CN114874204A - PROTAC molecule of targeting SARS-CoV-23C protease and application thereof - Google Patents
PROTAC molecule of targeting SARS-CoV-23C protease and application thereof Download PDFInfo
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- CN114874204A CN114874204A CN202110159614.4A CN202110159614A CN114874204A CN 114874204 A CN114874204 A CN 114874204A CN 202110159614 A CN202110159614 A CN 202110159614A CN 114874204 A CN114874204 A CN 114874204A
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- 238000003756 stirring Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 208000009421 viral pneumonia Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention relates to a compound shown as a formula (I) or a pharmaceutically acceptable salt or a solvent compound thereof, wherein M is 1 Represents a 3-chymotrypsin-like protease inhibitor moiety; m 2 Represents the E3 ubiquitin ligase ligand moiety; l represents a group having- (CH) 2 CH 2 O) q (CH 2 ) e (NH) f (O) g (CH 2 ) h CO(CH 2 ) i (CO) j -structural linking groups. The invention also relates to a preparation method of the compound and application of the compound in preparing 3-chymotrypsin-like protease inhibitorAnd the application of the anti-coronavirus medicine.
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to a PROTAC (protein degradation targeting chimeras) compound targeting a novel coronavirus (SARS-CoV-2) 3C protease, or a pharmaceutically acceptable salt or solvate thereof, a preparation method of the compound, and application of the compound in preparing a 3-chymotrypsin-like protease inhibitor, particularly an anti-coronavirus medicine.
Background
The pathogenic virus SARS-CoV-2 mainly attacks the lower respiratory tract system of human body and causes viral pneumonia; the medicine also can affect the gastrointestinal tract system, the heart, the kidney, the liver and the central nervous system, seriously threatens the life health and safety of human beings and brings great negative effects to the whole society. As soon as the application is filed, the global cases and the number of deaths are still in a sharp rising situation.
From the characteristics of the outbreak of SARS-CoV-2 in all regions of the world, the virus has long latent period, high concealment (no symptom infection, latent period infection, light initial symptoms and similar cold), strong infectivity (various infection routes), and brings great difficulty to prevention and treatment. Based on the characteristics of the virus, we need to make preparations for long-term co-existence with SARS-CoV-2, which after widespread, may become endemic in the population. Therefore, the research and development of specific drugs aiming at SARS-CoV-2 will be an important direction for preventing and treating novel coronavirus for a period of time in the future.
The 3-chymotrypsin-like protease (3C protease), also called main protease, is a key enzyme in the life cycle of viruses, and firstly releases the protease per se by self-cleavage of polyprotein, and then cuts at more than 11 sites on a peptide fragment to generate various proteins related to replication and transcription. The 3C protease plays an important role in regulating the life cycle of the virus and expressing genes, and has no obvious homology with the protein of the human body, so the 3C protease is an important target for developing the anti-coronary virus medicine.
GC376(CAS 1416992-39-6) is a covalent inhibitor of SARS-CoV-23C protease and inhibits the replication of novel coronaviruses in vitro. However, GC376 has difficulty completely blocking viral replication and cannot completely inhibit the viral infection process. Moreover, the existing structural modification modes for GC376 generally cannot provide GC376 with the capability of completely blocking virus replication, but on the contrary, these modification modes may also result in that GC376 cannot enter the active protein binding domain of 3C protease, cannot interact with the active protein binding domain thereof, and/or change the action mechanism of GC376 and 3C protease, thereby resulting in the loss of the binding capability of GC376 and 3C protease, failing to achieve effective inhibition of 3C protease, and further being difficult to achieve the purpose of completely blocking virus replication.
Therefore, there is a need in the art for a compound based on GC376, which not only can achieve 3C protease inhibitory activity equivalent to or stronger than that of GC376, but also can completely block replication of viruses, particularly novel coronaviruses, and inhibit the infection process thereof.
