CN113512025A - Indazole ester compound and pharmaceutical application thereof - Google Patents

Indazole ester compound and pharmaceutical application thereof Download PDF

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CN113512025A
CN113512025A CN202110873775.XA CN202110873775A CN113512025A CN 113512025 A CN113512025 A CN 113512025A CN 202110873775 A CN202110873775 A CN 202110873775A CN 113512025 A CN113512025 A CN 113512025A
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杨胜勇
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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-2MproCan be used for preparing SARS-CoV-2MproAnd (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

Indazole ester compound and pharmaceutical application thereof
Technical Field
The invention belongs to the technical field of organic synthetic drugs, and particularly relates to a SARS-CoV-2M inhibitorproThe indazole ester compound and the pharmaceutical application 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 it has been used clinicallyInterferon-alpha and the anti-HIV drug lopinavir/ritonavir ()
Figure BDA0003189610710000011
) Against SARS-CoV-2, but still has very limited efficacy and may have toxic side effects. The broad spectrum antiviral drug developed by Gilead Sciences, Inc, also explored the treatment of COVID-19, but more data was needed to demonstrate its efficacy. Therefore, there is still an urgent need to develop a safe and effective anti-SARS-CoV-2 drug.
The genomic RNA of coronaviruses is about 30knt long, has a 5 'cap structure and a 3' -poly-a tail, and contains at least 6 Open Reading Frames (ORFs). The first ORF (ORF1a/b) occupies approximately two thirds of the genome length, and translates two polyproteins directly: an a-1 frameshift exists between pp1a and pp1ab, 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.
MproThe proteolytic cleavage of the overlapping pp1a and pp1ab into functional proteins is a key step in the viral replication process. Enzymes necessary for viral replication, such as RdRp or nsp13, do not function fully to complete replication without prior proteolytic release. Thus, inhibition of viral MproCan prevent the generation of infectious virus particles, thereby alleviating the symptoms of the disease.
MproIs conserved among coronaviruses, and M is present in different coronavirusesproHave 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, MproThe unique substrate preference for glutamine at the P1 site (Leu-Gln ↓ (Ser, Ala, Gly)), which is the hostAbsence in protease indicates by targeting viral MproIt 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 MproBecomes an ideal antiviral target.
Therefore, there is a need to develop an M that can effectively inhibit SARS-CoV-2 virusproAn enzymatically active agent.
Disclosure of Invention
The purpose of the present invention is to provide a main protease (M) capable of efficiently utilizing SARS-CoV-2 viruspro) Active indazole ester compounds and pharmaceutical application thereof.
The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopic substitution form thereof:
Figure BDA0003189610710000021
wherein X is N or CRa，RaSelected from hydrogen, C1～6Alkyl radical, C1～6Alkoxy radical, C2～6Alkenyl radical, C2～6Alkynyl, L1M1Rb；L1Selected from 0 to 3 methylene groups, M1Selected from among none, CO, NH, CONH, NHCO, COO or OCO, RbIs selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and the substituents are respectively and independently selected from halogen and C1～4Alkyl radical, C1～4An alkoxy group;
R1selected from hydrogen, C1～6Alkyl, substituted or unsubstituted aryl, heteroaryl, said substituents being selected from halogen, C1～4Alkyl radical, C1～4An alkoxy group;
R2selected from hydrogen, C1～8Alkyl radical, C1～8Alkoxy radical, C2～6Alkenyl radical, C2～8Alkynyl, protecting group, L2Rc；L2Selected from 0 to 3 methylene groups, RcSelected from substituted or unsubstituted toThe following groups: aryl, heteroaryl, saturated 3-to 6-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted aryl, substituted heteroaryl, substituted aryl,
Figure BDA0003189610710000022
the substituent is selected from halogen, CN, L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReSelected from 3 to 5 membered ring, RfSelected from hydrogen, C1～3Alkyl radical, RgSelected from 3-to 5-membered ring, L3Selected from 0 to 3 methylene groups, L4Selected from 0 to 3 methylene groups;
R3selected from halogen, hydrogen,
