CN114957165A - Antiviral compound and preparation method and application thereof - Google Patents
Antiviral compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN114957165A CN114957165A CN202210168271.2A CN202210168271A CN114957165A CN 114957165 A CN114957165 A CN 114957165A CN 202210168271 A CN202210168271 A CN 202210168271A CN 114957165 A CN114957165 A CN 114957165A
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- CN
- China
- Prior art keywords
- alkyl
- cycloalkyl
- optionally substituted
- heterocyclyl
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 230000000840 anti-viral effect Effects 0.000 title description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 241000315672 SARS coronavirus Species 0.000 claims abstract description 6
- 241001678559 COVID-19 virus Species 0.000 claims abstract description 5
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims abstract description 5
- 241000711573 Coronaviridae Species 0.000 claims abstract description 4
- -1 stereoisomers Chemical class 0.000 claims description 89
- 125000000217 alkyl group Chemical group 0.000 claims description 88
- 125000000623 heterocyclic group Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 39
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 39
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- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000002947 alkylene group Chemical group 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 20
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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Abstract
The invention discloses a disease-resistant foodA toxic compound, a preparation method and application thereof, in particular to an anti-coronavirus compound which can be used as a PLPro inhibitor, and a preparation method and application thereof. The compound has a structure shown in a general formula I, has high inhibitory activity which is even dozens of times higher than that of a known PLPro inhibitor, can be used for broad-spectrum antivirus, and particularly for coronavirus (such as SARS-CoV, MERS-CoV and SARS-CoV-2), and has very good potential application prospect in the field of medicaments.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to an antiviral compound, a preparation method and application thereof, and especially relates to an anti-coronavirus compound capable of being used as a PLPro inhibitor, and a preparation method and application thereof.
Background
Many important infectious diseases in humans are caused by viruses. These diseases include rabies, smallpox, polio, hepatitis, pneumonia, yellow fever, immunodeficiency and various encephalitis diseases, many of which are highly contagious and produce acute discomfort and are often fatal, others such as rubella and cytomegalovirus cause congenital malformations. Coronaviruses are a large family of viruses, the genome of which is the largest among the currently known positive-stranded RNA viruses. Coronaviruses can be classified into four types according to differences in host, serotype gene sequence and structure: alpha, beta, gamma, and delta. Of these four classes, the α and β classes only infect mammals, and the γ and δ classes mainly infect birds; the genus alphacoronavirus includes human coronavirus (HCoV-229E, HCoV-NL63), Heps longwing coronavirus (HKU1, HKU8), canine coronavirus (CCoV), feline coronavirus (FCoV), etc.; the beta genus coronavirus includes human coronavirus (HCoV-OC43, HCoV-HKU1), novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), murine coronavirus, Hepialus coronavirus HKU9, etc.; gamma coronaviruses mainly include avian coronaviruses such as Infectious Bronchitis Virus (IBV); the delta genus coronavirus includes oriole coronavirus (BuCoV HKU11), hydrangeal coronavirus (WECoV), wild duck coronavirus (WiCoV), and black-water chicken coronavirus (CMCoV).
The papain (PLPro) is a hydrolase expressed on a genome nsp3 at the 5' end of the coronavirus, and has the main function of digesting a specific tetrapeptide structure LXGG between nsp1-2, nsp2-3 and nsp3-4 on a polyprotein pp1a, wherein the polyprotein needs to be hydrolyzed to become a mature functional protein and is a key protein for the multiplication of the coronavirus, and the PLpro can cut an ubiquitin unit of key immune protein of a host cell, so that the coronavirus is protected from immune attack of the host cell. Therefore, inhibition of the PLPro protein of coronavirus can not only inhibit the proliferation of coronavirus, but also enhance the monitoring of coronavirus by the host cell immune system, thereby reducing the cytokine storm. PLPro is crucial to the life cycle of the virus and can be used as a potential target for designing and screening anti-coronavirus drugs. PLpro inhibitors of different chemical structures have been developed, but the inhibitory activity is still to be further improved.
Disclosure of Invention
The present invention provides a compound having the structure:
wherein the content of the first and second substances,
Ar 1 is aryl or heteroaryl, which may be optionally substituted;
Ar 2 is aryl or heteroaryl, which may be optionally substituted;
b is heterocyclyl, which may be optionally substituted;
R 1 and R 2 Independently selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、 -R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、 -R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted; or, R 1 And R 2 Forms, with the carbon atom to which they are attached, a cycloalkyl or heterocyclyl group, which may be optionally substituted;
L 1 selected from: -NR 3 C(O)-、-NR 3 S(O) t -、-C(O)-、-C(O)O-、-NR 3 -、-C(O)NR 3 -、-S(O) t NR 3 -；
R 3 Selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy; or, R 3 And the nitrogen atom to which it is attached to L 2 Or L 3 Together form a heterocyclyl, which may be optionally substituted;
L 2 selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclyleneWhich may be optionally substituted;
L 3 selected from: a single bond, alkylene, heteroalkylene, which may be optionally substituted;
t is 1 or 2;
R L selected from the group consisting of: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、 -C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from the group consisting of: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted.
In one embodiment of the present invention, Ar 1 Has the following structure:
wherein, X 1 -X 7 Independently selected from: C. n;
R 5 represents one or more independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、 -R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、 -R L -N ═ CR' R ", which may be optionally substituted;
t、R L r ', and R' have the above definitions.
Specifically, R 5 Represents one or more independent substituents on the ring selected from: H. alkyl, halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl).
In a particular embodiment of the invention, X 1 -X 7 Are all C, i.e. Ar 1 Is naphthyl (e.g., 1-naphthyl, 2-naphthyl), having the structure:
in the examples of the present invention, Ar 1 Has the following structure:
specifically, X 1 -X 7 At least one (e.g., one, two, three, four, five, six, all) of N.
In one embodiment of the present invention, X 1 -X 7 One of them is N (the others are C); wherein, X 1 Is N; or, X 2 Is N; or, X 3 Is N; or, X 4 Is N; or, X 5 Is N; or, X 6 Is N; or, X 7 Is N. Specifically, Ar 1 May be a quinolyl group (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), which may be optionally substituted; ar (Ar) 1 It may also be isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), which may be optionally substituted.
In another embodiment of the present invention, X 1 -X 7 Two of them are N (the rest are C); specifically, Ar 1 May be a quinoxalinyl group (e.g., 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 8-quinazolinyl), which may be optionally substituted.
In another embodiment of the present invention, X 1 -X 7 Four of them are N (the rest are C); specifically, Ar 1 May be a pteridinyl group (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), which may be optionally substituted.
Specifically, in the present invention, t is 2.
In the formula I, R 1 Is H or alkyl (especially C1-6 alkyl, C1-3 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl); in one embodiment of the invention, R 1 Is H; in another embodiment of the invention, R 1 Is methyl.
In the formula I, R 2 Alkyl, especially C1-6 alkyl, C1-3 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl.
In one embodiment of the invention, in formula I, R 1 Is methyl, R 2 Is methyl.
In the formula I, R 1 And R 2 When different radicals (e.g. R) 1 Is H, R 2 Alkyl) and the carbon atom to which they are attached may be in the R configuration or the S configuration, in particular the R configuration.
In one embodiment of the invention, in formula I, R 1 And R 2 Together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl group, particularly a C3-6 cycloalkyl or heterocyclyl group, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacycloalkyl, thiacycloalkyl, azacycloalkyl, which may be optionally substituted; in one embodiment of the invention, R 1 And R 2 Together with the carbon atoms to which they are attached form a C3 cycloalkyl or heterocyclyl group, e.g., cyclopropyl, epoxypropyl, aziridinyl, which may be optionally substituted.
Specifically, among the above compounds
Is composed of
That is, the above-mentioned compound may have the following formulaThe structure is as follows:
wherein, W 1 And W 2 Independently selected from: C. n, O, respectively; and when W 1 Or W 2 When is O, the corresponding R 6 Or R 7 Is absent;
R 6 and R 7 Independently selected from: H. (═ O), alkyl, halogen, haloalkyl, hydroxy, alkoxy.
In particular, W 1 Is C, W 2 Is C; or, W 1 Is C, W 2 Is N; or, W 1 Is C, W 2 Is O.
Specifically, R 6 And R 7 Independently selected from: H. (═ O), C1-3 alkyl, -CF 3 A hydroxyl group; in one embodiment of the invention, R 6 And R 7 Are all H.
In the embodiment of the present invention, the above
Is composed of
In particular, in the formula I, L 2 Is a single bond or an alkylene group (e.g., C1-6 alkylene, C1-3 alkylene, e.g., methylene); in one embodiment of the invention, L 2 Is a single bond.
In particular, in the formula I, L 3 Is a single bond or an alkylene group (e.g., C1-6 alkylene, C1-3 alkylene, e.g., methylene); in one embodiment of the invention, L 3 Is a single bond.
In particular, in the formula I, L 1 is-NR 3 C (O) -or-NR 3 S(O) 2 -; in one embodiment of the invention, L 1 is-NHC (O) -.
Specifically, the above-mentioned compound may have the following structure:
more specifically, the above compounds may have the following structure:
specifically, R 3 Is H or alkyl (e.g., C1-6 alkyl, C1-3 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl); in one embodiment of the invention, R 3 Is H.
In particular, in the formula I, Ar 2 Has the following structure:
wherein, the first and the second end of the pipe are connected with each other,
n is 0 or 1;
Y 1 -Y 6 independently selected from: C. n, O, S, respectively;
R 8 represents one or more independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、 -R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、 -R L -N ═ CR' R ", which may be optionally substituted;
t、R L r ', and R' have the above definitions.
Specifically, R 8 Represents one or more independent substituents on the ring selected from: H. alkyl, halo-halogen, alkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl), cycloalkyl; more specifically, R 8 Selected from: H. c1-6 alkyl, F, Cl, Br, I, -CF 3 、-OH、 -OCH 3 、-NH 2 、
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In one embodiment of the invention, n is 1 and Ar is in formula VI 2 Has the following structure:
wherein, Y 1 -Y 5 Independently selected from: C. and N is added.
In one embodiment of the invention, in formula VI-1, Y 1 -Y 5 Are all C, i.e. Ar 2 Is phenyl, which may be optionally substituted.
In another embodiment of the invention, in formula VI-1, Y 1 -Y 5 At least one (e.g., one, two, three, four, five) is N.
In particular, in the formula VI-1, Y 1 -Y 5 One of them is N (the others are C); for example, Y 1 Is N; or, Y 2 Is N; or, Y 3 Is N; or, Y 4 Is N; or, Y 5 Is N.
In particular, in the formula VI-1, Y 1 -Y 5 Two of the N are N (the rest is C); for example, Y 1 And Y 2 Is N; or, Y 1 And Y 3 Is N; or, Y 1 And Y 4 Is N; or, Y 1 And Y 5 Is N; or, Y 2 And Y 3 Is N; or, Y 2 And Y 4 Is N; or, Y 2 And Y 5 Is N; or, Y 3 And Y 4 Is N; or, Y 3 And Y 4 Is N; or, Y 4 And Y 5 Is N.