Disclosure of Invention
In order to solve the technical problems, the invention combines computational chemistry, fully studies the action modes of GC376 and SARS-CoV-23C protease, and connects specific sites of GC376 and series derivatives thereof with ligands of E3 ubiquitin ligase through specific connecting arms with different properties to form PROTAC (protein degradation targeting chimeras) molecules shown in formula (I). According to the invention, through the use of a specific connecting arm and the modification of a specific group at a specific site of GC376, the binding capacity of GC376 and 3C protease is retained, the obtained compound with a ternary structure can be simultaneously bound with 3C protease and E3 ubiquitin ligase, and ubiquitin molecules are recruited to the surface of 3C protease through E3 ligase to cause the ubiquitination degradation of 3C protein, so that the compound is completely different from GC376 in action mechanismThe purpose of blocking the replication of the virus and inhibiting the infection process of the virus is realized. The cell experiment result shows that the compound can effectively inhibit the activity of the novel coronavirus, and part of the compound can even realize stronger in-vitro inhibition activity of the novel coronavirus than GC376, namely EC 50 The minimum can be 0.08 mu M. Because the action mechanism of the compound is completely different from that of GC376, the compound provides a brand new effective way for blocking the replication and infection of variant viruses, particularly variant novel coronavirus strains.
Specifically, the invention is realized by the following aspects:
in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein M is 1 Represents a 3-chymotrypsin-like protease inhibitor moiety;
M 2 represents the E3 ubiquitin ligase ligand moiety;
l has a structure represented by the following formula L:
-(CH 2 CH 2 O) q (CH 2 ) e (NH) f (O) g (CH 2 ) h CO(CH 2 ) i (CO) j -formula L
Wherein p is an integer of 0 to 5; q is an integer of 0 to 5; e is an integer of 0 to 6; f is an integer of 0 to 3; g is an integer of 0 to 3; h is an integer of 0 to 3; i is an integer of 0 to 5; j is an integer of 0 to 3.
A second aspect of the present invention provides a pharmaceutical composition comprising: a compound according to the first aspect of the invention or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.
A third aspect of the present invention provides a process for the preparation of a compound of formula (I) as defined above, which process comprises the steps of: (1) introducing a terminal alkynyl group on a 3-chymotrypsin-like protease inhibitor; (2) introducing an azide group on an E3 ubiquitin ligase ligand; and (3) click chemistry reacting the terminal alkynyl group with an azide group to covalently link the 3-chymotrypsin-like protease inhibitor to the E3 ubiquitin ligase ligand.
In a fourth aspect the present invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a 3-chymotrypsin-like protease inhibitor, particularly an anti-coronavirus medicament.
Detailed Description
It will be understood by those skilled in the art that the following embodiments are given by way of example only and are not intended to limit the scope of the present application in any way.
As used herein, unless otherwise indicated, the term "3-chymotrypsin-like protease inhibitor" refers to a compound having 3-chymotrypsin-like protease inhibitory activity. As a non-limiting example, compound GC376 and its derivatives were used as 3-chymotrypsin-like protease inhibitors. As used herein, unless otherwise indicated, the term "3-chymotrypsin-like protease inhibitor moiety (M) 1 ) "refers to a structural module obtained by substituting one or more hydrogen atoms on a 3-chymotrypsin-like protease inhibitor by a single bond, which is covalently linked to other structural modules by the single bond.
As used herein, unless otherwise indicated, the term "E3 ubiquitin ligase ligand" or "ligand of E3 ubiquitin ligase" refers to a compound capable of binding to E3 ubiquitin ligase. Without wishing to be bound by theory, E3 ubiquitin ligase ligands in the art can all be used in the present invention. As a non-limiting example, the E3 ubiquitin ligase ligand can be a VHL ligand or a CRBN ligand. As used herein, unless otherwise indicated, the term "E3 ubiquitin ligase ligand moiety (M) 2 ) "refers to a structural module obtained by substituting one or more hydrogen atoms on the E3 ubiquitin ligase ligand by a single bond, which is covalently linked to other structural modules by the single bond.
Herein, the term "C m-n "means that the moiety modified by the term has m to n carbon atoms (n is greater than m and both are integers). E.g. C 1-6 The moiety representing the modification thereof has 1 to 6 carbon atoms, for example, 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
As used herein, unless otherwise indicated, the term "cyclic group" includes aliphatic and aromatic cyclic groups, and refers to saturated or unsaturated ring systems composed of carbon atoms. The term "heterocyclyl" includes both aliphatic and aromatic heterocycles, and refers to a saturated or unsaturated ring system composed of carbon atoms and 1-3 heteroatoms independently selected from N, O or S, and which may be substituted or unsubstituted. As non-limiting examples of cyclic and heterocyclic groups, furyl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl may be cited, but are not limited thereto.