Figure BDA0003189610710000023
Figure BDA0003189610710000024
Wherein R isi1Selected from hydrogen, C1～6Alkyl, 3-to 6-membered saturated cycloalkyl, aryl, heteroaryl, Rj1Selected from hydrogen, C1～4Alkyl radical, Rh1Selected from hydrogen, halogenated or non-halogenated C1～8Alkyl, L5R0Benzyl, 3-to 6-membered saturated cycloalkyl, bridged cycloalkyl, L5Selected from 1 to 4 methylene groups, R0Selected from OH, phenyl, C1～6Alkoxy, N (R)0c)23-to 6-membered heterocycle, R0cIs selected from C1～3An alkyl group;
Ri2selected from hydrogen, C1～4Alkyl, unsubstituted or substituted by RxSubstituted aryl radicals, RxIs selected from C1～4Alkyl radical, C1～4Alkoxy radical, Rj2Selected from hydrogen, C1～4Alkyl radical, Rh2Selected from hydrogen, C1～4Alkyl, L6R0a,L6Selected from 1 to 3 methylene groups, R0aIs selected from OH;
Ri3is selected fromHydrogen, C1～4Alkyl, aryl, heteroaryl, Rj3Selected from hydrogen, C1～4Alkyl radical, Rh3、Rh4Each independently selected from hydrogen, C1～4Alkyl, or Rh3、Rh4Connecting to form a 3-6 membered saturated heterocyclic ring;
Ri4selected from hydrogen, A1The ring is a 5-6 membered ring;
Ri5selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, Rj4Selected from hydrogen, C1～4Alkyl radical, Rh5、Rh6Each independently selected from hydrogen, C1～4Alkyl, or Rh5、Rh6Connecting to form a 3-6 membered saturated heterocyclic ring;
Ri6selected from hydrogen, C1～4Alkyl radical, A2The ring is a 5-6 membered ring;
Ri7selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, Rj5Selected from hydrogen, C1～4Alkyl radical, Rh7Selected from hydrogen, C1～4An alkyl group;
Ri8、Rj6each independently selected from hydrogen, C1～4Alkyl, aryl, heteroaryl;
Rj7selected from benzyl, hydrogen, C1～4Alkyl, aryl, heteroaryl;
Ri9、Rj8each independently selected from hydrogen, C1～4Alkyl radical, C2～6Alkenyl, benzyl, aryl, heteroaryl, L7R0b、
Figure BDA0003189610710000031
L7Selected from 1 to 4 methylene groups, R0bSelected from 3-6 membered cycloalkyl;
Rj9selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl, Ri10、Rj10Each independently selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl;
Rj11selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl, Ri11Selected from hydrogen, C1～4Alkyl, 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:
Figure BDA0003189610710000032
Figure BDA0003189610710000041
wherein, Y1Is halogen, preferably chlorine; y is2Is halogen, preferably chlorine.
Further, X is N or CRa，RaSelected from hydrogen, C1～4Alkyl radical, C1～4Alkoxy radical, C2～4Alkenyl radical, C2～4Alkynyl, L1M1Rb；L1Selected from 0 to 2 methylene groups, M1Selected from among none, CO, NH, CONH, NHCO, COO or OCO, RbSelected from aryl, heteroaryl;
and/or, R2Selected from hydrogen, C1～7Alkyl radical, C1～7Alkoxy radical, C2～4Alkenyl radical, C2～4Alkynyl, protecting group, L2Rc；L2Selected from 0 to 2 methylene groups, RcSelected from the following substituted or unsubstituted groups: aryl, heteroaryl, saturated 3-to 5-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted aryl, substituted heteroaryl, substituted or substituted aryl, substituted heteroaryl, substituted or substituted aryl,
Figure BDA0003189610710000042
the substituent is selected from halogen, CN, L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReSelected from 5-membered heterocyclic ring, RfSelected from hydrogen, C1～3Alkyl radical, RgSelected from 5-membered heterocycles, L3Selected from 0 to 2 methylene groups, L4Selected from 0 to 1 methylene;
preferably, X is N or CRa，RaSelected from hydrogen, C1～3Alkyl radical, C1～3Alkoxy radical, L1M1Rb；L1Selected from 0 to 1 methylene group, M1Selected from among none, CO, NH, CONH, NHCO, COO or OCO, RbIs selected from phenyl;
and/or, R2Selected from hydrogen, C1～7Alkyl radical, C1～7Alkoxy radical, C2～3Alkenyl radical, C2～3Alkynyl, protecting group, L2Rc(ii) a The protecting group is preferably a Boc group, L2Selected from 0 to 1 methylene group, RcSelected from the following substituted or unsubstituted groups: phenyl, 6-membered heteroaryl, saturated 3-to 5-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl,
Figure BDA0003189610710000043
The 6-membered heteroaryl contains 1-2 nitrogen atoms, and the substituent is selected from halogen, CN and L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReIs selected from
Figure BDA0003189610710000044
RfSelected from hydrogen, C1～3Alkyl radical, RgIs selected from
Figure BDA0003189610710000045
L3Selected from 0 to 1 methylene group, L4Selected from 0 to 1 methylene group.
