Lactam compound as well as preparation method and medical application thereof

Abstract

The invention relates to a lactam compound, a preparation method thereof and application of the lactam compound in medicine. Specifically, the invention relates to a lactam compound as shown in a general formula (I), a preparation method of the lactam compound, a pharmaceutical composition containing the lactam compound and application of the lactam compound serving as a 3CL protease inhibitor to treatment of 3CL protease activity related diseases or symptoms. Wherein each group in the general formula (I) is defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a lactam compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a lactam compound represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the same, as well as its use as a 3CL protease inhibitor in the treatment of diseases or conditions related to 3CL protease activity. Background Art

[0002] Pneumonia (COVID-19) caused by infection with the new coronavirus (SARS-CoV-2) is an acute respiratory infectious disease.

[0003] At present, both at home and abroad, research on anti-SARS-CoV-2 drugs is being actively carried out. The ideal anti-SARS-CoV-2 drug can selectively interfere with the replication cycle of the SARS-CoV-2 virus, thereby inhibiting its replication process, while not affecting the normal physiological functions of the host cells. Related hot targets include: RNA polymerase (RdRp), SARS-CoVS protein (spike protein), ACE2 (angiotensin converting enzyme 2), 3CL hydrolase (3CL pro , M pro ), papain (PL pro )wait.

[0004] Among them, 3CL pro , also known as 3CL protease or main protease, is a cysteine ​​hydrolase that plays an important role in viral replication. The polyprotein precursor produced by the translation of viral RNA into host cells is mainly produced by 3CL protease (3CL pro ) and papain (PL pro ) after cutting, various functional proteins necessary for the virus are formed, and these proteins will further participate in the replication process of viral RNA. pro The activity will prevent viral infection and replication. pro There is no homologous protein in humans, which makes 3CL pro It has become an ideal target for the development of antiviral drugs. pro It is highly conserved among all coronaviruses. Studies have shown that the 3CL protease of SARS-CoV-2 and SARS-CoV differ by only 12 amino acids, with a homology of up to 96%, and the substrate binding pocket is 100% conserved, which can avoid drug resistance caused by viral mutations. At the same time, the 3CL protease inhibitors screened have a certain degree of broad-spectrum anti-coronavirus ability and can be extended to other types of coronavirus infections. At present, there are several 3CL protease inhibitors. pro Inhibitors targeting this target have been reported.

[0005] Therefore, it is of great significance to actively develop broad-spectrum 3CL protease inhibitors against SARS-CoV-2.

[0006] Currently published patent applications for 3CL protease inhibitors include WO2023002409A1, WO2021250648A1, WO2021226546A1, WO2021252644A1, WO2021212039A1, WO2022020242A1, WO2022013684A1, WO2022208262A1, WO2022212707A1, WO2022020711A1, etc. Summary of the invention

[0007] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] Z is a carbon atom or a nitrogen atom;

[0011] R 4b , R A1 Together with the atoms to which they are attached, they form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, the aryl group or the heteroaryl group are each independently optionally substituted by one or more R Y1 Replace; or R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace; or

[0012] R 4a , R 3b and R 3a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, nitro, NR 10 R 11 , OR 13 、S(O) r R 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replaced by; or R 4a for not existing;

[0013] R A1 is a hydrogen atom or RA ;

[0014] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] R 2 is selected from polycyclic aromatic groups or polycyclic heteroaromatic groups, wherein the polycyclic aromatic groups or polycyclic heteroaromatic groups are optionally replaced by one or more R 2a replaced by;

[0016] Each R A , R 2a , R Y1 , R Y2 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、S(O) r R 23 、S(O) r OR 23 、OS(O) r R 23 、S(O) r NR 20 R 21 NR 22 S(O) r R 23 、C(=NR 22 )R 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 、P(O)R 23 R 24 , OR 23, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently substituted with one or more R*;

[0017] Each R 10 , R 11 , R 13 , R 20 , R 21 , R 22 , R 23 and R 24 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, NR a R b 、C(O)NR a R b 、Alkylene NR a R b 、Alkylene C(O)NR a R b NR c C(O)R d NR c C(O)NR a R b 、C(O)R d 、C(O)OR d 、OC(O)R d 、OC(O)OR d , OR d 、S(O) r R d , cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted by one or more R*;

[0018] or R 10 , R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, or R 20 , R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R*;

[0019] Each R a , R b , R c and R d are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an amino group, S(O)r (alkyl), NH(alkyl), N(alkyl)2, C(O)NH2, C(O)NH(alkyl), C(O)N(alkyl)2, C(O)alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

[0020] or R a , R b and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is substituted by one or more R*;

[0021] Each R* is the same or different and is independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, amino, S(O) r (alkyl), NH(alkyl), N(alkyl)2, C(O)NH2, C(O)NH(alkyl), C(O)N(alkyl)2, C(O)alkyl, C(O)OH, C(O)Oalkyl, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

[0022] r is 0, 1, or 2; and

[0023] p is 0, 1, 2, 3, 4, 5 or 6.

[0024] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0025]

[0026] in:

[0027] Z is a carbon atom or a nitrogen atom;

[0028] R 4b , R A1 Together with the atoms to which they are attached, they form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, the aryl group or the heteroaryl group are each independently optionally substituted by one or more R Y1 Replace; or R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace; or

[0029] R 4a , R 3b and R 3a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, nitro, NR10 R 11 , OR 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replaced by; or R 4a for not existing;

[0030] R A1 is a hydrogen atom or R A ;

[0031] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0032] R 2 is selected from polycyclic aromatic groups or polycyclic heteroaromatic groups, wherein the polycyclic aromatic groups or polycyclic heteroaromatic groups are optionally replaced by one or more R 2a replaced by;

[0033] Each R A , R 2a , R Y1 , R Y2 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、S(O) r R 23 、S(O) r OR 23 、OS(O) r R 23 、S(O) r NR 20 R 21 NR 22 S(O) r R 23 、C(=NR 22)R 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 、P(O)R 23 R 24 , OR 23 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently substituted with one or more R*;

[0034] Each R 10 , R 11 , R 13 , R 20 , R 21 , R 22 , R 23 and R 24 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, NR a R b 、C(O)NR a R b 、Alkylene NR a R b 、Alkylene C(O)NR a R b NR c C(O)R d NR c C(O)NR a R b 、C(O)R d 、C(O)OR d 、OC(O)R d 、OC(O)OR d , OR d , cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted by one or more R*;

[0035] or R 10 , R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, or R 20 , R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R*;

[0036] Each Ra , R b , R c and R d are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, amino, NH(alkyl), N(alkyl), C(O)NH, C(O)NH(alkyl), C(O)N(alkyl), C(O)alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl and heteroaryl;

[0037] or R a , R b and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is substituted by one or more R*;

[0038] each R* is the same or different and is each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, amino, NH(alkyl), N(alkyl), C(O)NH, C(O)NH(alkyl), C(O)N(alkyl), C(O)alkyl, C(O)OH, C(O)Oalkyl, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl;

[0039] r is 0, 1, or 2; and

[0040] p is 0, 1, 2, 3, 4, 5 or 6.

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one or more R 2a Substituted 9- to 10-membered heteroaryl, R 2a As defined in Formula (I); in some embodiments, R 2 is optionally replaced by one or more R 2a Substituted isoquinolinyl, R 2a As defined in Formula (I); in some embodiments, R 2 It is isoquinolinyl.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3a A hydrogen atom.

[0043] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, amino, hydroxyl and C 1-6 Hydroxyalkyl; in some embodiments, R 3b It is cyano.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4a It is a hydrogen atom or does not exist.

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R A1 A hydrogen atom.

[0046] In some embodiments of the present disclosure, in the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, Z is a nitrogen atom.

[0047] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0048]

[0049] in:

[0050] Q 1 (CR Q1 R Q11 ) n1 、C(O)、NR Q12 , O or S;

[0051] Q 2 (CR Q2 R Q22 ) n2 、C(O)、NR Q23 , O or S;

[0052] R Q1 , R Q11 , R Q12 , R Q2 , R Q22 and R Q23 are the same or different and are each independently a hydrogen atom or R Y2 ;

[0053] n1 is 1, 2, 3, 4 or 5;

[0054] n2 is 1, 2, 3, 4 or 5;

[0055] m is 0, 1, 2, 3, 4, 5 or 6;

[0056] Ring A, R A , p, R 2a and R Y2 As defined in general formula (I).

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or (II-2) or a pharmaceutically acceptable salt thereof:

[0058]

[0059] in:

[0060] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II).