As used herein, the term "triazole moiety" refers to a1, 2, 3-triazole moiety. Those skilled in the art will appreciate that such triazole moieties are the product of an alkyne/azide cycloaddition reaction carried out under "click" chemistry conditions. The proteolytic targeting chimeric compounds of the invention having one or more triazole moieties in their linkage structure can be prepared by using click chemistry reactions. The term 'click chemistry' was created in 2001 by professor k. barry charples (k.barry sharp) to describe a series of chemical reactions defined by: its modular nature, high yield, stability of in vivo products, stereospecificity, high atom economy and high thermodynamic driving force. There are many 'click' reactions, several of which involve cycloaddition reactions between appropriate functional groups to produce stable cyclic structures.
As used herein, unless otherwise indicated, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. For example, the term "pharmaceutically acceptable salt" as used herein refers to an acid addition salt or a base addition salt of a compound of formula (I) with a pharmaceutically acceptable free acid or free base. The acid addition salts are obtained from the following acids: such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, tartaric acid, fumaric acid, malic acid, oxalic acid, succinic acid, and the like. The base addition salt includes sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, etc.
The solid and dashed bonds of the wedge shape are used herein, unless otherwise indicated (
And
) Representing an absolute configuration of a stereocenter.
Unless otherwise indicated, the stereoisomers mentioned herein include geometric isomers and enantiomers, all of which are within the scope of the present application.
Unless otherwise indicated, other terms used herein have the meanings commonly understood by those skilled in the art.
Embodiments of the aspects described herein may be illustrated by the following numbered paragraphs:
1. a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein:
M 1 represents a 3-chymotrypsin-like protease inhibitor moiety;
M 2 denotes E3 ubiquitinAn enzyme-linked ligand moiety;
l has a structure represented by the following formula L:
-(CH 2 CH 2 O) q (CH 2 ) e (NH) f (O) g (CH 2 ) h CO(CH 2 ) i (CO) j -formula L
Wherein p is an integer of 0 to 5; q is an integer of 0 to 5; e is an integer of 0 to 6; f is an integer of 0 to 3; g is an integer of 0 to 3; h is an integer of 0 to 3; i is an integer of 0 to 5; j is an integer of 0 to 3.
The inventors have combined the discovery of computational chemistry by making M 1 And M 2 Covalently linked via a linker arm of the specific length and structure described above, enables M to be attached 1 Smoothly enter into the active protein binding domain of the 3-chymotrypsin-like protease, thereby ensuring M 1 And M 2 Binding ability to 3-chymotrypsin-like protease and E3 ubiquitin ligase, respectively.
2. The compound of paragraph 1 or a pharmaceutically acceptable salt or solvate thereof, wherein the 3-chymotrypsin-like protease inhibitor moiety M 1 Having the formula (M) 1a ) The structure shown is as follows:
wherein R is 1 And R 2 Independently selected from the group consisting of H, halogen, hydroxyl, carbonyl, sulfonic acid, and carboxyl;
R 3 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl and C 2-6 Alkynyl;
D 1 and D 2 Independently selected from the group consisting of a single bond, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -O (CH) 2 ) n-, 3-8 membered cyclic or heterocyclic group, n is an integer selected from 1 to 5.
3. The compound of paragraph 2 or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 And R 2 Independently selected from the group consisting of H, hydroxyl, carbonyl, and sulfonic acid;
R 3 selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, pentyl and hexyl;
D 1 and D 2 Independently selected from the group consisting of a single bond, O (CH) 2 ) n, 3-8 membered cyclic or heterocyclic group, n is 1 or 2.
4. A compound according to paragraph 2 or 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 And R 2 Together with the carbon on which it is present, form any of the following structures: HOCH 2 -、HCO-、 HO(NaO 3 S)CH-、HO(HO 3 S)CH-。
In this regard, the corresponding structure on the GC376 compound is HO (NaO) 3 S) CH-. The inventors have unexpectedly discovered, in connection with computational chemistry, that R is on the structure 1 And R 2 Modified to be independently selected from the group consisting of H, halogen, hydroxyl, carbonyl, sulfonic acid and carboxyl, in particular R 1 And R 2 Together with the carbon on which they are located, form any of the following structures: HOCH 2 -、HCO-、HO(NaO 3 S)CH-、HO(HO 3 S) CH-, can achieve 3C protease inhibitory activity similar to that of GC376, even stronger.