Further, R3Selected from halogen, hydrogen,
Figure BDA0003189610710000051
Figure BDA0003189610710000052
Wherein R isi1Selected from hydrogen, C1～2Alkyl, 6-membered saturated cycloalkyl, phenyl, Rj1Selected from hydrogen, Rh1Selected from hydrogen, halogenated or non-halogenated C1～8Alkyl, L5R0Benzyl, 6-membered saturated cycloalkyl, bridged cycloalkyl, L5Selected from 2 to 3 methylene groups, R0Selected from OH, phenyl, methoxy, N (CH)3)23-membered oxygen heterocycle;
Ri2selected from hydrogen, unsubstituted or substituted by Rx1Substituted phenyl radicals, Rx1Is selected from C1～2Alkyl radical, C1～2An alkoxy group; rj2Selected from hydrogen, Rh2Selected from hydrogen, methyl, ethyl, L6R0a,L6Selected from 1 to 2 methylene groups, R0aIs selected from OH;
Ri3selected from hydrogen, C1～2Alkyl, phenyl, Rj3Selected from hydrogen, Rh3、Rh4Each independently selected from hydrogen, C1～4Alkyl, or Rh3、Rh4Linked to form a 6-membered saturated heterocyclic ring;
Ri4selected from hydrogen, A1The ring is a 5-membered heterocyclic ring;
Ri5selected from hydrogen, C1～2Alkyl, phenyl, Rj4Selected from hydrogen, Rh5、Rh6Each independently selected from hydrogen, C1～4Alkyl, or Rh5、Rh6Linked to form a 6-membered saturated heterocyclic ring;
Ri6selected from hydrogen, A2The ring is a 5-6 membered heterocyclic ring;
Ri7selected from hydrogen, C1～2Alkyl, phenyl, Rj5Selected from hydrogen, Rh7Is selected from C1～2An alkyl group;
Ri8、Rj6each independently selected from phenyl;
Rj7is selected from benzyl;
Ri9、Rj8each independently selected from hydrogen, C1～2Alkyl radical, C2～3An alkenyl group,Benzyl, L7R0b、
Figure BDA0003189610710000053
L7Selected from 1 to 2 methylene groups, R0bSelected from 6-membered unsaturated cycloalkyl;
Rj9is selected from C1～2Alkyl, phenyl, benzyl, Ri10、Rj10Each independently selected from hydrogen, C1～2An alkyl group;
Rj11selected from phenyl, Ri11Is selected from C1～2An alkyl group.
Further, the structure of the compound is shown as follows:
Figure BDA0003189610710000061
Figure BDA0003189610710000071
Figure BDA0003189610710000081
Figure BDA0003189610710000091
the invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or pharmaceutically acceptable salt thereof, or stereoisomer thereof, or optical isomer thereof, 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 thereof, or the stereoisomer thereof, or the optical isomer thereof, or the isotope substitution form thereof in preparing a medicament for preventing and/or treating viral pneumonia, preferably the viral pneumonia is the novel coronavirus pneumonia COVID-19.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
The minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, e.g. prefix Ca～bAlkyl represents any alkyl group containing from "a" to "b" carbon atoms. E.g. C1～6The alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
Similarly, C1～6The alkoxy group means a straight chain or branched chain alkoxy group having 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, "3-6 membered cycloalkyl" refers to cycloalkyl having 3-6 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 that the carrier, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
"salts" are acid and/or base salts of compounds with inorganic and/or organic acids and/or bases, and also include zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. 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-2MproActive indazole ester compounds, which can be used for preparing SARS-CoV-2MproAnd (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.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
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:
Figure BDA0003189610710000111
route B:
Figure BDA0003189610710000112
route C:
Figure BDA0003189610710000113
route D:
Figure BDA0003189610710000121
route E:
Figure BDA0003189610710000122
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
Figure BDA0003189610710000123
The starting material A (1equiv), methanol (1.5equiv), EDCI (1.5equiv), HOBT (1equiv) and DIEA (1.5equiv) were added in this order 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
Figure BDA0003189610710000124
Intermediate B-14(1equiv), iodine (2equiv) and potassium hydroxide (4equiv) 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%.