In particular of the formula VI-In 1, Y 1 -Y 5 Three of the N are N (the rest is C); for example, Y 1 、Y 2 And Y 3 Is N; or, Y 1 、Y 2 And Y 4 Is N; or, Y 1 、Y 2 And Y 5 Is N; or, Y 1 、Y 3 And Y 4 Is N; or, Y 1 、Y 3 And Y 5 Is N; or, Y 1 、Y 4 And Y 5 Is N; or, Y 2 、 Y 3 And Y 4 Is N; or, Y 2 、Y 3 And Y 5 Is N; or, Y 3 、Y 4 And Y 5 Is N.
Specifically, the above-mentioned compound may have the following structure:
wherein, the first and the second end of the pipe are connected with each other,
Y 2 -Y 5 independently selected from: C. n;
R 9 independently selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、 -R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、 -R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
R 10 represents one or two independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、 -R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、 -R L -N ═ CR' R ", which may be optionally substituted;
t、R L r 'and R' have the above-mentioned meanings.
More specifically, the above compounds may have the following structure:
specifically, in the above formula, Y 2 Is C, Y 5 Is N; or, Y 5 Is C, Y 2 Is N; or, Y 2 Is C, Y 5 Is C.
Specifically, in the above formula, R 9 Selected from: H. alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl), cycloalkyl; in one embodiment of the invention, R 9 Is alkyl, especially C1-6 alkyl, C1-3 alkyl, such as methyl, ethyl, n-propyl, isopropyl, especially methyl. In another embodiment of the invention, R 9 Is an alkoxy group, especially a C1-3 alkoxy group, such as methoxy, ethoxy, propoxy, especially methoxy. In another embodiment of the invention, R 9 Cycloalkyl, especially C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, especially cyclopropyl. In another embodiment of the invention, R 9 is-NH 2 -NH (C1-3 alkyl), -N (C1-3 alkyl) (C1-3 alkyl), for example, -NH 2 、
In particular-NH 2 . Preferably, R 9 Is methyl.
Specifically, in the above formula, R 10 Selected from: H. alkyl, halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl); furniture setBody to ground, R 10 Selected from: H. c1-6 alkyl, F, Cl, Br, I, -CF 3 、-OH、-OCH 3 、-NH 2 、
In one embodiment of the invention, formula VII-1 is
In particular
In some embodiments of the invention, formula VII-1 is
Specifically, R 10 Having the meaning of the invention as defined above, in particular H, C1-6 alkyl or halogen, for example H, methyl, F, Cl.
In other embodiments of the invention, formula VII-1 is
Specifically, R 10 Having the meaning of the invention as defined above, in particular H, C1-6 alkyl or halogen, for example H, methyl, F, Cl.
In one embodiment of the invention, formula VII-2 is
In another embodiment of the invention, in formula VI, n is 0 and Ar 2 Has the following structure:
wherein, Y 1 Selected from: C. n, O, S, respectively;
Y 2 -Y 4 independently selected from: C. and N is added.
Specifically, the above-mentioned compound may have the following structure:
wherein, Y 1 Selected from the group consisting of: C. n, O, S are provided.
In particular, in formula VIII, Y 1 Is O or S.
In particular, in the formula VIII, R 11 Selected from: H. alkyl, halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl); in one embodiment of the invention, R 11 Is H.
In one embodiment of the invention, formula VIII is
In another embodiment of the invention, in formula VI, n is 0 and Ar 2 Has the following structure:
wherein, Y 1 -Y 4 And Y 6 Independently selected from: C. and N is added.
In one embodiment of the present invention, Y 6 Is N; wherein, Y 1 -Y 4 At least one of which is N.
In one embodiment of the invention, B is a heteroalicyclic group, which may be optionally substituted.
Specifically, the heteroatoms in B are selected from: n, O, S, in particular N, i.e. preferably B is a nitrogen containing heterocyclic group.
In particular, B may be a monocyclic, bicyclic or polycyclic group (e.g., bridged, fused, spiro groups).
Specifically, in the above compounds, B may have the following structure:
wherein Z is 2 -Z 6 Independently selected from: C. n, O, S, respectively;
Z 1 selected from: C. n;
Z 7 absent or selected from: a single bond, C, N, O, S;
and Z is 1 -Z 6 At least one of them is selected from: n, O, S;
m1-m4 are independently selected from integers from 0-5 (e.g., 0, 1,2,3, 4, 5);
R 12 represents one or more independent substituents on the ring selected from: H. (═ O), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、
-R L -CN、-R L -OR'、 -R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、 -NR'-R L -OR”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
r' "is selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen,
t、R L R 'and R' have the above-mentioned meanings.
Specifically, in IX-1, B has the following structure:
wherein Z is 1 And Z 4 Independently selected from: C. n, O, S, and when Z is 4 When is O or S, R 13 Is absent;
Z 7 absent or selected from: single bond, alkylene, N, O, S;
R 13 and R 14 Independently selected from: H. (═ O), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、
-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-R L -N(S(O) t R')(S(O) t R”)、-NR'-R L -NR”R”'、-R L -NO 2 、 -R L -N ═ CR' R ", which may be optionally substituted;
r' "is selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen,
t、R L R 'and R' have the above-mentioned meanings.
In one embodiment of the invention, Z in formula IX-1-1 1 Is N.
In bookIn one embodiment of the invention, of the formula IX-1-1, Z 1 Is CH.
In one embodiment of the invention, Z in the formula IX-1-1 4 Is N.
In another embodiment of the invention, Z in formula IX-1-1 4 Is O.
In another embodiment of the invention, Z in formula IX-1-1 4 Is CH.
In one embodiment of the invention, Z in the formula IX-1-1 7 Absent, i.e. of the formula IX-1-1
In another embodiment of the invention, Z in formula IX-1-1 7 Is a single bond.
In another embodiment of the invention, Z in formula IX-1-1 7 Is alkylene, especially C1-3 alkylene, for example methylene, ethylene.
Specifically, in the formula IX-1-1, m1 and m2 are independently selected from 0, 1 or 2.
In particular, in the formula IX-1-1, R 14 Selected from: H. alkyl, aryl, -R L -CN、-R L -OR'、-R L -OC (O) R', wherein R L Is a single bond or an alkylene group (e.g., C1-3 alkylene); for example H, C1-6 alkyl, phenyl, -CH 2 -CN, in particular H or methyl.
Specifically, the above R 13 Selected from: H. alkyl, halogen, haloalkyl, cycloalkyl, heterocyclyl, -R L -NR'R”、-R L -OR'、-R L -C(O)OR'、 -R L -C(O)NR'R”、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR”R”'、-NR'-R L -OR”、
Wherein R is L Is a single bond or alkylene, R ', R ", and R'" are independently selected from: H. an alkyl group.
Specifically, B may have the following structure:
in particular
Wherein R is 13 、R 14 Having the corresponding definition of the invention, R 15 Is H or C1-6 alkyl (especially C1-3 alkyl, e.g. methyl, ethyl, n-propyl, isopropyl).
Specifically, the above R 14 Selected from: H. c1-6 alkyl (especially C1-3 alkyl, e.g. methyl, ethyl, n-propyl, isopropyl), aryl, -R L -CN、-R L -OR'、-R L -OC (O) R', wherein R L Is a single bond or an alkylene group (e.g., C1-3 alkylene); for example H, C1-6 alkyl, phenyl, -CH 2 -CN, in particular H or methyl.
Specifically, the above R 13 Selected from the following structures: -H, (═ O), F, Cl, Br, I, C1-6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl), -CF 3 、-OH、
In some embodiments of the invention, the above compound has the following structure:
in particular
The invention also provides pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compounds.
In some embodiments of the invention, the stereoisomers have the following structures:
the invention also provides a pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable auxiliary materials.
In particular, in the above pharmaceutical compositions, the above compounds of the invention may be used as the sole active ingredient or in combination with one or more other active ingredients for the same or different indications, wherein the above compounds of the invention and the other active ingredients may be formulated for simultaneous, separate or sequential administration.
Specifically, the pharmaceutically acceptable excipients may include sweetening agents (specifically, sucrose, xylitol, fructo-oligosaccharide, sodium cyclamate, stevioside, aspartame, etc.), flavoring agents (such as flavors, essences, etc.), mucilage agents (specifically, sodium alginate, acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.), clarifying agents (specifically, chitosan, gelatin, etc.), preservatives (specifically, benzoic acid and its salts, sorbic acid and its salts, parabens series, etc.), disintegrating agents (specifically, low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, starch, etc.), binders (specifically, hydroxypropylcellulose, hypromellose, povidone, copovidone, pregelatinized starch, etc.), lubricants (specifically, stearic acid, magnesium stearate, sodium fumarate, etc.), and the like, One or more of a wetting agent (specifically, polyoxyethylene sorbitan fatty acid ester, poloxamer, polyoxyethylene castor oil derivative, etc.), a suspending agent (specifically, hypromellose, hydroxypropyl cellulose, povidone, copovidone, sodium carboxymethyl cellulose, methyl cellulose, etc.), a stabilizer (specifically, citric acid, fumaric acid, succinic acid, etc.), a filler (specifically, starch, sucrose, lactose, microcrystalline cellulose, etc.), a binder (specifically, cellulose derivative, alginate, gelatin, polyvinylpyrrolidone, etc.), and the like.
Specifically, the above-mentioned pharmaceutical composition may be in any dosage form or administration form, and those skilled in the art may select it according to the circumstances, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), troches, syrups, solutions, emulsions, suspensions, controlled release preparations (e.g., immediate release preparations, sustained release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosa-adhering films), injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), intravenous drip injections, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories (e.g., rectal suppositories, vaginal suppositories), and the like, Pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, and the like; the administration form is, for example, oral administration or parenteral administration (for example, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal and the like administration forms).
The invention also provides the compound and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, and application of the pharmaceutical composition as a PLpro inhibitor, such as application as an antiviral drug.
The invention also provides the compound and pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, and application of the pharmaceutical composition in preparing medicaments for preventing and/or treating diseases or symptoms caused by or related to viral infection.
In particular, in the above application, the compound and the pharmaceutical composition have the corresponding definitions of the invention.
In one embodiment of the present invention, the virus is a coronavirus, for example, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2, etc., particularly SARS-CoV, MERS-CoV, SARS-CoV-2.
Specifically, the disease or disorder is a disease or disorder caused by or associated with coronavirus infection, such as COVID-19, SARS, MERS, etc.
The present invention also provides a method for preventing and/or treating a disease or disorder caused by or associated with a viral infection, comprising the step of administering to a subject an effective amount of the above-described compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, or the above-described pharmaceutical composition of the present invention.
In particular, in the above methods, the compound, the pharmaceutical composition, the disease or disorder has the corresponding definitions of the invention as described above.
In particular, the disease or disorder is a disease or disorder caused by or associated with coronavirus infection, such as COVID-19, SARS, MERS, and the like.
