Use of spirocyclic compounds in the preparation of 3CLpro protease inhibitors or drugs

Abstract

The present invention discloses the use of a spirocyclic compound in the preparation of a 3CLpro protease inhibitor or drug, belonging to the field of pharmaceutical technology. This application relates to the use of a spirocyclic compound in the preparation of a 3CLpro protease inhibitor or drug for treating and / or preventing diseases caused by coronavirus infection. The spirocyclic compound exhibits excellent inhibitory activity against major proteases and oxidase tolerance, exhibits good anti-coronavirus activity, and can be used to prevent or treat diseases caused by coronavirus infection, with promising pharmaceutical prospects.

Description

[0001] This application is a divisional case of the Chinese invention patent with application date of December 29, 2023, application number 2023118576791, and name "Spirocyclic compounds, preparation methods thereof and uses thereof". Technical Field

[0002] The present invention belongs to the field of medical technology and specifically relates to the use of a spirocyclic compound in the preparation of a 3CLpro protease inhibitor or a drug. More specifically, the present invention discloses the use of the spirocyclic compound in the preparation of a drug for preventing and / or treating diseases associated with 3CLpro protease or diseases caused by coronavirus infection. Background Art

[0003] While vaccines have been widely used as a means of boosting herd immunity, SARS-CoV-2 itself is prone to mutation, producing various mutant strains. When new mutants become prevalent, people vaccinated against the original strain can still become infected, rendering the vaccine ineffective. Therefore, the development of anti-coronavirus drugs remains a top priority.

[0004] Anti-coronavirus drugs currently under development can be divided into several categories based on their different mechanisms of action. Among them, two major protease inhibitors, such as primary protease inhibitors and RNA polymerase inhibitors, have attracted widespread attention in the industry due to their respective advantages. The following is an explanation of the relevant content of primary protease inhibitors:

[0005] The main protease (also known as 3CLpro, Mpro, or 3CL protease) is a three-domain cysteine ​​protease encoded by the viral genome that plays a crucial role in the replication of SARS-CoV-2. The SARS-CoV-2 genome encodes two polyproteins (pp1a and pp1ab) and four structural proteins. These polyproteins are cleaved by the key SARS-CoV-2 main protease at 11 different sites, producing shorter nonstructural proteins essential for viral replication. These nonstructural proteins include RdRp, helicase, and the main protease itself, which are responsible for various stages of SARS-CoV-2 viral replication. The main catalytic structure of the main protease is the Cys145-His41 catalytic dyad located in the cleft between domains I and II. This dyad and the substrate recognition pocket are highly conserved in the main protease of different coronavirus subtypes. Because the main protease plays a crucial role in viral replication and its active structure is relatively conserved, it could become a key drug target for anti-coronaviruses. Furthermore, since there are no proteins similar to the main protease in the human body, the safety of drugs that can inhibit the main protease can also be guaranteed. Therefore, the development of corresponding main protease inhibitor drugs targeting the main protease has good prospects.

[0006] The main protease typically has Cys145 and four active sites. Existing main protease inhibitors are designed by targeting Cys145. Based on the characteristics of the four active sites, corresponding molecular structures are designed to achieve specific binding with these sites, thereby inhibiting the activity of the main protease and preventing the replication of SARS-CoV-2 in the body.

[0007] Patent WO2021250648 and Pfizer's published literature disclose a main protease inhibitor: Among them is the representative specific compound PF-07321332 (Nimategravir) The drug has good anti-SARS-CoV-2 activity and has certain oral availability and safety, making it suitable for the treatment of COVID-19. However, when used orally, the drug still needs to be used in combination with ritonavir and its tolerance to oxidase is still low.

[0008] The exemplary specific compounds disclosed in patent WO2023009187 are shown in the following formula. Such compounds have poor oxidative stability.

[0009] Summary of the Invention

[0010] In order to overcome the defects of the prior art, such as the limited number of compounds that inhibit the main protease and poor oxidase tolerance, the present invention provides a spirocyclic compound for use in the preparation of a 3CLpro protease inhibitor or drug. Specifically, the spirocyclic compound or a pharmaceutically acceptable salt thereof is used in the preparation of a 3CLpro protease inhibitor or drug. The compound has comparable or better main protease activity inhibition ability and better oxidase tolerance than namatevir, achieving good antiviral activity and human liver microsomal stability. It is expected that in clinical use, it does not require concomitant use with drugs such as ritonavir, has a longer oxidative metabolism time in the body, reduces the number of oral doses per day, and is conducive to improving drug compliance.

[0011] The present invention provides the following technical solutions to solve the above technical problems.

[0012] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0013]

[0014] in,

[0015] X 1 is N or CH; X 2 -NR X2 , CR X3 or CR X4 R X5 ;

[0016] R X2 、R X3 、R X4 and R X5 are independently -H, -C 1-6 Alkyl or -C substituted by 1, 2 or 3 halogens 1-6 alkyl;

[0017] R 3 -H, oxo, halogen, C 1-6 Alkyl or -C substituted by 1, 2 or 3 halogens 1-6 alkyl;

[0018] is a single bond or a double bond;

[0019] R 1 and R 2 are independently H, -C(O)R 11 、-C(O)OR 12 、-S(O)2R 13 、-C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group, the “5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” and the “3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” are independently optionally replaced by one, two or three R a replace;

[0020] R 11 、R 12 and R 13 Independently -C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10 Aryl, "a 5-10 membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3" or "a 3-10 membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from N, O and S, and the number of heteroatoms is 1, 2 or 3", the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group, the “5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” and the “3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” are independently optionally replaced by one, two or three R b replace;

[0021] R 4 and R 5 are independently H, -C 1-10 Alkyl, -C 3-10 Cycloalkyl or -C 6-10 Aryl; said -C 1-10 Alkyl, the -C 3-10 Cycloalkyl and the -C 6-10 Aryl is optionally substituted independently by 1, 2 or 3 R c replace;

[0022] R a are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -C3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0023] R b are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0024] R c are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0025] R 6 is cyano; R 7 is hydrogen; R 8 is halogen; n is 0 or 1;

[0026] When X 1 CH, X 2 CR X3 or CR X4 R X5 , R 1 and R 2 One of the groups is H and the other is -C(O)R 11 、-C(O)OR 12 or -S(O)2R 13 , R 11 、R 12 and R 13 Independently -C 1-10 When alkyl, the -C 1-10 The alkyl group is replaced by 1, 2 or 3 R a replace.

[0027] In some embodiments, in the compound of Formula I or a pharmaceutically acceptable salt thereof, certain groups have the following definitions, and the definitions of the unmentioned groups are as described in any embodiment of the present invention (hereinafter referred to as "a preferred embodiment").

[0028] In a preferred embodiment, R X2 and R X3 In the -C 1-6 Alkyl groups may independently be -C 1-4 Alkyl groups, such as methyl.

[0029] In a preferred embodiment, R X2and R X3 wherein the -C 1-6 -C in the alkyl group 1-6 Alkyl groups may independently be -C 1-4 Alkyl groups, such as methyl.

[0030] In a preferred embodiment, R 1 、R 2 、R 11 、R 12 、R 13 、R 4 、R 5 、R a 、R b and R c In the -C 1-10 Alkyl and the -C substituted by 1, 2 or 3 halogens 1-6 -C in the alkyl group 1-6 Alkyl groups may independently be -C 1-6 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl.

[0031] In a preferred embodiment, R 1 、R 2 、R 11 、R 12 and R 13 In the -C 3-10 Cycloalkyl groups may independently be -C 3-6 Cycloalkyl, for example cyclopropyl or cyclobutyl.

[0032] In a preferred embodiment, R a and R c In the -C 3-6 Cycloalkyl groups may independently be cyclopropyl or cyclobutyl.

[0033] In a preferred embodiment, R 1 、R 2 、R 11 、R 12 and R 13 In the -C 6-10 Aryl groups may independently be phenyl or naphthyl.

[0034] In a preferred embodiment, R 1 and R 2 In the above, the “5-10 membered heteroaryl group whose heteroatoms are selected from 1, 2 or 3 of N, O and S, and whose number of heteroatoms is 1, 2 or 3” can independently be “a 5-1 membered heteroaryl group whose heteroatoms are selected from N, and whose number of heteroatoms is 1 or 2”, preferably “a 5-6 membered heteroaryl group whose heteroatoms are selected from N, and whose number of heteroatoms is 1 or 2”, more preferably pyridyl (e.g., ) or diazolyl (e.g., 1H-pyrazolyl, for example, ).

[0035] In a preferred embodiment, R X2 、R X3 、R X4 、R X5 、R a 、R b and R c wherein the halogen may be F.

[0036] In a preferred embodiment, the X 1 is N or CH.

[0037] In a preferred embodiment, the X 2 NR X2 or CR X3 .

[0038] In a preferred embodiment, the R X2 -C 1-6 alkyl.

[0039] In a preferred embodiment, the R X3 is H or -C substituted by 1, 2 or 3 halogens 1-6 alkyl.

[0040] In a preferred embodiment, the R 3 It is -H or oxo.

[0041] In a preferred embodiment, the R 1 -C(O)R 11 、-C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10 Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group and the "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" are independently optionally replaced by 1, 2 or 3 R a replace.

[0042] Preferably, the R 1 -C(O)R 11 、-C 1-4 Alkyl, -C 3-6 Cycloalkyl, phenyl or "a 5-6 membered heteroaryl group having 1 or 2 nitrogen atoms"; the -C1-4 Alkyl, the -C 3-6 The cycloalkyl group, the phenyl group and the "5-6 membered heteroaryl group wherein the heteroatom is nitrogen and the number of the heteroaryl group is 1 or 2" are independently optionally substituted by 1, 2 or 3 R a replace.

[0043] More preferably, the R 1 -C(O)R 11 , phenyl or "a 5-6 membered heteroaryl group whose heteroatom is nitrogen and whose number is 1 or 2"; the phenyl group and the "a 5-6 membered heteroaryl group whose heteroatom is nitrogen and whose number is 1 or 2" are independently optionally replaced by 1, 2 or 3 R a replace.

[0044] In a preferred embodiment, the R 1 Can

[0045] Preferred More preferred

[0046] In a preferred embodiment, the R 2 For H.

[0047] In a preferred embodiment, the R 11 -C 1-10 Alkyl, -C 3-10 Cycloalkyl or -C 6-10 Aryl; said -C 1-10 Alkyl, the -C 3-10 Cycloalkyl and the -C 6-10 Aryl is optionally substituted independently by 1, 2 or 3 R b replace.

[0048] Preferably, the R 11 -C 1-4 Alkyl, -C 3-6 Cycloalkyl or phenyl; the -C 1-4 Alkyl, the -C 3-6 The cycloalkyl group and the phenyl group are optionally substituted with 1, 2 or 3 halogens;

[0049] More preferably, the R 11 -C 3-6 Cycloalkyl.

[0050] In a preferred embodiment, the R 11 is -CF3, cyclopropyl or phenyl; preferably cyclopropyl.

[0051] In a preferred embodiment, the R 4 -C 1-10 Alkyl; the -C 1-10 The alkyl group is optionally substituted by 1, 2 or 3 R c replace.