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof:

[0062]

[0063] in:

[0064] The dotted line indicates whether the ring is aromatic or non-aromatic;

[0065] Q 3 (CR Q3 R Q33 ) n3 、C(O)、NR Q34 , (CR Q35 ) n31 , N, O or S;

[0066] Q 4 (CR Q4 R Q44 ) n4 、C(O)、NR Q45 , (CR Q46 ) n41 , N, O or S;

[0067] R Q3 , R Q33 , R Q34 , R Q35 , R Q4 , R Q44 , R Q45 and RQ46 are the same or different and are each independently a hydrogen atom or R Y1 ;

[0068] n3, n31, n4 and n41 are the same or different and are each independently 0, 1, 2, 3, 4 or 5;

[0069] G 1 CR G1 or N;

[0070] G 2 CR G2 or N;

[0071] G 3 CR G3 or N;

[0072] G 4 CR G4 or N;

[0073] R G1 , R G2 , R G3 and R G4 are the same or different and are each independently a hydrogen atom or R A ;

[0074] m is 0, 1, 2, 3, 4, 5 or 6;

[0075] Z, R 2a , R Y1 and R A As defined in general formula (I).

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III-1) or (III-2) or a pharmaceutically acceptable salt thereof:

[0077]

[0078] in:

[0079] Q 3 , Q 4 , Z, G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III).

[0080] In some embodiments of the present disclosure, the compounds represented by the general formula (II), (II-1), (II-2), (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein m is 0 or 1; in some embodiments, m is 0.

[0081] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (II-1), (II-2), (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 6-membered heteroaryl; and / or R A C 1-6 haloalkyl; preferably, ring A is a 6-membered heteroaryl; and / or R A C 1-6 Halogenated alkyl.

[0083] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (II-1), (II-2) or their pharmaceutically acceptable salts, wherein ring A is phenyl or a 6-membered heteroaryl; in some embodiments, ring A is a 6-membered heteroaryl; in some embodiments, ring A is phenyl; in some embodiments, ring A is pyridyl.

[0084] In some embodiments of the present disclosure, the compounds represented by the general formula (I), (II), (II-1), (II-2), (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein each R A are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, each R Aare the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R A C 1-6 haloalkyl; in some embodiments, R A It is trifluoromethyl.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2; in some embodiments, p is 1.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein Q 1 -Q 2 (CR Q1 R Q11 ) n1 -(CR Q2 R Q22 ) n2 , n1, n2, R Q1 , R Q11 , R Q2 and R Q22 As defined in formula (II); in some embodiments, Q 1 -Q 2 For (CH2) n11 , n11 is 2, 3, 4 or 5; in some embodiments, Q 1 -Q 2 For (CH2) n11 , n11 is 2 or 3; in some embodiments, Q 1 -Q 2 For (CH2) n11 , n11 is 2.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein R Q1 , R Q11 , R Q2 and R Q22 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, each R Q1 , R Q11 , RQ2 and R Q22 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R Q1 , R Q11 , R Q2 and R Q22 All are hydrogen atoms.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4b , R 4a Together with the carbon atom to which it is attached, it forms a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally substituted by one or more R Y2 Replacement, R Y2 As defined in Formula (I); in some embodiments, R 4b , R 4a Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally substituted by one or more R Y2 Replacement, R Y2 As defined in Formula (I); in some embodiments, R 4b , R 4a Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group; in some embodiments, R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl or cyclopentyl group; in some embodiments, R 4b , R 4a Together with the carbon atom to which it is attached it forms a cyclopropyl group.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R Y2 are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, each R Y2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0090] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein for RQ3 , R Q33 , R Q35 and R Q46 As defined in formula (III); in some embodiments, for R Q3 , R Q33 , R Q35 and R Q46 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, for In some embodiments, for In some embodiments, for

[0091] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein R Q3 , R Q33 , R Q4 , R Q44 , R Q35 and R Q46 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, R Q3 , R Q33 , R Q4 , R Q44 , R Q35 and R Q46 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Q3 , R Q33 , R Q4 , R Q44 , R Q35 and R Q46 All are hydrogen atoms.

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4b , R A1Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, a phenyl group or a 6-membered heteroaryl group, wherein the 6-membered heterocyclic group, the phenyl group or the 6-membered heteroaryl group are each independently optionally substituted by one or more R Y1 Replacement, R Y1 As defined in Formula (I); in some embodiments, R 4b , R A1 Together with the atoms to which they are attached, they form a morpholinyl or phenyl group, each of which is independently optionally substituted by one or more R Y1 Replacement, R Y1 As defined in Formula (I); in some embodiments, R 4b , R A1 Together with the atoms to which it is attached, it forms a morpholinyl or phenyl group.

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R Y1 are the same or different and are each independently selected from oxo, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, each R Y1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0094] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 1 CR G1 ; and / or G 3 CR G3 , R G1 and R G3 As defined in formula (III); in some embodiments, G 1 is CH; and / or G 3 CR G3 , R G3 C 1-6 haloalkyl; in some embodiments, G 1 is CH; and / or G 3 It is C-CF3.

[0095] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein R G3 C 1-6haloalkyl; in some embodiments, R G3 It is CF3.

[0096] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 2 is CH or N; and / or G 4 is CH or N; in some embodiments, G 2 CH, G 4 N or G 2 N, G 4 is CH; in some embodiments, G 2 For CH, G 4 is N; in some embodiments, G 2 N, G 4 is CH; in some embodiments, G 2 For CH, G 4 For CH.

[0097] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 1 CR G1 , R G1 As defined in formula (III); in some embodiments, G 1 CR G1 , R G1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, G 1 CR G1 , R G1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G 1 CR G1 , R G1 A hydrogen atom.

[0098] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 2 CR G2 , R G2 As defined in formula (III); in some embodiments, G 2 CRG2 , R G2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, G 2 CR G2 , R G2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G 2 CR G2 , R G2 is a hydrogen atom; in some embodiments, G 2 is N.

[0099] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 3 CR G3 , R G3 As defined in formula (III); in some embodiments, G 3 CR G3 , R G3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, G 3 CR G3 , R G3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G 3 CR G3 , R G3 C 1-6 haloalkyl; in some embodiments, G 3 CR G3 , R G3 It is CF3.

[0100] In some embodiments of the present disclosure, the compounds represented by the general formula (III), (III-1) and (III-2) or their pharmaceutically acceptable salts, wherein G 4 CR G4 , R G4As defined in formula (III); in some embodiments, G 4 CR G4 , R G4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, cyano, hydroxyl, C 1-6 hydroxyalkyl and amino; in some embodiments, G 4 CR G4 , R G4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, G 4 CR G4 , R G4 is a hydrogen atom; in some embodiments, G 4 is N.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is a carbon atom or a nitrogen atom; R 4b , R A1 Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, a phenyl group or a 6-membered heteroaryl group, wherein the 6-membered heterocyclic group, the phenyl group or the 6-membered heteroaryl group are each independently optionally substituted by one or more R Y1 Replace, each R Y1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Ring A is a 6-membered heteroaryl; R A C 1-6 Haloalkyl; p is 1; R 4a is a hydrogen atom or does not exist; R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b is cyano; R 2 is optionally replaced by one or more R 2a Substituted isoquinolinyl, each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is a carbon atom or a nitrogen atom; R 4b , R A1Together with the atoms to which they are attached, they form a 6-membered heterocyclic group, a phenyl group or a 6-membered heteroaryl group, wherein the 6-membered heterocyclic group, the phenyl group or the 6-membered heteroaryl group are each independently optionally substituted by one or more R Y1 Replace, each R Y1 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; ring A is phenyl or 6-membered heteroaryl; R A C 1-6 Haloalkyl; p is 1; R 4a is a hydrogen atom or does not exist; R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b is cyano; R 2 is optionally replaced by one or more R 2a Substituted isoquinolinyl, each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0103] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is a nitrogen atom; R 4b , R 4a Together with the carbon atom to which it is attached, it forms a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally substituted by one or more R Y2 Replace; each R Y2 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Ring A is a 6-membered heteroaryl; R A C 1-6 Haloalkyl; p is 1; R A1 is a hydrogen atom; R 3a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3b is cyano; R 2 is optionally replaced by one or more R 2a Substituted isoquinolinyl, each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0104] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-1), (II-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a are the same or different and are each independently selected from halogen, C1-6 Alkyl and C 1-6 haloalkyl; m is 0 or 1; ring A is a 6-membered heteroaryl; R A C 1-6 Haloalkyl; p is 1; Q 1 -Q 2 For (CH2) n11 , n11 is 2 or 3.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0 or 1; for R Q3 , R Q33 , R Q35 and R Q46 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 CH; G 3 CR G3 , R G3 C 1-6 Haloalkyl; G 2 CH, G 4 N or G 2 N, G 4 For CH.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0 or 1; for R Q3 , R Q33 , R Q35 and R Q46 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; G 1 CH; G 3 CR G3 , R G3 C 1-6 Haloalkyl; G 2 CH or N; G 4It is CH or N.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-1), (III-2) or a pharmaceutically acceptable salt thereof, wherein each R 2a Selected from halogen, C 1-6 Alkyl and C 1-6 Haloalkyl; m is 0 or 1; for G 1 CH; G 3 CR G3 , R G3 C 1-6 Haloalkyl; G 2 CH or N; G 4 It is CH or N.

