CN113512025B - Indazole ester compound and pharmaceutical application thereof - Google Patents
Indazole ester compound and pharmaceutical application thereof Download PDFInfo
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Abstract
The invention provides an indazole ester compound and a pharmaceutical application thereof. Specifically provided are compounds represented by formula I, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or isotopic substitution forms thereof. The compound can effectively inhibit SARS-CoV-2M pro Can be used for preparing SARS-CoV-2M pro And (3) an inhibitor. The compound has good application prospect in preparing medicaments for resisting novel coronavirus and medicaments for preventing and/or treating novel coronavirus pneumonia.
Description
Technical Field
The invention belongs to the technical field of organic synthetic drugs, and particularly relates to a SARS-CoV-2M inhibiting drug pro The indazole ester compounds and the pharmaceutical use thereof.
Background
The 2019-year coronavirus pneumonia (COVID-19, also known as novel coronavirus pneumonia) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2, also known as novel coronavirus) infection is an acute respiratory infectious disease. Although the interferon-alpha and the anti-HIV drug lopinavir/ritonavir (R) have been used clinically
) Against SARS-CoV-2, but still has very limited efficacy and may have toxic side effects. Rudeciclovir, a broad-spectrum antiviral drug developed by Gilled Sciences, inc., is also being explored for treatment of COVID-19, but more data is needed to demonstrate its efficacy. Therefore, there is still a strong need to develop a safe and effective anti-SARS-CoV-2 drug.
The genome RNA of coronavirus is about 30 ktt long, has 5 'cap structure and 3' -poly-a tail, and contains at least 6 open reading channelsOpen Reading Frame (ORF). The first ORF (ORF 1 a/b) occupies about two thirds of the genome length, and translates two polyproteins directly: pp1a and pp1ab, and a-1 frameshift between ORF1a and ORF1 b. These polyproteins consist of a main protease (abbreviated as M) pro (ii) a Also known as 3C-like proteases (3 CL) pro ) And one or two papain-like proteases (PLPs) to convert into 16 non-structural proteins. These non-structural proteins are involved in the production of subgenomic RNA, encoding four major structural proteins (envelope (E), membrane (M), spinous process (S), and nucleocapsid (N) proteins) and other accessory proteins to complete the viral replication and invasion process.
M pro The proteolytic cleavage of the overlapping pp1a and pp1ab into functional proteins is a critical step in the viral replication process. Enzymes essential for viral replication, such as RdRp or nsp13, do not function fully to achieve replication without prior proteolytic release. Thus, inhibition of viral M pro Can prevent the generation of infectious virus particles, thereby alleviating the symptoms of the disease.
M pro Is conserved among coronaviruses, and M is present in different coronaviruses pro Have some common features: the amino acids from N-to C-terminus are numbered in a paired fashion (-P4-P3-P2-P1 ↓p1'-P2' -P3 '), with cleavage sites between P1 and P1'. In particular, M pro A unique substrate preference for glutamine at the P1 site (Leu-Gln ↓ (Ser, ala, gly)), which is absent in the host protease, suggests that by targeting viral M pro It is feasible to achieve high selectivity. Thus, the absolute dependence of the virus on the correct function of this protease, coupled with the lack of a homologous human protease, makes M pro Becomes an ideal antiviral target.
Therefore, there is a need to develop an M that can effectively inhibit SARS-CoV-2 virus pro An enzymatically active agent.
Disclosure of Invention
The purpose of the present invention is to provide a master protease (M) capable of efficiently SARS-CoV-2 virus pro ) Active indazole ester compounds and pharmaceutical use thereof.