[0052] Preferably, the R 4 -C 1-4 Alkyl; the -C 1-4 The alkyl group is optionally replaced by 1 or 2 R c Substitution, said Rc is F, cyclopropyl, cyclobutyl or methyl; More preferably, said R 4 -C 1-4 Alkyl; the -C 1-4 The alkyl group is optionally substituted with 1 cyclopropyl group.

[0053] In a preferred embodiment, the R 4 for Preferably More preferred

[0054] In a preferred embodiment, the R 5 For H.

[0055] In a preferred embodiment, the R a are independently cyano, halogen, -C 1-10 Alkyl or -C 3-6 Cycloalkyl.

[0056] In a preferred embodiment, the R a It can be independently cyano, halogen, methyl or cyclopropyl; preferably cyano, F or methyl.

[0057] In a preferred embodiment, the R b are independently halogen, preferably F.

[0058] In a preferred embodiment, the R c are independently halogen, -C 1-10 Alkyl or -C 3-6 Cycloalkyl.

[0059] In a preferred embodiment, the R c It can be halogen, methyl, cyclopropyl or cyclobutyl; preferably cyclopropyl.

[0060] In a preferred embodiment, n is 0.

[0061] In a preferred embodiment, the Can Preferred

[0062] In a preferred embodiment, the Can Preferred More preferred

[0063] In a preferred embodiment, the compound represented by formula I may be a compound represented by formula IA,

[0064]

[0065] Wherein, * represents the chiral carbon atom of S configuration or R configuration;

[0066] Preferably, Formula IA is Formula IA-1 or Formula IA-2:

[0067]

[0068] In a preferred embodiment, the compound represented by Formula I may be a compound represented by Formula I-1, a compound represented by Formula I-2, or a compound represented by Formula I-3, preferably a compound represented by Formula I-2 or a compound represented by Formula I-3; more preferably a compound represented by Formula I-3:

[0069]

[0070] In a preferred embodiment, the compound represented by formula I-1 may be a compound represented by formula I-1-A and / or a compound represented by formula I-1-B.

[0071]

[0072] In a preferred embodiment, the compound represented by formula I-2 may be a compound represented by formula I-2-A and / or a compound represented by formula I-2-B.

[0073]

[0074] In a preferred embodiment, the compound represented by formula I-3 may be a compound represented by formula I-3-A and / or a compound represented by formula I-3-BA.

[0075]

[0076] In a preferred embodiment, each substituent in the compound represented by Formula I is represented by Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5 or Scheme 6:

[0077] Option 1:

[0078] The X 1 is N;

[0079] The X2 NR X2 , CR X3 or CR X4 R X5 ;

[0080] The R X2 、The R X3 、The R X4 and the R X5 are independently -H, -C 1-6 Alkyl or -C substituted by 1, 2 or 3 halogens 1-6 alkyl;

[0081] The R 3 is H or oxo;

[0082] described is a single bond or a double bond;

[0083] The R 1 and the R 2 are independently H, -C(O)R 11 、-C(O)OR 12 、-S(O)2R 13 、-C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10 Aryl, "a 5-10 membered heteroaryl group whose heteroatoms are 1, 2 or 3 selected from N, O and S" or "a 3-10 membered heterocycloalkyl group whose heteroatoms are 1, 2 or 3 selected from N, O and S", the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group, the “5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” and the “3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” are independently optionally replaced by one, two or three R a replace;

[0084] The R 11 、The R 12 and the R 13 Independently -C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10Aryl, "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" or "a 3-10 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group, the “5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” and the “3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms” are independently optionally replaced by one, two or three R b replace;

[0085] The R 4 and the R 5 are independently H, -C 1-10 Alkyl, -C 3-10 Cycloalkyl or -C 6-10 Aryl; said -C 1-10 Alkyl, the -C 3-10 Cycloalkyl and the -C 6-10 Aryl is optionally substituted independently by 1, 2 or 3 R c replace;

[0086] The R a are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0087] The R b are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0088] The R c are independently cyano, halogen, -C 1-10 Alkyl, -OC 1-10 Alkyl, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0089] The R 6 is cyano; said R 7 is H; the R8 is halogen; said n is 0 or 1;

[0090] Option 2:

[0091] The X 1 for CH;

[0092] The X 2 NR X2 , CR X3 or CR X4 R X5 ;

[0093] The R X2 、The R X3 、The R X4 and the R X5 are independently -H, -C 1-6 Alkyl, or -C substituted by 1, 2 or 3 halogens 1-6 alkyl;

[0094] The R 3 is -H or oxo;

[0095] described is a single bond or a double bond;

[0096] The R 1 and the R 2 are independently H, -C(O)R 11 or “a 5-10 membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S”;

[0097] The R 11 For 1, 2 or 3 R b Substituted -C 1-10 alkyl;

[0098] The R 4 and the R 5 are independently H, -C 1-10 Alkyl, -C 3-10 Cycloalkyl or -C 6-10 Aryl; said C 1-10 Alkyl, the -C 3-10 Cycloalkyl and the -C 6-10 The aryl group is optionally substituted by 1, 2 or 3 R c replace;

[0099] The R b are independently halogen;

[0100] The R c are independently cyano, halogen, -C 1-10Alkyl, -OC 1-10 Alkyl, -C 3-10 Cycloalkyl, -OC 3-6 Cycloalkyl or -C 6-10 aryl;

[0101] The R 6 is cyano; said R 7 is H; the R 8 is halogen; said n is 0 or 1;

[0102] Option 3:

[0103] The X 1 is N;

[0104] The X 2 NR X2 or CR X3 ;

[0105] The R X2 、The R X3 、The R X4 and the R X5 are independently -H, -C 1-6 Alkyl or -C substituted by 1, 2 or 3 halogens 1-6 alkyl;

[0106] The R 3 is -H or oxo;

[0107] described is a single bond or a double bond;

[0108] The R 1 H, -C(O)R 11 、-C 1-10 Alkyl, -C 3-10 Cycloalkyl, -C 6-10 Aryl or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; the -C 1-10 Alkyl, the -C 3-10 Cycloalkyl, the -C 6-10 The aryl group and the "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" are independently optionally replaced by 1, 2 or 3 R a replace;

[0109] The R 2 is H;

[0110] The R 11 -C 1-10 Alkyl, -C 3-10Cycloalkyl or -C 6-10 Aryl; said -C 1-10 Alkyl, the -C 3-10 Cycloalkyl and the -C 6-10 Aryl is optionally substituted independently by 1, 2 or 3 R b replace;

[0111] The R 4 -C 1-10 Alkyl; the -C 1-10 The alkyl group is optionally substituted by 1, 2 or 3 R c replace;

[0112] The R 5 is H;

[0113] The R a are independently cyano, halogen, -C 1-10 Alkyl or -C 3-6 Cycloalkyl;

[0114] The R b are independently halogen;

[0115] The R c are independently cyano, halogen, -C 1-10 Alkyl or -C 3-6 Cycloalkyl;

[0116] The R 6 is cyano; said R 7 is H; the R 8 is halogen; said n is 0;

[0117] Option 4:

[0118] The X 1 CH, X 2 for CH;

[0119] The R 3 is H;

[0120] described is a double bond;

[0121] The R 1 -C(O)R 11 or “a 5-10 membered heteroaryl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S”;

[0122] The R 2 is H;

[0123] The R 11 For 1, 2 or 3 R b Substituted -C1-10 alkyl;

[0124] The R 4 -C 1-10 Alkyl; the C 1-10 The alkyl group is optionally substituted by 1, 2 or 3 R c replace;

[0125] The R 5 is H;

[0126] The R b are independently halogen;

[0127] The R c are independently halogen;

[0128] The R 6 is cyano; said R 7 is H; the R 8 is halogen; said n is 0;

[0129] Option 5:

[0130] described for

[0131] The R 3 is -H or oxo;

[0132] The R 1 -C(O)R 11 、-C 1-4 Alkyl, -C 3-6 Cycloalkyl, phenyl or "a 5-6 membered heteroaryl group having 1 or 2 nitrogen atoms"; the -C 1-4 Alkyl, the -C 3-6 The cycloalkyl group, the phenyl group and the "5-6 membered heteroaryl group wherein the heteroatom is nitrogen and the number of the heteroaryl group is 1 or 2" are independently optionally substituted by 1, 2 or 3 R a replace;

[0133] The R 11 is -CF3, cyclopropyl or phenyl;

[0134] The R 2 is H;

[0135] The R 4 -C 1-4 Alkyl; the -C 1-4 The alkyl group is optionally substituted by 1, 2 or 3 R c replace;

[0136] The R 5 is H;

[0137] The R 6 is cyano; said R 7 is H; the R 8 is halogen; said n is 0; 1

[0138] Option 6:

[0139] described for

[0140] The R 3 is -H or oxo;

[0141] The R 1 -C(O)R 11 , phenyl or "a 5-6 membered heteroaryl group whose heteroatom is nitrogen and whose number is 1 or 2"; the phenyl group and the "a 5-6 membered heteroaryl group whose heteroatom is nitrogen and whose number is 1 or 2" are independently optionally replaced by 1, 2 or 3 R a replace;

[0142] The R 11 -C 3-6 Cycloalkyl;

[0143] The R 2 is H;

[0144] The R 4 -C 1-4 Alkyl; the -C 1-4 The alkyl group is optionally substituted with 1 cyclopropyl group;

[0145] The R 5 is H;

[0146] The R 6 is cyano; said R 7 is H; the R 8 is halogen; said n is 0.

[0147] In a preferred embodiment, the compound represented by formula I is selected from any one of the following compounds:

[0148]

[0149]

[0150] In a preferred embodiment, the compound represented by formula I is selected from any one of the following compounds:

[0151]

[0152]

[0153]

[0154]

[0155] The present invention also provides a method for preparing the compound of formula I, comprising the following steps: subjecting the compound of formula II to a dehydration reaction to obtain the compound of formula I;

[0156]

[0157] Among them, X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 8 As described in any one of the present invention, R 9 for

[0158] The present invention also provides a compound as shown in Formula II,

[0159] Among them, X 1 、X 2 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 and R 9 As described in any one of the present invention.

[0160] In a preferred embodiment, the compound represented by formula II is selected from any one of the following compounds:

[0161]

[0162]

[0163] The present invention also provides a compound as shown in formula III in, for R X2 、R X3 、R 1 、R 2 、R 3 、R 4 and R 5 As described in any one of the present invention.

[0164] In a preferred embodiment, the compound represented by formula III is selected from any one of the following compounds:

[0165]

[0166] The present invention also provides a pharmaceutical composition comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof (eg, a therapeutically effective amount of a pharmaceutically active ingredient), and a pharmaceutically acceptable carrier.

[0167] The present invention also provides a use of a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a 3CLpro protease inhibitor (e.g., in vivo or in vitro (such as a positive control in laboratory studies)).

[0168] The present invention also provides a use of a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or preventing diseases caused by coronavirus infection.

[0169] In a preferred embodiment, the coronavirus is one or more of 229Eα coronavirus, NL63α coronavirus, OC43β coronavirus, HKU1β coronavirus, Middle East Respiratory Syndrome Coronavirus (MERS-cov), Severe Acute Respiratory Syndrome Coronavirus (SARS-cov) and SARS-cov-2;

[0170] More preferably, the coronavirus is SARS-CoV-2.