[0108] Table A Typical compounds of the present disclosure include, but are not limited to:

[0109]

[0110]

[0111]

[0112]

[0113] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof:

[0114]

[0115] in:

[0116] R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace;

[0117] Z, R 3a , R 3b , R 2 and R Y2 As defined in general formula (I).

[0118] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof:

[0119]

[0120] in:

[0121] Q 1 , Q2 , R 2a and m are as defined in the general formula (II).

[0122] Another aspect of the present disclosure relates to a compound represented by general formula (II-1A) or a salt thereof:

[0123]

[0124] in:

[0125] Q 1 , Q 2 , R 2a and m are as defined in the general formula (II-1).

[0126] Another aspect of the present disclosure relates to a compound represented by general formula (II-2A) or a salt thereof:

[0127]

[0128] in:

[0129] Q 1 , Q 2 , R 2a and m are as defined in the general formula (II-2).

[0130] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof:

[0131]

[0132] in:

[0133] Z, R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in general formula (III). Another aspect of the present disclosure relates to a compound or a salt thereof represented by general formula (III-1A):

[0134]

[0135] in:

[0136] Z, R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2aand m are as defined in general formula (III-1). Another aspect of the present disclosure relates to a compound represented by general formula (III-2A) or a salt thereof:

[0137]

[0138] in:

[0139] Z, R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in general formula (III-2). Table B Typical compounds disclosed herein include but are not limited to:

[0140]

[0141]

[0142]

[0143] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0144]

[0145] The compound of the general formula (IA) or its salt is subjected to a substitution reaction with the compound of the general formula (IB) or its salt to obtain the compound of the general formula (I) or its pharmaceutically acceptable salt,

[0146] in:

[0147] X 1 is a halogen;

[0148] R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace;

[0149] Ring A, R A , R A1 , p, Z, R 3a , R 3b , R 2 and R Y2 As defined in general formula (I).

[0150] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0151]

[0152] The compound of general formula (IIA) or its salt is subjected to substitution reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt,

[0153] in:

[0154] X 1 is a halogen;

[0155] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II).

[0156] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0157]

[0158] The compound of the general formula (II-1A) or its salt is subjected to a substitution reaction with the compound of the general formula (IIB) or its salt to obtain the compound of the general formula (II-1) or its pharmaceutically acceptable salt.

[0159] in:

[0160] X 1 is a halogen;

[0161] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II-1).

[0162] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0163]

[0164] The compound of general formula (II-2A) or its salt is subjected to substitution reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II-2) or its pharmaceutically acceptable salt.

[0165] in:

[0166] X 1 is a halogen;

[0167] Q 1 , Q 2 , Ring A, R A , p, R2a and m are as defined in the general formula (II-2).

[0168] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) and (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0169]

[0170] The compound of general formula (II) or its pharmaceutically acceptable salt is separated and purified to obtain the compound of general formula (II-1) and (II-2) or its pharmaceutically acceptable salt.

[0171] in:

[0172] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II).

[0173] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0174]

[0175] The compound of general formula (IIIA) or its salt is subjected to a cyclization reaction to obtain a compound of general formula (III) or its pharmaceutically acceptable salt,

[0176] in:

[0177] for

[0178] R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III).

[0179] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0180]

[0181] The compound of the general formula (III-1A) or a salt thereof is subjected to a cyclization reaction to obtain a compound of the general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0182] in:

[0183] for

[0184] R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III-1).

[0185] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0186]

[0187] The compound of the general formula (III-2A) or its salt is subjected to a cyclization reaction to obtain a compound of the general formula (III-2) or its pharmaceutically acceptable salt,

[0188] in:

[0189] for

[0190] R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III-2).

[0191] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III-1) and (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0192]

[0193] The compound of general formula (III) or its pharmaceutically acceptable salt is separated and purified to obtain the compound of general formula (III-1) and (III-2) or its pharmaceutically acceptable salt.

[0194] in:

[0195] Z, Q 3 , Q 4 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III).

[0196] In some embodiments of the present disclosure, the compound represented by the general formula (IB) or (IIB) or a pharmaceutically acceptable salt thereof, wherein X 1 For I.

[0197] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure as shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0198] The present disclosure further relates to the use of the compounds shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of drugs for inhibiting 3CL proteases.

[0199] The present disclosure further relates to the use of compounds shown in general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of a medicament for treating and / or preventing a disease or condition mediated by 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and a herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0200] The present disclosure further relates to the use of compounds shown in general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and / or preventing viral infections; the viruses are preferably coronaviruses, picornaviruses, rhinoviruses, noroviruses and herpes simplex virus type 1 (HSV-1), and are further preferably coronaviruses; the coronaviruses are preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and are more preferably SARS-CoV-2.

[0201] The present disclosure further relates to a method for inhibiting 3CL protease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0202] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by 3CL protease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or condition is a viral infection; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0203] The present disclosure further relates to a method for treating and / or preventing viral infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0204] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0205] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting 3CL protease.

[0206] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for inhibiting 3CL protease.

[0207] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing a disease or condition mediated by 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0208] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing a disease or condition mediated by 3CL protease; preferably, the disease or condition is a viral infection; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0209] The present disclosure further relates to a compound shown in general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing viral infection; the virus is preferably a coronavirus, a picornavirus, a rhinovirus, a norovirus and herpes simplex virus type 1 (HSV-1), and more preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and more preferably SARS-CoV-2.

[0210] The present disclosure further relates to a compound shown in the general formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing viral infection; the virus is preferably a coronavirus (Coronavirus), a picornavirus (Picornavirus), a rhinovirus (Rhinovirus), a norovirus (Norovirus) and a herpes simplex virus type 1 (HSV-1), and is further preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and is more preferably SARS-CoV-2.

[0211] The diseases or conditions mediated by 3CL proteases described in the present disclosure are preferably selected from viral infection, chronic obstructive pulmonary disease, Alzheimer's disease, motor neuron disease, multiple sclerosis, Parkinson's disease, mastocytosis, asthma, cognitive impairment, ischemic stroke and tumors; the viruses are preferably coronaviruses, picornaviruses, rhinoviruses, noroviruses and herpes simplex virus type 1 (HSV-1), and are further preferably coronaviruses; the coronaviruses are preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, and are more preferably SARS-CoV-2; the tumors are preferably gastrointestinal tumors, lymphomas, glioblastomas, pancreatic tumors, prostate cancer, liver cancer, breast cancer, colorectal cancer, lung cancer and head and neck cancer.

[0212] Preferably, the lymphoma described in the present disclosure is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); the lung cancer is non-small cell lung cancer (NSCLC) (e.g., squamous cell carcinoma of the lung and adenocarcinoma of the lung, wherein adenocarcinoma of the lung is preferably bronchioalveolar carcinoma) and small cell lung cancer (SCLC); the liver cancer is hepatocellular carcinoma (HCC); the pancreatic cancer is pancreatic ductal adenocarcinoma; the colorectal cancer is colon cancer and rectal cancer; and the prostate cancer is hormone-refractory prostate cancer.

[0213] As a general guide, the active compounds of the present disclosure are preferably in a unit dosage form, or in a form that a patient can self-administer in a single dose. The unit dosage form of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages can be 0.1 to 1000 mg.

[0214] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0215] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0216] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotope substitution.

[0217] In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

[0218] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, lozenges, pastilles, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any known method for preparing pharmaceutical compositions in the art, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0219] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0220] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0221] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0222] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, a mineral oil or a mixture thereof. A suitable emulsifier can be a naturally occurring phospholipid, and the emulsion can also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such preparations can also contain a demulcent, a preservative, a coloring agent and an antioxidant.

[0223] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0224] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0225] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0226] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0227] Terminology

[0228] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0229] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0230] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0231] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0232] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0233] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0234] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

[0235] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0236] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0237] The term "spirocycloalkyl" refers to a polycyclic system in which one carbon atom (called spiro atom) is shared between the rings, and the rings may contain one or more double bonds, or the rings may contain one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but not including -OO-, -OS- or -SS-), provided that at least one all-carbon ring is contained and the connection point is on the all-carbon ring, and it has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). The spirocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospirocycloalkyl. Non-limiting examples include:

[0238] Its connection point can be at any position;

[0239] wait.