Specifically, the subject is an animal; in one embodiment of the present invention, the above-mentioned subject is a mammal, such as human, monkey, cat, dog, mouse, bat, etc.; in another embodiment of the present invention, the subject is an avian.
The invention adopts a protein structure-based drug design (structure-defined drug design) means to obtain a novel PLPro small-molecule inhibitor. Compared with the reported inhibitors, the novel compounds show higher protein biochemical level activity, and the IC50 of some molecules is lower than 100nM, so that the novel compounds have basic activity characteristics of clinical drugs and have very good potential application prospects in the field of drugs.
Drawings
FIG. 1 shows the inhibition curve of GRL0617 as a positive control.
FIG. 2 is a graph showing the inhibition curves of the compound prepared in example 1.
FIG. 3 is a graph showing the inhibition curves of the compound prepared in example 9.
FIG. 4 is a graph showing the inhibition curves of the compound prepared in example 14.
FIG. 5 is a graph showing the inhibition curves of the compound prepared in example 15.
FIG. 6 is a graph showing the inhibition curves of the compound prepared in example 23.
FIG. 7 is a graph showing the inhibition curves of the compound prepared in example 35.
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
The term "alkyl" refers to a hydrocarbon chain radical that is straight or branched and free of unsaturation, and that is attached by a single bond to the rest of the molecule. Typical alkyl groups contain 1 to 12 (e.g., 1,2,3, 4, 5,6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. If an alkyl group is substituted with a cycloalkyl group, it corresponds to a "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. If an alkyl group is substituted with an aryl group, it is correspondingly an "aralkyl" radical, such as benzyl, benzhydryl or phenethyl. If an alkyl group is substituted with a heterocyclyl group, it is correspondingly a "heterocyclylalkyl" radical. "alkylene" generally refers to an alkanediyl group having two free valences, typically alkylene containing from 1 to 12 (e.g., 1,2,3, 4, 5,6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, and the like.
The term "alkoxy" refers to a substituent formed by substituting a hydrogen in a hydroxyl group with an alkyl group, and typically alkoxy contains 1 to 12 (e.g., 1,2,3, 4, 5,6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.
The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) mono-or polycyclic group, which may contain 1 to 4 mono-and/or fused rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g. 3, 4, 5,6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, and the like.
The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl groups and/or fused aryl groups, such as containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, with typical aryl groups being aryl groups containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, and the like. "arylene" refers to a divalent group derived from an aromatic hydrocarbon by the removal of two hydrogen atoms.
The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing from 1 to 3 monocyclic and/or fused rings and from 3 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the invention contain 1,2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups, such as, but not limited to, coumarins, include 8-coumarins, quinolines, including 8-quinolines, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl, and the like. Suitable heteroalicyclic groups in the compounds of the present invention contain 1,2 or 3 heteroatoms selected from N, O or an S atom. Examples of heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathienylalkyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxetanyl, thietanyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiopentyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinylalkyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indolyl, and quinolizinyl, and the like.
The above groups may be substituted in one or more available positions by one or more suitable groups such as: OR ',' O, SR ', SOR', SO 2 R'、OSO 2 R'、OSO 3 R'、NO 2 、NHR'、N(R') 2 、＝N-R'、N(R')COR'、N(COR') 2 、N(R')SO 2 R'、 N(R')C(＝NR')N(R')R'、N 3 CN, halogen, COR ', COOR', OCOR ', OCOOR', OCONHR ', OCON (R') 2 、CONHR'、 CON(R') 2 、CON(R')OR'、CON(R')SO 2 R'、PO(OR') 2 、PO(OR')R'、PO(OR')(N(R')R')、C 1 -C 12 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, aryl and heterocyclyl, wherein each R' group is independently selected from: hydrogen, OH, NO 2 、NH 2 SH, CN, halogen, COH, COalkyl, COOH, C 1 -C 12 Alkyl radical, C 3 -C 10 Cycloalkyl radical, C 2 -C 12 Alkenyl radical, C 2 -C 12 Alkynyl, aryl and heterocyclyl. Where these groups are themselves substituted, the substituents may be selected from the foregoing list.
"halogen" means bromine, chlorine, iodine or fluorine. Haloalkyl means a radical in which a hydrogen atom of an alkyl group is replaced by a halogen atom (F, Cl, Br, I), such as-CH 2 Rh、-CHRh 2 、-CRh 3 Wherein Rh is F, Cl, Br or I; such as-CF 3 。
The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, irritating, and allergic, and capable of achieving or providing clinically acceptable pharmacokinetic, absorption, distribution, and metabolic properties of a drug molecule for its intended purpose. The salt of the invention comprises acid salt or basic salt which is pharmaceutically acceptable for acid groups, basic groups or amphoteric groups of the compound. A list of suitable salts can be found in s.m. large, et al, j.pharm.sci.,66,1-19 (1977).
The pharmaceutically acceptable salts of the present invention include acid addition salts and base addition salts.
Such acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts derived from organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate, and salts of amino acids such as arginate, gluconate, galacturonate, and the like. Acid addition salts may be prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner.
The base addition salts according to the invention are salts with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals useful as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1, 2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.
The term "solvate" is understood to mean any form of the compound of the invention in which the compound is attached to another molecule by non-covalent bonds (usually a polar solvent), including in particular hydrates and alcoholates, such as methanolate. Preferred solvates are hydrates.
The term "prodrug" is used in its broadest sense and encompasses derivatives that are convertible in vivo to the compounds of the invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Preferably, the prodrug having a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid esters are readily esterified from any carboxylic acid moiety present in the molecule. Prodrugs can generally be prepared by known methods, such as those described in Burger "Medicinal Chemistry and Drug Discovery sixth edition (Donald J. Abraham ed., 2001, Wiley) and" Design and Applications of drugs "(H.Bundgaard ed., 1985, Harwood Academic Publishers).
Any reference herein to a compound is intended to represent such a particular compound, and certain variations or forms thereof. In particular, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of the double bond may also be present, whereby in some cases the molecule may exist as the (E) -isomer or as the (Z) -isomer (trans and cis isomers). If a molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same or different from that of the other double bonds of the molecule. In addition, the compounds referred to herein may exist as atropisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the invention.
The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
THU1: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.90(dd,J＝7.2,1.4Hz,2H),7.81(d,J＝8.2Hz, 1H),7.58(ddd,J＝8.4,6.7,1.4Hz,1H),7.54–7.47(m,1H),7.45(t,J＝7.7Hz,1H),7.01(d,J＝8.4Hz,1H),6.87(dt,J＝ 8.5,2.6Hz,1H),6.65(d,J＝2.6Hz,1H),3.12(p,J＝3.1Hz,4H),2.83(p,J＝2.6Hz,4H),2.54(d,J＝1.5Hz,3H),1.99 (s,3H),1.45(t,J＝3.3Hz,2H),1.32–1.30(m,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.38,148.30,137.28,136.79, 134.18,132.09,130.92,128.42,128.30,127.87,126.67,125.62,125.13,124.71,124.51,117.65,114.66,53.98,43.71, 34.21,16.86,13.47.MS(ESI,m/z):C26H29N3O,[M+H]+400.47.
example 2:
THU2: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.95–7.83(m,2H),7.80(d,J＝8.2Hz,1H), 7.57(ddd,J＝8.4,6.7,1.5Hz,1H),7.50(ddd,J＝8.0,6.7,1.3Hz,1H),7.44(dd,J＝8.2,7.1Hz,1H),7.00(d,J＝8.4Hz, 1H),6.85(dd,J＝8.4,2.7Hz,1H),6.63(d,J＝2.7Hz,1H),3.77–3.67(m,4H),3.03–2.91(m,4H),1.98(s,3H),1.50– 1.42(m,2H),1.31(t,J＝3.5Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.51,149.12,137.22,136.80,134.17,132.10, 130.81,128.41,128.30,127.86,126.15,125.59,125.10,124.71,124.51,116.97,114.03,66.45,49.28,34.19,16.84,13.47. MS(ESI,m/z):C25H26N2O2,[M+H]+387.31.
example 3:
THU3: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.90(t,J＝8.2Hz,2H),7.82(d,J＝8.2Hz,1H), 7.59(ddd,J＝8.4,6.7,1.4Hz,1H),7.51(t,J＝7.5Hz,1H),7.45(t,J＝7.7Hz,1H),6.95(d,J＝8.5Hz,1H),6.68(dd,J＝ 8.5,2.8Hz,1H),6.40(d,J＝2.8Hz,1H),3.52(t,J＝5.2Hz,2H),3.46(t,J＝6.2Hz,2H),3.00(t,J＝5.2Hz,2H),2.92– 2.84(m,2H),1.98(s,3H),1.91(p,J＝6.1Hz,2H),1.46(t,J＝3.5Hz,2H),1.32(t,J＝3.5Hz,2H). 13 C NMR(101MHz, Methanol-d 4 )δ172.92,145.91,137.43,136.79,134.20,132.09,131.16,128.44,128.21,127.84,125.58,125.08,124.71, 124.48,122.23,112.92,110.14,47.10,46.72,34.24,27.21,16.60,13.34.MS(ESI,m/z):C26H29N3O,[M+H]+400.31.
example 4:
THU4: 1 H NMR(400MHz,DMSO-d 6 )δ8.99(s,1H),8.69(d,J＝8.4Hz,1H),7.94(d,J＝8.1Hz,1H),7.82(t,J＝ 8.7Hz,2H),7.52(ddd,J＝33.2,16.1,7.8Hz,3H),6.95(d,J＝8.5Hz,1H),6.67(d,J＝8.6Hz,1H),6.41(s,1H),5.76(s, 1H),3.61(s,2H),3.32(d,J＝12.8Hz,4H),2.89–2.73(m,3H),2.15–2.02(m,2H),1.94(s,3H),1.37(s,2H),1.19(s, 2H). 13 C NMR(101MHz,DMSO-d 6 )δ170.20,146.50,138.04,133.97,132.27,131.56,128.95,128.81,128.10,126.15, 125.88,125.59,125.51,123.06,113.39,111.21,56.85,55.72,47.13,44.40,43.92,34.64,24.35,18.30,14.51.MS(ESI, m/z):C26H29N3O,[M+H]+414.25.
example 5:
THU5: 1 H NMR(400MHz,Methanol-d 4 )δ8.64–8.55(m,1H),7.95–7.86(m,3H),7.82(t,J＝7.3Hz,1H),7.60 (ddd,J＝8.4,6.8,1.5Hz,1H),7.52(td,J＝7.7,1.3Hz,1H),7.46(ddd,J＝8.3,7.1,3.5Hz,1H),6.87(d,J＝3.1Hz,1H), 3.62–3.54(m,2H),3.44(t,J＝6.2Hz,2H),2.88(s,2H),2.79(d,J＝6.1Hz,2H),2.52(s,3H),2.12(s,3H),2.05(p,J＝ 6.2Hz,2H),1.53–1.44(m,2H),1.36–1.33(m,2H). 13 C NMR(101MHz,Methanol-d 4 )δ170.54,143.02,132.82,132.45, 128.46,128.33,127.95,125.68,125.17,124.71,124.37,117.87,56.96,56.40,44.71,18.94,13.39.MS(ESI, m/z):C26H30N4O,[M+H]+415.22.