5. The compound of any one of paragraphs 2-4 or a pharmaceutically acceptable salt or solvate thereof, wherein D is 1 And D 2 Independently selected from the group consisting of a single bond, -O (CH) 2 ) -, furyl, thienyl, pyridyl, oxazolyl, isoxazolyl, pyrazolyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl.
6. The compound of any one of paragraphs 2-5 or a pharmaceutically acceptable salt or solvate thereof, wherein D is 1 And D 2 Independently selected from the group consisting of a single bond, -O (CH) 2 ) -, phenyl and cyclohexyl.
7. The method as recited in any one of paragraphs 2-6A compound or a pharmaceutically acceptable salt or solvate thereof, wherein-D 1 -D 2 -is selected from the group consisting of a single bond,
The group consisting of.
8. The compound of any one of paragraphs 2-7 or a pharmaceutically acceptable salt or solvate thereof, wherein-D 1 -D 2 -is selected from the group consisting of a single bond,
The group consisting of.
The inventors have found that 1 -D 2 Stronger 3C protease inhibitory activity can also be achieved when it is a single bond or when it contains a 3-8 membered cyclic group or heterocyclic group (particularly, phenyl group or cycloalkyl group). In particular, when the substituent on the 3-to 8-membered cyclic group or heterocyclic group is at the para position, a significantly stronger 3C protease inhibitory activity can be achieved.
9. The compound of any one of paragraphs 2-8 or a pharmaceutically acceptable salt or solvate thereof, wherein M is 1 Having the formula (M) 1b ) The structure shown is as follows:
wherein each group is as defined in the corresponding paragraph.
10. The compound of any of paragraphs 1-9 or a pharmaceutically acceptable salt or solvate thereof, wherein said 3-chymotrypsin-like protease is a 3-chymotrypsin-like protease of a novel coronavirus.
Without wishing to be bound by theory, the 3-chymotrypsin-like protease of the invention may be any viral 3-chymotrypsin-like protease. As a non-limiting example, the 3-chymotrypsin-like protease is a 3-chymotrypsin-like protease of a novel coronavirus.
11. The compound of any one of paragraphs 1-10 or a pharmaceutical thereofThe above acceptable salt or solvate, wherein, M 1 Any one of structures having the following formula:
12. the compound of paragraph 11 or a pharmaceutically acceptable salt or solvate thereof, wherein M is 1 Any one of structures having the following formula:
13. the compound of any one of paragraphs 1-12 or a pharmaceutically acceptable salt or solvate thereof, wherein the E3 ubiquitin ligase ligand is a VHL ligand or CRBN ligand having the structure:
14. the compound of paragraph 13 or a pharmaceutically acceptable salt or solvate thereof, wherein said E3 ubiquitin ligase ligand moiety M 2 Any one of structures having the following formula:
15. the compound of any one of paragraphs 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure shown below in formula (II):
wherein each group is as defined in the corresponding paragraph.
16. The compound of any one of paragraphs 1-15 or a pharmaceutically acceptable salt or solvate thereof, wherein p is an integer from 1-2; q is an integer of 0 to 3; e is an integer of 2 to 5; f is an integer of 0 to 1; g is an integer of 0 to 1; h is an integer of 0 to 1; i is an integer of 0 to 2; j is an integer of 0 to 1.
17. The compound of any one of paragraphs 1-16 or a pharmaceutically acceptable salt or solvate thereof, wherein the total number of carbon atoms in L is selected from an integer from 7 to 9.
The present inventors have found that controlling the total number of carbon atoms in L to be an integer of 7 to 9, making L have a specific length, helps to ensure M at the same time 1 And M 2 Binding ability to 3-chymotrypsin-like protease and E3 ubiquitin ligase, respectively.
18. The compound of any one of paragraphs 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein L has one of the structures shown below:
-(CH 2 CH 2 O) 3 (CH 2 ) 2 CO-formula L 1-1
-CH 2 CH 2 O(CH 2 ) 2 NHCO(CH 2 ) 2 CO-formula L 1-2
-(CH 2 ) 5 OCH 2 CO-formula L 1-3 。
19. A compound of any one of paragraphs 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure as shown in formula (III) or formula (IV):
wherein each group is as defined in the corresponding paragraph.
20. The compound of any one of paragraphs 1-19 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure as shown in formula (V) or formula (VI):
wherein each group is as defined in the corresponding paragraph.
21. The compound of any one of paragraphs 1-20 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of the compounds represented by the following structures:
22. a pharmaceutical composition comprising: a compound of any one of paragraphs 1-21, or a pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier.