[0171] The present invention also provides a use of a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating coronavirus disease 2019 (COVID-19).

[0172] The present invention also provides a method for treating diseases related to coronavirus infection, comprising administering to a subject in need of such treatment a compound shown in the above formula I (preferably, administering to a subject in need of such treatment a therapeutically effective amount of a compound shown in the above formula I), or a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0173] Definition of terms

[0174] Unless otherwise specified, the terms used in the present invention have the following definitions. Definitions of terms not mentioned below are as commonly understood by those skilled in the art to which the present invention belongs.

[0175] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable base in a neat solution or a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a neat solution or a suitable inert solvent. When the compound contains both relatively acidic and relatively basic functional groups, it can be converted into either a base addition salt or an acid addition salt.

[0176] At the end of the structural fragment It means that the structural fragment is connected to the rest of the molecule through this site. For example, It refers to cyclopropyl.

[0177] With wedge-shaped and dotted keys Indicates the absolute configuration of a stereocenter.

[0178] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0179] The term "oxo" refers to =O or -O - , oxygen atoms replace two hydrogens or lone pairs of electrons on the same carbon or nitrogen atom, in the form of =O or -O - .

[0180] For example

[0181] The term "alkyl" refers to a saturated, straight-chain or branched, monovalent hydrocarbon radical having a specified number of carbon atoms. For example, C 1-10 Alkyl refers to an alkyl group having 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms, such as C 1-6 Alkyl, such as C 1-4 Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0182] The term "cycloalkyl" refers to a saturated, monocyclic hydrocarbon group having the specified number of carbon atoms, for example, C 3-10 Cycloalkyl refers to a cycloalkyl group having 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9 or 10) ring carbon atoms, such as C 3-6 Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0183] The term "heterocyclyl" refers to a saturated, monocyclic hydrocarbon substituent having the specified number of ring atoms (e.g., 3-10 members), the specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and the specified heteroatom species (one or more of N, O, and S). The heterocyclyl is attached to the remainder of the molecule through a carbon atom or a heteroatom; the heterocyclyl is attached to the remainder of the molecule through a ring containing heteroatoms or a ring containing no heteroatoms. For example, a 3-10 membered heterocyclyl.

[0184] The term "aryl" refers to a radical having the specified number of carbon atoms (e.g., C 6-10 ) is a cyclic, aromatic, monovalent hydrocarbon group, which is a single ring or a bicyclic ring (for example, 2). When it is a bicyclic ring, the single rings share two atoms and a bond. For example, C 6-10 Aryl, specific examples include but are not limited to oxyphenyl or naphthyl.

[0185] The term "heteroaryl" refers to a monovalent group with a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). The heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom. For example, a 5-10 membered heteroaryl group, or a 5-6 membered heteroaryl group with one or two nitrogen atoms as the heteroatom, is provided. Specific examples include, but are not limited to: ).

[0186] In general, the term "substituted with" indicates that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Furthermore, when a group is substituted with one or more of the specified substituents, the substituents are independent of each other, i.e., the one or more substituents may be different or the same. Unless otherwise indicated, a substituent group may be substituted at every substitutable position of the substituted group. When more than one position in a given structure is substitutable with one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0187] The expression "a group B optionally substituted by one or more groups A" means that the group B may be unsubstituted or substituted by one or more groups A. For example, the C 1-6 The alkyl group is optionally substituted by 1, 2 or 3 R 3-2 Substitution refers to C 1-6 The alkyl group may be unsubstituted or substituted with 1, 2 or 3 R 3-2 replaced.

[0188] When a substituent is listed without indicating the atom via which it is bonded to a compound included in the general chemical formula but not specifically mentioned, such substituent may be bonded via any atom thereof. Combinations of substituents and / or variations thereof are permissible only if such combinations result in stable compounds.

[0189] When a group is listed without specifying that it has a substituent, such group is only meant to be unsubstituted. For example, when "C 1-6 When there is no limitation of "unsubstituted or substituted" before "alkyl", it only refers to "C 1-6 Alkyl" itself or "unsubstituted C 1-6 alkyl".

[0190] Additionally, it should be noted that, unless explicitly stated otherwise, the term "independently" used in the present invention should be broadly interpreted to mean that the individual entities described are independent of each other and can independently represent the same or different specific groups. More specifically, the term "independently" can mean that the specific options represented by the same symbol in different groups do not affect each other, or that the specific options represented by the same symbol in the same group do not affect each other.

[0191] The term "one or more" or "one or more than two" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0192] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0193] The term "prevent" refers to reducing the risk of developing a disease.

[0194] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat or prevent a disease or condition described herein. The amount of a compound that is effective will vary depending on the compound, the condition and its severity, and the age of the patient being treated, but can be adjusted as needed by one skilled in the art. Doses outside of this range may also be used depending on the dosage form and the severity of the disease.

[0195] The term "subject" refers to any animal, typically a mammal, such as a human, for whom treatment or disease prevention is desired. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0196] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0197] The reagents and raw materials used in the present invention are commercially available.

[0198] The positive progress of the present invention is that: in the application disclosed in the present invention, the compound has equivalent or better main protease activity inhibition ability and better oxidase tolerance, achieves good anti-coronavirus activity and excellent human liver microsome stability, does not need to be used in conjunction with ritonavir, etc. in clinical use, has a longer oxidative metabolism time in the body, reduces the number of oral administrations per day, and is conducive to improving drug compliance. DETAILED DESCRIPTION

[0199] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0200] Test conditions:

[0201] Prep-HPLC test parameters:

[0202] Instrument: Agilent;

[0203] Analytical column: Xtimate C18, 5 μm, 4.6*150 mm;

[0204] Mobile phase: A: 0.05% TFA in H2O, B: 0.05% TFA in ACN;

[0205] Wavelength: 214nm / 254nm;

[0206] Flow rate: 1ml / min.

[0207] Chiral-HPLC test parameters:

[0208] Chromatographic column: Daicel IH 250*4.6mm,5μm;

[0209] Mobile phase A: HEX + 0.2% DEA;

[0210] Mobile phase B: IPAMEOH + 0.2% DEA;

[0211] Detection wavelength: 254nm;

[0212] Flow rate: 1 mL / min;

[0213] Injection volume: 10 μL;

[0214] Column temperature: RT;

[0215] Run time: 14 minutes

[0216] Isocratic elution program: mobile phase A:mobile phase B=80:20 (V / V).

[0217] Example 1 Synthesis of intermediate

[0218] Example 1.1 Synthesis of intermediate s1

[0219]

[0220] Step 1:

[0221]

[0222] To a solution of s1-1 (67.0 g, 328 mmol) and NaOH (13.1 g, 328 mmol) in H2O (800 mL) was added a 38% aqueous solution of HCHO (45 mL, 623 mmol). The mixture was stirred at 25 ° C for 3 hours. It was then stirred at 110 ° C for 3 hours. LC-MS showed that the reaction was complete. HCl was added to the reaction mixture at 0 ° C to quench pH = 7, and then the mixture was precipitated to obtain a brown solid. The brown solid was washed with water, filtered and concentrated under reduced pressure to give s1-2 (51.3 g, 72.2%), a brown solid.

[0223] LCMS: m / z = 217.2 [M+H] + .

[0224] 1 H NMR: (400MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.45 (d, J = 8.0Hz, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.08 ( t,J=7.2Hz,1H),7.02-6.96(t,J=7.2Hz,1H),4.28-4.12(m,2H),3.62-3.58(m,2H),3.14(br dd,J=5.1,16.2Hz,2H),2.81(br dd,J=10.3,16.2Hz,1H).

[0225] Step 2:

[0226]

[0227] To a solution of s1-2 (51.3 g, 237 mmol) in MeOH (1000 mL) was added SOCl2 (98.7 g, 830 mmol) at 0°C. The mixture was stirred at 70°C for 4 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water and quenched with NaHCO3 at 0°C. It was then extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give s1-3 (43.3 g, 79.3%) as a white solid.

[0228] LCMS: m / z = 231.4 [M+H] + .

[0229] Step 3:

[0230]

[0231] To a solution of s1-3 (43.2 g, 188 mmol) in DCM (1000 mL) was added TEA (23.6 g, 233 mmol) and Boc2O (45.0 g, 206 mmol). The mixture was stirred at 25 ° C for 16 hours. LC-MS showed that the reaction was complete. HCl was added to the reaction mixture at 0 ° C to pH = 6 to quench, and then the mixture was diluted with water and extracted with DCM. The organic layers after extraction were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-11% ethyl acetate / petroleum ether gradient elution) to give s1-4 (60.2 g, 97%) as a white solid.

[0232] LCMS: m / z=331.1[M+H] + .

[0233] 1 H NMR(400MHz, CHLOROFORM-d)δ=8.42-7.78(m,1H),7.52(d,J=7.6Hz,1H),7.33(dd,J=2.5,7.9Hz,1H),7.20-7.16(m,2H),5.50-5.17( m,1H),4.98-4.77(m,1H),4.66-4.49(m,1H),3.64(d,J=8.2Hz,3H),3.45(d,J=15.5Hz,1H),3.19-3.05(m,1H),1.56(d,J=1.7Hz,9H).

[0234] Step 4:

[0235]

[0236] To a solution of s1-4 (31.0 g, 93.8 mmol) in THF (400 mL) and H2O (400 mL) were added NBS (16.7 g, 93.8 mmol) and HOAc (407 g, 6.78 mol). The mixture was stirred at -5°C for 1 hour. LC-MS showed that the reaction was complete. Saturated Na2SO3 solution (200 mL) was added to the reaction mixture to quench the reaction, and then NaHCO3 solution was added to the mixture at 0°C until pH = 7. The above mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give s1-5 (32.0 g, 98% yield) as a white solid. The configuration of compound s1-5 was determined with reference to WO2023009187.

[0237] LCMS: m / z=347.2[M+H] + .

[0238] 1 H NMR (400MHz, DMSO-d6) δ = 10.67 (s, 1H), 7.27-7.22 (m, 1H), 7.12-6.97 (m, 2H), 6.91 (d, J = 7.8Hz, 1H), 4.67-4 .57(m,1H),3.75-3.68(m,3H),3.59-3.47(m,2H),2.44-2.35(m,1H),2.31-2.19(m,1H),1.41-1.37(m,9H).

[0239] Step 5:

[0240]

[0241] To a solution of compound s1-5 (500 mg, 1.44 mmol) in MeOH (5 mL) in a sealed tube was added NH4OH (20.6 mL, 144 mmol), and the mixture was stirred at 80° C. for 16 hours. The mixture was concentrated to give compound s1-6 (425 mg, yield 94%) as a white solid.

[0242] LCMS: m / z (ES+) = 354.2 [M+Na] + .

[0243] Step 6:

[0244]

[0245] A solution of compound s1-6 (1 g, 3.00 mmol) in HCl / dioxane (10 mL) was stirred at 25° C. for 3 hours. The mixture was concentrated to give compound s1 (1.2 g, crude) as a white solid.

[0246] LCMS: m / z (ES+) = 232.0 [M+H] + .