1HNMR(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
Figure BDA0003189610710000131
Intermediate C-14(1equiv), methyl iodide (1.5equiv) and cesium carbonate (1.5equiv) were added to DMF and 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%.
1HNMR(400MHz,CDCl3)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
Figure BDA0003189610710000132
Dissolving the intermediate D-14(1equiv) in a mixed solvent of DMF and TEA-5: 1, and mixing methyl acrylate (10equiv) and PdCl2(dppf) (0.1equiv) and TBAB (2equiv) 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%.
1HNMR(400MHz,CDCl3)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
Figure BDA0003189610710000133
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 give a white solid (i.e., compound 14) with a yield of 80%.
1HNMR(400MHz,CDCl3)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
Figure BDA0003189610710000141
Intermediate D-14(1equiv), dissolved in toluene, followed by Pd (OAc)2(0.1equiv) and AgOAc (4equiv) were added to the reaction mixture to ensure that the reaction was carried out under nitrogen, and the reaction was carried out at 110 ℃ for 8 hours and monitored by TLC. 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) with a yield of 80%.
1HNMR(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
Figure BDA0003189610710000142
Compound H (1equiv), 2-bromopropane (1.5equiv) and potassium hydroxide (1.5equiv) 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.
1HNMR(400MHz,CDCl3)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
Figure BDA0003189610710000151
Mixing intermediate D-14(1equiv), benzylthiol (0.9equiv), Pd2(dba)3(0.05equiv), DIEA (2equiv) and Xantphos (i.e. 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 0.1equiv) 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. TLC monitoring reaction, EA extraction after reaction, saturated saline solution washing, anhydrous sodium sulfate drying, column colorThe spectrum was separated to give a pale yellow solid (i.e., compound 30) in 80% yield.
1H NMR(400MHz,CDCl3)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
Figure BDA0003189610710000152
The raw material Q (1equiv), bromoethane (1.2equiv) and potassium carbonate (1.5equiv) 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.
1H NMR(400MHz,CDCl3)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
Figure BDA0003189610710000153
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
Figure BDA0003189610710000161
Referring to the synthetic procedure of scheme a, compound 40 is prepared:
Figure BDA0003189610710000162
example 8: preparation of Compound 37 with reference to scheme A
Replacing the raw material A with
Figure BDA0003189610710000163
Referring to the synthetic procedure of scheme a, compound 37 is prepared:
Figure BDA0003189610710000164
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
Figure BDA0003189610710000165
Figure BDA0003189610710000171
Figure BDA0003189610710000181
Figure BDA0003189610710000191
Figure BDA0003189610710000201
Figure BDA0003189610710000211
Figure BDA0003189610710000221
Figure BDA0003189610710000231
Figure BDA0003189610710000241
Figure BDA0003189610710000251
Figure BDA0003189610710000261
Figure BDA0003189610710000271
Figure BDA0003189610710000281
Figure BDA0003189610710000291
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 on MproAssay for level of inhibition of enzyme Activity
(1) Experimental methods
Recombinant SARS-CoV-2Mpro(final concentration 750nM) was mixed with serial dilutions of test compound in 25. mu.L assay buffer (20mM Tris-HCl, pH 7.5, 150mM NaCl, 1mM EDTA, 2mM DTT) and incubated for 10 min. The reaction was initiated by adding 25. mu.L of fluorogenic substrate (MCA-AVLQ ↓: SGFR-Lys (Dnp) -Lys-NH2) 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 addedmaxV with reaction by addition of DMSOmaxAnd using it to generate an IC50Curve line. For each compound, the semi-Inhibitory Concentration (IC) against SARS-CoV-2Mpro was measured at 9 concentrations and 3 independent replicates50) The value is obtained. What is needed isThe experimental data were analyzed using GraphPad Prism software.