23. A method of making a compound of any one of paragraphs 1-21, comprising the steps of:
(1) introducing a terminal alkynyl group on a 3-chymotrypsin-like protease inhibitor;
(2) introducing an azide group on an E3 ubiquitin ligase ligand; and
(3) and (3) carrying out click chemistry reaction on the terminal alkynyl group and the azide group, so that the 3-chymotrypsin-like protease inhibitor is connected with the E3 ubiquitin ligase ligand through a covalent bond.
24. Use of a compound of any one of paragraphs 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of paragraph 22, for the preparation of a 3-chymotrypsin-like protease inhibitor.
25. Use of a compound of any one of paragraphs 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of paragraph 22 for the manufacture of an anti-coronavirus medicament.
Unless otherwise indicated, the terms "patient," "subject," and "individual" are used interchangeably herein and refer to a human or non-human animal (e.g., a primate, rodent, etc.).
Unless otherwise indicated, in the present context, the values of parameters representing the amounts or physicochemical properties of the ingredients or the reaction conditions, etc., are to be understood as being modified in all cases by the term "about". When the invention is described by the term "about", the term "about" denotes an error value that is present, e.g. denotes a variation within a range of ± 10%, e.g. ± 1% of a particular value.
In this document, unless otherwise indicated, singular terms encompass plural terms, and plural terms encompass singular terms.
As used herein, unless otherwise specified the terms "comprises, comprising, and containing" or equivalent means that elements, components, and steps other than those listed are included in the open ended representation.
Examples
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples. The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, devices and the like used in the following examples are commercially available or can be prepared by those skilled in the art according to the ordinary skill in the art, unless otherwise specified.
Example 1: preparation of Compounds A, B and C
Compounds a1, B1 and C1 were synthesized by the following scheme 1, compound 4 from shanghai shao far reagent ltd and compound 1 and 4-O-propynylbenzyl alcohol from alatin reagent ltd.
Preparation examples 1 to 1: synthesis of Compounds A1, B1 and C1
Step 1 synthesis of intermediate 2: compound 1(1.3 g, 7.60mmol) and 4-O-propynylbenzyl alcohol (0.9 g, 5.55mmol) were dissolved in dry acetonitrile (30mL), triethylamine 1.5mL was added, reaction was carried out at room temperature, after 2 hours, the solution was concentrated, silica gel column separated, mobile phase: petroleum ether/ethyl acetate 4/1 gave 1.75 g of a white solid in 95% yield.
Step 2 synthesis of intermediate 3: compound 2(2.47 g, 7.73mmol) was dissolved in 30mL tetrahydrofuran, 15mL of 1M aqueous LiOH was added, the mixture was stirred at room temperature, after 2 hours, the system was neutralized with acidic resin to neutrality, the resin was filtered off, and the mixture was concentrated to give a white solid which was used in the next reaction.
Step 3 synthesis of intermediate 5: after compound 3(2.1g, 6.6mmol) and compound 4(1.23g, 6.6mmol) were dissolved in 30mL dry DMF under nitrogen protection and HATU (5.0g, 13.2mmol) and DIPEA (1.7g, 13.2mmol) were added and reacted at room temperature for 4 hours, DMF was concentrated off and isolated on a silica gel column, mobile phase: petroleum ether/ethyl acetate 1/5 gave 2.63g of product as a white solid in 82% yield.
Step 4 synthesis of compound a 1: compound 5(1.5g, 3.1mmol) was dissolved in 20mL of dry THF under nitrogen protection, and LiBH was added dropwise 4 Then, 15mL of absolute ethanol was added to the solution of THF (2M, 4.8mL), and the reaction was allowed to proceed at room temperature overnight. After the reaction is completed, the pH value of the reaction system is adjusted to 2.0 by using 1M hydrochloric acid, ethyl acetate and saturated NaCl solution are used for extraction, an organic phase is dried by using anhydrous sodium sulfate, and the organic phase is filtered, concentrated and separated by using a silica gel column. Mobile phase: ethyl acetate/methanol 20/1 gave 882mg of product as a white solid in 62% yield.
Step 5 synthesis of compound B1: compound A1(400mg, 0.90mmol) was dissolved in dry dichloromethane (5mL) under nitrogen, Dess-Martin Periodinane (DMP) (570mg, 1.35mmol) was added under ice water bath, reacted at room temperature, concentrated after 2 hours, and isolated on silica gel column. Mobile phase: ethyl acetate/methanol 20/1 gave 288mg of product as a white solid in 70% yield.