[0240] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0241] Its connection point can be at any position;

[0242]

[0243] wait.

[0244] The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0245] Its connection point can be at any position.

[0246] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0247] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-) in the ring, and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 6 ring atoms (i.e., a 4- to 6-membered heterocyclic group), or a heterocyclic group having 5 to 7 ring atoms (i.e., a 5- to 7-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

[0248] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0249] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0250] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), more preferably a spiro heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan monospiro heterocyclic radical. Non-limiting examples include:

[0251] wait.

[0252] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and further preferably has a fused heterocyclic group of 6 to 10 ring atoms (i.e., a 6 to 10-membered fused heterocyclic group), and more preferably a 6-membered or 7-membered fused heterocyclic group. The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan bicyclic fused heterocyclic group. Non-limiting examples include:

[0253]

[0254] wait.

[0255] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), further preferably a bridged heterocyclic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered bridged heterocyclic group), and more preferably a 6-, 7-, or 8-membered bridged heterocyclic group. According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0256]

[0257] wait.

[0258] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0259] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc. The polycyclic aromatic group also includes a phenyl group fused with one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused with one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group or the naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

[0260] wait.

[0261] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0262] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl) or a heteroaryl having 9 or 10 ring atoms (i.e., a 9- or 10-membered heteroaryl).

[0263] The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0264] The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0265]

[0266] wait.

[0267] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0268] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule are reacted. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.

[0269] The term "hydroxy protecting group" refers to a group that is introduced on a hydroxy group and is easily removed, and is used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0270] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0271] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0272] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0273] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0274] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0275] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0276] The term "haloalkenyl" refers to an alkenyl group substituted with one or more halogens, wherein alkenyl is as defined above.

[0277] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0278] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0279] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0280] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0281] The term "methylidene" refers to =CH2.

[0282] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0283] The term "hydroxy" refers to -OH.

[0284] The term "thiol" refers to -SH.

[0285] The term "amino" refers to -NH2.

[0286] The term "cyano" refers to -CN.

[0287] The term "nitro" refers to -NO2.

[0288] The term "oxo" or "oxo" refers to "=0".

[0289] The term "carbonyl" refers to C=O.

[0290] The term "carboxy" refers to -C(O)OH.

[0291] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0292] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereoisomers is usually completed by chromatography.

[0293] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or or include both and For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0294] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, i.e., in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

[0295]

[0296] For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

[0297]

[0298] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0299] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p. 33 p. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0300] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0301] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0302] "Optionally" or "optionally" means that the event or environment described later can but does not necessarily occur, and includes two situations in which the event or environment occurs or does not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the situation in which alkyl is substituted with halogen or cyano and the situation in which alkyl is not substituted with halogen and cyano.

[0303] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0304] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their pharmaceutically acceptable salts and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0305] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0306] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0307] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0308] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0309] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0310] Synthesis method of the disclosed compound

[0311] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0312] Solution 1

[0313] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0314]

[0315] The compound of the general formula (IA) or its salt is subjected to a substitution reaction with the compound of the general formula (IB) or its salt under alkaline conditions, optionally in the presence of a condensing agent and a ligand, to obtain a compound of the general formula (I) or its pharmaceutically acceptable salt,

[0316] in:

[0317] X 1 is a halogen;

[0318] R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace;

[0319] Ring A, R A , R A1 , p, Z, R 3a , R 3b , R 2 and R Y2 As defined in general formula (I).

[0320] Solution 2

[0321] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0322]

[0323] The compound of general formula (IIA) or its salt and the compound of general formula (IIB) or its salt undergo substitution reaction under alkaline conditions, optionally in the presence of a condensing agent and a ligand, to obtain a compound of general formula (II) or its pharmaceutically acceptable salt,

[0324] in:

[0325] X 1 is a halogen;

[0326] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II).

[0327] Option 3

[0328] The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0329]

[0330] The compound of the general formula (II-1A) or its salt is subjected to a substitution reaction with the compound of the general formula (IIB) or its salt under alkaline conditions, optionally in the presence of a condensing agent and a ligand, to obtain a compound of the general formula (II-1) or its pharmaceutically acceptable salt.

[0331] in:

[0332] X 1 is a halogen;

[0333] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II-1).

[0334] Option 4

[0335] The present invention discloses a method for preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0336]

[0337] The compound of the general formula (II-2A) or its salt is subjected to a substitution reaction with the compound of the general formula (IIB) or its salt under alkaline conditions, optionally in the presence of a condensing agent and a ligand, to obtain a compound of the general formula (II-2) or its pharmaceutically acceptable salt.

[0338] in:

[0339] X 1 is a halogen;

[0340] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II-2).

[0341] Option 5

[0342] The present invention discloses a method for preparing a compound represented by general formula (II-1) and (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0343]

[0344] The compound of general formula (II) or its pharmaceutically acceptable salt is separated and purified by chiral preparation to obtain the compound of general formula (II-1) and (II-2) or its pharmaceutically acceptable salt.

[0345] in:

[0346] Q 1 , Q 2 , Ring A, R A , p, R 2a and m are as defined in the general formula (II).

[0347] Option 6

[0348] The present invention discloses a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0349]

[0350] The compound of general formula (IIIA) or its salt undergoes a cyclization reaction in the presence of a catalyst to obtain a compound of general formula (III) or its pharmaceutically acceptable salt,

[0351] in:

[0352] for

[0353] R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III).

[0354] Option 7

[0355] The present invention discloses a method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0356]

[0357] The compound of the general formula (III-1A) or a salt thereof undergoes a cyclization reaction in the presence of a catalyst to obtain a compound of the general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0358] in:

[0359] for

[0360] R Q3 , R Q33 , G 1 , G 2, G 3 , G 4 , R 2a and m are as defined in the general formula (III-1).

[0361] Option 8

[0362] The present invention discloses a method for preparing a compound represented by general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0363]

[0364] The compound of the general formula (III-2A) or a salt thereof undergoes a cyclization reaction in the presence of a catalyst to obtain a compound of the general formula (III-2) or a pharmaceutically acceptable salt thereof,

[0365] in:

[0366] for

[0367] R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III-2).

[0368] Option 9

[0369] The present invention discloses a method for preparing a compound represented by general formula (III-1) and (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0370]

[0371] The compound of general formula (III) or its pharmaceutically acceptable salt is separated and purified by chiral preparation to obtain the compound of general formula (III-1) and (III-2) or its pharmaceutically acceptable salt.

[0372] in:

[0373] Z, Q 3 , Q 4 , G 1 , G 2 , G 3 , G 4 , R 2a and m are as defined in the general formula (III).

[0374] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride tetrahydrofuran solution or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; preferably cesium carbonate.

[0375] The catalyst in the above substitution reaction is cuprous iodide.

[0376] The ligand described in the above substitution reaction is trans-N,N'-dimethyl-1,2-cyclohexanediamine.

[0377] The catalysts used in the above cyclization reaction are diisopropyl azodicarboxylate and triphenylphosphine.

[0378] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0379] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0380] Example

[0381] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0382] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0383] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0384] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMOQExactive)

[0385] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0386] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0387] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0388] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0389] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0390] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0391] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0392] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0393] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0394] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0395] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0396] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0397] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0398] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0399] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0400] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0401] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0402] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: n-hexane / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0403] Example 1

[0404] (R)-6-(isoquinolin-4-yl)-5-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-4,6-diazaspiro[2.4]heptane-7-yl

[0405] Formonitrile 1-P1

[0406] (S)-6-(isoquinolin-4-yl)-5-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-4,6-diazaspiro[2.4]heptane-7-carbonitrile 1-P2

[0407]

[0408] first step

[0409] tert-Butyl (1-formylcyclopropyl)carbamate 1b

[0410] Tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate 1a (5.0 g, 26.70 mmol, Shaoyuan) was dissolved in dichloromethane (50 mL), and Dess-Martin periodinane (12.5 g, 29.47 mmol, Titan) was added under ice bath, and the mixture was returned to room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1b (3.85 g, yield: 77.8%). MS m / z (ESI): 186.1 [M+1].