example 6:
THU6: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.91–7.82(m,2H),7.78(d,J＝8.2Hz,1H), 7.60(ddd,J＝8.4,6.7,1.4Hz,1H),7.50(ddd,J＝8.1,6.7,1.2Hz,1H),7.46–7.40(m,1H),7.30(d,J＝8.6Hz,1H),6.74 (d,J＝8.6Hz,1H),3.49–3.40(m,4H),2.58(t,J＝5.0Hz,4H),2.39(s,3H),2.29(s,3H),1.50(dt,J＝7.4,3.5Hz,2H), 1.31(dt,J＝7.4,3.5Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ168.24,156.11,145.49,141.94,137.01,134.24,132.07, 128.56,127.86,127.59,125.65,125.15,124.80,124.29,122.92,110.00,54.01,44.40,44.25,33.73,17.01,13.31.MS(ESI, m/z):C25H28N4O,[M+H]+401.33.
example 7:
THU7: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.2Hz,1H),7.91(dd,J＝7.5,5.4Hz,2H),7.82(dd,J＝18.4, 7.6Hz,2H),7.61(t,J＝7.4Hz,1H),7.52(t,J＝7.4Hz,1H),7.50–7.44(m,1H),7.28(d,J＝7.0Hz,1H),3.92(s,3H), 3.40(s,4H),1.97(s,3H),1.60(s,2H),1.37(s,2H). 13 C NMR(101MHz,Methanol-d 4 )δ163.75,152.53,146.34,142.06, 136.27,134.16,132.01,128.50,128.37,128.18,125.87,125.31,124.79,124.34,122.67,113.07,43.51,42.64,34.23,15.16, 13.41.MS(ESI,m/z):C24H26N4O,[M+H]+387.31.
example 8:
THU8: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.91(dt,J＝7.2,1.6Hz,2H),7.82(d,J＝8.2Hz, 1H),7.59(ddd,J＝8.4,6.8,1.4Hz,1H),7.51(ddd,J＝8.1,6.8,1.3Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),6.99(d,J＝8.3 Hz,1H),6.58(dd,J＝8.3,2.7Hz,1H),6.34(d,J＝2.7Hz,1H),4.43(s,1H),4.13(s,1H),3.55(dd,J＝10.9,2.4Hz,1H), 3.25(d,J＝10.9Hz,1H),3.08(dd,J＝11.1,1.9Hz,1H),2.77(s,3H),2.23(d,J＝11.3Hz,1H),2.20–2.10(m,1H),1.97 (s,3H),1.47(dt,J＝6.8,3.3Hz,2H),1.32(t,J＝3.5Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.50,143.71,137.63, 136.79,134.17,131.18,128.41,128.34,127.86,125.59,125.12,124.72,124.51,123.52,114.02,111.07,65.61,60.23, 56.42,51.81,40.32,34.18,33.80,16.69,13.49.MS(ESI,m/z):C27H29N3O,[M+H]+412.32.
example 9:
THU9: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.90(d,J＝7.5Hz,2H),7.81(d,J＝8.2Hz,1H), 7.58(ddd,J＝8.3,6.7,1.4Hz,1H),7.48(dt,J＝22.5,7.6Hz,2H),7.03(dd,J＝8.4,3.8Hz,1H),6.90(dd,J＝8.4,2.7Hz, 1H),6.67(dd,J＝7.2,2.7Hz,1H),3.55(dd,J＝6.5,3.8Hz,1H),3.19(s,6H),3.10(dd,J＝6.2,4.0Hz,1H),2.00(s,3H), 1.46(t,J＝3.4Hz,2H),1.31(t,J＝3.4Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.26,156.66,148.26,137.42, 136.78,134.17,132.09,130.99,128.42,128.35,127.88,127.17,125.63,125.14,124.72,124.51,117.95,114.95,47.11, 43.64,34.20,16.87,13.51.MS(ESI,m/z):C26H29N5O,[M+H]+428.35.
example 10:
THU10: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.91(d,J＝7.7Hz,2H),7.82(d,J＝8.1Hz, 1H),7.59(t,J＝7.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.46(t,J＝7.6Hz,1H),7.05(d,J＝8.4Hz,1H),6.91(dd,J＝9.8, 7.2Hz,1H),6.72–6.66(m,1H),3.57(t,J＝5.1Hz,1H),3.23(s,6H),3.18–3.08(m,1H),2.00(s,3H),1.47(s,2H),1.32 (s,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.22,148.18,137.49,136.78,134.18,132.09,130.99,128.41,128.35, 127.87,127.26,125.59,125.11,124.72,124.50,117.97,114.98,45.09,43.57,34.20,16.84,13.51.MS(ESI, m/z):C27H31N7O,[M+H]+470.64.
example 11:
THU11:H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.4Hz,1H),7.90(dd,J＝7.7,4.2Hz,2H),7.81(d,J＝8.3Hz, 1H),7.67–7.37(m,3H),7.00(d,J＝8.4Hz,1H),6.87(d,J＝8.6Hz,1H),6.64(s,1H),3.11(s,4H),2.80(s,4H),1.98(s, 3H),1.45(s,2H),1.31(s,2H).MS(ESI,m/z):C25H28N4O,[M+H]+401.33.
example 12:
THU12: 1 H NMR(400MHz,MeOD)δ8.62(dd,J＝8.4,2.7Hz,1H),7.94–7.86(m,2H),7.82(d,J＝8.2Hz,1H), 7.58(ddd,J＝8.4,6.7,1.5Hz,1H),7.54–7.39(m,2H),6.97(t,J＝7.8Hz,1H),6.70(ddd,J＝24.9,8.4,2.7Hz,1H),6.46 (dd,J＝6.8,2.6Hz,1H),3.22(td,J＝8.6,5.3Hz,3H),3.12–2.96(m,4H),2.87–2.68(m,3H),2.58(s,2H),2.45(s,1H), 1.99(d,J＝14.5Hz,3H),1.46(q,J＝4.7,4.0Hz,2H),1.32(t,J＝3.4Hz,2H).MS(ESI,m/z):C28H31N3O, [M+H]+426.29.
example 13:
THU13: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.5Hz,1H),7.90(d,J＝7.6Hz,2H),7.81(d,J＝8.2Hz, 1H),7.59(t,J＝7.7Hz,1H),7.48(dt,J＝21.4,7.6Hz,2H),7.01(d,J＝8.4Hz,1H),6.87(dd,J＝8.3,2.6Hz,1H),6.64(d, J＝2.7Hz,1H),3.65(d,J＝12.6Hz,2H),3.24(tt,J＝12.2,4.1Hz,1H),2.85(s,6H),2.64(t,J＝12.3Hz,2H),2.04(d,J ＝12.0Hz,2H),2.00(s,3H),1.73–1.61(m,2H),1.46(t,J＝4.9Hz,2H),1.33(h,J＝5.3Hz,2H). 13 C NMR(101MHz, Methanol-d 4 )δ172.42,148.21,137.32,136.82,134.19,132.09,130.95,128.41,128.28,127.87,126.35,125.64,125.16, 124.70,124.50,118.06,115.03,63.59,53.39,39.11,34.26,25.88,16.80,13.45.MS(ESI,m/z):C28H33N3O, [M+H]+428.38.
example 14:
THU14: 1 H NMR(400MHz,Methanol-d 4 )δ8.59(d,J＝8.5Hz,1H),7.95–7.86(m,2H),7.81(d,J＝8.3Hz,1H), 7.57(t,J＝7.8Hz,1H),7.53–7.37(m,2H),7.06(d,J＝8.4Hz,1H),6.95(dd,J＝8.5,2.8Hz,1H),6.70(d,J＝2.9Hz, 1H),5.49(d,J＝2.1Hz,1H),3.72–3.58(m,2H),3.47–3.37(m,2H),3.23(t,J＝12.4Hz,1H),2.91(t,J＝12.6Hz,1H), 2.69(t,J＝11.9Hz,1H),1.99(d,J＝2.2Hz,3H),1.45(s,2H),1.34(dd,J＝6.8,2.0Hz,4H),1.31(s,2H).MS(ESI, m/z):C26H29N3O,[M+H]+400.23.
example 15:
THU15: 1 H NMR(400MHz,Methanol-d 4 )δ9.19(s,1H),8.58(d,J＝8.4Hz,1H),7.89(dd,J＝7.3,3.3Hz,3H),7.81 (d,J＝8.3Hz,1H),7.62–7.53(m,1H),7.50(t,J＝7.4Hz,1H),7.44(t,J＝7.7Hz,1H),7.04(d,J＝8.3Hz,1H),6.92(dd, J＝8.4,2.7Hz,1H),6.68(d,J＝2.7Hz,1H),3.71(d,J＝3.3Hz,2H),3.40(t,J＝4.8Hz,4H),1.99(d,J＝3.9Hz,3H), 1.44(q,J＝4.5Hz,2H),1.30(q,J＝4.6Hz,2H).MS(ESI,m/z):C27H29N3O3,[M-H]+442.22.
example 16:
THU16: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.5Hz,1H),7.92(dd,J＝7.2,3.9Hz,2H),7.84(d,J＝8.3 Hz,1H),7.60(d,J＝7.8Hz,2H),7.49(dt,J＝16.8,7.8Hz,2H),7.43–7.31(m,2H),3.76–3.55(m,5H),2.37–2.19(m, 4H),2.11(d,J＝2.1Hz,3H),1.51(s,2H),1.35(s,2H). 13 C NMR(101MHz,Methanol-d 4 )δ170.05,138.74,136.51, 134.15,132.14,132.05,128.53,128.42,128.00,125.76,125.18,124.74,124.37,121.25,118.75,53.31,45.26,34.20,27.65, 17.34,13.63.MS(ESI,m/z):C26H29N3O,[M+H]+400.23.
example 17:
THU17: 1 H NMR(400MHz,Methanol-d 4 )δ8.59(d,J＝8.3Hz,1H),7.95–7.86(m,2H),7.81(d,J＝8.2Hz,1H), 7.58(t,J＝7.5Hz,1H),7.54–7.39(m,3H),7.31(d,J＝7.4Hz,2H),4.12(s,1H),3.87–3.44(m,6H),2.05(s,3H),1.49 (q,J＝4.9Hz,2H),1.32(t,J＝3.3Hz,2H),1.12(d,J＝5.2Hz,3H).MS(ESI,m/z):C26H29N3O,[M+H]+400.23.
example 18:
THU18: 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J＝8.3Hz,1H),8.14(s,1H),7.94(dd,J＝13.0,7.6Hz,2H), 7.83(d,J＝8.3Hz,1H),7.64-7.44(m,3H),6.96(s,1H),6.60(s,1H),3.06(s,4H),3.00(s,4H),2.29(s,3H),1.59(s,2H), 1.44(s,2H).