The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, an optical isomer or an isotopic substitution form thereof:
wherein X is N or CR a ，R a Selected from hydrogen, C 1～6 Alkyl radical, C 1～6 Alkoxy radical, C 2～6 Alkenyl radical, C 2～6 Alkynyl, L 1 M 1 R b ；L 1 Selected from 0 to 3 methylene groups, M 1 Selected from among none, CO, NH, CONH, NHCO, COO or OCO, R b Is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and the substituents are respectively and independently selected from halogen and C 1～4 Alkyl radical, C 1～4 An alkoxy group;
R 1 selected from hydrogen, C 1～6 Alkyl, substituted or unsubstituted aryl, heteroaryl, said substituents being selected from halogen, C 1～4 Alkyl radical, C 1～4 An alkoxy group;
R 2 selected from hydrogen, C 1～8 Alkyl radical, C 1～8 Alkoxy radical, C 2～6 Alkenyl radical, C 2～8 Alkynyl, protecting group, L 2 R c ；L 2 Selected from 0 to 3 methylene groups, R c Selected from the group consisting of substituted or unsubstituted: aryl, heteroaryl, saturated 3-to 6-membered cycloalkyl, fused cycloalkyl bicycloalkyl, heterofused ring, heterobicyclic group,
The substituent is selected from halogen, CN, L 3 COOR f Halogenated or non-halogenated C 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OL 4 R g (ii) a Wherein R is d Is selected from C 1～3 Alkyl, phenyl, benzyl, R e Selected from 3-to 5-membered rings, R f Selected from hydrogen, C 1～3 Alkyl radical, R g Selected from 3-to 5-membered rings, L 3 Selected from 0 to 3 methylene groups, L 4 Selected from 0 to 3 methylene groups;
R 3 selected from halogen, hydrogen,
Wherein R is i1 Selected from hydrogen, C 1～6 Alkyl, 3-to 6-membered saturated cycloalkyl, aryl, heteroaryl, R j1 Selected from hydrogen, C 1～4 Alkyl radical, R h1 Selected from hydrogen, halogenated or non-halogenated C 1～8 Alkyl, L 5 R 0 Benzyl, 3-to 6-membered saturated cycloalkyl, bridged cycloalkyl, L 5 Selected from 1 to 4 methylene groups, R 0 Selected from OH, phenyl, C 1～6 Alkoxy, N (R) 0c ) 2 3-to 6-membered heterocycle, R 0c Is selected from C 1～3 An alkyl group;
R i2 selected from hydrogen, C 1～4 Alkyl, unsubstituted or substituted by R x Substituted aryl, R x Is selected from C 1～4 Alkyl radical, C 1～4 Alkoxy radical, R j2 Selected from hydrogen, C 1～4 Alkyl radical, R h2 Selected from hydrogen, C 1～4 Alkyl, L 6 R 0a ,L 6 Selected from 1 to 3 methylene groups, R 0a Is selected from OH;
R i3 selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, R j3 Selected from hydrogen, C 1～4 Alkyl radical, R h3 、R h4 Each independently selected from hydrogen, C 1～4 Alkyl, or R h3 、R h4 Connecting to form a 3-6 membered saturated heterocycle;
R i4 selected from hydrogen, A 1 The ring is a 5-6 membered ring;
R i5 selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, R j4 Selected from hydrogen, C 1～4 Alkyl radical, R h5 、R h6 Each independently selected from hydrogen, C 1～4 Alkyl, or R h5 、R h6 Connecting to form a 3-to 6-membered saturated heterocycle;
R i6 selected from hydrogen, C 1～4 Alkyl radical, A 2 The ring is a 5-6 membered ring;
R i7 selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, R j5 Selected from hydrogen, C 1～4 Alkyl radical, R h7 Selected from hydrogen, C 1～4 An alkyl group;
R i8 、R j6 each independently selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl;
R j7 selected from benzyl, hydrogen, C 1～4 Alkyl, aryl, heteroaryl;
R i9 、R j8 each independently selected from hydrogen, C 1～4 Alkyl radical, C 2～6 Alkenyl, benzyl, aryl, heteroaryl, L 7 R 0b 、
L 7 Selected from 1 to 4 methylene groups, R 0b Selected from 3 to 6 membered cycloalkyl;
R j9 selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, benzyl, R i10 、R j10 Each independently selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, benzyl;
R j11 selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, benzyl, R i11 Selected from hydrogen, C 1～4 Alkyl, aryl, heteroaryl, benzyl.
Further, the structure of the compound is shown as formula II-1, formula II-2, formula II-3 or formula II-4:
wherein, Y 1 Is halogen, preferably chlorine; y is 2 Is halogen, preferably chlorine.