[0411] Step 2

[0412] tert-Butyl (1-(cyano(isoquinolin-4-ylamino)methyl)cyclopropyl)carbamate 1c

[0413] Under nitrogen protection, compound 1b (2.0 g, 10.80 mmol) was dissolved in 1,2-dichloroethane (25 mL), and 4-aminoisoquinoline (1.56 g, 10.82 mmol, Bid) and tetraethyl titanate (4.92 g, 21.56 mmol, Titan) were added in sequence. The reaction solution was stirred at room temperature for 2 hours, and then trimethylsilyl cyanide (3.21 g, 32.35 mmol, Bid) was added at 10°C. After the reaction solution was warmed to room temperature, it was stirred for 16 hours and the reaction was complete. The reaction solution was quenched with water (30 mL), extracted with dichloromethane (50 mL×2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1c (2.27 g, yield: 62.1%).

[0414] MS m / z(ESI):339.2[M+1].

[0415] Step 3

[0416] tert-Butyl 7-cyano-6-(isoquinolin-4-yl)-5-oxo-4,6-diazaspiro[2.4]heptane-4-carboxylate 1d

[0417] Compound 1c (2.27 g, 6.71 mmol) was dissolved in acetonitrile (60 mL), and N,N'-carbonyldiimidazole (2.72 g, 16.77 mmol, Shaoyuan) and N,N-diisopropylethylamine (2.17 g, 16.79 mmol, Titan) were added, and the reaction solution was stirred at room temperature for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1d (2 g, yield: 81.8%).

[0418] MS m / z(ESI):365.2[M+1].

[0419] Step 4

[0420] 6-(Isoquinolin-4-yl)-5-oxo-4,6-diazaspiro[2.4]heptane-7-carbonitrile 1e

[0421] Compound 1d (300 mg, 0.82 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2 mL, Titan) was added, and the reaction solution was stirred at room temperature for 1 hour. It was concentrated under reduced pressure, diluted with dichloromethane (20 mL), washed with saturated sodium carbonate solution (50 mL × 1), extracted with dichloromethane (50 mL × 2), and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1e (200 mg, yield: 92.2%). The product was used directly in the next step without purification.

[0422] MS m / z(ESI):265.1[M+1].

[0423] Step 5

[0424] 6-(Isoquinolin-4-yl)-5-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-4,6-diazaspiro[2.4]heptane-7-carbonitrile 1

[0425] Compound 1e (200 mg, 0.75 mmol) was dissolved in 1,4-dioxane (4 mL), and 5-iodo-2-(trifluoromethyl)pyridine (227 mg, 0.83 mmol, Shaoyuan), cuprous iodide (29 mg, 0.15 mmol, Shaoyuan), trans-N,N'-dimethyl-1,2-cyclohexanediamine (43 mg, 0.30 mmol, Shaoyuan) and cesium carbonate (493 mg, 1.51 mmol, Titan) were added. The nitrogen was replaced three times in the reaction, and the reaction solution was stirred at 120°C for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-55%, flow rate: 30mL / min) to give the title product 1 (180mg, yield: 58.1%).

[0426] MS m / z(ESI):410.1[M+1].

[0427] 1H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.82(d,1H),8.75(s,1H),8.31(d,1H),8.17(dd,1H),8.11–8.07(m,1H),8. 05(d,1H),7.97(ddd,1H),7.84(ddd,1H),5.77(s,1H),1.37–1.30(m,1H),1.23–1.16(m,2H),1.13–1.06(m,1H).

[0428] Step 6

[0429] (R)-6-(isoquinolin-4-yl)-5-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-4,6-diazaspiro[2.4]heptane-7-yl

[0430] Formonitrile 1-P1

[0431] (S)-6-(isoquinolin-4-yl)-5-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)-4,6-diazaspiro[2.4]heptane-7-carbonitrile 1-P2

[0432] Compound 1 (100 mg, 0.24 mmol) was chirally prepared (separation conditions: CHIRALPAK AY-H chiral preparative column, 20 mm×250 mm, 5 um; mobile phase: n-hexane / ethanol / 7 M ammonia methanol=60 / 40 / 0.5 (V / V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title product (45 mg, yield: 45%).

[0433] Single configuration compound (short retention time, 45 mg, yield: 45%):

[0434] MS m / z(ESI):410.1[M+1].

[0435] Chiral HPLC analysis: retention time 13.458 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK AY-H chiral preparative column, 20 mm×250 mm, 5 um; mobile phase: n-hexane / ethanol / 7 M ammonia methanol=60 / 40 / 0.5 (V / V / V).

[0436] 1H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.82(d,1H),8.74(s,1H),8.31(d,1H),8.17(dd,1H),8.08(d,1H),8.05(d ,1H),7.97(ddd,1H),7.86–7.81(m,1H),5.77(s,1H),1.37–1.30(m,1H),1.23–1.16(m,2H),1.12–1.08(m,1H).

[0437] Single configuration compound (longer retention time, 45 mg, yield: 45%):

[0438] MS m / z(ESI):410.1[M+1].

[0439] Chiral HPLC analysis: retention time 26.535 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK AY-H chiral preparative column, 20 mm×250 mm, 5 um; mobile phase: n-hexane / ethanol / 7 M ammonia methanol=60 / 40 / 0.5 (V / V / V).

[0440] 1 H NMR(500MHz,DMSO-d6)δ9.46(s,1H),8.82(d,1H),8.74(s,1H),8.31(d,1H),8.17(dd,1H),8.08(d,1H),8.05 (d,1H),7.97(ddd,1H),7.84(ddd,1H),5.77(s,1H),1.38–1.29(m,1H),1.23–1.16(m,2H),1.13–1.05(m,1H).

[0441] Example 2

[0442] (3R,3aR)-2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[2,3-b][1,4]oxazine-3-carbonitrile 2-P1

[0443] (3R,3aS)-2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[2,3-b][1,4]oxazine-3-carbonitrile 2-P2

[0444] (3S,3aS)-2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[2,3-b][1,4]oxazine-3-carbonitrile 2-P3

[0445] (3S,3aR)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[2,3-b][1,4]oxazine-3-carbonitrile 2-P4

[0446]

[0447]

[0448] first step

[0449] 2-(Benzyloxy)-3-iodo-6-(trifluoromethyl)pyridine 2b

[0450] 3-iodo-6-(trifluoromethyl)pyridine-2-ol 2a (1 g, 3.46 mmol, prepared by the method disclosed in Example A11 on page 29 of the specification of patent application "WO2010012758") was dissolved in N,N-dimethylformamide (DMF) (10 mL), and tetrabutylammonium iodide (200 mg, 600.5 μmol, Titan) and potassium carbonate (750 mg, 5.4 mmol) were added. Benzyl bromide (700 mg, 4.1 mmol, Shanghai Titan) was added under nitrogen protection, and the reaction was stirred at 80°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2b (1.4 g, yield: 106%).

[0451] MS m / z(ESI):380.0[M+1].

[0452] Step 2

[0453] tert-Butyl (3-((tert-butyldiphenylsilyl)oxy)-1-cyano-1-(isoquinolin-4-ylamino)propan-2-yl)carbamate 2e

[0454] Under nitrogen atmosphere, tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-3-oxyprop-2-yl)carbamate 2c (2.8 g, 6.6 mmol, prepared by the method disclosed in the document "J. Med. Chem. 2004, 47, 21, 5167-5182") was dissolved in dichloroethane (50 mL), and isoquinolin-4-amine 2d (950 mg, 6.6 mmol, Shao Yuan) and tetraethyl titanate (3 g, 13.2 mm ol, Shaoyuan), stirred for 2 hours and then cooled to 0°C, trimethylsilyl cyanide (1.97 g, 19.9 mmol, Shaoyuan) was added, and the mixture was returned to room temperature and stirred for 16 hours. Water (30 mL) was added to the reaction solution to quench, and the mixture was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2e (2.6 g, yield: 67.2%)

[0455] MS m / z(ESI):581.1[M+1].

[0456] Step 3

[0457] tert-Butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-4-cyano-3-(isoquinolin-4-yl)-2-oxoylideneimidazolidine-1-carboxylate 2f

[0458] Compound 2e (2.5 g, 4.3 mmol) was dissolved in acetonitrile (30 mL), and then N, N'-carbonyldiimidazole (1.9 g, 11.4 mmol, Shaoyuan) and N, N-diisopropylethylamine (1.5 g, 11.4 mmol, Titan) were added, and the reaction was stirred at 80 ° C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2f (1.6 g, yield: 60.3%)

[0459] MS m / z(ESI):607.1[M+1].

[0460] Step 4

[0461] 5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(isoquinolin-4-yl)-2-oxoylideneimidazolidin-4-carbonitrile 2g

[0462] Compound 2f (1.54 g, 2.5 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2 mL, Titan) was added under ice bath. The temperature was maintained and stirred for 5 hours, and then the mixture was naturally returned to room temperature for 2 hours. The reaction solution was added dropwise into saturated sodium bicarbonate solution (20 mL) for quenching, and extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2g (1.27 g, yield: 99.1%).