13 C NMR(100MHz,Chloroform-d)δ166.75,153.44,140.70,138.05,134.60,133.13,132.66,128.70,127.70,127.63, 126.15,125.78,125.05,124.69,124.37,116.99,49.86,45.82,35.89,22.49,18.70.MS(ESI,m/z):C24H26N4O, [M+H]+387.21.
example 19:
THU19: 1 H NMR(400MHz,DMSO-d 6 )δ9.07(s,1H),8.93(s,2H),8.66(d,J＝8.2Hz,1H),7.94(d,J＝8.1Hz,1H), 7.88–7.78(m,2H),7.60–7.45(m,3H),7.02(d,J＝8.4Hz,1H),6.90(dd,J＝8.4,2.7Hz,1H),6.64(d,J＝2.6Hz,1H), 3.32–3.08(m,8H),1.93(s,3H),1.36(q,J＝4.5Hz,2H),1.18(q,J＝4.8Hz,2H). 13 C NMR(100MHz,DMSO-d 6 )δ 174.15,150.16,138.20,134.77,133.99,132.27,129.28,127.86,127.58,127.06,126.34,126.07,125.79,125.53,125.10, 110.71,106.31,49.10,45.55,35.92,17.69,16.34.MS(ESI,m/z):C25H28N4O3S,[M+H]+465.19.
example 20:
THU20: 1 H NMR(400MHz,Methanol-d 4 )δ8.62(d,J＝8.4Hz,1H),7.96–7.85(m,2H),7.81(d,J＝8.2Hz,1H), 7.64–7.53(m,1H),7.47(ddd,J＝19.5,8.4,7.2Hz,2H),6.93(d,J＝8.4Hz,1H),6.48(dd,J＝8.3,2.7Hz,1H),6.26(d,J ＝2.6Hz,1H),3.40–3.34(m,1H),3.29(dd,J＝9.0,2.3Hz,1H),3.16(td,J＝9.4,6.9Hz,1H),3.01(t,J＝8.4Hz,1H), 2.95–2.83(m,1H),2.32(s,6H),2.27–2.16(m,1H),1.97(s,3H),1.85(dq,J＝12.0,9.2Hz,1H),1.45(t,J＝3.4Hz,2H), 1.34–1.27(m,2H). 13 C NMR(101MHz,Methanol-d 4 )δ172.95,145.54,137.14,136.87,134.20,132.12,130.78,128.39, 128.22,127.81,125.50,125.05,124.70,124.56,121.69,112.63,109.85,65.29,51.43,46.50,42.79,34.20,29.30,16.97, 16.68,13.41.MS(ESI,m/z):C27H31N3O,[M+H]+414.25.
example 21:
THU21:1H NMR(400MHz,Methanol-d 4 )δ8.64(d,J＝8.3Hz,1H),7.94–7.85(m,2H),7.80(d,J＝8.2Hz,1H), 7.61(ddd,J＝8.4,6.8,1.4Hz,1H),7.51(ddd,J＝8.1,6.8,1.2Hz,1H),7.48–7.40(m,1H),6.79(s,1H),6.51(s,1H), 5.50(s,2H),2.91(s,8H),2.58(s,3H),2.05(s,3H),1.51–1.44(m,2H),1.31(s,2H). 13 C NMR(101MHz,Methanol-d 4 )δ 143.75,132.12,128.37,128.21,127.72,125.55,125.06,124.68,124.54,118.97,116.55,54.71,53.39,34.23,18.00,13.49. MS(ESI,m/z):C26H30N4O,[M+H]+415.25.
example 22:
THU22: 1 H NMR(400MHz,Methanol-d 4 )δ8.67(d,J＝8.5Hz,1H),7.89(dd,J＝7.6,4.0Hz,2H),7.80(d,J＝8.3 Hz,1H),7.60(t,J＝7.7Hz,1H),7.55–7.39(m,3H),6.62(d,J＝1.8Hz,1H),3.26(s,4H),3.15(s,4H),2.76(s,3H),1.48 (q,J＝5.0,4.5Hz,2H),1.32(q,J＝2.4Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ163.24,150.54,138.40,136.71, 134.10,132.08,128.62,128.36,127.88,125.65,125.07,124.68,124.33,120.67,106.96,53.23,42.98,34.23,13.81.MS (ESI,m/z):C23H25N3OS,[M+H]+392.18.
example 23:
THU23： 1 H NMR(400MHz,DMSO-d6)δ9.34(s,1H),9.09(s,1H),8.67(d,J＝8.3Hz,1H),7.93(d,J＝8.0Hz,1H), 7.82(t,J＝7.7Hz,2H),7.62-7.43(m,3H),7.01(d,J＝8.5Hz,1H),6.90(d,J＝8.3Hz,1H),6.66(s,1H),3.27(s,4H), 3.15(s,4H),1.93(s,3H),1.37(s,2H),1.18(s,2H).
13 C NMR(101MHz,DMSO-d6)δ169.88,148.00,138.31,138.01,133.94,132.25,131.44,128.92,128.87,128.11, 126.78,126.14,125.88,125.62,125.51,117.54,115.24,46.16,42.89,34.57,18.44,14.56.MS(ESI,m/z):C25H27N3O, [M+H]+386.22.
example 24:
THU24: 1 H NMR(400MHz,Methanol-d 4 )δ8.65–8.54(m,1H),8.01–7.84(m,2H),7.80(d,J＝8.2Hz,1H),7.58 (ddd,J＝8.4,6.8,1.4Hz,1H),7.50(ddd,J＝8.1,6.8,1.2Hz,1H),7.43(dd,J＝8.3,7.1Hz,1H),7.07(d,J＝8.5Hz,1H), 6.87–6.74(m,2H),3.45(dd,J＝6.7,3.7Hz,4H),3.35(dd,J＝6.7,3.7Hz,4H),2.10(s,3H),1.45(t,J＝3.5Hz,2H),1.34 –1.27(m,2H). 13 C NMR(101MHz,Methanol-d 4 )δ173.68,150.49,137.74,135.52,133.41,130.82,129.90,129.82, 129.44,127.18,126.61,126.08,125.74,120.07,115.20,47.98,44.02,35.97,19.79,14.88.MS(ESI,m/z):C25H27N3O, [M+H]+386.22.
example 25:
THU25: 1 H NMR(400MHz,Methanol-d 4 )δ8.60(d,J＝8.4Hz,1H),7.88(dt,J＝7.1,1.8Hz,2H),7.80(d,J＝8.2 Hz,1H),7.57(ddd,J＝8.4,6.8,1.4Hz,1H),7.49(ddd,J＝8.1,6.7,1.2Hz,1H),7.43(dd,J＝8.3,7.1Hz,1H),7.06(d,J＝ 8.3Hz,1H),6.80–6.71(m,2H),3.86(d,J＝13.6Hz,2H),3.57(d,J＝12.4Hz,2H),3.24–3.15(m,2H),3.07–2.96(m, 2H),2.94(s,3H),2.11(s,3H),1.47–1.40(m,2H),1.30(t,J＝3.5Hz,2H). 13 C NMR(101MHz,Methanol-d 4 )δ173.50, 151.80,138.59,138.21,135.56,133.50,130.21,129.76,129.72,129.62,129.24,127.01,126.50,126.07,125.85,119.17, 114.20,54.50,47.30,43.57,35.69,19.90,14.94.MS(ESI,m/z):C26H29N3O,[M+H]+400.23.
example 26:
THU26: 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.67(d,J＝8.3Hz,1H),7.98–7.89(m,1H),7.82(t,J＝7.9 Hz,2H),7.63–7.38(m,3H),6.98(d,J＝8.4Hz,1H),6.86(dd,J＝8.3,2.7Hz,1H),6.62(d,J＝2.7Hz,1H),3.52(d,J＝ 5.2Hz,4H),3.35-3.45(m,6H),3.35-3.45(m,3H),3.02(t,J＝5.2Hz,2H),2.95(t,J＝5.2Hz,2H),2.02(s,3H),1.92(s, 3H),1.39-1.31(m,2H),1.21-1.11(m,2H). 13 C NMR(101MHz,DMSO-d6)δ170.06,168.78,148.88,138.15,138.04, 133.96,132.26,131.34,128.92,128.84,128.10,126.12,126.05,125.86,125.62,125.51,117.35,115.14,52.86,49.38, 49.03,48.81,45.86,43.28,41.09,34.59,29.47,22.54,21.61,21.51,18.41,14.54.MS(ESI,m/z):C30H38N4O, [M+H]+471.31.
example 27:
THU27: 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.67(d,J＝8.3Hz,1H),7.97-7.89(m,1H),7.82(t,J＝8.2Hz, 2H),7.61-7.43(m,3H),6.98(d,J＝8.3Hz,1H),6.86(dd,J＝8.4,2.7Hz,1H),6.61(d,J＝2.7Hz,1H),3.54-3.50(m,4H), 3.38-3.44(m,8H),3.38-3.44(m,3H),3.02(t,J＝5.1Hz,2H),2.95(t,J＝5.2Hz,2H),2.02(s,3H),1.92(s,3H),1.36(q,J ＝4.6,4.1Hz,2H),1.17(q,J＝4.7Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ170.06,168.80,148.88,138.13,138.04, 133.96,132.25,131.34,128.92,128.83,128.09,126.12,126.05,125.87,125.62,125.50,117.36,115.15,53.12,49.38, 49.02,48.77,45.94,45.87,44.61,41.09,40.86,34.59,21.60,20.73,18.42,14.53.MS(ESI,m/z):C31H40N4O, [M+H]+485.32.
example 28:
THU28: 1 H NMR(400MHz,DMSO-d 6 )δ9.13(d,J＝18.1Hz,1H),8.68(t,J＝7.6Hz,1H),8.30(s,2H),7.92 (d,J＝8.1Hz,1H),7.82(d,J＝7.6Hz,2H),7.58–7.37(m,3H),7.01(dd,J＝16.6,8.2Hz,1H),6.96–6.85(m, 1H),6.77–6.59(m,1H),4.37(s,2H),3.50(qd,J＝16.3,15.2,8.9Hz,1H),3.43–3.25(m,2H),3.00(q,J＝6.0Hz, 1H),1.92(s,3H),1.37(dd,J＝7.6,5.0Hz,2H),1.18(d,J＝5.7Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ169.59, 143.27,138.77,138.29,138.03,137.94,133.94,133.91,132.28,132.26,131.64,131.55,128.91,128.88,128.86, 128.15,128.11,126.26,126.16,125.90,125.73,125.63,125.50,125.10,114.88,112.65,60.99,55.40,45.82,43.78, 43.41,37.24,34.61,34.52,19.02,18.57,18.45,14.62,14.58.MS(ESI,m/z):C24H25N3O,[M+H]+372.46.
