CN115894504A - Coronavirus 3CL protease inhibitor and application thereof - Google Patents
Coronavirus 3CL protease inhibitor and application thereof Download PDFInfo
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- CN115894504A CN115894504A CN202211403173.9A CN202211403173A CN115894504A CN 115894504 A CN115894504 A CN 115894504A CN 202211403173 A CN202211403173 A CN 202211403173A CN 115894504 A CN115894504 A CN 115894504A
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical field of chemical medicines, and relates to a coronavirus 3CL protease inhibitor and application thereof.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and relates to a coronavirus 3CL protease inhibitor and application thereof.
Background
Coronaviruses (CoV) are a family of enveloped positive-stranded RNA-pathogenic viruses that cause acute and chronic diseases including central nervous system disease, common cold, lower respiratory tract infections, and diarrhea. Upon entry into the host cell, the coronavirus is broken down to release the nucleocapsid and viral genome. The host cell ribosome translates the Open Reading Frames (ORFs) 1a and 1b of the viral genome into polyproteins pp1a and pp1b, respectively, for encoding 16 non-structural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. 3C-like cysteine protease (3 CLpro) and papain (PLpro) catalyze the cleavage of PP to nsp2-16, which in turn forms the replication-transcription complex (RTC). The loss of activity of these proteases leads to the cessation of the viral life cycle.
The 3C-like protease (3 CLpro), also called main protease (Mpro), is entirely composed of 306 amino acids, and can further cleave new corona polyprotein, thereby generating helicase, RNA-dependent RNA polymerase and other related replication elements, which play an important role in virus proliferation and assembly. The native 3CLpro monomer consists of three domains, and the two monomers interact to form a pocket structure containing the substrate binding site. The active center is located in the gap between domains I and II, and the catalytic sites are Cys at position 145 and His at position 41. Paxlovid acts on the target of 3C-like protease (3 CLpro), and inhibits the replication of the virus by inhibiting the 3CLpro of the virus, inhibiting the RNA replication and the generation of related non-structural proteins.
Currently, the target of action of PF-07321332 in pfizer is 3C-like protease (3 CLpro), which inhibits replication of virus by inhibiting 3CLpro, RNA replication and generation of related non-structural proteins. PF-07321332 has received FDA emergency drug marketing approval for the treatment of new coronavirus infections. However, when PF-07321332 is used for treating new coronary pneumonia, other prescription drugs, such as antilipemic statins, anticoagulants and antidepressants, increase the toxic and side effects of these drugs, and even may cause death and other serious adverse reactions. Although some compounds have been reported to inhibit 3CLpro activity in studies, they have not been approved as coronavirus therapies.
In view of the above, there is an urgent need in the art for safer, more effective, and more convenient anti-neocoronal drugs.
Disclosure of Invention
In view of the problems with the prior art, the present application provides a coronavirus 3CL protease inhibitor and methods of using the same for treating a variety of specific diseases or conditions.
In a first aspect, the present application provides a compound represented by the general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof:
in a second aspect, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a third aspect, the present invention also provides a use of a therapeutically effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, wherein the disease is a 3C-like protease inhibitor related disease, in particular, the condition is selected from a disorder such as new crown pneumonia.
Specifically, the invention is realized by the following technical scheme:
a compound represented by the general formula (I), or an isomer, racemate or pharmaceutically acceptable salt thereof, comprising:
wherein R is 1 Selected from hydrogen, halogen, alkoxy, n =1, 2, 3 or 4; r 2 、R 3 Independently selected from hydrogen, alkyl, and R 2 、R 3 Not hydrogen at the same time.
In a preferred embodiment of the present invention, the alkyl group is selected from C 1-6 Said alkoxy group being selected from C 1-6 Alkoxy group of (2).
In a preferred embodiment of the present invention, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1, 2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1, 2-dimethylbutyl, and 1-ethylbutyl.
In a preferred embodiment of the present invention, the alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1, 2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1, 2-dimethylbutoxy, and 1-ethylbutoxy.
In a preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.
As a preferable technical means of the present invention, the above
Is selected from->
Wherein +>
Representing a connecting bond.
As a preferred embodiment of the present invention, R 2 、R 3 Independently selected from hydrogen, methyl or ethyl, and R 2 、R 3 Not hydrogen at the same time.
In a preferred embodiment of the present invention, the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
in a preferred embodiment of the present invention, the pharmaceutically acceptable salt is prepared by mixing the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base.