[0463] MS m / z(ESI):507.0[M+1].

[0464] Step 5

[0465] 1-(2-(Benzyloxy)-6-(trifluoromethyl)pyridin-3-yl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(isoquinolin-4-yl)-2-oxoylideneimidazolidin-4-carbonitrile 2h

[0466] Compound 2b (894 mg, 2.4 mmol), compound 2g (894 mg, 1.8 mmol), cuprous iodide (140 mg, 735 μmol, Sinopharm), trans-N,N'-dimethyl-1,2-cyclohexanediamine (204 mg, 1.4 mmol, Titan), cesium carbonate (1.6 g, 4.8 mmol, Titan) were dissolved in 1,4-dioxane (15 mL), replaced with nitrogen three times, stirred at 120°C for 16 hours, and the reaction solution was diluted with water (15 mL) after cooling to room temperature, extracted with ethyl acetate (15 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2h (724 mg, yield: 40.2%).

[0467] MS m / z(ESI):758.4[M+1].

[0468] Step 6

[0469] 1-(2-(Benzyloxy)-6-(trifluoromethyl)pyridin-3-yl)-5-(hydroxymethyl)-3-(isoquinolin-4-yl)-2-oxoimidazolidine

[0470] -4-Carbononitrile 2i

[0471] Compound 2h (724 mg, 955.3 μmol) was dissolved in tetrahydrofuran (6 mL), and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (1.1 mL, Titan) was added under ice bath, and the temperature was maintained for reaction for 1 hour. Water (15 mL) was added to the reaction solution under ice bath to quench, and the solution was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2i (480 mg, yield: 96.7%).

[0472] MS m / z(ESI):520.2[M+1].

[0473] Step 7

[0474] 1-(2-Hydroxy-6-(trifluoromethyl)pyridin-3-yl)-5-(hydroxymethyl)-3-(isoquinolin-4-yl)-2-oxo-imidazolidin-4-yl

[0475] Formonitrile 2j

[0476] Compound 2i (460 mg, 885.5 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL, Titan) was added, and the reaction was stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane, neutralized with N,N-diisopropylethylamine to pH 8-9, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2j (334 mg, yield: 87.8%).

[0477] MS m / z(ESI):430.1[M+1].

[0478] Step 8

[0479] 2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyridin

[0480] [2,3-b][1,4]oxazine-3-carbonitrile 2

[0481] Compound 2j (254 mg, 591.6 μmol) was dissolved in tetrahydrofuran (5 mL), and diisopropyl azodicarboxylate (250 mg, 1.2 mmol, Shaoyuan) and triphenylphosphine (317 mg, 1.2 mmol, Sinopharm) were added in sequence. The reaction was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by HPLC (Waters-2545, chromatographic column: YMC Triart-ExrsC18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give the title compound 2 (90 mg, yield: 37%).

[0482] MS m / z(ESI):412.5[M+1].

[0483] 1 H NMR (500MHz, CD3OD): δ9.38(d,1H),8.70(d,1H),8.61(dd,1H),8.27(dd,1H),8.16(t,1H),7.9 4(t,1H),7.83(t,1H),7.51(dd,1H),5.63(dd,1H),5.01(td,1H),4.88(dd,1H),4.61(dt,1H).

[0484] Step 9

[0485] Compound 2 was chirally prepared, and its corresponding components were collected and concentrated under reduced pressure to obtain the title compounds 2-P1, 2-P2, 2-P3, and 2-P4.

[0486] Example 3

[0487] 7-(Isoquinolin-4-yl)-6-oxo-5-(6-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-8-carbonitrile 3

[0488] (R)-7-(Isoquinolin-4-yl)-6-oxo-5-(6-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-8-carbonitrile 3-P1

[0489] (S)-7-(Isoquinolin-4-yl)-6-oxo-5-(6-(trifluoromethyl)pyridin-3-yl)-5,7-diazaspiro[3.4]octane-8-carbonitrile 3-P2

[0490]

[0491] Referring to Example 1, the first step compound 1a was replaced with tert-butyl (1-(hydroxymethyl)cyclobutyl)carbamate to obtain the title compound 3 (4.2 mg, yield: 5%).

[0492] MS m / z(ESI):424.1[M+1].

[0493] 1 H NMR (500MHz, DMSO-d6): δ9.45(s,1H),8.91(d,1H),8.70(s,1H),8.37-8.21(m,2H),8.11(d,1H),8.01(d,1H),7.95(t ,1H),7.83(t,1H),6.07(s,1H),2.63-2.57(m,2H),2.052-1.98(m,1H),1.86(q,1H),1.67(d,1H),1.53-1.41(m,1H).

[0494] Chiral HPLC analysis of compound 3: retention time 5.209 minutes (45.6%), 13.415 minutes (54.3%) (CHIRALCEL OD-H 150*4.6mm, 5um; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A: B is 70:30, flow rate: 1mL / min).

[0495] Compound 3 (10 mg) was separated by chiral column (retention time 13.6 min, 16.0 min; Gilson-281, CHIRALPAK IC, 20 mm×250 mm, 5 um; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7 M ammonia methanol solution), gradient ratio: A: B is 70:30, flow rate: 20 mL / min) to give the title product (3 mg, yield: 30%), (3.5 mg, yield: 30%).

[0496] Single configuration compound (short retention time (retention time 13.6 minutes in chiral resolution), 3 mg, yield: 30%): MS m / z (ESI): 424.1 [M+1].

[0497] HPLC analysis: retention time 1.32 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0498] 1H NMR (500MHz, CD3OD): δ9.37(s,1H),8.85(d,1H),8.66(s,1H),8.28(d,1H),8.19(dd,1H),8.07(d,1H),8.03(d,1H),8.00-7.9 4(m,1H),7.83(t,1H),5.84(s,1H),2.69(d,1H),2.63-2.59(m,1H),2.19(t,1H),2.03(d,1H),1.97-1.91(m,1H),1.77(s,1H).

[0499] Single configuration compound (longer retention time (retention time 16.0 minutes in chiral resolution), 3.5 mg, yield: 30%):

[0500] MS m / z(ESI):424.1[M+1].

[0501] HPLC analysis: retention time 1.32 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0502] 1 H NMR (500MHz, CD3OD): δ9.33(s,1H),8.81(d,1H),8.62(s,1H),8.24(d,1H),8.15(dd,1H),8.01(dd,2H),7.93( t,1H),7.79(t,1H),5.81(s,1H),2.66-2.58(m,2H),2.16(s,1H),2.05-1.97(m,1H),1.92(d,1H),1.73(s,1H). .

[0503] Example 4

[0504] (3R,3aR)-2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[4,3-b][1,4]oxazine-3-carbonitrile 4-P1

[0505] (3R,3aS)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[4,3-b][1,4]oxazine-3-carbonitrile 4-P2

[0506] (3S,3aS)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[4,3-b][1,4]oxazine-3-carbonitrile 4-P3

[0507] (3S,3aR)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-d]pyrido[4,3-b][1,4]oxazine-3-carbonitrile 4-P4

[0508]

[0509] Referring to Example 2, the first step compound 2a was replaced by 5-iodo-2-(trifluoromethyl)pyridine-4-ol to obtain the title compounds 4-P1, 4-P2, 4-P3, and 4-P4.

[0510] MS m / z(ESI):412.4[M+1].

[0511] Example 5

[0512] (R)-2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-f]quinoline-3-carbonitrile 5

[0513]

[0514] MS m / z(ESI):405.1[M+1].

[0515] Example 6

[0516] (R)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[3,4-h]isoquinoline-3-carbonitrile 6

[0517]

[0518] MS m / z(ESI):405.1[M+1].

[0519] Example 7

[0520] 2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo[1,5-d][1,4]oxazine-3-carbonitrile 7

[0521]

[0522] first step

[0523] 2-(Benzyloxy)-1-iodo-4-(trifluoromethyl)benzene 7b

[0524] 2-iodo-5-(trifluoromethyl)phenol 7a (1.93 g, 6.71 mmol, prepared by the method disclosed in the document "Bulletin of the Chemical Society of Japan, 2012, vol.85, #2, p.201-208") was dissolved in acetonitrile (20 mL), potassium carbonate (2.32 g, 16.8 mmol) was added, and benzyl bromide (1.4 g, 8.2 mmol, Shanghai Titan) was added under nitrogen protection. The reaction was stirred at 80°C for 16 hours, and the reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7b (1.97 g, yield: 77.7%).