(2) Results of the experiment
TABLE 2 Compound of the invention vs. MproEnzyme activity inhibiting IC50Value of
Figure BDA0003189610710000301
Figure BDA0003189610710000311
It can be seen that the compounds of the present invention are effective in inhibiting SARS-CoV-2MproCan be used for preparing SARS-CoV-2MproInhibitors, 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-2MproCan be used for preparing SARS-CoV-2MproAnd (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 (10)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof:
Figure FDA0003189610700000011
wherein X is N or CRa，RaSelected from hydrogen, C1～6Alkyl radical, C1～6Alkoxy radical, C2～6Alkenyl radical, C2～6Alkynyl, L1M1Rb；L1Selected from 0 to 3 methylene groups, M1Selected from among none, CO, NH, CONH, NHCO, COO or OCO, RbIs selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, and the substituents are respectively and independently selected from halogen and C1～4Alkyl radical, C1～4An alkoxy group;
R1selected from hydrogen, C1～6Alkyl, substituted or unsubstituted aryl, heteroaryl, said substituents being selected from halogen, C1～4Alkyl radical, C1～4An alkoxy group;
R2selected from hydrogen, C1～8Alkyl radical, C1～8Alkoxy radical, C2～6Alkenyl radical, C2～8Alkynyl, protecting group, L2Rc；L2Selected from 0 to 3 methylene groups, RcSelected from the following substituted or unsubstituted groups: aryl, heteroaryl, saturated 3-to 6-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted aryl, substituted heteroaryl, substituted aryl,
Figure FDA0003189610700000012
the substituent is selected from halogen, CN, L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReSelected from 3 to 5 membered ring, RfSelected from hydrogen, C1～3Alkyl radical, RgSelected from 3-to 5-membered ring, L3Selected from 0 to 3 methylene groups, L4Selected from 0 to 3 methylene groups;
R3selected from halogen, hydrogen,
Figure FDA0003189610700000013
Figure FDA0003189610700000014
Wherein R isi1Selected from hydrogen, C1～6Alkyl, 3-to 6-membered saturated cycloalkyl, aryl, heteroaryl, Rj1Selected from hydrogen, C1～4Alkyl radical, Rh1Selected from hydrogen, halogenated or non-halogenated C1～8Alkyl, L5R0Benzyl, 3-to 6-membered saturated cycloalkyl, bridged cycloalkyl, L5Selected from 1 to 4 methylene groups, R0Is selected from
OH, phenyl, C1～6Alkoxy, N (R)0c)23-to 6-membered heterocycle, R0cIs selected from C1～3An alkyl group;
Ri2selected from hydrogen, C1～4Alkyl, unsubstituted or substituted by RxSubstituted aryl radicals, RxIs selected from C1～4Alkyl radical, C1～4Alkoxy radical, Rj2Selected from hydrogen, C1～4Alkyl radical, Rh2Selected from hydrogen, C1～4Alkyl, L6R0a,L6Selected from 1 to 3 methylene groups, R0aIs selected from OH;
Ri3selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, Rj3Selected from hydrogen, C1～4Alkyl radical, Rh3、Rh4Each independently selected from hydrogen, C1～4Alkyl, or Rh3、Rh4Connecting to form a 3-6 membered saturated heterocyclic ring;
Ri4selected from hydrogen, A1The ring is a 5-6 membered ring;
Ri5selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, Rj4Selected from hydrogen, C1～4Alkyl radical, Rh5、Rh6Each independently selected from hydrogen, C1～4Alkyl, or Rh5、Rh6Connecting to form a 3-6 membered saturated heterocyclic ring;
Ri6selected from hydrogen, C1～4Alkyl radical, A2The ring is a 5-6 membered ring;
Ri7selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, Rj5Selected from hydrogen, C1～4Alkyl radical, Rh7Selected from hydrogen, C1～4An alkyl group;