example 29:
THU29: 1 H NMR(400MHz,Methanol-d 4 )δ8.62(d,J＝8.4Hz,1H),7.96–7.85(m,2H),7.83(d,J＝8.2Hz, 1H),7.60(ddd,J＝8.4,6.7,1.4Hz,1H),7.52(ddd,J＝8.0,6.8,1.2Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),7.07(d, J＝8.3Hz,1H),6.96(dd,J＝8.4,2.6Hz,1H),6.71(d,J＝2.6Hz,1H),4.12(q,J＝7.1Hz,2H),3.71(t,J＝12.2Hz, 2H),3.57(d,J＝12.3Hz,1H),3.26(d,J＝12.4Hz,1H),3.02(t,J＝12.7Hz,1H),2.95(s,3H),2.77(dd,J＝13.5, 10.8Hz,1H),2.03(s,2H),2.02(s,2H),1.47(q,J＝4.9Hz,2H),1.42(d,J＝6.4Hz,3H),1.35–1.30(m,2H),1.26 (t,J＝7.1Hz,3H).MS(ESI,m/z):C27H31N3,[M+H]+414.25.
example 30:
THU30: 1 H NMR(400MHz,Chloroform-d)δ8.48–8.42(m,1H),7.93(dd,J＝7.1,1.3Hz,1H),7.92–7.88 (m,1H),7.81(d,J＝8.2Hz,1H),7.57(ddd,J＝8.4,6.8,1.5Hz,1H),7.53–7.43(m,2H),7.00(d,J＝8.5Hz,1H), 6.77(dd,J＝8.4,2.7Hz,1H),6.66(d,J＝2.7Hz,1H),6.42(s,1H),3.35–3.27(m,4H),3.11–3.02(m,4H),2.08 (s,3H),1.60–1.53(m,2H),1.42–1.37(m,2H).MS(ESI,m/z):C26H26N4O,[M+H]+411.21.
example 31:
THU31: 1 H NMR(400MHz,Methanol-d4)δ8.62(d,J＝8.5Hz,1H),7.98–7.87(m,2H),7.82(d,J＝8.2Hz, 1H),7.58(ddd,J＝8.4,6.8,1.5Hz,1H),7.51(ddd,J＝8.0,6.7,1.3Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),6.99(d, J＝8.3Hz,1H),6.57(dd,J＝8.4,2.6Hz,1H),6.34(d,J＝2.6Hz,1H),3.73(q,J＝7.2Hz,1H),3.50(dd,J＝10.4, 7.3Hz,1H),3.43(td,J＝9.0,3.2Hz,1H),3.20(q,J＝8.3Hz,1H),2.80(s,6H),2.52–2.38(m,2H),2.10(dq,J＝ 16.4,8.3Hz,1H),1.98(s,3H),1.46(q,J＝4.9Hz,2H),1.32(q,J＝3.7,2.9Hz,2H). 13 C NMR(101MHz, Methanol-d4)δ172.70,145.07,137.42,136.84,134.19,132.12,130.90,128.38,128.32,127.83,125.52,125.06, 124.71,124.53,122.89,113.37,110.44,65.26,46.28,41.30,34.20,27.24,16.64,13.49.MS(ESI,m/z): C27H31N3O,[M+H]+414.25.
example 32:
THU32: 1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝8.4Hz,1H),7.92(dt,J＝8.3,2.6Hz,2H),7.83(d,J ＝8.2Hz,1H),7.58(ddd,J＝8.4,6.8,1.4Hz,1H),7.51(ddd,J＝8.1,6.8,1.3Hz,1H),7.46(dd,J＝8.3,7.1Hz, 1H),7.18(dd,J＝7.9,1.9Hz,1H),7.12(d,J＝7.9Hz,1H),6.97(d,J＝1.9Hz,1H),3.51–3.39(m,2H),3.16– 3.02(m,2H),2.89–2.76(m,1H),2.05(s,3H),1.99(d,J＝14.2Hz,2H),1.89–1.74(m,2H),1.47(d,J＝5.6Hz, 2H),1.35–1.30(m,2H). 13 C NMR(101MHz,Methanol-d4)δ172.14,141.30,137.34,136.79,134.17,133.45, 132.11,130.46,128.41,128.37,127.87,127.31,125.61,125.11,124.71,124.55,124.46,44.14,38.95,34.16,29.50, 17.29,13.61.MS(ESI,m/z):C26H28N2O,[M+H]+385.22.
example 33:
THU33: 1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝8.5Hz,1H),7.92(d,J＝7.5Hz,2H),7.83(d,J＝8.3 Hz,1H),7.59(t,J＝7.9Hz,1H),7.53(d,J＝7.7Hz,1H),7.47(t,J＝6.1Hz,1H),7.01(s,1H),6.80(d,J＝2.4Hz, 1H),3.02(t,J＝4.8Hz,4H),2.27(d,J＝2.5Hz,3H),2.04(d,J＝2.5Hz,3H),1.47(q,J＝5.3,4.0Hz,2H),1.33(s, 2H). 13 C NMR(101MHz,Methanol-d4)δ171.92,147.42,136.77,135.14,134.39,134.18,133.04,132.08,131.00, 128.38,127.87,125.57,125.11,124.73,124.45,117.60,43.93,34.19,17.19,16.13,13.54.MS(ESI,m/z): C26H29N3O,[M+H]+400.23.
example 34:
THU34: 1 H NMR(400MHz,Methanol-d4)δ9.29(s,1H),8.61(d,J＝8.4Hz,1H),7.92(d,J＝7.5Hz,2H), 7.83(d,J＝8.2Hz,1H),7.59(t,J＝7.8Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(t,J＝7.6Hz,1H),7.37(d,J＝7.9 Hz,1H),7.16(t,J＝4.4Hz,2H),6.06(s,1H),3.80(t,J＝2.9Hz,2H),3.46–3.38(m,2H),2.70(d,J＝6.4Hz,2H), 2.08(d,J＝2.5Hz,3H),1.47(s,2H),1.33(s,2H). 13 C NMR(101MHz,Methanol-d4)δ172.07,137.27,136.99, 136.75,134.51,134.46,134.18,132.08,130.29,128.40,128.32,127.87,125.61,125.56,125.11,124.69,124.47, 123.03,118.65,43.03,41.43,34.22,24.70,17.42,13.47.MS(ESI,m/z):C26H26N2O,[M+H]+383.20.
example 35:
THU35: 1 H NMR(400MHz,Methanol-d4)δ8.63(d,J＝8.4Hz,1H),7.92(d,J＝7.6Hz,2H),7.83(d,J＝8.3 Hz,1H),7.59(t,J＝7.6Hz,1H),7.51(t,J＝7.6Hz,1H),7.47(t,J＝7.7Hz,1H),7.07(d,J＝8.4Hz,1H),6.75(dd, J＝8.4,2.7Hz,1H),6.51(d,J＝2.8Hz,1H),4.51(d,J＝6.4Hz,2H),3.77(d,J＝12.0Hz,2H),3.66(d,J＝12.2 Hz,2H),3.02(dt,J＝12.3,6.8Hz,1H),2.01(s,3H),1.96(d,J＝10.4Hz,1H),1.47(d,J＝5.6Hz,2H),1.34(d,J＝ 5.6Hz,2H). 13 C NMR(101MHz,Methanol-d4)δ172.63,145.29,137.57,136.81,134.18,132.11,131.10,128.39, 127.86,125.57,125.09,124.72,124.52,123.57,116.37,111.73,108.87,58.69,34.21,28.85,27.17,16.67,13.53. MS(ESI,m/z):C26H27N3O,[M+H]+398.22.
example 36:
THU36: 1 H NMR(400MHz,Methanol-d4)δ8.60(dd,J＝8.4,1.1Hz,1H),7.95–7.88(m,2H),7.83(d,J＝8.2Hz,1H),7.59(ddd,J＝8.4,6.8,1.4Hz,1H),7.52(ddd,J＝8.1,6.8,1.3Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H), 7.09(d,J＝8.5Hz,1H),7.00(dd,J＝8.4,2.7Hz,1H),6.76(d,J＝2.7Hz,1H),3.49–3.44(m,2H),3.42(dd,J＝ 6.8,2.9Hz,2H),3.25(s,2H),2.01(s,3H),1.51–1.44(m,2H),1.35–1.31(m,2H),1.13(td,J＝6.0,4.0Hz,2H), 1.02(td,J＝5.9,2.3Hz,2H). 13 C NMR(101MHz,Methanol-d4)δ171.96,146.88,137.55,136.70,134.18,132.08, 131.16,128.42,128.38,128.34,127.90,125.59,125.12,124.72,124.47,118.26,115.30,54.04,46.48,43.25,37.51, 34.22,16.87,13.49,9.20.MS(ESI,m/z):C27H29N3O,[M+H]+412.23.
example 37:
THU37: 1 H NMR(400MHz,Methanol-d4)δ8.61(d,J＝8.5Hz,1H),7.91(t,J＝6.9Hz,2H),7.83(d,J＝8.3 Hz,1H),7.60(t,J＝7.7Hz,1H),7.52(t,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,1H),6.92(d,J＝13.1Hz,1H),6.79(d, J＝8.8Hz,1H),3.20(dd,J＝6.4,3.6Hz,4H),2.05(d,J＝2.2Hz,3H),1.47(s,2H),1.33(s,2H). 13 C NMR(101 MHz,Methanol-d4)δ170.97,154.54,136.65,135.93,135.84,134.19,133.29,132.05,131.92,128.44,128.39, 127.91,125.61,125.13,124.73,124.40,118.41,117.87,117.66,43.51,34.24,17.11,13.50.MS(ESI,m/z): C25H26FN3O,[M+H]+404.21.
example 38:
THU38: 1 H NMR(400MHz,Methanol-d4)δ8.63(d,J＝8.4Hz,1H),7.95–7.88(m,2H),7.82(d,J＝8.2Hz, 1H),7.60(ddd,J＝8.4,6.8,1.4Hz,1H),7.52(ddd,J＝8.2,6.9,1.2Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),6.80(d, J＝1.8Hz,2H),3.86(s,3H),3.40–3.35(m,4H),3.24(dd,J＝6.6,3.6Hz,4H),2.12(s,3H),1.51–1.44(m,2H), 1.36–1.28(m,2H). 13 C NMR(101MHz,Methanol-d4)δ171.61,153.21,136.78,135.67,134.19,133.04,132.08, 129.03,128.42,128.36,127.86,125.60,125.11,124.72,124.47,118.09,113.66,54.87,43.40,34.28,17.83,13.52. MS(ESI,m/z):C26H29N3O2,[M+H]+416.23.
example 39:
THU39: 1 H NMR(400MHz,Methanol-d4)δ9.25(s,1H),8.60(d,J＝8.5Hz,1H),7.96–7.87(m,2H),7.83 (d,J＝8.3Hz,1H),7.60(t,J＝7.6Hz,1H),7.52(t,J＝7.5Hz,1H),7.47(t,J＝7.8Hz,1H),7.24(s,1H),6.86(s, 1H),3.36(d,J＝4.8Hz,4H),3.17(t,J＝5.1Hz,4H),2.03(s,3H),1.47(s,2H),1.35(d,J＝5.5Hz,2H). 13 C NMR (101MHz,Methanol-d4)δ170.69,145.14,136.61,136.46,134.19,132.34,132.05,129.51,128.45,128.42,127.94, 125.61,125.14,124.74,124.36,119.08,43.73,34.24,26.57,16.93,13.52.MS(ESI,m/z):C25H26ClN3O,[M+H]+ 420.18.