[0525] Step 2

[0526] 1-(2-(Benzyloxy)-4-(trifluoromethyl)phenyl)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-(isoquinoline-4-

[0527] 2-Oxoimidazolidine-4-carbonitrile 7c

[0528] Compound 7b (2.62 g, 6.92 mmol), compound 2g (3.5 g, 6.9 mmol), cuprous iodide (527 mg, 2.76 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (786 mg, 5.52 mmol), and cesium carbonate (4.5 g, 13.8 mmol) were dissolved in 1,4-dioxane (50 mL), replaced with nitrogen, and stirred at 120°C for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with water and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7c (1.46 g, yield: 27.9%).

[0529] MS m / z(ESI):757.4[M+1].

[0530] Step 3

[0531] 1-(2-(Benzyloxy)-4-(trifluoromethyl)phenyl)-5-(hydroxymethyl)-3-(isoquinolin-4-yl)-2-oxoimidazolidine-4-carbonitrile 7d

[0532] Compound 7c (1.46 g, 1.93 mmol) was dissolved in tetrahydrofuran (15 mL), and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (2.3 mL, Shanghai Titan) was added under ice bath, and the mixture was naturally returned to room temperature for 2 hours. Water was added to the reaction solution to quench, and the mixture was concentrated under reduced pressure to obtain the crude title compound 7d (1 g), which was used directly in the next step without purification.

[0533] MS m / z(ESI):519.0[M+1].

[0534] Step 4

[0535] 1-(2-Hydroxy-4-(trifluoromethyl)phenyl)-5-(hydroxymethyl)-3-(isoquinolin-4-yl)-2-oxoimidazolidine-4-carbonitrile 7e

[0536] Compound 7d (1 g, 1.93 mmol) was dissolved in trifluoroacetic acid (6 mL), and trifluoromethanesulfonic acid (0.6 mL) was added dropwise under ice bath. The mixture was naturally restored to room temperature with stirring for 4 hours. The pH of the reaction solution was adjusted to 5-6 with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 7e (826 mg, yield: 99%).

[0537] MS m / z(ESI):429.1[M+1].

[0538] Step 5

[0539] 2-(Isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo[1,5-d][1,4]oxazine-3-carbonitrile 7

[0540] Compound 7e (69 mg, 161 μmol) was dissolved in tetrahydrofuran (2 mL), and diisopropyl azodicarboxylate (65.1 mg, 322.1 μmol) and triphenylphosphine (84.5 g, 322.1 μmol) were added under ice bath, and the mixture was stirred and reacted at room temperature for 16 hours. Saturated ammonium chloride solution was added to the reaction solution for quenching, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure after removing the desiccant. The residue was purified by preparative HPLC (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to obtain the title compound 7 (17 mg, yield: 25.6%).

[0541] MS m / z(ESI):411.0[M+1].

[0542] 1 H NMR (500MHz, CD3OD): δ9.37(s,1H),8.67(s,1H),8.27(d,1H),8.13(dd,2H),7.94(t, 1H),7.82(t,1H),7.29(d,2H),5.46(d,1H),4.83(s,1H),4.78(dt,1H),4.30(t,1H).

[0543] Example 7-p1, 7-p2, 7-p3, 7-p4

[0544] (3S,3aS)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo

[0545] [1,5-d][1,4]oxazine-3-carbonitrile 7-p1

[0546] (3R,3aR)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo

[0547] [1,5-d][1,4]oxazine-3-carbonitrile 7-p2

[0548] (3S,3aR)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo

[0549] [1,5-d][1,4]oxazine-3-carbonitrile 7-p3

[0550] (3R,3aS)-2-(isoquinolin-4-yl)-1-oxo-7-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzo[b]imidazo

[0551] [1,5-d][1,4]oxazine-3-carbonitrile 7-p4

[0552]

[0553] Compound 7 (370 mg) was separated by chiral column (Waters SFC 150, column: DAICELCHIRALPAK IG, 20*250mm, 10μm; mobile phase A: Supercritical CO2, mobile phase B: methanol (0.1% 7M ammonia methanol solution), gradient ratio: A: B is 55:45, flow rate: 120mL / min) to obtain the title compound (168mg, yield: 45.4%), (156mg, yield: 42.1%), (22mg, yield: 5.9%), (21mg, yield: 5.6%).

[0554] Single configuration compound (shortest retention time): (168 mg, yield: 45.4%).

[0555] Chiral HPLC analysis: retention time 1.547 minutes, purity: 98.7% (chromatographic column: DAICELCHIRALPAK IG, 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: methanol (containing 0.1% diethylamine), gradient ratio: A:B is 60:40, flow rate: 1.5mL / min).

[0556] 1 H NMR (500MHz, CD3OD): δ9.24(d,1H),8.63(s,1H),8.08(tt,3H),7.84-7.76(m,1H),7.68(td,1 H),7.24(d,1H),7.19(dt,1H),5.36(dd,1H),4.69(dq,1H),4.58(ddt,1H),4.20-4.07(m,1H).

[0557] Single configuration compound (short retention time): (156 mg, yield: 42.1%).

[0558] Chiral HPLC analysis: retention time 2.332 minutes, purity: 99.8% (chromatographic column: DAICELCHIRALPAK IG, 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: methanol (containing 0.1% diethylamine), gradient ratio: A:B is 60:40, flow rate: 1.5mL / min).

[0559] 1H NMR (500MHz, CD3OD): δ9.25(s,1H),8.63(s,1H),8.08(td,3H),7.81(ddd,1H),7.69(dd, 1H),7.25(d,1H),7.20(dd,1H),5.37(d,1H),4.71(dd,1H),4.60(ddd,1H),4.15(t,1H).

[0560] Single configuration compound (longer retention time): (22 mg, yield: 5.9%)

[0561] Chiral HPLC analysis: retention time 2.854 minutes, purity: 90.7% (chromatographic column: DAICELCHIRALPAK IG, 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: methanol (containing 0.1% diethylamine), gradient ratio: A:B is 60:40, flow rate: 1.5mL / min).

[0562] 1 H NMR (500MHz, CD3OD): δ9.38(s,1H),8.69(s,1H),8.33(d,1H),8.28(d,1H),8.14(d,1H),7.97- 7.90(m,1H),7.82(t,1H),7.33(d,1H),7.30(dd,1H),5.71(d,1H),4.84(td,2H),4.45(t,1H).

[0563] Single configuration compound (longest retention time): (21 mg, yield: 5.6%)

[0564] Chiral HPLC analysis: retention time 4.657 minutes, purity: 98.8% (chromatographic column: DAICELCHIRALPAK IG, 100*3mm, 3μm; mobile phase A: Supercritical CO2, mobile phase B: methanol (containing 0.1% diethylamine), gradient ratio: A:B is 60:40, flow rate: 1.5mL / min).

[0565] 1H NMR (500MHz, CD3OD): δ9.38(d,1H),8.69(d,1H),8.33(dd,1H),8.27(dd,1H),8.14(dd,1H),7 .97-7.90(m,1H),7.82(td,1H),7.36-7.25(m,2H),5.71(dd,1H),4.83(dt,2H),4.44(td,1H).

[0566] Biological evaluation

[0567] The present disclosure is further described and explained below in conjunction with test examples, but these test examples are not meant to limit the scope of the present disclosure.

[0568] Test Example 1: Detection of antiviral activity of HCoV-OC43 virus compounds

[0569] Experimental Materials:

[0570] Reagent name Item# supplier Huh-7 cells ATCC CCL-171 ATCC HCoV-OC43 virus ATCC VR-759 ATCC Fetal bovine serum, FBS 35-081-CV Corning Penicillin-Streptomycin dual antibody solution 15140-122 Gibco Cell culture medium:MEM 11095-080 Gibco DPBS 21-031-CV Corning <![CDATA[TrypLE TM Express enzyme (1×)]]> 12605-010 Gibco CellTiter-Glo G7573 Promega

[0571] instrument:

[0572]

[0573]

[0574] Experimental procedures :

[0575] 1×10 5 / mL density of Huh-7 cells were inoculated into a 96-well plate, and 0.1mL of cell suspension was added to each well. After Huh-7 cells were cultured in a 96-well cell culture plate to form a monolayer, 200TCID50 of HCoV-OC43 virus was added to infect the cells. In a 96-well V-bottom plate, the test compound was half-logarithmically diluted with DMSO and added to the 96-well plate Huh-7 cells. The cell plate with virus and compound was incubated in a 37°C, 5% CO2 incubator. After 5-6 days, 100μL of cell lysate was added to each well and lysed for 30min. After mixing the luciferase substrate with the cell lysate at a ratio of 1:1, the fluorescence signal was detected by a microplate reader, and the inhibitory effect of the compound on the HCoV-OC43 virus was evaluated based on the cell activity results.