[0247] 1 H NMR(400MHz, DMSO-d6)δ9.02(brs,1H),8.04(s,1H),7.77(s,1H),7.64(d,J=7.6Hz,1H),7.29–7.27(m,1H), 7.26–7.24(m,1H),7.02–6.98(m,1H),4.61(s,2H),3.46–3.43(m,1H),2.51–2.49(m,2H),2.26–2.25(m,2H).

[0248] Example 1.2 Synthesis of intermediate s2

[0249]

[0250] Step 1:

[0251]

[0252] Under N2, Burgess reagent (2.04g, 8.50mmol) was added to a solution of THF (20mL) of compound s1-6 (564mg, 1.70mmol), and the mixture was stirred at 25°C for 3 hours. The mixture was poured into saturated NaHCO3 solution (20mL), then extracted with ethyl acetate (10mLx3). The organic phase was washed with salt water (10mL), then dried and concentrated with Na2SO4, and the resulting residue was purified by silica gel column chromatography to obtain compound s2-1 (444mg, 83% yield), a white solid.

[0253] 1 H NMR (400MHz, CDCl3) δ8.74(s,1H),7.30(d,J=8.0Hz,1H),7.06(t,J=7.6Hz,1H),6.99(d,J=7.6Hz,2H),4.86(dt, J=47.2,7.8Hz,1H),3.89–3.70(m,2H),2.92–2.78(m,1H),2.54(dd,J=13.2,8.3Hz,1H),1.54(d,J=44.0Hz,9H).

[0254] Step 2:

[0255]

[0256] To TFA (2mL) and ACN (2mL) solution of compound s2-1 (120mg, 0.383mmol) was added anisole (124mg, 1.15mmol), and the solution was then stirred at 25°C for 1 hour. The mixture was concentrated, and the residue was quenched with saturated NaHCO (20mL), then extracted with ethyl acetate (15mLx3). The organic phase was washed with salt water (15mL), then Na was used SO It was dried and concentrated. The obtained residue was purified by silica gel column chromatography to obtain compound s2 (64mg, 78% yield), a white solid.

[0257] 1 H NMR (400MHz, CDCl3): δ8.23(s,1H),7.26–7.19(m,2H),7.07(td,J=7.6,0.8Hz,1H),6.94(d,J=7.8Hz,1H),4.42(dd, J=8.4,6.5Hz,1H),3.57(d,J=11.2Hz,1H),3.17(d,J=11.2Hz,1H),2.69(dd,J=13.6,6.3Hz,1H),2.56–2.52(m,1H).

[0258] Example 1.3 Synthesis of Intermediate 26a

[0259]

[0260] Step 1:

[0261]

[0262] To a solution of 26-1 (4.0 g, 27.36 mmol) and 2,6-lutidine (5.86 g, 54.73 mmol) in DCM (20 mL) was added Tf2O (9.26 g, 32.82 mmol) at 0°C. After addition, the mixture was stirred at 0°C for 0.5 h. The reaction mixture was extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, then filtered and concentrated under low pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 1:0 to 5:1) to give compound 26-2 (4.81 g, 63% yield) as a brown oil.

[0263] Step 2:

[0264]

[0265] To a solution of 26-3 (2.29 g, 9.38 mmol) and 26-2 (3.91 g, 14.06 mmol) in MeCN (10 mL) was added K2CO3 (2.59 g, 18.75 mmol) at 25°C. The resulting mixture was stirred at 50°C under N2 for 1.5 h. The reaction mixture was diluted with H2O (10 mL) and then extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under low pressure. The crude product was purified by silica gel chromatography (PE:EtOAc = 10:1 to PE:EtOAc = 5:1) to afford compound 26-4 (2.13 g, 5.72 mmol, 61%) as a brown oil.

[0266] MS (ESI+) m / z 373.10 [M+H] + .

[0267] Step 3:

[0268]

[0269] To a solution of 26-4 (290 mg, 778.70 μmol) in THF (5 mL) and water (1 mL) was added LiOH·H2O (100 mg, 2.38 mmol). The mixture was stirred at 25°C for 3 h. The mixture was then concentrated, diluted with water (10 mL), adjusted to pH 3-4 with 2 mol / L HCl, and extracted with EtOAc (20 mL x 2). The organic layers were combined and concentrated to afford 26a as a yellow oil.

[0270] MS (ESI+) m / z 359.10 [M+H] + .

[0271] Intermediate 27a was synthesized by a method similar to the above method, adjusting compound 26-3 to That's it.

[0272]

[0273] LCMS: m / z=320[M+1] + .

[0274] Example 1.4 Synthesis of Intermediate 3a

[0275]

[0276] Step 1:

[0277]

[0278] At 0 ° C, 3-1 (5.0 g, 38.7 mmol) was mixed with H2O (50 mL) and an aqueous solution of HBr (60 mL, 48 wt%), and a solution of sodium nitrite (4.5 g, 65.22 mmol) in H2O (10 mL) was added dropwise to the mixture. The mixture was further stirred at 0 ° C for 30 min and heated to 25 ° C overnight. The residue was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to give compound 3-2 (7.50 g crude product) as a yellow oil.

[0279] LC-MS[M+1] + =192.9,194.9.

[0280] Step 2:

[0281]

[0282] To a solution of 3-2 (7.5 g, 38.9 mmol) in EtOH (120 mL) was added SOCl2 (18.49 g, 155.4 mmol, 11.3 mL) at 0°C, and the mixture was further stirred at 25°C for 1 h. The solvent of the mixture was removed and purified by flash silica gel chromatography (PE:EA=100:1) to give 3-3 (5.5 g, 64.0% yield) as a colorless oil.

[0283] LC-MS[M+1] + =220.9,222.9.

[0284] Step 3:

[0285]

[0286] To a mixture of 3-4 (2.1 g, 18.90 mmol), 3-3 (5.43 g, 24.57 mmol), and DMF (20 mL) was added NaH (1.13 g, 28.35 mmol) at 0°C and stirred at 0°C for 1 h. The mixture was quenched with cold water, extracted with EA, and washed with brine. Compound 3-5 was purified by flash silica gel chromatography (PE:EA = 1:1) to afford compound 3-5 as a white solid (3.4 g, 72% yield).

[0287] LC-MS[M+1] + =252.2.

[0288] Step 4:

[0289]

[0290] At 25°C in an oxygen atmosphere, 3-5 (500 mg, 2.0 mmol), cyclopropylboronic acid (854.6 mg, 10.0 mmol), pyridine-N-oxide (PNO, A mixture of 1,4-dimethoxy-2-nitropropene (567.7 mg, 6.0 mmol), Cu(OAc)2 (1.2 g, 5.9 mmol), and pyridine (1.6 g, 19.9 mmol) in DCM (5 mL) was stirred for 12 h. The solvent was removed from the mixture and purified by flash silica gel chromatography (PE:EA=70:30) to afford compound 3-6 (100.0 mg, 17% yield) as a white solid.

[0291] LC-MS[M+1] + =292.10.

[0292] Step 5:

[0293]

[0294] To a solution of 3-6 (100 mg, 343.2 μmol) in THF (1 mL) and H₂O (1 mL) was added LiOH·H₂O (13.7 mg, 343.2 μmol). The mixture was stirred at 25°C for 1 h. The resulting mixture was extracted with EA, and the aqueous layer was acidified to pH 5 with HCl (2 mol / L) and extracted with EA. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated to afford compound 3a (80.00 mg, crude) as a white solid.

[0295] LC-MS[M+1] + =264.2.

[0296] The following compounds were synthesized by methods similar to the above methods:

[0297]

[0298]

[0299] Example 1.5 Synthesis of Intermediate 10a

[0300]

[0301] Step 1:

[0302]

[0303] To a solution of 10-1 (700 mg, 2.9 mmol) in DMSO (3 mL) was added cyclopropylamine (246.7 mg, 4.3 mmol) and DIEA (1.1 g, 8.6 mmol). The mixture was stirred at 130°C for 1 hour. The crude product was purified by reverse phase HPLC (ACN / H2O: 0-100%) to afford compound 10-2 (520 mg, 82%) as a yellow solid.

[0304] LCMS: m / z = 220.2 [M+H] + .

[0305] Step 2:

[0306]

[0307] To a solution of 10-2 (300 mg, 1.4 mmol) in dioxane (10 mL) was added Cs2CO3 (1.3 g, 4.1 mmol) and 10-3 (368.5 mg, 1.8 mmol). The mixture was stirred at 80 ° C for 2 hours. The reaction mixture was extracted with EA, the organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 10-4 (450 mg, crude product) as a yellow oil.

[0308] LCMS: m / z=346.0[M+H] + .

[0309] Step 3:

[0310]

[0311] To a solution of 10-4 (450 mg, 1.3 mmol) in THF (2 mL) and H₂O (2 mL) was added LiOH·H₂O (109.4 mg, 2.6 mmol). The mixture was stirred at 25°C for 2 hours. The mixture was adjusted to pH 4 with HCl (1 mol / L) and concentrated directly. The resulting product was purified by reverse phase HPLC (ACN / H₂O: 0-50%) to afford compound 10a (224.4 mg, 52%) as a yellow solid.

[0312] LCMS: m / z=332.2[M+H] + .

[0313] 1H NMR (400MHz, CHLOROFORM-d) δ = 7.04 (s, 1H), 6.41 (br s,1H),5.38(dd,J=5.6,9.6Hz,1H),2.92(qt,J=3.7,7.2Hz,1H),2.11-1.97(m,2H),0.92-0.86(m,2H),0.69-0.60(m,3H),0.51(br d,J=7.0Hz,2H),0.14(br dd,J=2.6,13.6Hz,2H).

[0314] The following compounds were synthesized by methods similar to the above methods:

[0315] Intermediate 16a:

[0316] Yellow solid

[0317]

[0318] LCMS: m / z = 404.0 [M+H] + .

[0319] 1 H NMR(400MHz, DMSO-d6)δ:9.20(s,1H),7.88–7.80(m,2H),7.39(t,J=9.7Hz,1H),7.16(t,J =8.9Hz,1H),5.26(dd,J=5.2,10.2Hz,1H),2.16–2.09(m,1H),2.03–1.96(m,1H),0.60(br s,1H),0.35(ddd,J=4.7,8.4,13.3Hz,2H),0.15–0.08(m,1H),0.00–-0.06(m,1H).

[0320] Example 1.6 Synthesis of Intermediate 12a

[0321]

[0322] Step 1:

[0323]

[0324] To a solution of 12-1 (300 mg, 2.10 mmol) in water (5 mL) was added an aqueous solution of HBr (1.85 mL, 40%). Then, an aqueous solution of NaNO2 (173 mg, 2.51 mmol) (5 mL) was added to the mixture at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was extracted with EA (30 mL x 2). The organic phase was separated, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 12-2 as a yellow oil.

[0325] 1 H NMR (400MHz, DMSO-d6) δ: 14.62–12.21 (m, 1H), 4.25 (t, J = 7.3Hz, 1H), 2.50–2.32 (m, 1H), 2.03–1.99 (m, 2H), 1.88–1.55 (m, 6H).