In a preferred embodiment of the present invention, at least one hydrogen atom of the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof is substituted with deuterium as an isotope.
The invention further provides a pharmaceutical composition, which is characterized by comprising a therapeutically effective amount of the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The invention further provides a medical application of the compound, or an isomer, a racemate or a pharmaceutically acceptable salt thereof, in particular an application in preparing a medicament for treating diseases, wherein the diseases are related to 3C-like protease inhibitors, and are particularly selected from diseases such as neocoronary pneumonia.
For clarity, general terms used in the description of the compounds are defined herein.
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to refer 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.
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent found in the present invention and a pharmaceutically acceptable acid or base.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, atropisomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers, as well as D and L isomers, atropisomers, and the like, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The atoms of the molecules of the compound are isotopes, and the compound can generally prolong the half-life period, reduce the clearance rate, stabilize the metabolism, improve the in vivo activity and the like through isotopic derivatization. Also, an embodiment is included wherein at least one atom is replaced with an atom having the same number of atoms (proton number) and different number of masses (sum of protons and neutrons). Examples of isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which each include 2 H、 3 H、 13 C、 14 C、 15 N、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 And (4) Cl. In particular, radioisotopes which emit radiation as they decay, e.g. 3 H or 14 C can be used for topographic examination of pharmaceutical formulations or in vivo compounds. The stable isotope is neither attenuated or changed with its amount, nor is it radioactive, so it can be safely used. When the atoms constituting the molecule of the compound of the present invention are isotopes, isotopes can be converted according to the general methods by substituting reagents used in the synthesis with reagents containing the corresponding isotopes.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with a radioisotope, such as deuterium (I), (II), (III), (IV) and (IV) 2 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
Further, the compounds of the present invention are isotopically deuterated (C) on one or more hydrogen atoms 2 H) After substitution, the compound of the invention has the effects of prolonging half-life period, reducing clearance rate, stabilizing metabolism, improving in vivo activity and the like after deuteration.
The preparation method of the isotope derivative generally comprises: phase transfer catalysis processes. For example, a preferred deuteration method employs a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu) 4 HSO 4 ). The exchange of methylene protons of diphenylmethane compounds using a phase transfer catalyst results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated silanes) in the presence of an acid (e.g., methanesulfonic acid) or with lewis acids such as aluminum trichloride using sodium deuterated borate.
The term "pharmaceutically acceptable carrier" refers to any formulation vehicle or medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on the carrier, reference may be made to Remington: the Science and Practice of pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is not toxic but yet achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
The beneficial effects of the invention include:
(1) IC of the Compounds of the invention relative to Prior Art control Compounds 50 The activity is obviously improved, and a better virus inhibition effect is expected;
(2) The PK of the compounds of the invention is significantly improved over the prior art control compounds, and it is expected that once-a-day dosing can be achieved without the use of ritonavir.
Detailed Description
The present application will be described in further detail with reference to examples, but the embodiments of the present application are not limited thereto.
Example 1
Synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3-4-methoxyindole-2-carbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl-2-oxospiro-3, 3-pyrrolidine-5-carbonitrile
Step A: synthesis of tert-butyl (1R, 2S, 5S) -2- (3R, 5) -5' -carbamoyl-2-oxospiro-indoline-3, 3' -pyrrolidine-1 ' -carbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-3-carboxylate
1R,2S, 5S-3-tert-butoxycarbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (954 mg, 3.74 mmol) was dissolved in dichloromethane/N, N-dimethylformamide 4:1 (20 ml) at room temperature, HATU (1.56 g, 4.11 mmol), morpholine (1.33 g, 13.1 mmol), followed by 2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide (1.00 g, 3.74 mmol) were added at zero temperature and stirred at room temperature for 6 hours.
After the reaction was completed, water (50 ml) was added for quenching, dichloromethane extraction (100 ml × 3) was performed, organic phases were combined, washed with water (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was passed through a reverse column (acetonitrile: water 5:95 to 40). LC-MS: [ M + H ] + =467.
And B, step B: synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro-indoline-3, 3 '-pyrrolidine-5' -carboxamide
Tert-butyl (1R, 2S, 5S) -2- (3R, 5) -5' -carbamoyl-2-oxospiro-indoline-3, 3' -pyrrolidine-1 ' -carbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-3-carboxylate (400 mg, 0.426 mmol) was added to 4 mol of 20 ml dioxane hydrochloride at room temperature, followed by stirring at room temperature for 2 hours.