example 40:
THU40: 1 H NMR(400MHz,MeOD)δ8.65–8.57(m,1H),7.91(dd,J＝7.2,1.3Hz,2H),7.83(d,J＝8.1Hz,1H), 7.59(ddd,J＝8.4,6.8,1.4Hz,1H),7.55–7.42(m,2H),7.01(d,J＝8.5Hz,1H),6.64(dd,J＝8.4,2.7Hz,1H),6.41(d,J ＝2.7Hz,1H),3.89(d,J＝4.8Hz,1H),3.53–3.40(m,3H),3.23(td,J＝9.0,5.9Hz,1H),2.75(s,3H),2.51–2.43(m,1H), 2.23–2.13(m,1H),1.98(s,3H),1.50–1.44(m,2H),1.36–1.28(m,2H). 13 C NMR(101MHz,MeOD)δ172.63,144.88, 137.42,136.77,134.18,132.11,130.97,128.38(d,J＝2.0Hz),127.87,125.58,125.10,124.71,124.51,123.59,114.01, 111.01,58.40,53.41,50.16,45.87,34.21,30.77,27.46,16.70,13.52.MS(ESI,m/z):C26H29N3O,[M+H]+400.23.
example 41:
THU41: 1 H NMR(400MHz,DMSO)δ8.69(d,J＝8.3Hz,1H),7.96–7.89(m,1H),7.82(dd,J＝9.5,7.6Hz, 2H),7.63–7.41(m,3H),6.93(d,J＝8.3Hz,1H),6.45(dd,J＝8.3,2.6Hz,1H),6.23(d,J＝2.6Hz,1H),3.45(d,J ＝10.5Hz,2H),3.27–3.05(m,5H),2.33(d,J＝33.6Hz,1H),2.07(dt,J＝12.6,7.9Hz,1H),1.92(d,J＝5.6Hz, 6H),1.36(dt,J＝6.8,3.2Hz,2H),1.18(q,J＝3.5,2.6Hz,2H). 13 C NMR(101MHz,DMSO)δ170.28,145.53, 138.34,138.10,133.95,132.28,131.30,128.91,128.83,128.08,126.12,125.86,125.68,125.50,122.03,113.10, 110.94,70.65,46.80,44.61,34.57,34.34,23.57,18.34,14.55.MS(ESI,m/z):C28H31N3O,[M+H]+426.25.
example 42:
THU42: 1 H NMR(400MHz,MeOD)δ8.61(d,J＝8.4Hz,1H),7.91(d,J＝7.5Hz,2H),7.82(d,J＝8.2Hz, 1H),7.59(t,J＝7.6Hz,1H),7.48(dt,J＝20.5,7.6Hz,2H),7.01(d,J＝8.3Hz,1H),6.64(dd,J＝8.4,2.6Hz,1H), 6.42(d,J＝2.5Hz,1H),3.54–3.42(m,3H),3.23(td,J＝8.8,5.7Hz,2H),2.75(s,3H),2.45(dt,J＝14.1,6.5Hz, 1H),2.22–2.14(m,1H),1.98(s,3H),1.49–1.44(m,2H),1.36–1.30(m,2H). 13 C NMR(101MHz,MeOD)δ 172.61,144.85,137.42,136.78,134.18,132.11,130.98,128.37(d,J＝2.2Hz),127.87,125.58,125.10,124.71, 124.51,123.66,114.05,111.06,58.40,50.21,45.93,34.23,30.81,27.47,16.70,13.53,-1.45.MS(ESI,m/z): C26H29N3O,[M+H]+400.23.
example 43:
THU43:1H NMR(400MHz,MeOD)δ8.64–8.58(m,1H),7.94–7.87(m,2H),7.82(d,J＝8.2Hz,1H),7.59 (ddd,J＝8.4,6.8,1.4Hz,1H),7.55–7.43(m,2H),7.04(d,J＝8.3Hz,1H),6.71(dd,J＝8.3,2.6Hz,1H),6.50(d, J＝2.6Hz,1H),4.01(s,1H),3.78–3.57(m,1H),3.53(dt,J＝7.9,6.1Hz,2H),3.39(dd,J＝10.9,3.4Hz,1H), 2.47(ddd,J＝15.4,13.6,7.3Hz,1H),2.15(dq,J＝9.7,4.8Hz,1H),1.98(s,3H),1.47(t,J＝3.4Hz,2H),1.33– 1.31(m,2H). 13 C NMR(101MHz,MeOD)δ172.46,144.11,137.41,136.73,134.17,132.10,131.10,128.38, 127.89,125.63,125.13,124.70,124.49,114.63,111.63,52.23,50.01,46.68,34.26,28.93,16.77,13.54,-1.44.MS (ESI,m/z):C25H27N3O,[M+H]+386.22.
example 44:
THU44: 1 H NMR(400MHz,MeOD)δ8.62(d,J＝8.4Hz,1H),7.94–7.86(m,2H),7.82(d,J＝8.2Hz,1H), 7.59(ddd,J＝8.4,6.8,1.4Hz,1H),7.55–7.42(m,2H),7.05(d,J＝8.4Hz,1H),6.76(dd,J＝8.3,2.6Hz,1H), 6.55(d,J＝2.6Hz,1H),4.01(d,J＝9.8Hz,1H),3.80–3.62(m,1H),3.62–3.50(m,2H),3.41(dd,J＝11.0,3.4 Hz,1H),2.48(dq,J＝14.2,7.3Hz,1H),2.21–2.09(m,1H),1.99(s,3H),1.51–1.45(m,2H),1.32(dd,J＝6.7, 1.7Hz,2H). 13 C NMR(101MHz,MeOD)δ172.36,143.73,137.37(d,J＝8.8Hz),136.70,134.17,132.10,131.16, 128.38,127.91,125.65,125.31,125.14,124.70,124.49,115.00,111.99,72.17,52.55,49.93,34.29,28.91,16.80, 13.54,-1.43.MS(ESI,m/z):C25H27N3O,[M+H]+386.22.
example 45:
THU45: 1 H NMR(400MHz,MeOD)δ8.61(d,J＝8.5Hz,1H),7.92(d,J＝7.7Hz,2H),7.83(d,J＝8.3Hz, 1H),7.59(t,J＝7.8Hz,1H),7.49(dt,J＝20.5,7.9Hz,2H),7.10(d,J＝8.4Hz,1H),6.97(d,J＝8.4Hz,1H),6.77 (s,1H),3.70–3.52(m,3H),3.49(d,J＝10.4Hz,2H),3.38(d,J＝5.9Hz,1H),3.28(d,J＝9.9Hz,4H),2.01(d,J ＝2.3Hz,3H),1.48(d,J＝2.9Hz,2H),1.33(s,2H). 13 C NMR(101MHz,MeOD)δ171.34,141.46,137.87,136.69, 134.16,132.09,131.41,130.37,128.40(d,J＝2.9Hz),127.92,125.68,125.14,124.71,124.48,118.45,115.69, 56.45,50.21,40.71,34.25,26.58,17.05,13.59.MS(ESI,m/z):C27H29N3O,[M+H]+412.23.
example 46:
THU46: 1 H NMR(400MHz,MeOD)δ8.74(d,J＝8.5Hz,1H),7.97(dd,J＝7.1,1.2Hz,1H),7.90(d,J＝8.2 Hz,1H),7.82(d,J＝8.2Hz,1H),7.63(ddd,J＝8.5,6.8,1.4Hz,1H),7.51(dd,J＝8.2,6.8Hz,1H),7.49–7.44(m, 1H),7.40(d,J＝2.8Hz,1H),7.32(d,J＝8.8Hz,1H),7.23(dd,J＝8.8,2.8Hz,1H),3.55(dd,J＝6.6,3.8Hz,4H), 3.40(dd,J＝6.7,3.8Hz,4H),1.60–1.55(m,2H),1.39–1.34(m,2H). 13 C NMR(101MHz,MeOD)δ167.75, 150.18,136.53,134.13,132.15,128.93,128.39,128.00,127.80,125.78,125.32,125.19,124.67,124.51,122.26, 119.17,53.41,45.46,43.13,34.42,13.72.MS(ESI,m/z):C24H26N4O,[M+H]+387.21.
example 47:
THU47: 1 H NMR(400MHz,MeOD)δ8.66(d,J＝8.3Hz,1H),7.95–7.88(m,1H),7.80(d,J＝8.2Hz,1H), 7.70(d,J＝7.4Hz,1H),7.48(q,J＝7.3Hz,3H),7.14(d,J＝8.4Hz,1H),7.01(dd,J＝8.5,2.6Hz,1H),6.86(d,J ＝2.6Hz,1H),3.39(s,8H),2.13(s,3H),2.01(s,6H). 13 C NMR(101MHz,MeOD)δ170.30,147.79,141.54, 138.14,135.10,131.08,130.32,129.31,127.75,127.66,125.54,124.86,124.48,123.72,118.03,115.01,56.39, 46.70,43.34,28.30,17.03.MS(ESI,m/z):C25H29N3O,[M+H]+388.23.
example 48:
THU48: 1 H NMR(400MHz,MeOD)δ8.61(d,J＝8.4Hz,1H),7.91(dd,J＝7.6,3.7Hz,2H),7.83(d,J＝8.2 Hz,1H),7.60(t,J＝7.6Hz,1H),7.49(dt,J＝22.4,7.6Hz,2H),7.08(d,J＝2.2Hz,1H),6.84(d,J＝2.4Hz,1H), 3.46–3.39(m,4H),3.35(d,J＝3.8Hz,4H),1.94(s,3H),1.50(d,J＝5.6Hz,2H),1.34(d,J＝5.6Hz,2H). 13 C NMR(101MHz,MeOD)δ173.15,149.61,146.70,138.36,136.79,134.17,132.10,128.37,128.29,127.82,125.54, 125.05,124.69,124.54,111.90,105.14,104.47,48.69,44.39,34.17,26.58,13.42,11.49.MS(ESI,m/z): C25H28N4O,[M+H]+401.23.
example 49:
THU49: 1 H NMR(400MHz,MeOD)δ8.58(d,J＝8.5Hz,1H),7.91(t,J＝7.1Hz,2H),7.83(d,J＝8.3Hz, 1H),7.63–7.42(m,3H),7.07(d,J＝2.7Hz,1H),6.64(d,J＝2.8Hz,1H),3.31(s,8H),1.95(s,3H),1.47(d,J＝ 2.9Hz,2H),1.32(d,J＝7.3Hz,2H). 13 C NMR(101MHz,MeOD)δ171.14,148.51,139.40,136.52,135.45, 134.16,132.04,128.43,127.97,125.68,125.17,124.73(d,J＝3.7Hz),124.41,117.89,113.55,45.93,43.10,34.27, 14.39,13.48.MS(ESI,m/z):C25H26ClN3O,[M+H]+420.18.