Further, X is N or CR a ，R a Selected from hydrogen, C 1～4 Alkyl radical, C 1～4 Alkoxy radical, C 2～4 Alkenyl radical, C 2～4 Alkynyl, L 1 M 1 R b ；L 1 Selected from 0 to 2 methylene groups, M 1 Selected from among none, CO, NH, CONH, NHCO, COO or OCO, R b Selected from aryl, heteroaryl;
and/or, R 2 Selected from hydrogen, C 1～7 Alkyl radical, C 1～7 Alkoxy radical, C 2～4 Alkenyl radical, C 2～4 Alkynyl, protecting group, L 2 R c ；L 2 Selected from 0 to 2 methylene groups, R c Selected from the following substituted or unsubstituted groups: aryl, heteroaryl, saturated 3-5 membered cycloalkyl, fused cycloalkyl, bicycloalkyl, heterofused cyclic, heterobicyclic, and the like,
The substituent is selected from halogen, CN, L 3 COOR f C, halogenated or not halogenated 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OL 4 R g (ii) a Wherein R is d Is selected from C 1～3 Alkyl, phenyl, benzyl, R e Selected from 5-membered heterocyclic ring, R f Selected from hydrogen, C 1～3 Alkyl radical, R g Selected from 5-membered heterocycles, L 3 Selected from 0 to 2 methylene groups, L 4 Selected from 0 to 1 methylene;
preferably, X is N or CR a ，R a Selected from hydrogen, C 1～3 Alkyl radical, C 1～3 Alkoxy radical, L 1 M 1 R b ； L 1 Selected from 0 to 1 methylene group, M 1 Selected from among none, CO, NH, CONH, NHCO, COO or OCO, R b Is selected from phenyl;
and/or, R 2 Selected from hydrogen, C 1～7 Alkyl radical, C 1～7 Alkoxy radical, C 2～3 Alkenyl radical, C 2～3 Alkynyl, protecting group, L 2 R c (ii) a The protection isThe radical is preferably a Boc radical, L 2 Selected from 0 to 1 methylene, R c Selected from the group consisting of substituted or unsubstituted: phenyl, 6-membered heteroaryl, saturated 3-to 5-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, heterofused cycloalkyl, heterobicyclic group,
The 6-membered heteroaryl contains 1-2 nitrogen atoms, and the substituent is selected from halogen, CN and L 3 COOR f C, halogenated or not halogenated 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OL 4 R g (ii) a Wherein R is d Is selected from C 1～3 Alkyl, phenyl, benzyl, R e Is selected from
R f Selected from hydrogen, C 1～3 Alkyl radical, R g Is selected from
L 3 Selected from 0 to 1 methylene group, L 4 Selected from 0 to 1 methylene group.
Further, R 3 Selected from halogen, hydrogen,
Wherein R is i1 Selected from hydrogen, C 1～2 Alkyl, 6-membered saturated cycloalkyl, phenyl, R j1 Selected from hydrogen, R h1 Selected from hydrogen, halogenated or non-halogenated C 1～8 Alkyl, L 5 R 0 Benzyl, 6-membered saturated cycloalkyl, bridged cycloalkyl, L 5 Selected from 2 to 3 methylene groups, R 0 Selected from OH, phenyl, methoxy, N (CH) 3 ) 2 3-membered oxygen heterocycle;
R i2 selected from hydrogen, unsubstituted or substituted by R x1 Substituted phenyl radicals, R x1 Is selected from C 1～2 Alkyl radical, C 1～2 An alkoxy group; r is j2 Selected from hydrogen, R h2 Selected from hydrogen, methyl, ethyl, L 6 R 0a ,L 6 Selected from 1 to 2 methylene groups, R 0a Is selected from OH;
R i3 selected from hydrogen, C 1～2 Alkyl, phenyl, R j3 Selected from hydrogen, R h3 、R h4 Each independently selected from hydrogen, C 1～4 Alkyl, or R h3 、R h4 Linked to form a 6-membered saturated heterocyclic ring;
R i4 selected from hydrogen, A 1 The ring is a 5-membered heterocyclic ring;
R i5 selected from hydrogen, C 1～2 Alkyl, phenyl, R j4 Selected from hydrogen, R h5 、R h6 Each independently selected from hydrogen, C 1～4 Alkyl, or R h5 、R h6 Linked to form a 6-membered saturated heterocyclic ring;
R i6 selected from hydrogen, A 2 The ring is a 5-6 membered heterocyclic ring;
R i7 selected from hydrogen, C 1～2 Alkyl, phenyl, R j5 Selected from hydrogen, R h7 Is selected from C 1～2 An alkyl group;
R i8 、R j6 each independently selected from phenyl;
R j7 is selected from benzyl;
R i9 、R j8 each independently selected from hydrogen, C 1～2 Alkyl radical, C 2～3 Alkenyl, benzyl, L 7 R 0b 、
L 7 Selected from 1 to 2 methylene groups, R 0b Selected from 6-membered unsaturated cycloalkyl;
R j9 is selected from C 1～2 Alkyl, phenyl, benzyl, R i10 、R j10 Each independently selected from hydrogen, C 1～2 An alkyl group;
R j11 selected from phenyl, R i11 Is selected from C 1～2 An alkyl group.