Step 6 synthesis of compound C1: compound B1(90mg, 0.197mmol) was dissolved in ethyl acetate (4mL) and absolute ethanol (2.4mL), and sodium bisulfite (20mg, at 185. mu. L H) was added 2 O), at 50 ℃, after 3 hours, the reaction solution was cooled to room temperature, filtered, and the solid was washed with anhydrous ethanol and dried to obtain a solid, compound C1, 88mg in total, with a yield of 80%.
Preparation examples 1 to 2: synthesis of Compounds A2, B2 and C2
According to scheme 1, except that 4-O-propynylbenzyl alcohol is replaced by
(this compound was purchased from Jiangsuiekang biomedical research & development Co., Ltd.) except for the above, the same procedure as the synthesis of the compounds A1, B1 and C1 was used to obtain the compounds A2, B2 and C2 as white solids in yields of 47%, 34% and 29%, respectively.
Preparation examples 1 to 3: synthesis of Compounds A3, B3 and C3
According to the scheme 1, the same procedures as those for the synthesis of the compounds A1, B1 and C1 were carried out except that 4-O-propynylbenzyl alcohol was replaced with propynol (this compound is available from Aladdin reagent Co., Ltd.) to obtain the compounds A3, B3 and C3 as white solids in yields of 50%, 40% and 32%, respectively. The structures of compounds a2, B2 and C2 and A3, B3 and C3 are shown below:
example 2: attachment of linker arm to E3 ligase ligand (Compound V)
Compounds V-C7-N3, V-C8-N3 and V-C9-N3 and compounds R-C7-N3, R-C8-N3 and R-C9-N3 were synthesized by route 2 above. Wherein the compounds V and R are purchased from Beijing Bailingwei science and technology Limited company, the connecting arms 1,2 and 3 are purchased from Kanglong chemical-Innovation (Beijing) New drug technology corporation, and the connecting arms 4, 5 and 6 are respectively prepared by the connecting arms 1,2 and 3 according to the method of literature (Synthesis, 2007, 19, 3051-3055).
Preparation example 2-1: synthesis of Compounds V-C7-N3, V-C8-N3 and V-C9-N3
Compound V (210mg,0.49mmol) and linker arm 1(120mg,0.64mmol) were dissolved in dry DMF (5mL), HATU (370mg,0.97mmol) was added, stirring at room temperature for 40 min, DIPEA (253mg, 1.96mmol) was added, after 2 h reaction at room temperature the starting material was reacted completely, concentrated, passed through a silica gel column, mobile phase: ethyl acetate/methanol 15/1 gave 235mg of a white solid in 80% yield.
As shown in scheme 2, the same procedures as those for the synthesis of the compound V-C7-N3 were carried out to obtain the compound V-C8-N3 as a white solid and the compound V-C9-N3 as a white solid in yields of 85% and 82%, respectively.
Preparation examples 2 to 2: synthesis of Compounds R-C7-N3, R-C8-N3 and R-C9-N3
Compound R (250mg,0.92mmol) and linker arm 4(282mg,1.37mmol) were dissolved in dry tetrahydrofuran (5mL), the solution refluxed for four hours, then concentrated, silica gel column separated, mobile phase: ethyl acetate/methanol 15/1 gave 317mg of a white solid in 78% yield.
As shown in scheme 2, the same procedures as for the synthesis of the compound R-C7-N3 were employed to obtain the compound R-C8-N3 as a white solid and the compound R-C9-N3 as a white solid in yields of 81% and 80%, respectively.
Example 3: the modules A/B/C are respectively connected with ligands of E3 ligase through different connecting groups
Preparation example 3-1: synthesis of Compound A1-C9-V
Compound A1(15mg, 0.03mmol) and V-C9-N3(21mg, 0.03mmol) were dissolved in a mixed solvent of methanol (2mL) and dichloromethane (2mL), cuprous chloride (1mg) was added, and the reaction was carried out at room temperature for 3 hours, concentration, HPLC separation, separation conditions: angilent C18 column (4 μm, 9.4X 250mm), 10 → 70% MeCN, 20min, 2.5mL/min, UV monitoring at 256 nm. 26mg of a white foamy solid was obtained in a yield of 80%.