After completion of the reaction, the reaction liquid was directly spin-dried to obtain crude 300 mg of a white solid (3R, 5 'S) -1' - ((1R, 2S, 5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro-indoline-3, 3 '-pyrrolidine-5' -carboxamide as a direct substance for the next step. LC-MS: [ M + H ] + =367.
And C: synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro-indoline-3, 3 '-pyrrolidine-5' -carboxamide
4-methoxyindole-2-carboxylic acid (156 mg, 0.815 mmol) was added to dichloromethane/N, N-dimethylformamide 4:1 (20 ml), HATU (340 mg, 0.897 mmol), morpholine (288 mg, 2.86 mmol) and then (3 r, 5's) -1' - ((1r, 2s, 5s) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro-indoline-3, 3 '-pyrrolidine-5' -carboxamide (300 mg, 0.815 mmol) were added at zero and stirred at rt for 6 h.
After the reaction was completed, water (50 ml) was added and quenched, dichloromethane was extracted (100 ml × 3), and the organic phases were combined, washed with water (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was passed through a reverse column (acetonitrile: water 5:95 to 60). LC-MS: m + H + =540.
Step D: synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3-4-methoxyindole-2-carbonyl-6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl-2-oxospiro-3, 3-pyrrolidine-5-carbonitrile
(3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro-indoline-3, 3 '-pyrrolidine-5' -carboxamide (70 mg, 0.129 mmol) was added to dichloromethane (50 ml) at room temperature followed by primary Gieser reagent (154 mg, 0.645 mmol) and stirred at room temperature for 16 hours.
After the reaction was completed, water (100 ml) was added to quench, dichloromethane extraction (50 ml. Times.3) was performed, and organic phases were combined, washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was subjected to a reverse column (acetonitrile: water 5 to 50)
(yield: 38%). LC-MS: [ M + H ] + =524
1 H NMR(400MHz，Chloroform-d)δ9.86(s，1H)，8.36(s，1H)，7.27-7.17(m，2H)，7.17-7.00(m，3H)，6.92(d，J＝7.8Hz，1H)，6.86(td，J＝7.6，1.0Hz，1H)，6.51(d，J＝7.8Hz，1H)，5.09(t，J＝8.3Hz，1H)，4.41-4.27(m，2H)，4.09(d，J＝10.2Hz，1H)，3.98(s，3H)，3.18(qd，J＝7.4，4.8Hz，1H)，2.84(dd，J＝13.2，8.3Hz，1H)，2.53(dd，J＝13.2，8.2Hz，1H)，1.89-1.83(m，1H)，1.13(s，3H)，0.95(s，3H)，0.90(q，J＝4.8，3.6Hz，2H).
Examples 2 to 10
Referring to the preparation method of example 1, compounds 2 to 10 of the following formulae were prepared, respectively:
comparative example 1
Synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carbonitrile (Compound 111)
Synthetic route
Step A: synthesis of (1R,2S,5S) -2- ((3R,5 'S) -5' -carbamoyl-2-oxospiro [ indoline-3, 3 '-pyrroline ] -1' -carbonyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester
(3R, 5S) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide hydrochloride (404 mg, 1.5 mmol), (1R, 2S, 5S) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (343 mg, 1.51 mmol) was dissolved in anhydrous DMF (2 ml) and dichloromethane (8 ml) at room temperature, and N-methylmorpholine (0.6 ml, 5.28 mmol), HATU (631 mg, 1.66 mmol) were added and stirred at room temperature overnight.
After the reaction was completed, the reaction was quenched by addition of saturated sodium bicarbonate (10 ml), extracted with dichloromethane (10 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol = 30: 1) to obtain 283 mg of a white solid product (1R, 2S, 5S) -2- ((3R, 5' S) -5' -carbamoyl-2 oxospiro [ indoline-3, 3' -pyrroline]-1' -carbonyl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester (yield 36.1%). LC-MS: [ M + H ]] + ＝441.2。
Step B Synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide hydrochloride
(1R,2S,5S) -2- ((3R,5 ' S) -5' -carbamoyl-2 oxospiro [ indoline-3, 3' -pyrroline) at room temperature]-1' -carbonyl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester was dissolved in methylene chloride (6 ml), 4M dioxane hydrochloride (1.6 ml) was added, stirred at room temperature for 2h, and spin-dried to give 240 mg of a white solid product (3R, 5 'S) -1' - ((1R, 2S, 5S) -3-azabicyclo [3.1.0]]Hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3' -pyrrolidine]-5' -carboxamide hydrochloride (yield 100%). LC-MS: [ M + HCl + H ]] + ＝341.2。
Step C Synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide
(3R, 5 'S) -1' - ((1R, 2S, 5S) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide hydrochloride (160 mg, 0.4 mmol), 4-methoxy 1H-indole-2-carboxylic acid (122 mg, 0.64 mmol) were dissolved in anhydrous DMF (5 ml) at 0 deg.C, DIPEA (0.3 ml, 1.4 mmol), HATU (243 mg, 0.64 mmol) were added, and stirring was carried out at 0 deg.C for 2 hours.