[0326] Step 2:

[0327]

[0328] To a solution of 12-2 (405 mg, 1.90 mmol) in MeOH (3 mL) was added SOCl2 (116 mg, 977 μmol). The mixture was stirred at 70°C for 16 hours. The reaction mixture was then concentrated under reduced pressure to obtain 12-3 as a yellow oil.

[0329] Step 3:

[0330]

[0331] To a solution of 2,4-difluoroaniline (1.4 g, 10.9 mmol) in THF (80 mL) was added NaHMDS (1 mol / L, 24.7 mL) at 0°C under N2. After 1 hour, a solution of 12-4 (2.0 g, 8.2 mmol) in THF (10 mL) was added to the mixture. The reactants were then stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated NH4Cl (50 mL) at 0°C, and then diluted with H2O (50 mL). The two phases were separated, and the aqueous phase was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. 12-5 (1.6 g, 67%) was obtained as a yellow solid by flash silica gel chromatography.

[0332] LCMS: m / z = 292.3 [M+H] + .

[0333] Step 4:

[0334]

[0335] To a solution of 12-5 (250 mg, 859 μmol) in dioxane (5 mL) were added CsCO (839 mg, 2.60 mmol) and 12-3 (247 mg, 1.12 mmol). The mixture was stirred at 80°C for 16 hours. The reaction mixture was extracted with EA (40 mL × 2), and the organic phase was separated, washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC to give 12a (115 mg, 32.1%) as a white solid.

[0336] LCMS: m / z=418.2[M+H] + .

[0337] 1 H NMR(400MHz, DMSO-d6)δ:13.83–12.83(m,1H),9.22–9.11(m,1H),7.92–7.82(m,1H),7.73(s,1H),7.40-7.36(m,1H),7.20–7.11(m,1H) ,5.17–5.08(m,1H),2.34–2.26(m,1H),2.25–2.15(m,2H),2.02–1.90(m,1H),1.87–1.72(m,3H),1.71–1.63(m,1H),1.58–1.47(m,1H).

[0338] The following compounds were synthesized by methods similar to the above methods:

[0339]

[0340] LCMS: m / z=372.3[M+H] + .

[0341] 1 H NMR(400MHz,DMSO-d6)δ:9.99(s,1H),7.93(s,1H),7.75(s,1H),7.67(s,1H),7.58(s,1H),5.17–5.13(m,1H),3.75(s,3 H),2.05–1.98(m,1H),1.92–1.89(m,1H),0.50–0.46(m,1H),0.28–0.23(m,2H),0.05–0.02(s,1H),0.00–-0.11(m,1H).

[0342] Example 1.7 Synthesis of Intermediate 15a

[0343]

[0344] Step 1

[0345]

[0346] To a solution of 15-1 (5.00 g, 26.1 mmol) in MeCN (125 mL) was added N,O-bis(trimethylsilyl)acetamide ( The mixture was stirred at 80°C for 2 hours. CH3I (5.60 g, 39.1 mmol) was then added to the mixture at 25°C, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was extracted with EA. The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Flash silica gel chromatography gave 15-2 (1.30 g, 24.0%) as a white solid.

[0347] LCMS: m / z=205.9, 207.9[M+H] + .

[0348] Step 2

[0349]

[0350] A solution of 15-2 (1.10 g, 5.50 mmol) in DMF (20 mL) was purged with N2 three times. NaH (329 mg, 8.20 mmol) was then added to the mixture at 0°C and stirred for 30 min. A solution of 15-3 (1.70 g, 8.20 mmol) in DMF (10 mL) was then added to the reaction mixture. The mixture was stirred at 90°C for 16 hours. NH4Cl (100 mL) was added to the mixture at 25°C to quench the reaction, followed by extraction with EtOAc (100 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to afford 15-4 (1.70 g, 93.0%) as a colorless oil.

[0351] LCMS: m / z=332.0, 334.0 [M+H] + .

[0352] Step 3

[0353]

[0354] Compound 15-4 (500 mg, 1.50 mmol) was dissolved in cyclopropylamine (6 mL) and stirred at 80° C. for 2 h. The reaction mixture was cooled to room temperature and then filtered. The filter cake was concentrated under reduced pressure to afford compound 15-5 as a white oil.

[0355] LCMS: m / z=309.3[M+H] + .

[0356] Step 4

[0357]

[0358] To a solution of 15-5 (464 mg, 1.50 mmol) in DCE (5 mL) was added hydroxy(trimethyl)stannane ( The mixture was stirred at 80°C for 16 hours. H2O (2 mL) was added to the mixture to quench the mixture, which was then filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (ACN:H2O: 0-20%) to afford 15a (160 mg, 36.1%) as a white solid.

[0359] LCMS: m / z = 295.2 [M+H] + .

[0360] 1 H NMR(400MHz,DMSO-d6)δ:5.09–4.98(m,1H),3.53(s,3H),2.00–1.91(m,1H),1.85–1.75 (m,1H),0.83–0.60(m,2H),0.32–0.22(m,6H),0.06–0.00(m,1H),-0.05–-0.12(m,1H).

[0361] Example 1.8 Synthesis of Intermediate 18a

[0362]

[0363] Step 1

[0364]

[0365] To a solution of 15-4 (500 mg, 602 μmol) and 1-methylpyrazole-4-amine (190 mg, 1.96 mmol) in dioxane (10 mL) were added Pd2(dba)3 (137 mg, 151 μmol), Xantphos (87.1 mg, 151 μmol) and Cs2CO3 (1.47 g, 4.52 mmol). The mixture was placed under N2 and stirred at 100 ° C under N2 atmosphere for 16 hours. The reaction mixture was extracted with EtOAc (150 mL x 2). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography to give 18-1 (280 mg, 53.4%) as a yellow solid.

[0366] LCMS: m / z=349.2[M+H] + .

[0367] Step 2

[0368]

[0369] To a mixed solution of 18-1 (267 mg, 766 μmol) in THF (2 mL), H₂O (2 mL), and MeOH (2 mL) was added NaOH (184 mg, 4.60 mmol). The mixture was stirred at 0°C for 2 hours. The pH of the reaction solution was adjusted to 4 with HCl (1 mol / L), and extracted with EtOAc (20 mL × 3). The organic phase was separated, washed with 30 mL of brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (H₂O) to give 18a (30 mg, 11.7%) as a white solid.

[0370] LCMS: m / z=335.3[M+H] + .

[0371] 1 H NMR (400MHz, DMSO-d6) δ: 9.10 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H), 4.99 (dd, J = 4.9, 10.3Hz, 1H), 3.81 (s,3H),3.47(s,3H),2.08–1.93(m,2H),0.59–0.49(m,1H),0.30–0.22(m,2H),0.00–-0.20(m,2H).

[0372] The following compounds were synthesized by methods similar to the above methods:

[0373]

[0374] Example 1.9 Synthesis of Intermediate 22a

[0375]

[0376] Step 1:

[0377]

[0378] 22-1 (3 g, 15.9 mmol), 4-amino-3-fluoro-benzonitrile (2.59 g, 19.1 mmol), Pd2(dba)3 (1.45 g, 1.59 mmol), Xantphos (918 mg, 1.59 mmol), Cs2CO3 (15.5 g, 47.6 mmol) and dioxane (30 mL) were mixed, degassed and purged with N2 three times, and then the mixture was stirred at 80°C under N2 atmosphere for 3 hours. The reaction mixture was diluted with EA (30 mL) and H2O (40 mL), and a yellow solid was separated and filtered. The filter cake was concentrated under vacuum to give compound 22-2 (2.9 g, crude) as a yellow solid.

[0379] LCMS: m / z=245.1[M+H] + .

[0380] Step 2:

[0381]

[0382] To a solution of 22-2 (1.2 g, 4.91 mmol) in ACN (10 mL) was added TMSCl (1.07 g, 9.83 mmol) and NaI (1.47 g, 9.83 mmol). The mixture was stirred at 50° C. for 2 h. The reaction mixture was filtered to obtain a residue as a brown solid 22-3 (1.3 g, crude product).

[0383] LCMS: m / z = 231.0 [M+H] + .

[0384] Step 3:

[0385]

[0386] To a solution of 22-3 (500 mg, 2.17 mmol) in DMF (20 mL) were added 22-4 (576 mg, 2.39 mmol), NaI (325 mg, 2.17 mmol), and Cs2CO3 (1.42 g, 4.34 mmol). The mixture was stirred at 80°C for 3 hours. The reaction mixture was extracted with EA (150 mL*2). The organic phase was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give 22-5 (290 mg, 34.2%) as a white solid.

[0387] LCMS: m / z=391.2[M+H] + .

[0388] Step 4:

[0389]

[0390] To a solution of 22-5 (270 mg, 691 μmol) in THF (10 mL) and H₂O (2 mL) was added LiOH·H₂O (58.1 mg, 1.38 mmol). The mixture was stirred at 25°C for 20 min. The mixture was extracted with EA. The aqueous layer was separated, and the pH of the aqueous layer was adjusted to 5-6 by adding 1 mol / L HCl, and then extracted again with EA. The organic layers were combined, washed with brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to afford 22a (230 mg, crude) as a yellow solid.

[0391] LCMS: m / z=363.2[M+H] + .

[0392] The following compounds were synthesized by methods similar to the above methods:

[0393]

[0394] Example 2 Synthesis of Compounds

[0395] Synthesis of compound 26:

[0396]

[0397] Step 1:

[0398] To a solution of 26a in DMF (4 mL) were added s1 (200.00 mg, 579.25 μmol, TFA), HATU (413.78 mg, 1.09 mmol) and NMM (256.84 mg, 2.54 mmol) at 0°C, and the mixture was stirred at 0°C for 2 h. The mixture was quenched with NH4Cl (10 mL, aq, sat.), extracted with ethyl acetate (10 mL*2), and the organic layer was concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10 / 1 to 0 / 1) to give 26a-1.

[0399] MS (ESI+) m / z = 594.10 [M+Na] + .

[0400] Step 2:

[0401] To a solution of 26a-1 (130 mg, 227.42 μmol) in THF (8 mL) was added 5% Pd / C (100 mg, 227.42 μmol, 5% purity). The mixture was degassed three times and then stirred at 25°C under a H2 atmosphere for 1 h. The mixture was filtered and concentrated to afford 26a-2 (100.00 mg, crude) as a yellow solid, which was used in the next step without purification.

[0402] MS (ESI+) m / z = 460.20 [M+Na] + .

[0403] Step 3:

[0404] To a solution of 26a-2 (90 mg, 205.72 μmol) in DCM (5 mL) was added TFAA (216.04 mg, 1.03 mmol, 142.98 μL) and TEA (208.17 mg, 2.06 mmol, 286.73 μL). The mixture was stirred at 30 ° C for 3 h. The mixture was washed with water (5 mL * 3). The organic layer was concentrated and purified by prep-HPLC to obtain compound 26 (9.2 mg) as a white solid.

[0405] MS (ESI+) m / z = 538.10 [M+Na] + .