Further, the structure of the compound is shown as follows:
the invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt, or stereoisomer, or optical isomer, or isotope substitution form thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the optical isomer thereof, or the isotopic substitution form thereof in preparing a coronavirus main protease inhibitor.
Further, the coronavirus main protease inhibitor can inhibit the activity of coronavirus main protease; and/or, the coronavirus is a novel coronavirus SARS-CoV-2.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, or the optical isomer thereof, or the isotope substitution form thereof in preparing the anti-coronavirus medicament, preferably, the coronavirus is novel coronavirus SARS-CoV-2.
The invention also provides the application of the compound, or the pharmaceutically acceptable salt, the stereoisomer, the optical isomer or the isotope substitution form thereof in preparing a medicament for preventing and/or treating viral pneumonia, preferably the viral pneumonia is novel coronavirus pneumonia COVID-19.
Definitions of terms used in relation to the present invention: unless otherwise indicated, the initial definitions provided for by a group or term herein apply to that group or term throughout the specification; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
The minimum and maximum values of the content of carbon atoms in hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl represents any alkyl group containing "a" to "b" carbon atoms. For example, C 1～6 Alkyl refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms.
Similarly, C 1～6 Alkoxy means a straight or branched chain alkoxy group containing 1 to 6 carbon atoms.
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring which has a conjugated pi-electron system. The aryl group may be substituted or unsubstituted.
"heteroaryl" refers to a heteroaromatic group containing one to more heteroatoms. The hetero atoms referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic. For example, "3-to 6-membered cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms in the ring.
"Bicycloalkylalkyl" refers to polycyclic cycloalkyl groups in which two rings are connected by a single bond.
"bridged cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two non-adjacent carbon atoms.
"fused cycloalkyl" refers to a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.
"Heterocyclyl" refers to a polycyclic heterocyclic group in which two rings are connected by a single bond.
"Heterofused cyclic" refers to polycyclic heterocyclic groups in which two rings share two adjacent carbon or heteroatoms.
"isotopically substituted form" refers to compounds wherein one or more than two atoms are replaced by their corresponding isotopes, for example, compounds wherein hydrogen is replaced by protium, deuterium, or tritium.
By "pharmaceutically acceptable" is meant a carrier, cargo, diluent, excipient, and/or salt that is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form, and with the recipient.
"salts" are acidic and/or basic salts formed from compounds with inorganic and/or organic acids and/or bases and also include zwitterionic (inner) salts and also quaternary ammonium salts, for example alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound with a certain amount of an acid or a base as appropriate (e.g., an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
The "pharmaceutically acceptable salt" in the present invention may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
The experimental result shows that the invention provides a medicine which can effectively inhibit SARS-CoV-2M pro Active indazole ester compounds, which can be used to prepare SARS-CoV-2M pro And (3) an inhibitor. The compound of the invention has good application prospect in preparing anti-SARS-CoV-2 medicines and medicines for preventing and/or treating novel coronavirus pneumonia.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
The target compounds of the present invention were synthesized with reference to the following schemes a to E, and the structures and characteristics of the target compounds are shown in table 1.
Route a:
route B:
route C:
route D:
route E:
the following are specific preparation examples.
Example 1: preparation of Compound 14 according to scheme A
(I) Intermediate B-14 preparation of methyl 1H-indazole-7-carboxylic acid
The starting material A (1 equiv), methanol (1.5 equiv), EDCI (1.5 equiv), HOBT (1 equiv) and DIEA (1.5 equiv) were added in sequence to dry DMF and reacted at room temperature for 8 hours, and the reaction was monitored by TLC. After the reaction is finished, extracting with EA, washing with water, drying with anhydrous sodium sulfate, and separating by column chromatography to obtain a white solid. The yield thereof was found to be 90%.
(II) intermediate C-14 preparation of methyl 3-iodo-1H-indazole-7-carboxylic acid
Intermediate B-14 (1 equiv), iodine (2 equiv) and potassium hydroxide (4 equiv) were added to DMF and reacted at room temperature for 3 hours, and the reaction was monitored by TLC. After the reaction is finished, quenching is carried out by using a saturated sodium sulfite solution, and then, suction filtration, water washing and drying in an oven are carried out to obtain a white solid with the yield of 85%.