After the reaction was completed, the reaction was quenched by addition of water (10 ml), and a yellow solid precipitated, followed by filtration, washing with water (10 ml. Times.3) and washing with ethyl acetate (10 ml. Times.3) to give 160 mg of a yellow solid product (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0]]Hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3' -pyrrolidine]-5' -carboxamide (yield 74.0%). LC-MS: [ M + H ]] - ＝512.2。
Step D Synthesis of (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carbonitrile
(3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carboxamide (160 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (10 ml) at room temperature, primary gibbs reagent (446 mg, 1.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours.
After the reaction was completed, the reaction was quenched by addition of saturated sodium bicarbonate (15 ml), extracted with dichloromethane (10 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate = 1: 1) to give 58 mg of a white solid product (3R, 5 'S) -1' - ((1R, 2S, 5S) -3- (4-methoxy-1H-indole-2-carbonyl) -3-azabicyclo [3.1.0] hexane-2-carbonyl) -2-oxospiro [ indoline-3, 3 '-pyrrolidine ] -5' -carbonitrile.
LC-MS：[M + H] - ＝494.2。
1 H NMR(400MHz，DMSO-d 6 )δ11.66(s，1H)，10.78(s，1H)，7.27-7.22(m，1H)，7.16-6.87(m，6H)，6.52(d，J＝7.6Hz，1H)，5.21(t，J＝8.3Hz，1H)，4.92(d，J＝5.6Hz，1H)，4.23-4.01(m，3H)，3.98-3.85(m，4H)，2.71-2.60(m，1H)，1.93-1.83(m，1H)，1.81-1.70(m，1H)，0.90-0.79(m，1H)，0.73-0.63(m，1H).
Example 11 related Activity assay
The inhibitory activity of the compounds on the novel coronavirus (SARS-CoV-2) 3CLpro protease was examined by in vitro enzymatic assays. PF-07321332 was selected as a positive control compound.
1. Compounds were performed with DMSO 1:3 serial dilutions 10 concentration points, each concentration duplicate wells, were added to the assay plate. Negative control wells containing enzyme and substrate but no compound served as no inhibition controls. The positive control wells contained substrate, enzyme and high concentration of PF-07321332 as a 100% inhibition control.
2. The Mpro protease was added to the compound-containing assay plate and incubated with the compound for 30 minutes at room temperature.
3. The reaction substrate was then added and incubated in a 30 ℃ incubator for 60 minutes.
4. And (5) detecting the fluorescence reading by using a multifunctional microplate reader reading plate.
5. The median Inhibitory Concentration (IC) of the compounds against 3CLpro protease was calculated using GraphPad Prism software analysis 50 ) The value is obtained.
And (3) test results: IC (integrated circuit) 50 As shown in table 1 below:
TABLE 1.3 CLpro protease IC 50 Data of
| Compound (I) | IC 50 |
| 101 | 0.0085μM |
| 102 | 0.0079μM |
| 103 | 0.0083μM |
| 104 | 0.0082μM |
| 105 | 0.0066μM |
| 106 | 0.0054μM |
| 107 | 0.0086μM |
| 108 | 0.0085μM |
| 109 | 0.0077μM |
| 110 | 0.0075μM |
| 111 | 0.0932μM |
Wherein the IC of the compounds of the invention relative to the control Compound 111 50 The activity is obviously improved.
EXAMPLE 12 Compound liver microsome stability study
(1) Experimental materials
Human and rat liver microsomes were purchased from Reid liver disease research (Shanghai) Inc.