Ri8、Rj6each independently selected from hydrogen, C1～4Alkyl, aryl, heteroaryl;
Rj7selected from benzyl, hydrogen, C1～4Alkyl, aryl, heteroaryl;
Ri9、Rj8each independently selected from hydrogen, C1～4Alkyl radical, C2～6Alkenyl, benzyl, aryl, heteroaryl, L7R0b、
Figure FDA0003189610700000021
L7Selected from 1 to 4 methylene groups, R0bSelected from 3-6 membered cycloalkyl;
Rj9selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl, Ri10、Rj10Each independently selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl;
Rj11selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl, Ri11Selected from hydrogen, C1～4Alkyl, aryl, heteroaryl, benzyl.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, wherein: the structure of the compound is shown as formula II-1, formula II-2, formula II-3 or formula II-4:
Figure FDA0003189610700000022
wherein, Y1Is halogen, preferably chlorine; y is2Is halogen, preferably chlorine.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, wherein: x is N or CRa，RaSelected from hydrogen, C1～4Alkyl radical, C1～4Alkoxy radical, C2～4Alkenyl radical, C2～4Alkynyl, L1M1Rb；L1Selected from 0 to 2 methylene groups, M1Is selected fromNone, CO, NH, CONH, NHCO, COO or OCO, RbSelected from aryl, heteroaryl;
and/or, R2Selected from hydrogen, C1～7Alkyl radical, C1～7Alkoxy radical, C2～4Alkenyl radical, C2～4Alkynyl, protecting group, L2Rc；L2Selected from 0 to 2 methylene groups, RcSelected from the following substituted or unsubstituted groups: aryl, heteroaryl, saturated 3-to 5-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted or substituted heteroaryl, substituted aryl, substituted heteroaryl, substituted or substituted aryl, substituted heteroaryl, substituted or substituted aryl,
Figure FDA0003189610700000031
the substituent is selected from halogen, CN, L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReSelected from 5-membered heterocyclic ring, RfSelected from hydrogen, C1～3Alkyl radical, RgSelected from 5-membered heterocycles, L3Selected from 0 to 2 methylene groups, L4Selected from 0 to 1 methylene;
preferably, X is N or CRa，RaSelected from hydrogen, C1～3Alkyl radical, C1～3Alkoxy radical, L1M1Rb；L1Selected from 0 to 1 methylene group, M1Selected from among none, CO, NH, CONH, NHCO, COO or OCO, RbIs selected from phenyl;
and/or, R2Selected from hydrogen, C1～7Alkyl radical, C1～7Alkoxy radical, C2～3Alkenyl radical, C2～3Alkynyl, protecting group, L2Rc(ii) a The protecting group is preferably a Boc group, L2Selected from 0 to 1 methylene group, RcSelected from the following substituted or unsubstituted groups: phenyl, 6-membered heteroaryl, saturated 3-to 5-membered cycloalkyl, fused cycloalkyl, bicycloalkyl, hetero-fused cyclic, hetero-bicycloalkyl, heteroaryl, heteroarylalkyl, heteroaryl, heteroarylalkyl, heteroaryl, substituted or substituted heteroaryl,
Figure FDA0003189610700000032
The 6 yuanThe heteroaryl contains 1-2 nitrogen atoms, and the substituent is selected from halogen, CN and L3COORfC, halogenated or not halogenated1～3Alkyl, halogenated or non-halogenated C1～3Alkoxy, OL4Rg(ii) a Wherein R isdIs selected from C1～3Alkyl, phenyl, benzyl, ReIs selected from
Figure FDA0003189610700000033
RfSelected from hydrogen, C1～3Alkyl radical, RgIs selected from
Figure FDA0003189610700000034
L3Selected from 0 to 1 methylene group, L4Selected from 0 to 1 methylene group.