Preparation 3-2 Synthesis of other target Compounds: the other target compounds shown in Table 1 were obtained from the corresponding starting materials, respectively, by the same procedures as those for the synthesis of the compounds A1-C9-V, as shown in scheme 3.
Example 4: application of compound of the invention in anti-SARS-CoV-2
Vero cells from African green monkey kidney were cultured in DMEM (Gibco, USA) medium containing 10% fetal bovine serum (FBS, Gibco, USA), penicillin at 100U/ml and streptomycin at 0.1 mg/ml.
All infection experiments were performed in the biosafety tertiary (BLS-3) laboratory. 20mM drug was diluted from 2. mu.M to 0.03125. mu.M in a DMEM (1% double antibody) gradient, two-fold. GC376 was used as a positive control and 0.1% DMSO was used as a blank control. Diluted drug was added to 96-well plates at 60 μ L per well. In a 96-well plate to which 60. mu.L of the drug had been added, 60. mu.L of 200TCID 50/100. mu.L of a novel coronavirus (Nature communications, 2020, 11(1), 1-8) was added at a final virus concentration of 100TCID 50/100. mu.L. Incubating at 37 deg.C for 1 hr, washing the plate, adding 100 μ L of incubated virus-drug mixture into each well, setting virus control (only virus and no drug), blank control (no drug and no virus), positive control (GC376), observing cytopathic condition for 72 hr, calculating inhibition rate according to cytopathic condition, and automatically calculating EC by Graphpad 50 . The results are shown in table 2 below:
TABLE 2 inhibitory Activity of the Compounds on novel coronaviruses
| Compound (I) | EC 50 (μM) | Compound (I) | EC 50 (μM) |
| A1-C9-V | 0.75 | A1-C8-V | 0.75 |
| B1-C9-V | 0.08 | B1-C8-V | 0.12 |
| C1-C9-V | 0.21 | C1-C8-V | 0.34 |
| A2-C9-V | 1.21 | A2-C8-V | 1.45 |
| B2-C9-V | 0.35 | B2-C8-V | 1.01 |
| C2-C9-V | 0.42 | C2-C8-V | 1.10 |
| A3-C9-V | 1.21 | A3-C8-V | 12.68 |
| B3-C9-V | 0.95 | B3-C8-V | 10.15 |
| C3-C9-V | 1.01 | C3-C8-V | 10.12 |
| A1-C7-V | 0.81 | A1-C7-R | 0.25 |
| B2-C8-R | 0.62 | C3-C9-R | 2.15 |
| GC376 | 0.61 |
As shown in the results of table 2, the compounds of the present invention can achieve a novel coronavirus 3C protease inhibitory activity equivalent to or stronger than that of GC376, and can effectively block the replication and infection processes of the novel coronavirus through a completely different mechanism of action from that of GC 376.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
Claims (3)
1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein:
M 1 represents a 3-chymotrypsin-like protease inhibitor moiety;
M 2 represents the E3 ubiquitin ligase ligand moiety;
l has a structure represented by the following formula L:
-(CH 2 CH 2 O) q (CH 2 ) e (NH) f (O) g (CH 2 ) h CO(CH 2 ) i (CO) j -formula L
Wherein p is an integer of 0 to 5; q is an integer of 0 to 5; e is an integer of 0 to 6; f is an integer of 0 to 3; g is an integer of 0 to 3; h is an integer of 0 to 3; i is an integer of 0 to 5; j is an integer of 0 to 3.
2. A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein the 3-chymotrypsin-like protease inhibitor moiety M 1 Having the formula (M) 1a ) The structure shown is as follows:
wherein R is 1 And R 2 Independently selected from the group consisting of H, halogen, hydroxyl, carbonyl, sulfonic acid, and carboxyl;
R 3 is selected from C 1-6 Alkyl radical, C 2-6 Alkenyl and C 2-6 Alkynyl;
D 1 and D 2 Independently selected from the group consisting of a single bond, C 1-6 Alkyl radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, -O (CH) 2 ) n-, 3-8 membered cyclic or heterocyclic group, n is an integer selected from 1 to 5.
3. A compound according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 And R 2 Independently selected from the group consisting of H, hydroxyl, carbonyl, and sulfonic acid; r 3 Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, pentyl and hexyl; d 1 And D 2 Independently selected from the group consisting of a single bond, O (CH) 2 )、O(CH 2 ) 2 3-8 membered cyclic or heterocyclic group.
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