1 HNMR(400MHz,DMSO)δ13.65(s,1H),8.10(d,J＝7.2Hz, 1H),7.78(d,J＝8.0Hz,1H),7.35(t,J＝7.7Hz,1H),3.96(s,3H).
(III) intermediate D-14: preparation of methyl 3-iodo-1-methyl-1H-indazole-7-carboxylic acid
Intermediate C-14 (1 equiv), methyl iodide (1.5 equiv) and cesium carbonate (1.5 equiv) were added to DMF, reacted at 80 ℃ for 2 hours, and the reaction was monitored by TLC. And after the reaction is finished, quenching the reaction by using a saturated ammonium chloride solution, extracting by using EA (aqueous extraction) and washing by using saturated saline solution, drying the extract by using anhydrous sodium sulfate, concentrating by using a vacuum pump, and separating by using column chromatography to obtain a white solid with the yield of 60%.
1 HNMR(400MHz,CDCl 3 )δ8.02(d,J＝7.3Hz,1H),7.68(d,J＝ 8.1Hz,1H),7.23(t,J＝7.7Hz,1H),4.30(s,3H),3.99(s,3H).
(IV) intermediate E-14: preparation of methyl (E) -3- (3-methoxy-3-oxoprop-1-en-1-yl) -1-methyl-1H-indazole-7-carboxylic acid
Intermediate D-14 (1 equiv) was dissolved in a mixed solvent of DMF: TEA =5, and methyl acrylate (10 equiv), pdCl were added 2 (dppf) (0.1 equiv) and TBAB (2 equiv) were added to the reaction solution, and reacted at 80 ℃ for 6 hours under nitrogen protection, and the reaction was monitored by TLC. After the reaction, the reaction mixture was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white solid with a yield of 80%.
1 HNMR(400MHz,CDCl 3 )δ8.09(dd,J＝8.1,0.9Hz,1H),8.02– 7.92(m,2H),7.29(d,J＝7.5Hz,1H),6.80(d,J＝16.2Hz,1H),4.29(s, 3H),4.00(s,3H),3.84(s,3H).
(V) preparation of Compound 14 methyl 3- (3-methoxy-3-propionyl) -1-methyl-1H-indazole-7-carboxylic acid
Dissolving the intermediate E-14 in methanol, adding a catalyst palladium carbon, then ventilating, enabling the whole reaction system to be in a hydrogen environment, reacting for 5 hours at 50 ℃, and monitoring the reaction by TLC. After the reaction was completed, the reaction mixture was filtered with celite, and the filtrate was concentrated and separated by column chromatography to obtain a white solid (i.e., compound 14) in 80% yield.
1 HNMR(400MHz,CDCl 3 )δ7.92(dd,J＝7.3,0.9Hz,1H),7.87 (dd,J＝8.0,0.9Hz,1H),7.14(t,J＝7.7Hz,1H),4.18(s,3H),3.98(s, 3H),3.68(s,3H),3.28(t,J＝7.7Hz,2H),2.86(t,J＝7.7Hz,2H).
Example 2: preparation of Compound 50 according to scheme B
Compound 50: preparation of methyl 3- (3-methoxy-3-oxo-1-phenylpropyl) -1-methyl-1H-indazole-7-carboxylate
Intermediate D-14 (1 equiv), dissolved in toluene, followed by Pd (OAc) 2 (0.1 equiv) and AgOAc (4 equiv) were added to the reaction mixture to ensure that the reaction was carried out under nitrogen, and the reaction was monitored by TLC for 8 hours at 110 ℃. After the reaction, the reaction solution was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a white intermediate.
Then, the white intermediate product is dissolved in methanol, a catalyst palladium carbon is added, then ventilation is carried out, the whole reaction system is in a hydrogen environment, the reaction is carried out for 5 hours at the temperature of 50 ℃, and the reaction is monitored by TLC. After the reaction was completed, the reaction mixture was filtered with celite, and the filtrate was concentrated and separated by column chromatography to obtain a white solid (i.e., compound 50) in 80% yield.
1 HNMR(400MHz,Chloroform-d)δ7.85(dd,J＝7.3,1.2Hz,1H), 7.58(dd,J＝8.0,1.2Hz,1H),7.36–7.30(m,2H),7.30–7.23(m,3H), 7.23–7.16(m,1H),7.00(dd,J＝8.1,7.3Hz,1H),4.94(t,J＝7.6Hz, 1H),4.22(s,3H),3.96(s,3H),3.62(s,3H),3.51(dd,J＝16.2,8.1Hz, 1H),3.06(dd,J＝16.2,7.2Hz,1H).