4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, wherein:
R3selected from halogen, hydrogen,
Figure FDA0003189610700000041
Figure FDA0003189610700000042
Wherein R isi1Selected from hydrogen, C1～2Alkyl, 6-membered saturated cycloalkyl, phenyl, Rj1Selected from hydrogen, Rh1Selected from hydrogen, halogenated or non-halogenated C1～8Alkyl, L5R0Benzyl, 6-membered saturated cycloalkyl, bridged cycloalkyl, L5Selected from 2 to 3 methylene groups, R0Selected from OH, phenyl, methoxy, N (CH)3)23-membered oxygen heterocycle;
Ri2selected from hydrogen, unsubstituted or substituted by RxSubstituted phenyl radicals, RxIs selected from C1～2Alkyl radical, C1～2An alkoxy group; rj2Selected from hydrogen, Rh2Selected from hydrogen and methylEthyl group, L6R0a,L6Selected from 1 to 2 methylene groups, R0aIs selected from OH;
Ri3selected from hydrogen, C1～2Alkyl, phenyl, Rj3Selected from hydrogen, Rh3、Rh4Each independently selected from hydrogen, C1～4Alkyl, or Rh3、Rh4Linked to form a 6-membered saturated heterocyclic ring;
Ri4selected from hydrogen, A1The ring is a 5-membered heterocyclic ring;
Ri5selected from hydrogen, C1～2Alkyl, phenyl, Rj4Selected from hydrogen, Rh5、Rh6Each independently selected from hydrogen, C1～4Alkyl, or Rh5、Rh6Linked to form a 6-membered saturated heterocyclic ring;
Ri6selected from hydrogen, A2The ring is a 5-6 membered heterocyclic ring;
Ri7selected from hydrogen, C1～2Alkyl, phenyl, Rj5Selected from hydrogen, Rh7Is selected from C1～2An alkyl group;
Ri8、Rj6each independently selected from phenyl;
Rj7is selected from benzyl;
Ri9、Rj8each independently selected from hydrogen, C1～2Alkyl radical, C2～3Alkenyl, benzyl, L7R0b、
Figure FDA0003189610700000043
L7Selected from 1 to 2 methylene groups, R0bSelected from 6-membered unsaturated cycloalkyl;
Rj9is selected from C1～2Alkyl, phenyl, benzyl, Ri10、Rj10Each independently selected from hydrogen, C1～2An alkyl group;
Rj11selected from phenyl, Ri11Is selected from C1～2An alkyl group.
5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, wherein: the structure of the compound is shown as follows:
Figure FDA0003189610700000051
Figure FDA0003189610700000061
Figure FDA0003189610700000071
Figure FDA0003189610700000081
6. a pharmaceutical composition characterized by: the pharmaceutical composition is a preparation prepared by taking the compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotope substitution form thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, for the preparation of a coronavirus main protease inhibitor.
8. Use according to claim 7, 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.
9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, for the manufacture of a medicament for combating coronavirus, preferably the coronavirus is the novel coronavirus SARS-CoV-2.
10. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or an isotopically substituted form thereof, for the manufacture of a medicament for the prevention and/or treatment of viral pneumonia, preferably viral pneumonia which is a novel coronavirus pneumonia CODVI-19.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023131167A1 (en) 2022-01-04 2023-07-13 海思科医药集团股份有限公司 Compound for inhibiting and degrading irak4, and pharmaceutical composition and pharmaceutical application thereof
RU2816391C1 (en) * 2023-02-06 2024-03-28 Федеральное Государственное бюджетное учреждение "27 Научный центр" Министерства обороны Российской Федерации Improved method of producing 5-chloropyridin-3-yl-1n-indole-4-carboxylate

Citations (9)

* Cited by examiner, † Cited by third party
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
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
WO2020113233A1 (en) * 2018-11-30 2020-06-04 Kymera Therapeutics, Inc. Irak degraders and uses thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
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
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
WO2020113233A1 (en) * 2018-11-30 2020-06-04 Kymera Therapeutics, Inc. Irak degraders and uses thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
AKAJI, KENICHI等: "Advances in the design of ligands interacting with 3CL protease of novel coronaviruses causing infectious respiratory syndrome", 《AMINO ACIDS, PEPTIDES, AND PROTEINS》 *
DING, RUI等: "Discovery of Irreversible p97 Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
GHOSH, ARUN K等: "Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
JOULE, J. A.: "Product class 13: indole and its derivatives", 《SCIENCE OF SYNTHESIS》 *
KLIMKOWSKI, VALENTINE J.等: "D-Phenylglycinol-derived non-covalent factor Xa inhibitors: Effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
LAVAGNINO, MARISSA N.等: "HARC as an open-shell strategy to bypass oxidative addition in Ullmann-Goldberg couplings", 《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 *
SHEEHAN, SCOTT M.等: "A four component coupling strategy for the synthesis of D-phenylglycinamide-derived non-covalent factor Xa inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
VERMA, MADHUSUDAN; BANSAL, DEEPANSHU: "Verma, Madhusudan; Bansal, Deepanshu", 《CHEMRXIV》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023131167A1 (en) 2022-01-04 2023-07-13 海思科医药集团股份有限公司 Compound for inhibiting and degrading irak4, and pharmaceutical composition and pharmaceutical application thereof
RU2816391C1 (en) * 2023-02-06 2024-03-28 Федеральное Государственное бюджетное учреждение "27 Научный центр" Министерства обороны Российской Федерации Improved method of producing 5-chloropyridin-3-yl-1n-indole-4-carboxylate

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