[0406] 1H NMR (400MHz, DMSO-d6) δ10.72(d,J=9.9Hz,1H),10.39(s,0.4H),10.06(s,0.6H),7.97-7.93(m,1H),7.74-7.63(m 1H),7.29-7.01(m,2H),6.91-6.78(m,2H),6.52-6.44(m,1H),5.78-5.73(m,1H),5.20-5.12(m,1H),4.08-3 .62(m,2H),2.68-2.59(m,1H),2.47-2.43(m,1H),2.09-1.77(m,2H),1.39-1.28(m,1H),0.96-0.69(m,6H).

[0407] Synthesis of compound 11:

[0408]

[0409] Step 1:

[0410]

[0411] To a solution of 11a (60 mg, 161.5 μmol) and s1 (37.3 mg, 161.5 μmol) in DMF (2 mL) were added NMM (65.3 mg, 646.3 μmol) and HATU (122.8 mg, 323.1 μmol). The reaction mixture was stirred at 25 ° C for 1 h. The reaction was then quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (DCM: MeOH = 10: 1) to obtain 11a-1 (80.0 mg, 80%) as a white solid.

[0412] LC-MS[M+1] + =585.3.

[0413] Step 2:

[0414]

[0415] To a solution of 11a-1 (75.0 mg, 128.3 μmol) in DCM (5 mL) was added Berns reagent (306.6 mg, 1.2 mmol), and the mixture was stirred for 2 h at 25 ° C. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give 11-P1 (11 mg, 15%) as a white solid and 11-P2 (13 mg, 18%) as a white solid.

[0416] Among them, one is compound 11-P1 and the other is compound 11-P2.

[0417] 11-P1

[0418] LC-MS: m / z = 567.0 [M+1] + .

[0419] 1H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),9.97(s,1H),7.98(s,1H),7.71(s,1H),7.51(s,1H), 7.13(td,J=7.6,1.2Hz,1H),6.93(d,J=7.2Hz,1H),6.86–6.80(m,2H),5.72(d,J=8.0Hz,1H), 5.23–5.19(m,1H),4.12–4.09(m,2H),3.82(s,3H),2.67–2.60(m,1H),2.52–2.47(m,1H),2. 07–1.86(m,2H),0.70–0.62(m,1H),0.44–0.31(m,2H),0.22–0.16(m,1H),0.10–0.04(m,1H).

[0420] 11-P2

[0421] LC-MS: m / z = 567.0 [M+1] + .

[0422] 1H NMR(400MHz, DMSO-d6)δ:10.71(s,1H),10.15(s,1H),8.02(s,1H),7.75(s,1H),7.44(s,1H),7.26(td,J=7.6,8.0 Hz,1H),7.19(d,J=7.2Hz,1H),7.00(td,J=7.2,1.2Hz,1H),6.90(d,J=8.0Hz,1H),5.57(d,J=8.0Hz,1H),5.23–5. 19(m,1H),4.03(d,J=10.4Hz,1H),3.94(d,J=10.4Hz,1H),3.83(s,3H),2.68–2.62(m,1H),2.52–2.44(m,1H),2.0 4–1.97(m,1H),1.89–1.80(m,1H),0.66–0.60(m,1H),0.36–0.30(m,1H),0.21–0.08(m,2H),0.008–0.005(m,1H).

[0423] The following compounds were synthesized by methods similar to the above methods:

[0424] Compound 12: synthesized from compound 12a.

[0425] LC-MS: m / z = 613.5 [M+1] + .

[0426] 1 H NMR(400MHz,DMSO-d6)δ:10.72–10.71(m,1H),9.24(s,0.5H),9.05(s,0.5H),7. 88–7.73(m,1H),7.64(s,0.6H),7.58(s,0.4H),7.41–7.34(m,1H),7.20–7.05(m, 2.8H),6.94–6.80(m,2.2H),5.57–5.47(m,1H),5.23–5.18(m,1H),4.08–3.89(m, 2H),2.69–2.59(m,1H),2.48–2.44(m,1H),2.22–2.08(m,3H),2.04–1.49(m,6H).

[0427] Chiral HPLC: The ratio of the two isomers is 1:1.

[0428] There are two stereoisomers of compound 12.

[0429] Compound 13: synthesized from compound 13a.

[0430] Compound 13 was purified by Prep-HPLC to obtain the following two isomers.

[0431] Among them, one is compound 13-P1 and the other is compound 13-P2.

[0432] 13--P1

[0433] LC-MS: m / z = 530.4 [M+1] + .

[0434] 1H NMR(400MHz,DMSO-d6)δ:10.65(s,1H),9.27(s,1H),7.86(s,1H),7.53(s,1H),7.24 –7.07(m,1H),6.93–6.81(m,3H),5.89–5.45(m,1H),5.05–4.98(m,1H),3.79(s,4H), 3.73–3.68(m,1H),3.40(s,3H),2.67–2.60(m,1H),2.46–2.33(m,1H),2.11–1.82(m ,2H),0.66–0.56(m,1H),0.38–0.22(m,2H),0.09–0.03(m,1H),-0.12–-0.15(m,1H).

[0435] 13-P2

[0436] LC-MS: m / z = 530.4 [M+1] + .

[0437] 1 H NMR(400MHz, DMSO-d6)δ:10.71(s,1H),9.37(s,1H),7.94(s,1H),7.57(s,1H),7.26(td,J=7.6,1. 2Hz,1H),7.03–6.96(m,2H),6.90(d,J=7.6Hz,1H),5.37–5.31(m,1H),5.23–5.19(m,1H),3.81–3.7 8(m,3H),3.50(s,3H),3.41–3.36(m,2H),2.40–2.32(m,1H),2.24–2.16(m,1H),2.02–1.95(m,1H), 1.63–1.56(m,1H),0.66–0.60(m,1H),0.34–0.20(m,2H),0.06–0.016(m,1H),-0.20–-0.25(m,1H).

[0438] Compound 14: synthesized from compound 14a.

[0439] Compound 14 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0440] Among them, one is compound 14-P1 and the other is compound 14-P2.

[0441] 14-P1

[0442] LC-MS: m / z = 562.3 [M+1] +.

[0443] 1 H NMR(400MHz,DMSO-d6)δ:10.73(s,1H),8.29(s,1H),7.83–7.70(m,1H),7.37–7.24(m,2 H),7.11–6.90(m,4H),5.37–5.31(m,1H),5.25(t,J=8.4Hz,1H),3.55(d,J=10.4Hz,1H) ,3.41–3.36(m,4H),2.57–2.54(m,1H),2.43–2.37(m,1H),2.27–2.20(m,1H),1.62–1.5 4(m,1H),0.68–0.59(m,1H),0.36–0.20(m,2H),0.06–0.02(m,1H),-0.15–-0.22(m,1H).

[0444] 14-P2

[0445] LC-MS: m / z = 562.3 [M+1] + .

[0446] 1 H NMR(400MHz,DMSO-d6)δ:10.68(s,1H),8.27(s,1H),7.77–7.65(m,1H),7.36–7.31(m,1H),7 .26–7.06(m,2H),6.94–6.84(m,3H),5.51-5.47(m,1H),5.05(t,J=8.0Hz,1H),3.70(d,J=10 .8Hz,1H),3.57(d,J=10.4Hz,1H),3.30(s,3H),2.61–2.53(m,1H),2.46–2.41(m,1H),2.11– 1.85(m,2H),0.70–0.64(m,1H),0.35–0.30(m,2H),0.13–0.06(m,1H),-0.07–-0.13(m,1H).

[0447] Compound 15: synthesized from compound 15a.

[0448] Compound 15 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0449] Among them, one is compound 15-P1 and the other is compound 15-P2.

[0450] 15-P1:

[0451] LC-MS: m / z = 490.30 [M+H] + .

[0452] 1 H NMR(400MHz,CD3OD)δ:7.28–7.21(m,1H),7.07–6.90(m,3H),5.57–5.53(m,1 H),5.44–5.32(m,1H),3.51–3.45(m,2H),3.39(s,3H),2.62(d,J=8.0Hz,1H), 2.48–2.32(m,1H),2.31–2.23(m,1H),2.06–2.00(m,1H),1.78–1.58(m,1H),0 .75–0.62(m,3H),0.59–0.25(m,4H),0.11–0.03(m,1H),-0.08–-0.18(m,1H).

[0453] 15-P2:

[0454] LC-MS: m / z = 490.30 [M+H] + .

[0455] 1 H NMR(400MHz,CD3OD)δ:7.30–7.23(m,1H),7.07–6.94(m,3H),5.43–5.32( m,1H),5.25–5.19(m,1H),3.66–3.60(m,1H),3.51–3.45(m,4H),2.63–2. 52(m,2H),2.38–2.00(m,2H),1.65–1.57(m,1H),0.91–0.88(m,1H),0.75 –0.51(m,4H),0.41–0.26(m,2H),0.15–0.03(m,1H),-0.13–-0.18(m,1H).

[0456] Compound 17: synthesized from compound 17a.

[0457] Compound 17 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0458] Among them, one is compound 17-P1 and the other is compound 17-P2.

[0459] 17-P1

[0460] LC-MS: m / z = 580.0 [M+1] + .

[0461] 1 H NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.56(s,1H),7.31–7.17(m,3H),7.00–6.8 6(m,3H),5.56–5.48(m,1H),5.10–5.04(m,1H),3.71(d,J=10.4Hz,1H),3.58(d,J =10.8Hz,1H),3.21(s,3H),2.67–2.57(m,1H),2.47–2.41(m,1H),2.12–1.88(m,2 H),0.68–0.54(m,1H),0.40–0.24(m,2H),0.12-0.06(m,1H),-0.10–-0.19(m,1H).

[0462] 17-P2

[0463] LC-MS: m / z = 580.0 [M+1] + .

[0464] 1 H NMR (400MHz, DMSO-D6) δ10.74(s,1H),8.63(s,1H),7.31–7.24(m,3H),7.04–6.97(m,2H),6. 91(d,J=8.0Hz,1H),5.40–5.36(m,1H),5.23(t,J=8.8Hz,1H),3.51(d,J=10.4Hz,1H),3.41( d,J=10Hz,1H),3.26(s,3H),2.59–2.52(m,1H),2.43–2.38(m,1H),2.28–2.22(m,1H),1.63– 1.55(m,1H),0.63–0.59(m,1H),0.34–0.21(m,2H),0.07–0.01(m,1H),-0.20–-0.27(m,1H).

[0465] Compound 18: synthesized from compound 18a.

[0466] Compound 18 was purified by Prep-HPLC to obtain the following two isomers.

[0467] Among them, one is compound 18-P1 and the other is compound 18-P2.

[0468] 18-P1:

[0469] LC-MS: m / z = 530.30 [M+H] + .

[0470] 1H NMR(400MHz,DMSO-d6)δ:10.66(s,1H),8.72(s,1H),7.59(s,1H),7.25–7.13(m,1H),7.00–6.80 (m,3H),6.39(s,1H),5.49–5.36(m,1H),5.09–4.99(m,1H),3.74(s,3H),3.68(d,J=11.2Hz,1H), 3.56(d,J=11.2Hz,1H),3.35(s,3H),2.60–2.54(m,1H),2.47–2.40(m,1H),2.20–2.03(m,1H),1 .91–1.81(m,1H),0.68–0.57(m,1H),0.39–0.23(m,2H),0.11–0.03(m,1H),-0.10–-0.18(m,1H).