Example 3: preparation of Compound 23 according to scheme C
Compound H (1 equiv), 2-bromopropane (1.5 equiv) and potassium hydroxide (1.5 equiv) were added to DMF at 0 ℃ for reaction, monitored by TLC, quenched with saturated ammonium chloride after 1 hour of reaction, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatographed to give white solid (i.e., compound 23) in 80% yield.
1 HNMR(400MHz,CDCl 3 )δ7.90(d,J＝7.5Hz,1H),7.57(d,J＝ 8.2Hz,1H),7.36(d,J＝2.9Hz,1H),7.24(dd,J＝10.4,5.3Hz,1H), 7.14(d,J＝3.1Hz,1H),4.70(dt,J＝13.4,6.7Hz,1H),3.98(s,3H), 1.53(d,J＝6.7Hz,6H).
Example 4: preparation of Compound 30 according to scheme D
Mixing intermediate D-14 (1 equiv), benzylthiol (0.9 equiv), pd 2 (dba) 3 (0.05 equiv), DIEA (2 equiv) and Xantphos (i.e., 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 0.1 equiv) were added to a round-bottomed flask with a stirrer, and 1, 4-dioxane was added thereto, and the reaction was carried out under anhydrous and oxygen-free conditions under nitrogen protection at 100 ℃ for 10 hours. The reaction was monitored by TLC and, after completion of the reaction, EA was extracted, washed with saturated brine, dried over anhydrous sodium sulfate and column chromatographed to give a pale yellow solid (i.e. compound 30) in 80% yield.
1 H NMR(400MHz,CDCl 3 )δ7.92(dd,J＝7.3,0.9Hz,1H),7.68 (dd,J＝8.0,0.9Hz,1H),7.30–7.18(m,5H),7.12–7.04(m,1H),4.25 (s,3H),4.24(s,2H),3.97(s,3H).
Example 5: preparation of Compound 34 according to scheme E
The raw material Q (1 equiv), bromoethane (1.2 equiv) and potassium carbonate (1.5 equiv) were put in a THF solution and stirred at room temperature for 10 hours. The reaction was monitored by TLC, after completion of the reaction, the reaction was quenched with saturated ammonium chloride, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, and column chromatographed to give a white solid (i.e., compound 34) in 50% yield.
1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝7.1Hz,1H),7.82(d,J＝ 7.8Hz,1H),7.04(s,1H),4.08–4.00(m,2H),3.97(s,3H),3.54(s,1H), 1.36(t,J＝7.2Hz,3H).
Example 6: preparation of Compounds 3, 4, 28, 35 according to scheme A
Replacing the raw material A with
Referring to the synthetic procedure of scheme a, compounds 3, 4, 28, 35 were prepared.
Example 7: preparation of Compound 40 with reference to scheme A
Replacing the raw material A with
Referring to the synthetic procedure of scheme a, compound 40 is prepared:
example 8: reference scheme A preparation of Compound 37
Replacing the raw material A with
Referring to the synthetic procedure of scheme a, compound 37 is prepared:
the remaining compounds in Table 1 were prepared according to one of the schemes A-E.
TABLE 1 Structure, characterization and synthetic routes to the compounds of interest of the present invention
The beneficial effects of the compounds of the present invention are demonstrated by the following experimental examples.
Experimental example 1 Compound of the present invention vs. M pro Assay for level of inhibition of enzyme Activity
(1) Experimental methods
Recombinant SARS-CoV-2M pro (final concentration 750 nM) was mixed with serial dilutions of test compound in 25. Mu.L assay buffer (20 mM Tris-HCl, pH 7.5, 150mM NaCl,1mM EDTA,2mM DTT) and incubated for 10 min. The reaction was initiated by the addition of 25. Mu.L of fluorogenic substrate (MCA-AVLQ ↓ SGFR-Lys (Dnp) -Lys-NH 2) at a final concentration of 20. Mu.M, and the fluorescence signal at 320nm (excitation)/405 nm (emission) was measured with a microplate reader. Calculating V of the reaction to which different concentrations of test compound were added max V with reaction by addition of DMSO max And using it to generate an IC 50 Curve line. For each compound, the semi-Inhibitory Concentration (IC) against SARS-CoV-2Mpro was measured at 9 concentrations and 3 independent replicates 50 ) The value is obtained. All experimental data were analyzed using GraphPad Prism software.
