C6 alkyl or
The R 4-2 is independently C 1～C6 alkyl;
The R 4-3 is independently C 1～C6 alkyl;
The R 4-4 is independently C 1～C6 alkyl;
The R 4-5 is independently C 1～C6 alkyl;
scheme 6:
Wherein m is 3, Y is N; z is CH; n is 0; r 1 is C 6～C10 aryl substituted with R 1-1; r 3 is C 3～C6 cycloalkyl; r 4 is independently C 1～C6 alkyl or nitro; the R 1-1 groups are independently carboxyl groups.
11. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claim 8 to 10,
The aromatic compound shown in the formula I isAnd/or
And/or, when R 1 is C 6～C10 aryl substituted with R 1-1, the C 6～C10 aryl is phenyl;
And/or, in R 2, the C 6～C10 aryl is phenyl;
And/or, when R 3 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or, when R 4 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the halogen is fluorine, chlorine, bromine or iodine;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, when R 4 is C 1～C6 alkyl substituted with halogen, the number of halogen is 1,2 or 3;
And/or, when R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-2, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-3, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-4, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
And/or, in R 4-5, the C 1～C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.
12. An aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, which satisfies one or more of the following conditions:
(1) When R 3 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(2) When R 3 is C 3～C6 cycloalkyl, the C 3～C6 cycloalkyl is cyclopropyl;
(3) When R 4 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(4) When R 4 is C 1～C6 alkyl substituted with halogen, the halogen is fluorine;
(5) When R 4 is C 1～C6 alkyl substituted with halogen, the C 1～C6 alkyl is methyl;
(6) When R 4 is C 1～C6 alkyl substituted by halogen, the number of the halogen is 1 or 3;
(7) When R 4-1 is C 1～C6 alkyl, the C 1～C6 alkyl is methyl;
(8) In R 4-2, the C 1～C6 alkyl is methyl;
(9) In R 4-3, the C 1～C6 alkyl is methyl;
(10) In R 4-4, the C 1～C6 alkyl is methyl;
(11) In R 4-5, the C 1～C6 alkyl group is methyl.
13. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11,
R 1 is
And/or when R 4 isWhen said/>For/>
And/or when R 4 isWhen said/>For/>
14. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13,
R 1 is
15. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13,
For/>
16. The aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 8 to 10, wherein the aromatic compound of formula I is any one of:
17. use of an aromatic compound of formula I as defined in any one of claims 8 to 16 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions.
18. The use of an aromatic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 17, wherein the disorder associated with ATG5-ATG16L and/or ATG5-TECAIR protein-protein interactions is colon cancer or breast cancer.
19. A pharmaceutical composition comprising an aromatic compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 8 to 16, and substance X, which is a pharmaceutical excipient and/or Olaparib.
20. A pharmaceutical composition comprising compound 1 and substance X, wherein the substance X is Olaparib,
/>
21. Use of an aromatic compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19 or 20 according to any one of claims 8-16 in the manufacture of a medicament for the treatment and/or prophylaxis of colon or breast cancer.
22. A method for preparing aromatic compound shown in formula I, which is any one of the following schemes,
Scheme 1: in a solvent, in the presence of alkali, carrying out hydrolysis reaction on the ester compound shown in the formula A to obtain the aromatic compound shown in the formula I,
Wherein R 5 isOr is/>Substituted C 6～C10 aryl, R 5-1 is C 1～C6 alkyl, m, X, Z, Y, n, R 1、R3 and R 4 are as defined in any one of claims 8 to 16;
Scheme 2: in a solvent, a compound shown as a formula B and a compound shown as a formula C react in the presence of alkali to obtain an aromatic compound shown as a formula I,
Wherein m, Z, Y, n, R 1、R3 and R 4 are as defined in any one of claims 8 to 16.
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| US20060070135A1 (en) * | 1998-07-24 | 2006-03-30 | Michel Tremblay | Compositions and methods for inhibiting the enzymatic activity of PTP-1B |
| US8476458B2 (en) * | 2007-06-21 | 2013-07-02 | The Wistar Institute | Methods and compositions for modulating P300/CBP activity |
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| CN110862383A (en) * | 2018-08-28 | 2020-03-06 | 复旦大学 | Histone acetyltransferase P300 small-molecule inhibitor, medicinal composition thereof and application thereof |
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