[0471] 18-P2:

[0472] LC-MS: m / z = 530.30 [M+H] + .

[0473] 1H NMR (400MHz, DMSO-d6) δ: 10.72 (s, 1H), 8.70 (s, 1H), 7.60 (d, J = 2.4Hz, 1H), 7.26 (d, J = 7.2Hz, 1H), 7. 03–6.89(m,3H),6.46(d,J=2.4,1H),5.36–5.32(m,1H),5.23–5.19(m,1H),3.74(s,3H),3.49(d,J=10 .4Hz,1H),3.44(s,3H),3.38(d,J=10.4Hz,1H),2.57–2.52(m,1H),2.43–2.32(m,1H),2.25–2.18(m,1 H),1.62–1.54(m,1H),0.66–0.58(m,1H),0.34–0.22(m,2H),0.06–0.01(m,1H),-0.18–-0.24(m,1H).

[0474] Compound 19: synthesized from compound 19a.

[0475] Compound 19 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0476] Among them, one is compound 19-P1 and the other is compound 19-P2.

[0477] 19-P1:

[0478] LC-MS: m / z = 580.4 [M+H] + .

[0479] 1 H NMR(400MHz,CD3OD)δ:8.15–7.94(m,1H),7.32–7.13(m,2H),7.09–6.87(m,3H),5.94–5.87(m,0. 2H),5.63–5.59(m,0.8H),5.19–5.03(m,1H),3.83(d,J=10.8Hz,1H),3.68–3.57(m,1.6H),3.46(s ,2.4H),2.89–2.77(m,0.2H),2.63(d,J=8.4Hz,1.8H),2.33–2.26(m,1H),1.86–1.77(m,0.8H),1 .75–1.66(m,0.2H),0.78–0.68(m,1H),0.46–0.33(m,2H),0.14–0.08(m,1H),0.00–-0.07(m,1H).

[0480] 19-P2:

[0481] LC-MS: m / z = 580.4 [M+H] + .

[0482] 1 H NMR(400MHz,CD3OD)δ:8.15–8.08(m,1H),7.31–7.24(m,2H),7.08–6.97(m ,2H),6.94(d,J=8.0Hz,1H),5.49–5.46(m,1H),5.24(t,J=8.8Hz,1H),3.62 –3.52(m,5H),2.65–2.53(m,2H),2.42–2.36(m,1H),1.69–1.57(m,1H),0.7 7–0.67(m,1H),0.44–0.26(m,2H),0.11–0.01(m,1H),-0.09–-0.16(m,1H).

[0483] Compound 20: synthesized from compound 20a.

[0484] Compound 20 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0485] Among them, one is compound 20-P1 and the other is compound 20-P2.

[0486] 20-P1:

[0487] LC-MS: m / z = 518.2 [M+H] + .

[0488] 1 H NMR(400MHz,CD3OD)δ:7.24–7.20(m,1H),7.04–6.94(m,2H),6.90(d,J=8.0Hz,1H),5.58 –5.53(m,1H),5.06–5.01(m,1H),3.80(d,J=10.8Hz,1H),3.60(d,J=10.4Hz,1H),3.46(s, 3H),2.69–2.56(m,2H),2.31–2.24(m,1H),2.00–1.87(m,1H),1.83–1.60(m,1H),0.98–0. 86(m,4H),0.76–0.67(m,1H),0.44–0.32(m,2H),0.12–0.06(m,1H),-0.03–-0.09(m,1H).

[0489] 20-P2:

[0490] LC-MS: m / z = 518.3 [M+H] + .

[0491] 1 H NMR(400MHz,CD3OD)δ:7.28(td,J=7.6,0.8Hz,1H),7.07–6.94(m,3H),5.44– 5.40(m,1H),5.23(t,J=8.8Hz,1H),3.61–3.47(m,5H),2.64–2.53(m,2H),2. 40–2.33(m,1H),1.96–1.89(m,1H),1.66–1.58(m,1H),0.99–0.87(m,4H),0. 76–0.66(m,1H),0.43–0.29(m,2H),0.09–0.03(m,1H),-0.07–-0.15(m,1H).

[0492] Compound 16: synthesized from compound 16a.

[0493] LC-MS: m / z = 599.3 [M+H] + .

[0494] 1H NMR(400MHz,DMSO-d6)δ:10.72(s,1H),9.27(s,0.5H),9.08(s,0.5H),7.81–7.74(m, 1H),7.67–7.59(m,1H),7.41–7.34(m,1H),7.28–7.12(m,3H),6.92–6.84(m,2H),5.7 2–5.59(m,1H),5.24–5.20(m,1H),4.11–3.97(m,2H),2.69–2.52(m,2H),2.11–1.82( m,2H),0.73–0.60(m,1H),0.48–0.31(m,1H),0.21–0.10(m,2H),-0.02–-0.04(m,1H).

[0495] Chiral HPLC: The ratio of one pair of isomers is 55:45.

[0496] There are two stereoisomers of compound 16.

[0497] Compound 22: synthesized from compound 22a.

[0498] Compound 22 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0499] Among them, one is compound 22-P1 and the other is compound 22-P2.

[0500] LCMS::m / z=558.1[M+H] + .

[0501] 22-P1:

[0502] 1H NMR(400MHz,DMSO-d6)δ=10.73(br s,1H),8.58–8.46(m,2H),7.92(dd,J=1.8,11.3Hz,1H),7.73(dd,J=1.1,8.5Hz,1H),7.30(d, J=4.9Hz,1H),7.11(d,J=4.8Hz,1H),7.00–6.94(m,1H),6.81(d,J=7.8Hz,1H),6.73–6.60(m,2 H),5.87(dd,J=5.9,7.4Hz,1H),5.20(t,J=7.9Hz,1H),4.09(d,J=10.8Hz,1H),3.95(d,J=10.6 Hz,1H),2.65–2.58(m,1H),2.50–2.37(m,3H),1.36(d,J=18.1Hz,3H),1.31(d,J=18.0Hz,3H).

[0503] 22-P2:

[0504] 1 H NMR (400MHz, DMSO-d6) δ=10.77–10.53(m,1H),8.90–8.74(m,1H),8.60(t,J=8.4Hz,1H),7.93(dd,J =1.8,11.2Hz,1H),7.78–7.69(m,1H),7.33–7.19(m,3H),7.12(d,J=4.8Hz,1H),7.03(t,J=7.7Hz,1 H),6.91(d,J=7.7Hz,1H),5.82(dd,J=5.0,7.8Hz,1H),5.20(dd,J=6.4,8.8Hz,1H),3.94(d,J=10.6 Hz,1H),3.79(d,J=10.3Hz,1H),2.65(dd,J=8.8,13.4Hz,1H),2.49–2.34(m,3H),1.35–1.21(m,6H).

[0505] Compound 3: synthesized from compound 3a.

[0506] Compound 3 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0507] Among them, one is compound 3-P1 and the other is compound 3-P2.

[0508] 3-P1

[0509] LC-MS: m / z = 459.3 [M+1] +.

[0510] 1 H NMR(400MHz, DMSO-d6)δ10.73(s,1H),7.22–7.17(m,1H),6.87–6.79(m,5H),5.59(t,J=7.6Hz,1H),5.14-5.11(m,1H),4.01–3.66(m,2H),2.65–2 .60(m,2H),2.03–1.94(m,1H),1.88-1.81(m,2H),0.66–0.59(m,3H),0.5 2–0.44(m,2H),0.39–0.32(m,2H),0.19–0.10(m,1H),0.07–0.04(m,1H).

[0511] 3-P2

[0512] LC-MS: m / z = 459.30 [M+1] + .

[0513] 1 H NMR(400MHz,DMSO-d6)δ10.70(s,1H),7.28-7.24(m,1H),7.17-7.15(m,1H),7.03– 6.97(m,1H),6.93–6.84(m,3H),5.50(t,J=7.5Hz,1H),5.23-5.19(m,1H),4.01–3. 82(m,2H),2.75–2.63(m,2H),2.06–1.87(m,2H),1.82–1.70(m,1H),0.81–0.61(m, 5H),0.35–0.29(m,1H),0.24–0.20(m,1H),0.12–0.08(m,1H),-0.02–-0.07(m,1H).

[0514] Compound 4: Synthesized from compound 4a

[0515] LCMS: m / z=513.0[M+1] + .

[0516] 1H NMR(400MHz, DMSO-d6)δ10.72(s,1H),8.66(d,J=2.0Hz,0.5H),8.40(d,J=2.2Hz,0.5H),8.25-8.19(m,1H),7 .20-7.00(m,7H),6.99(d,J=1.9Hz,2H),5.68-5.58(m,1H),5.25-5.16(m,1H),4.16(d,J=10.7Hz,0.5H),4.02 (dd,J=20.0,10.6Hz,1H),3.82(d,J=10.6Hz,0.5H),2.67-2.61(m,1H),2.03-1.96(m,1H),1.92-1.85(m,1H) ,1.81-1.73(m,1H),1.23(s,1H),0.72-0.59(m,1H),0.48-0.30(m,1H),0.23-0.15(m,1H),0.13-0.06(m,1H).

[0517] Compound 8: Synthesized from compound 8a

[0518] Compound 8 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0519] Both are white solids, one of which is compound 8-P1 and the other is compound 8-P2.

[0520] 8-P1

[0521] LC-MS m / z=514.3[M+H] + .

[0522] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.99(s,1H),8.23-8.21(d,J=4.8Hz,1H),7.76-7 .71(m,1H),7.31-7.27(m,1H),7.21-7.17(m,2H)7.06-6.98(m,1H),6.94-6.83(m,3H), 5.66(t,J=7.6Hz,1H),5.20-5.15(m,1H),4.15-4.09(m,2H),2.68-2.59(m,1H),2.52-2 .49(m,1H),2.02-1.85(m,2H),0.72-0.72(m,1H),0.44-0.36(m,2H),0.22-0.16(m,2H).

[0523] 8-P2

[0524] LC-MS m / z=514.3[M+H] + .

[0525] 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),9.25(s,1H),8.22(d,J=4.8Hz,1H),7.78–7.71(d,J=4.8Hz,1H),7.34–7.2 7(m,2H),7.20–7.16(m,1H),7.06–7.05(m,1H),7.02–6.98(m,1H)6.94–6.89(m,2H),5.60(t,J=8.0Hz,1H),5.25 –5.20(m,1H),4.01–3.99(m,1H),3.83–3.83(m,1H),2.69–2.62(m,1H),2.49–2.49(m,1H),2.03–1.96(m,1H),1. 82–1.73(m,1H),0.75–0.65(m,1H),0.37–0.30(m,1H),0.21–0.15(m,1H),0.11–0.07(m,1H),0.00–-0.05(m,1H).

[0526] Compound 5: Synthesized from compound 5a

[0527] LCMS: m / z=531.0[M+H] + .

[0528] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),8.74(s,0.6H),8.48(s,0.4H),8.03 -8.01(m,1H),7.12-7.01(m,4H),6.94-6.90(m,4H),5.62-5.60(m,1H),5.23-5.21(m,1H),4.13-3.98( m,2H),2.71-2.59(m,1H),2.46(m,1H),1.99-1.78(m,2H),0.85(m,1H),0.62-0.34(m,3H),0.19(m,1H).