(2) Results of the experiment
TABLE 2 Compound of the invention vs. M pro Enzyme activity inhibited IC 50 Value of
It can be seen that the compounds of the present invention are effective in inhibiting SARS-CoV-2M pro Can be used for preparing SARS-CoV-2M pro Inhibitors, agents against the novel coronavirus, and agents for the prophylaxis and/or treatment of the novel coronavirus pneumonia.
In conclusion, the invention provides an indazole ester compound shown as a formula I, which can effectively inhibit SARS-CoV-2M pro Can be used for preparing SARS-CoV-2M pro And (3) an inhibitor. The compound has good application prospect in preparing medicaments for resisting novel coronavirus and medicaments for preventing and/or treating novel coronavirus pneumonia.
Claims (16)
1. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as formula II-1, formula II-2, formula II-3 or formula II-4:
wherein, Y 1 Is halogen; y is 2 Is halogen;
x is N;
R 2 selected from hydrogen, C 1～7 Alkyl radical, C 1～7 Alkoxy radical, C 2～3 Alkenyl radical, C 2～3 Alkynyl, protecting group, L 2 R c (ii) a The protecting group is Boc group, L 2 Selected from 0 to 1 methylene, R c Selected from the following substituted or unsubstituted groups: phenyl, 6-membered heteroaryl, saturated 3-to 5-membered cycloalkyl,
The 6-membered heteroaryl contains 1-2 nitrogen atoms, and the substituent is selected from halogen, CN and L 3 COOR f C, halogenated or not halogenated 1～3 Alkyl, halogenated or non-halogenated C 1～3 Alkoxy, OL 4 R g (ii) a Wherein R is d Is selected from C 1～3 Alkyl, phenyl, benzyl, R e Is selected from
R f Selected from hydrogen, C 1～3 Alkyl radical, R g Is selected from
L 3 Selected from 0 to 1 methylene group, L 4 Selected from 0 to 1 methylene;
R 3 is selected from
Wherein R is i1 Selected from hydrogen, C 1～2 Alkyl, 6-membered saturated cycloalkyl, phenyl, R j1 Selected from hydrogen, R h1 Selected from hydrogen, halogenated or non-halogenated C 1～8 Alkyl, L 5 R 0 Benzyl, 6-membered saturated cycloalkyl, L 5 Selected from 2 to 3 methylene groups, R 0 Selected from OH, phenyl, methoxy, N (CH) 3 ) 2 3-membered oxygen heterocycle;
R i2 selected from hydrogen, unsubstituted or substituted by R x Substituted phenyl radicals, R x Is selected from C 1～2 Alkyl radical, C 1～2 An alkoxy group; r j2 Selected from hydrogen, R h2 Selected from hydrogen, methyl, ethyl, L 6 R 0a ,L 6 Selected from 1 to 2 methylene groups, R 0a Is selected from OH;
R i3 selected from hydrogen, C 1～2 Alkyl, phenyl, R j3 Selected from hydrogen, R h3 、R h4 Each independently selected from hydrogen, C 1～4 Alkyl, or R h3 、R h4 Linked to form a 6-membered saturated heterocyclic ring;
R i4 selected from hydrogen, A 1 The ring is a 5-membered heterocyclic ring;
R i5 selected from hydrogen, C 1～2 Alkyl, phenyl, R j4 Selected from hydrogen, R h5 、R h6 Each independently selected from hydrogen, C 1～4 Alkyl, or R h5 、R h6 Linked to form a 6-membered saturated heterocyclic ring;
R i6 selected from hydrogen, A 2 The ring is a 5-6 membered heterocyclic ring;
R i7 selected from hydrogen, C 1～2 Alkyl, phenyl, R j5 Selected from hydrogen, R h7 Is selected from C 1～2 An alkyl group;
R i8 、R j6 each independently selected from phenyl;
R j7 is selected from benzyl;
R i9 、R j8 each independently selected from C 1～2 Alkyl radical, C 2～3 Alkenyl, benzyl, L 7 R 0b 、
L 7 Selected from 1 to 2 methylene groups, R 0b Selected from 6-membered unsaturated cycloalkyl;
R j9 is selected from C 1～2 Alkyl, phenyl, benzyl, R i10 、R j10 Each independently selected from hydrogen, C 1～2 An alkyl group;
R j11 selected from phenyl, R i11 Is selected from C 1～2 An alkyl group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: y is 1 Is chlorine; y is 2 Is chlorine.