Reagent: DMSO (dimethyl sulfoxide), acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
The instrument comprises the following steps: sammerfel LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
(2) Experimental methods
Precisely weighing a certain amount of compound, dissolving in DMSO to obtain 10mM stock solution, and adding diluent (ACN: H) 2 0= 1: 1) the stock solution was diluted to 100. Mu.M of working solution, and then diluted with 0.1M potassium phosphate buffer solution to 3. Mu.M of administration solution for use. Adding 75 μ L liver microsome into 925 μ L0.1M potassium phosphate buffer solution, mixing to obtain 1.5mg/mL liver microsome suspension, and pre-incubating at 37 deg.C for 10min. Preparation of point 0: and adding 6mM NADPH solution into 15 mu L of the liver microsome suspension, immediately adding 150 mu L of propranolol acetonitrile solution for precipitation, adding 15 mu L of the administration solution, and uniformly mixing for later use. 20min and 60min sample preparation: mu.L of the dosing solution was added to 15. Mu.L of the liver microsome suspension and 15. Mu.L of 6mM NADPH solution, mixed well and incubated at 37 ℃ for 20min and 60min, respectively. The sample preparation was a double-well parallel operation. When the samples are incubated to relevant time points, 150 mu L of propranolol acetonitrile solution is added to stop the reaction. All the samples were centrifuged at 4000rpm for 5min, 100. Mu.L of supernatant was added to 100. Mu.L of ultrapure water and mixed well for LC-MS/MS analysis. The LC-MS/MS detection conditions were as follows:
a chromatographic column: waters ACQUITYTM PREMIER HSS T3, 50 x 2.1mm,1.8 μm.
Mobile phase: water (0.1% formic acid) -acetonitrile were subjected to gradient elution according to the following table
| Time (min) | Water (with 0.1% formic acid) | Acetonitrile |
| 0 | 85％ | 15％ |
| 0.6 | 85％ | 15％ |
| 1 | 20％ | 80％ |
| 2.3 | 20％ | 80％ |
| 2.31 | 85％ | 15％ |
| 3 | 85％ | 15％ |
(3) Data analysis
The test substance/Internal Standard (IS) peak area ratio IS converted into the remaining percentage (remaining percentage%), and the formula IS as follows:
the ratio of the sample to the IS peak area was 100 times as large as the ratio of the sample to the IS peak area at the time point of% remaining rate = the ratio of the sample to the IS peak area at each time point/t =0
The slope was calculated based on the remaining rate at each time point, and the half-life of each test substance in liver microsomes was calculated. The results are given in Table 2 below.
TABLE 2 stability data for liver microsomes
The results show that the 101 compound has better metabolic stability in liver microsome and hardly metabolizes in human liver microsome, which indicates that the human body does not need to use a combined metabolic enzyme inhibitor.
EXAMPLE 13 rat pharmacokinetic Studies of Compounds
(1) Experimental Material
SD rat: male, 180-250g, purchased from Experimental animals technology, inc. of Wei Tong Hua, beijing.
Reagent: DMSO (dimethylsulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.
The instrument comprises: sammerfel LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometry).
(2) Experimental method
Weighing the compound, dissolving the compound in a DMSO-PEG-400-physiological saline (5, v/v/v) system, after intravenous or intragastric administration of rats, collecting 200 mu L of venous blood in an EDTA-K2 anticoagulation EP tube at 15min, 30min, 1h, 2h, 5h, 7h and 24h (iv group plus collection 5 min), centrifuging at 12000rpm for 2min, and freezing and storing the blood plasma at-80 ℃ for testing. A predetermined amount of the sample was dissolved in DMSO to 2mg/mL to prepare a stock solution. Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000 and 3000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. And (3) taking 30 mu L of plasma (10 times of plasma dilution after intravenous administration for 5min, 15min and 30 min), adding 200 mu L of acetonitrile solution of internal standard propranolol (50 ng/mL), uniformly mixing by vortex, adding 100 mu L of purified water, uniformly mixing by vortex again, centrifuging at 4000rpm for 5min, and taking supernatant for LC-MS analysis. The LC-MS detection conditions were as follows:
a chromatographic column: saimerfil HYPERSIL GOLD C-18UPLC column, 100 × 2.1mm,1.7 μm.
Mobile phase: water (0.1% formic acid) -acetonitrile were subjected to gradient elution according to the following table.
| Time (min) | Water (with 0.1% formic acid) | Acetonitrile (ACN) |
| 0 | 90％ | 10％ |
| 0.6 | 90％ | 10％ |
| 1 | 10％ | 90％ |
| 2.6 | 10％ | 90％ |
| 2.61 | 90％ | 10％ |
| 4 | 90％ | 10％ |
3. Data processing
After LC-MS detection of blood concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and non-compartmental modeling, and the results are shown in Table 3.