[0529] Compound 7: Synthesized from compound 7a

[0530] LC-MS: m / z = 525.3 [M+H] + .

[0531] 1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.57(s,1H),8.16(s,1H),7.65(s,1H),7.23–7.16(m,2H) ,7.02–6.98(m,2H),6.91–6.82(m,2H),5.59–5.54(m,1H),5.24–5.19(m,1H),3.97–3.94(m,1H) ,3.77–3.63(m,1H),2.67–2.61(m,1H),2.51–2.47(m,1H),2.02–1.96(m,1H),1.79–1.72(m,1H) ,0.96–0.91(m,5H),0.61–0.57(m,1H),035–0.29(m,1H),0.12–0.06(m,2H),0.03–-0.07(m,1H).

[0532] Compound 6: synthesized from compound 6a.

[0533] Compound 6 was purified by Prep-HPLC to obtain the following two stereoisomers.

[0534] Among them, one is compound 6-P1 and the other is compound 6-P2.

[0535] 6-P1

[0536] LCMS: m / z=499.30[M+1] + .

[0537] NMR: 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),9.34(s,1H),8.07(s,1H),7.61(s,1H),7.16–7.06(m,1 H),6.95(s,2H),6.84(dq,J=15.4,7.28Hz,3H),5.67(t,J=7.6Hz,1H),5.16(dd,J=8.75,6.61H z,1H),4.07(s,2H),3.80(s,3H),2.63(dd,J=13.4,8.89Hz,1H),2.49-2.45(m,1H),1.94-1.86 (m,2H),0.71–0.58(m,1H),0.46–0.29(m,2H),0.17(dq,J=8.4,4.6Hz,1H),0.08–0.04(m,1H).

[0538] 6-P2

[0539] LCMS: m / z=499.30[M+1] + .

[0540] NMR: 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),9.61(s,1H),8.08(s,1H),7.62(s,1H),7.23(td,J=7.70,1.09Hz,1 H),7.15(d,J=7.2Hz,1H),7.07–6.75(m,5H),5.57-5.50(m,1H),5.23-5.15(m,1H),3.92(d,J=7.2Hz,1H), 3.80-3.70(m,4H),2.64–2.57(m,1H),2.45–2.36(m,1H),1.99–1.82(m,1H),1.71(dt,J=14.97,7.90Hz,1 H),0.56(dq,J=9.05,4.88Hz,1H),0.29(tt,J=9.10,4.04Hz,1H),0.19–0.03(m,2H),-0.04–-0.11(m,1H).

[0541] Compound 10: synthesized from compound 10a.

[0542]

[0543] LC-MS[M+H] + =527.30.

[0544] 1HNMR (400MHz, DMSO-d6) δ10.71–10.69(d,J=7.2Hz,1H),7.95–7.94(d,J=4.8Hz,0.5H),7.74–7.73(d,J=5.2Hz,0.5H),7.42( s,0.5H),7.38(s,0.5H),7.25–7.17(m,1.5H),7.01–6.97(m,0.5H),6.91–6.80(m,2H),5.66–5.59(m,0.5H),5.54-5.50(m,0. 5H),5.22–5.18(m,1H),4.07–3.39(m,1.5H),3.89–3.87(d,J=10.4Hz,0.5H),2.85–2.72(m,1H),2.67–2.59(m,1H),2.49–2. 46(m,1H),2.00–2.54(m,1H),1.89–1.76(m,1H),0.70–0.56(m,5H),0.45–0.28(m,2H),0.20–0.15(m,1H),0.10–0.04(m,1H).

[0545] Chiral HPLC: the ratio of one pair of isomers was 55%:45%.

[0546] There are two stereoisomers of compound 10.

[0547] Biochemical tests

[0548] Test 1: 3CLpro protease inhibition assay

[0549] The test substance (example compound) was diluted 3-fold in series with DMSO, with a total of 10 test points. The above solution was added to a 384-well microplate using an ECHO workstation, and each test point was tested in duplicate. 25 μL of 3CLpro protease solution was added to each well of the microplate containing the test substance. After the solution was mixed, it was pre-incubated at room temperature for 30 minutes. After the incubation was completed, 5 μL of substrate (Dabcyl-KTSAVLQ∥SGFRKM-E (Edans)) was added. The final concentrations of protease 3CLpro and substrate were 25 nM and 25 μM, respectively. For the 100% inhibition (HPE, hundred percent effect) control sample, 1 μM compound GC376 was added. For the 0% inhibition (ZPE, zero percent effect) control sample, no compound was added. The final concentration of the DMSO solution was 1%. Each test point was normalized using a background control to exclude background fluorescence interference. After incubation at 30°C for 60 minutes, the fluorescence signal (RFU) was detected at Ex / Em=340nm / 490nm using a microplate reader M2e (SpectraMax). The inhibitory activity was calculated using the following formula: Inhibition % = [(sample-average ZPE) / (average HPE-average ZPE)]*100%.

[0550] 3CLpro protease solution: 20 mM Tris-HCl (pH 7.3), 100 mM NaCl, 1 mM EDTA, 5 mM TCEP and 0.1% BSA.

[0551] HEP: 100% inhibition control sample, containing substrate + 3CLpro protease solution + 1 μM GC376.

[0552] ZPE: 0% inhibition control sample, containing substrate + 3CLpro protease solution, without analyte.

[0553] Sample: Compound activity test sample. Contains substrate + 3CLpro protease solution + test substance.

[0554] Background control: contains the test substance + substrate, without protease.

[0555] Draw the inhibition curve and calculate the half-maximal inhibitory concentration (IC) 50 ,The results are shown in Table 1.

[0556] The compound of the present invention has 3CLpro protease inhibitory activity comparable to that of nematevir.

[0557] Test 2: In vitro SARS-CoV-2 replicon antiviral assay

[0558] The test substance was serially diluted 3-fold with DMSO solution for a total of 8 test points. 0.3 μL of the test substance solution was added to a 384-well microplate, and each test point was tested in duplicate. RNA replicons were obtained by in vitro transcription (in vitro transcribed RNA was purified using the RNeasy MinElute Cleanup Kit (QIAGEN 74204), OD260 / 280≈2, RNA Conc≥1000 ng / uL). Huh7 cells were transfected with purified SARS-CoV-2 replicon RNA (the constructed replicon was derived from GenBank: NC045512, T7 promoter was added to the 5' end, the ORFs of the S and E genes were deleted, and the EGFP and bsd genes were inserted instead, respectively. Poly A was retained at the 3' end, the HDV ribozyme sequence and T7 terminator were added, and the cells were connected to the BAC vector (GENWIZ). The linearized in vitro transcribed and purified RNA was electroporated into the cells.) and inoculated at 4000 / well. Serially diluted compounds were added to 384-well microplates and then incubated at 37°C and 5% CO2 for 1 day. The final volume of the cell culture was 60 μL per well and the final DMSO concentration in the assay plate was 0.5%.

[0559] Fluorescence intensity was measured using Acumen Cellista (TTP LabTech), and the antiviral activity of the compounds was calculated based on the inhibition of GFP expression. Cell viability was determined using CellTiter Glo according to the manufacturer's instructions.

[0560] The antiviral activity and cell viability of the compounds were expressed as % inhibition and % viability, respectively, and were calculated using the following formula:

[0561] Inhibition rate (%) = (CPD-average ZPE) / (average HPE-average ZPE)*100

[0562] Cell viability (%) = (CPD - average HPE) / (average ZPE - average HPE) * 100

[0563] CPD: measured value of the sample containing the analyte

[0564] ZPE: Mean value of virus control

[0565] HPE: average value of blank control (containing only culture medium).

[0566] The natural log-transformed inhibition rate-response was fitted using a nonlinear four-parameter model to calculate the EC 50 and CC 50 The results are shown in Table 1. GraphPad Prism was used as the software.

[0567] The compound of the present invention has antiviral activity and cell viability comparable to those of namatevir.

[0568] Table 1

[0569] Compound number <![CDATA[IC 50 (nM)]]> <![CDATA[EC 50 (nM)]]> <![CDATA[CC 50 (nM)]]> Nirmatrelvir A A >1000 1 A A >1000 2 A A >1000 3 B A >1000 4 A A >1000 5 A A >1000 6 A A >1000 8 A A >1000 10 A A >1000 11 A A >1000 12 A A >1000 13 A A >1000 14 A A >1000 15 A A >1000 16 A A >1000 17 A A >1000 18 A A >1000 19 A A >1000 20 A B >1000 22 A A >1000 24 A A >1000 25 A A >1000 26 A A >1000 27 B B >1000

[0570] Note: A≤100, B 100-1000, C>1000.

[0571] Test 3: Human liver microsome stability

[0572] The analyte was dissolved in DMSO to a 10 mM stock solution and diluted to 100 μM with ACN:H₂O (v / v) at a ratio of 1:1 to prepare a working solution. The working solution was diluted to 1 μM in potassium phosphate buffer (100 mM, pH 7.4) containing MgCl₂ (3 mM), NADPH (1 mM), and HLM (1 mg / mL, human liver microsomes) to a final volume of 200 μL and incubated on a shaker at 37°C. Incubations were performed in the presence and absence of the selective CYP3A inhibitor ketoconazole (1 μM). At selected time points (0, 5, 15, 30, 45, 60, and 80 min), 200 μL of acetonitrile (containing 300 ng / mL tolbutamide) was added to 100 μL of sample. The mixture was shaken for 5 min and centrifuged at 3700 rpm for 15 min. The supernatant was transferred to a 96-well plate, diluted with mobile phase A (0.1% formic acid in water), and analyzed by liquid chromatography-mass spectrometry (LC-MS / MS). 1 / 2 Calculation formula t 1 / 2 =-0.693 / k, the data are shown in Table 2, where k is the slope of the linear fitting of the peak area ratio-time after natural logarithm transformation.

[0573] Compounds 1-25 of the present invention have better human liver microsomal stability (ie, oxidase stability) than Nematevir, and compounds 26 and 27 have human liver microsomal stability (ie, oxidase stability) comparable to Nematevir.

[0574] Table 2

[0575] Compound number Human liver microsome half-life t1 / 2 (min) Nirmatrelvir C 5 B 12 B 13 B 14 A 16 B 17 B 18 A 20 A 22 B 26 C

[0576] Note: t1 / 2 (min): A>100, B 30~100, C<30.

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a 3CLpro protease inhibitor or a drug, characterized in that: The drug is a drug for treating and / or preventing diseases caused by coronavirus infection, and the compound is selected from any one of the following compounds:

2. The use according to claim 1, characterized in that The coronavirus is one or more of 229Eα coronavirus, NL63α coronavirus, OC43β coronavirus, HKU1β coronavirus, Middle East Respiratory Syndrome Coronavirus, Severe Acute Respiratory Syndrome Coronavirus and SARS-cov-2.

3. The use according to claim 1, characterized in that The coronavirus is SARS-CoV-2.

4. The use according to any one of claims 1 to 3, characterized in that The compound is selected from any one of the following compounds:

5. A compound, characterized in that The compound is selected from any one of the following compounds:

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