3. A compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: the structure of the compound is shown as follows:
4. a pharmaceutical composition characterized by: the pharmaceutical composition is a preparation prepared by taking the compound of any one of claims 1 to 3, or pharmaceutically acceptable salt or stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a coronavirus main protease inhibitor.
6. Use according to claim 5, characterized in that: the coronavirus main protease inhibitor can inhibit the activity of coronavirus main protease; and/or, the coronavirus is a novel coronavirus SARS-CoV-2.
7. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for the treatment of a coronavirus.
8. Use according to claim 7, characterized in that: the coronavirus is novel coronavirus SARS-CoV-2.
9. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament for the prevention and/or treatment of viral pneumonia.
10. Use according to claim 9, characterized in that: the viral pneumonia is novel coronavirus pneumonia COVID-19.
11. Use of a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the preparation of a coronavirus main protease inhibitor:
12. use according to claim 11, characterized in that: the coronavirus main protease inhibitor can inhibit the activity of coronavirus main protease; and/or, the coronavirus is a novel coronavirus SARS-CoV-2.
13. Use of a compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a medicament against coronavirus:
14. use according to claim 13, characterized in that: the coronavirus is novel coronavirus SARS-CoV-2.
15. The application of the following compounds or pharmaceutically acceptable salts thereof or stereoisomers thereof in preparing medicaments for preventing and/or treating viral pneumonia:
16. use according to claim 15, characterized in that: the viral pneumonia is novel coronavirus pneumonia COVID-19.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641325A (en) * | 2007-03-26 | 2010-02-03 | 安斯泰来制药株式会社 | Ornithine derivative |
| WO2014099833A1 (en) * | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Indazole compounds as aldosterone synthase inhibitors |
| CN105985322A (en) * | 2015-03-03 | 2016-10-05 | 苏州翔实医药发展有限公司 | Amino pyrazine compound and application thereof |
| WO2017040451A1 (en) * | 2015-09-03 | 2017-03-09 | Bristol-Myers Squibb Company | Triazolopyridine inhibitors of myeloperoxidase |
| CN109121414A (en) * | 2016-02-01 | 2019-01-01 | 拜奥克里斯特制药公司 | Benzopyrazoles compound and its analog |
| CN109153643A (en) * | 2016-03-04 | 2019-01-04 | 范德比尔特大学 | Substituted indole MCL-1 inhibitors |
| CN110891935A (en) * | 2017-04-18 | 2020-03-17 | 泰普斯特医疗公司 | Bicyclic compounds and their use in cancer therapy |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004069792A2 (en) * | 2003-02-03 | 2004-08-19 | Janssen Pharmaceutica N.V. | Quinoline-derived amide modulators of vanilloid vr1 receptor |
| SG11202105424PA (en) * | 2018-11-30 | 2021-06-29 | Kymera Therapeutics Inc | Irak degraders and uses thereof |
-
2021
- 2021-07-30 CN CN202110873775.XA patent/CN113512025B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101641325A (en) * | 2007-03-26 | 2010-02-03 | 安斯泰来制药株式会社 | Ornithine derivative |
| WO2014099833A1 (en) * | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Indazole compounds as aldosterone synthase inhibitors |
| CN105985322A (en) * | 2015-03-03 | 2016-10-05 | 苏州翔实医药发展有限公司 | Amino pyrazine compound and application thereof |
| WO2017040451A1 (en) * | 2015-09-03 | 2017-03-09 | Bristol-Myers Squibb Company | Triazolopyridine inhibitors of myeloperoxidase |
| CN109121414A (en) * | 2016-02-01 | 2019-01-01 | 拜奥克里斯特制药公司 | Benzopyrazoles compound and its analog |
| CN109153643A (en) * | 2016-03-04 | 2019-01-04 | 范德比尔特大学 | Substituted indole MCL-1 inhibitors |
| CN110891935A (en) * | 2017-04-18 | 2020-03-17 | 泰普斯特医疗公司 | Bicyclic compounds and their use in cancer therapy |
Non-Patent Citations (1)
| Title |
|---|
| HARC as an open-shell strategy to bypass oxidative addition in Ullmann-Goldberg couplings;Lavagnino, Marissa N.等;《Proceedings of the National Academy of Sciences of the United States of America》;20200817;第117卷(第35期);图3 * |
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