TABLE 3 rat PK data
The results show that: after the compound 101 is administrated by gastric lavage, the oral administration absorption of the rat is better, the oral administration half-life is longer, the rat PK and the stability of in vitro rat liver microsomes have better correlation, and the analysis of the compound 101 by combining the stability data of in vitro human liver microsomes is expected to be taken once a day by a single drug in a human body.
Example 14 on hERG-HEK293 cell hERG current effect
The test method comprises the following steps: human embryonic kidney cells (hERG-HEK 293 cells) stably expressing the hERG channel are selected for the test. The hERG-HEK293 cell is clamped by a full-automatic patch clamp system to form a full-cell voltage clamp mode, and the hERG current is induced by corresponding voltage. The cells were administered with 0.3% DMSO-containing extracellular fluid (negative control) 0.3, 1, 3, 10 and 30. Mu.M of Compound A, respectively. Different cells were selected for administration of positive controls (cisapride) containing 0.3% DMSO in extracellular fluid (negative control) 1, 10, 100, and 1000 nM. And recording the tail current of the hERG channel, and obtaining the peak value of the tail current under each concentration. The current inhibition rate after the compound A and the positive control sample are added is calculated. Curve fitting and IC50 calculation of compound a and positive control concentration-response relationship were done using GraphPad Prism software.
And (3) test results: IC of inhibition rate of cisapride on hERG current in the range of test concentration under the test condition 50 The value is in the historical range, which shows that the test system is stable and reliable, and the test result is accurate. .
TABLE 4 inhibition ratio IC of hERG current 50 Data of
EXAMPLE 15 in vitro efficacy of the Compound against New coronavirus Omicron BA.2 Strain
Test method for antiviral Activity:
vero cells were treated at 1X10 4 Density of each cell per well was inoculated into a 96 well cell culture plate and 5% CO 2 And cultured in an incubator at 37 ℃. After waiting for the cells to be completely adherent, 2 hours before infection were replaced with a medium containing 2% FBS and the corresponding compounds were added to the indicated concentrations (initial concentration of test compound 10. Mu.M, 4-fold dilution) together with the addition of p-gp inhibitor CP-100356 (final concentration 2. Mu.M), followed by inoculation of the new coronavirus Omicron BA.2 strain at MOI 0.05, and after 72 hours of infection, cell supernatants were collected for RNA extraction and virus copy number was determined by qPCR.
The half maximal Effective Concentration (EC) of the compound was calculated using a nonlinear fit analysis of the inhibition of the samples using GraphPad Prism software 50 ) The value is obtained.
TABLE 5 in vitro activity and cytotoxicity of test compounds against Omicron BA.2 Strain
| Compound numbering | Antiviral Activity of EC 50 (nM) |
| Compound 101 | 5.65 |
| Compound 105 | 7.22 |
| Compound 106 | 4.61 |
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A compound represented by the general formula (I), or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, wherein:
wherein R is 1 Selected from hydrogen, halogen, alkoxy, n =1, 2, 3 or 4; r 2 、R 3 Independently selected from hydrogen, alkyl, and R 2 、R 3 Not hydrogen at the same time.
2. The compound according to claim 1, or an isomer, racemate or pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of C 1-6 Said alkoxy group being selected from C 1-6 Alkoxy group of (a); the halogen is selected from fluorine, chlorine, bromine and iodine.
3. The compound according to claim 1 or 2, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1, 2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1, 2-dimethylbutyl, and 1-ethylbutyl.
The alkoxy group is selected from the group consisting of methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1, 2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, sec-hexoxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1, 2-dimethylbutoxy, 1-ethylbutoxy.
4. The compound according to claim 1, or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, wherein the compound is
Selected from the group consisting of>
5. The compound according to claim 1, or an isomer, racemate or pharmaceutically acceptable salt thereof, wherein R is 2 、R 3 Independently selected from hydrogen, methyl or ethyl, and R 2 、R 3 Not hydrogen at the same time.
6. The compound according to claim 1, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
7. the compound according to claims 1 to 6, or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is prepared from the compound, or an isomer, a racemate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable acid or base.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or its isomer, or racemate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. The use of a compound according to any one of claims 1 to 6, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, in particular, in the manufacture of a medicament for the treatment of a disease associated with a 3C-like protease inhibitor agent.
10. Use according to claim 9, in particular preferably from the group of disorders such as neocoronary pneumonia.
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