[0576] Table 1 Inhibitory activity of compounds against HCoV-OC43 virus

[0577]

[0578] Conclusion: The compounds disclosed in the present invention have good inhibitory effects on HCoV-OC43 virus.

[0579] Test Example 2: Detection of antiviral activity of HCoV-229E virus compounds

[0580] Experimental Materials:

[0581] Reagent name Item# supplier MRC-5 cells ATCC CCL-171 ATCC HcoV-229E virus ATCC VR-740 ATCC Fetal bovine serum, FBS 35-081-CV Corning Penicillin-Streptomycin dual antibody solution 15140-122 Gibco Cell culture medium:MEM 11095-080 Gibco DPBS 21-031-CV Corning <![CDATA[TrypLE TM Express enzyme (1×)]]> 12605-010 Gibco CellTiter-Glo G7573 Promega

[0582] instrument:

[0583]

[0584]

[0585] Experimental procedures :

[0586] 1×10 5 / mL density of MRC-5 cells were inoculated into 96-well plates, 0.1mL of cell suspension was added to each well, and the cells were cultured in a 37°C, 5% CO2 incubator. After the MRC-5 cells were cultured in a 96-well cell culture plate to form a monolayer, 200TCID50 of HcoV-229E virus was added to infect the cells. In a 96-well V-bottom plate, the test compound was half-logarithmically diluted with DMSO and added to the 96-well plate MRC-5 cells. The cell plate with the virus and compound was incubated in a 37°C, 5% CO2 incubator. After 4 days, 100μL of cell lysis solution was added to each well and lysed for 30min. After mixing the luciferase substrate with the cell lysate at a ratio of 1:1, the fluorescence signal was detected by a microplate reader, and the inhibitory effect of the compound on the HcoV-229E virus was evaluated based on the cell activity results.

[0587] Table 2 Inhibitory activity of compounds against HCoV-229E virus

[0588]

[0589] Conclusion: The compounds disclosed in the present invention have good inhibitory effects on HCoV-229E virus.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Z is a carbon atom or a nitrogen atom; R 4b , R A1 Together with the atoms to which they are attached, they form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, the aryl group or the heteroaryl group are each independently optionally substituted by one or more R Y1 Replace; or R 4b , R 4a Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently optionally substituted by one or more R Y2 replace; or R 4a , R 3b and R 3a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, nitro, NR 10 R 11 , OR 13 、S(O) r R 13 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R 03 replaced by; or R 4a for not existing; R A1 is a hydrogen atom or R A ; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 2 is selected from polycyclic aromatic groups or polycyclic heteroaromatic groups, wherein the polycyclic aromatic groups or polycyclic heteroaromatic groups are optionally replaced by one or more R 2a replaced by; Each R A , R 2a , R Y1 , R Y2 and R 03 are the same or different and are each independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、Alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 NR 22 C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 、S(O) r R 23 、S(O) r OR 23 、OS(O) r R 23 、S(O) r NR 20 R 21 NR 22 S(O) r R 23 、C(=NR 22 )R 23 、C(=NR 22 )NR 20 R 21 、S(=NR 22 )(O)R 23 、P(O)R 23 R 24 , OR 23 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently substituted with one or more R*; Each R 10 , R 11 , R 13 , R 20 , R 21 , R 22 , R 23 and R 24 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyl group, NR a R b 、C(O)NR a R b 、Alkylene NR a R b 、Alkylene C(O)NR a R b NR c C(O)R d NR c C(O)NR a R b 、C(O)R d 、C(O)OR d 、OC(O)R d 、OC(O)OR d , OR d 、S(O) r R d , cycloalkyl, heterocyclyl, aryl and heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently substituted by one or more R*; or R 10 , R 11 and the nitrogen atom to which it is attached together form a heterocyclic group, or R 20 , R 21 and the nitrogen atom to which it is attached together form a heterocyclic group, which is optionally substituted by one or more R*; Each R a , R b , R c and R d are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an amino group, S(O) r (alkyl), NH(alkyl), N(alkyl) 2 、C(O)NH 2 、C(O)NH(alkyl), C(O)N(alkyl) 2 , C(O)alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl; or R a , R b and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is substituted by one or more R*; Each R* is the same or different and is independently selected from oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, amino, S(O) r (alkyl), NH(alkyl), N(alkyl) 2 、C(O)NH 2 、C(O)NH(alkyl), C(O)N(alkyl) 2 , C(O)alkyl, C(O)OH, C(O)Oalkyl, nitro, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, cycloalkyloxy, heterocyclyloxy, aryl, and heteroaryl; r is 0, 1, or 2; and p is 0, 1, 2, 3, 4, 5 or 6.

2. The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally replaced by one or more R 2a Substituted isoquinolinyl, R 2a As defined in claim 1.

3. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, in: Q 1 (CR Q1 R Q11 ) n1 、C(O)、NR Q12 , O or S; Q 2 (CR Q2 R Q22 ) n2 、C(O)、NR Q23 , O or S; R Q1 , R Q11 , R Q12 , R Q2 , R Q22 and R Q23 are the same or different and are each independently a hydrogen atom or R Y2 ; n1 is 1, 2, 3, 4 or 5; n2 is 1, 2, 3, 4 or 5; m is 0, 1, 2, 3, 4, 5 or 6; Ring A, R A ,p,R 2a and R Y2 As defined in claim 1.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, in: The dotted line indicates whether the ring is aromatic or non-aromatic; Q 3 is (CR Q3 R Q33 ) n3 , C(O), NR Q34 , (CR Q35 ) n31 , N, O or S; Q 4 is (CR Q4 R Q44 ) n4 , C(O), NR Q45 , (CR Q46 ) n41 , N, O or S; R Q3 , R Q33 , R Q34 , R Q35 , R Q4 , R Q44 , R Q45 and R Q46 are the same or different and are each independently a hydrogen atom or R Y1 ; n3, n31, n4 and n41 are the same or different and are each independently 0, 1, 2, 3, 4 or 5; G 1 CR G1 or N; G 2 CR G2 or N; G 3 CR G3 or N; G 4 CR G4 or N; R G1 , R G2 , R G3 and R G4 are the same or different and are each independently a hydrogen atom or R A ; m is 0, 1, 2, 3, 4, 5 or 6; Z, R 2a , R Y1 and R A As defined in claim 1.

5. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 4, wherein m is 0.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 5, wherein Ring A is phenyl or a 6-membered heteroaryl group; and / or R A C 1-6 Halogenated alkyl.

7. A compound or a pharmaceutically acceptable salt thereof represented by the general formula (I) according to any one of claims 3, 5 or 6, wherein Q 1 -Q 2 for (CH 2 ) n11 , n11 is 2, 3, 4 or 5.

8. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, wherein for R Q3 , R Q33 , R Q35 and R Q46 As defined in claim 4.

9. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6 and 8, wherein G 1 CR G1 ; and / or G 3 CR G3 , R G1 and R G3 As defined in claim 4.

10. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 6, 8 and 9, wherein R G3 C 1-6 Halogenated alkyl.

11. A compound represented by general formula (I) according to any one of claims 4 to 6 and 8 to 10, or a pharmaceutically acceptable salt thereof, wherein G 2 is CH or N; and / or G 4 It is CH or N.

12. A compound represented by general formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

13. A compound represented by general formula (IIA) or a salt thereof: in: Q 1 , Q 2 , R 2a and m as defined in claim 3.

14. A compound represented by general formula (IIIA) or a salt thereof: in: Z, R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m as defined in claim 4.

15. A compound or a salt thereof selected from the following compounds:

16. A method for preparing the compound represented by general formula (II) according to claim 3 or a pharmaceutically acceptable salt thereof, the method comprising: include: The compound of general formula (IIA) or its salt is subjected to substitution reaction with the compound of general formula (IIB) or its salt to obtain the compound of general formula (II) or its pharmaceutically acceptable salt, in: X 1 is a halogen; Q 1 , Q 2 , Ring A, R A ,p,R 2a and m as defined in claim 3.

17. A method for preparing the compound represented by general formula (III) according to claim 4 or a pharmaceutically acceptable salt thereof, the method comprising: include: The compound of general formula (IIIA) or its salt is subjected to a cyclization reaction to obtain a compound of general formula (III) or its pharmaceutically acceptable salt, in: for R Q3 , R Q33 , G 1 , G 2 , G 3 , G 4 , R 2a and m as defined in claim 4.

18. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of the compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for inhibiting 3CL protease.

20. Use of a compound represented by general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing viral infection; the virus is preferably a coronavirus; the coronavirus is preferably SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, MERS-CoV and SARS-CoV, more preferably SARS-CoV-2.

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