example 50:
THU50: 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.04–7.96(m,3H),7.60(d,J＝1.9Hz,1H),7.57– 7.47(m,2H),7.41(t,J＝7.6Hz,1H),7.35(dd,J＝7.8,1.2Hz,1H),7.21(dq,J＝8.7,1.0Hz,1H),6.85(dd,J＝8.6, 1.9Hz,1H),4.13(t,J＝6.3Hz,1H),3.53(dt,J＝6.4,5.7Hz,2H),3.28(ddd,J＝5.7,3.4,1.2Hz,4H),2.70–2.55 (m,4H),2.51(t,J＝5.7Hz,2H),2.43(d,J＝0.8Hz,3H),2.13(q,J＝0.7Hz,4H). 13 C NMR(100MHz, Methanol-d4)δ168.39,148.46,134.40,133.66,133.46,133.27,132.91,130.42,127.79,127.72,126.30,125.96, 125.14,124.85,124.50,116.72,114.34,59.75,58.15,53.14,49.19,35.89,20.80,18.80.MS(ESI,m/z): C27H31N3O2,[M+H]+430.24.
example 51:
THU51： 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.00(ddt,J＝5.8,3.5,1.6Hz,3H),7.60(d,J＝1.9Hz, 1H),7.57–7.47(m,2H),7.41(t,J＝7.6Hz,1H),7.35(dd,J＝7.8,1.2Hz,1H),7.21(dq,J＝8.7,1.0Hz,1H),6.85 (dd,J＝8.6,1.9Hz,1H),3.37–3.28(m,4H),3.18–3.08(m,4H),2.87(s,3H),2.43(d,J＝0.8Hz,3H),2.13(q,J ＝0.8Hz,4H). 13 C NMR(100MHz,Methanol-d4)δ168.39,148.48,134.40,133.66,133.46,133.27,132.91,130.44, 127.79,127.72,126.30,125.96,125.14,124.85,124.50,116.75,114.36,48.88,45.38,35.89,34.50,20.80,18.80. MS(ESI,m/z):C26H29N3O3S,[M+H]+464.19.
example 52:
THU52: 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.05(s,1H),8.67(d,J＝8.3Hz,1H),8.00–7.88(m, 1H),7.82(t,J＝8.1Hz,2H),7.64–7.42(m,3H),7.01(d,J＝8.4Hz,1H),6.90(dd,J＝8.5,2.7Hz,1H),6.66(d,J ＝2.7Hz,1H),3.63(dd,J＝30.7,12.6Hz,4H),3.15(d,J＝15.5Hz,2H),3.01–2.76(m,4H),2.51(s,3H),1.93(s, 2H),1.37(q,J＝4.6,4.1Hz,2H),1.21–1.10(m,2H). 13 C NMR(101MHz,DMSO-d6)δ169.90,147.65,138.13, 138.03,133.94,132.25,131.45,128.92,128.84,128.11,126.81,126.18,125.91,125.66,125.50,117.45,115.17, 55.43,53.71,53.02,51.20,46.13,45.66,34.61,18.49,17.16,14.55.MS(ESI,m/z):C27H31N3O4S, [M+H]+494.20.
example 53:
THU53: 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),8.68(d,J＝8.2Hz,1H),7.94(d,J＝7.9Hz,1H),7.82 (t,J＝8.7Hz,2H),7.66–7.40(m,3H),6.97(d,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.6Hz,1H),6.60(d,J＝2.6Hz, 1H),3.22(t,J＝6.1Hz,2H),3.04(d,J＝5.2Hz,4H),2.79(s,6H),2.65(t,J＝6.1Hz,2H),2.57(t,J＝4.8Hz,4H), 1.94(s,3H),1.36(q,J＝4.9Hz,2H),1.17(d,J＝6.5Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ170.11,148.93, 138.13,138.04,133.97,132.26,131.31,128.94,128.86,128.10,126.08,125.85,125.62,125.54,116.82,114.64, 55.38,53.41,52.71,52.14,48.57,43.21,34.59,18.42,14.52.MS(ESI,m/z):C29H36N4O,[M+H]+457.29.
example 54:
THU54: 1 H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.05(s,1H),8.68(d,J＝8.3Hz,1H),7.93(d,J＝8.0 Hz,1H),7.82(t,J＝6.9Hz,2H),7.52(m,3H),7.01(d,J＝8.4Hz,1H),6.90(dd,J＝8.3,2.6Hz,1H),6.66(d,J＝ 2.6Hz,1H),3.67(d,J＝11.4Hz,2H),3.52(d,J＝10.9Hz,2H),3.34(d,J＝9.3Hz,2H),3.06(p,J＝12.1,11.4Hz, 4H),2.88(t,J＝7.6Hz,2H),1.93(s,3H),1.37(d,J＝5.4Hz,2H),1.19(d,J＝5.7Hz,2H). 13 C NMR(101MHz, DMSO-d6)δ171.95,169.88,147.64,138.29,138.02,133.95,132.26,131.44,128.93,128.11,126.76,126.15, 125.88,125.63,125.52,117.45,115.12,66.82,51.47,51.19,46.08,34.59,28.89,18.43,14.56.MS(ESI,m/z): C28H31N3O3,[M+H]+458.24.
example 55:
THU55: 1 H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.52(s,1H),9.09(s,1H),8.68(d,J＝8.4Hz,1H), 7.93(d,J＝8.0Hz,1H),7.82(t,J＝8.3Hz,2H),7.52(m,3H),7.02(d,J＝8.4Hz,1H),6.91(dd,J＝8.4,2.6Hz, 1H),6.67(d,J＝2.6Hz,1H),3.74–3.66(m,2H),3.57(s,1H),3.23(dd,J＝13.0,8.7Hz,2H),3.11(d,J＝9.5Hz, 2H),1.94(s,3H),1.38(d,J＝5.7Hz,2H),1.19(d,J＝5.0Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ169.75, 168.76,147.70,138.28,138.00,133.95,132.25,131.52,128.90,128.81,128.09,127.34,126.15,125.89,125.60, 125.48,118.04,115.65,66.82,54.83,48.57,45.90,42.21,34.64,18.46,14.51.MS(ESI,m/z):C26H27N3O3, [M+H]+430.21.
example 56:
THU56: 1 H NMR(400MHz,DMSO-d6)δ8.44(s,1H),8.00(ddt,J＝5.8,3.5,1.6Hz,3H),7.57–7.47(m,2H), 7.41(t,J＝7.7Hz,1H),7.38–7.32(m,2H),7.06(dd,J＝8.9,1.8Hz,1H),7.00(d,J＝8.9Hz,1H),3.94(s,3H), 3.30–3.18(m,4H),3.08–2.94(m,4H),2.39(p,J＝3.2Hz,1H),2.22–2.07(m,4H). 13 C NMR(100MHz, Methanol-d4)δ167.84,153.99,145.14,134.28,133.27,132.93,127.79,127.72,126.30,125.96,125.14,124.79, 124.50,122.58,119.28,115.75,113.00,56.53,49.65,45.44,35.89,18.63.MS(ESI,m/z):C25H27N3O2, [M+H]+402.21.
example 57:
THU57: 1 H NMR(400MHz,DMSO-d6)δ9.25(s,2H),9.09(s,1H),8.66(d,J＝8.3Hz,1H),7.93(dd,J＝8.0,1.6 Hz,1H),7.82(t,J＝6.7Hz,2H),7.65–7.41(m,3H),6.87(dd,J＝8.6,2.7Hz,1H),6.77(d,J＝8.6Hz,1H),6.60(d,J＝ 2.6Hz,1H),3.32–3.20(m,4H),3.20–3.05(m,4H),1.42–1.32(m,2H),1.18(q,J＝4.7Hz,2H),0.32–0.19(m,4H). 13 C NMR(101MHz,Methanol-d4)δ128.43,128.37,127.90,126.86,125.66,125.16,124.74,124.53,118.65,115.39, 48.28,48.07,47.85,47.64,47.43,47.21,47.00,43.04,13.46,11.68,6.59.MS(ESI,m/z):C27H29N3O,[M+H]+412.23.
example 58:
THU58: 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),8.67(d,J＝8.5Hz,1H),8.01(s,1H),7.93(d,J＝8.3 Hz,1H),7.82(t,J＝7.5Hz,2H),7.52(ddt,J＝30.1,15.3,7.5Hz,3H),6.98(d,J＝8.4Hz,1H),6.83(d,J＝8.0Hz, 1H),6.60(d,J＝2.8Hz,1H),5.74(d,J＝1.7Hz,1H),3.60(s,2H),3.26(s,4H),1.92(s,3H),1.36(d,J＝5.5Hz, 2H),1.18(d,J＝5.4Hz,2H). 13 C NMR(100MHz,Methanol-d4)δ169.98,168.39,147.60,134.40,133.52,133.32, 133.27,132.91,130.21,127.79,127.72,126.30,125.96,125.14,124.85,124.50,117.28,114.75,52.46,48.47,40.01, 35.89,20.80,18.80.MS(ESI,m/z):C25H25N3O2,[M+H]+400.19.
example 59:
THU59: 1 H NMR(400MHz,Methanol-d 4 )δ8.60(d,J＝8.4Hz,1H),7.93(d,J＝8.0Hz,1H),7.88(d,J＝7.1 Hz,1H),7.83(d,J＝8.3Hz,1H),7.61(t,J＝7.7Hz,1H),7.53(t,J＝7.5Hz,1H),7.46(t,J＝7.7Hz,1H),6.99(s, 1H),6.53(s,1H),3.84(s,2H),3.48(d,J＝11.9Hz,2H),3.37(d,J＝11.9Hz,2H),2.91(s,3H),2.31(s,3H),2.05(s, 3H),1.97(s,4H),1.46(d,J＝5.1Hz,2H),1.32(d,J＝6.9Hz,2H).MS(ESI,m/z):C29H33N3O,[M+H]+439.26.
example 60:
THU60: 1 H NMR(400MHz,Methanol-d 4 )δ8.61(d,J＝8.5Hz,1H),7.95–7.88(m,2H),7.83(d,J＝8.2Hz, 1H),7.61(ddd,J＝8.4,6.8,1.4Hz,1H),7.52(ddd,J＝8.1,6.8,1.2Hz,1H),7.46(dd,J＝8.3,7.1Hz,1H),7.07(d, J＝8.4Hz,1H),6.93(dd,J＝8.4,2.8Hz,1H),6.74(d,J＝2.8Hz,1H),4.01(s,4H),1.98(s,3H),1.51–1.44(m, 2H),1.37–1.31(m,2H).MS(ESI,m/z):C25H23N3O3,[M+H]+414.17.
example 61:
THU61: 1 H NMR(400MHz,Chloroform-d)δ8.47–8.39(m,1H),7.92(dd,J＝7.1,1.3Hz,1H),7.88–7.82 (m,1H),7.78(d,J＝8.2Hz,1H),7.48–7.39(m,3H),7.38–7.29(m,5H),6.94(d,J＝8.4Hz,1H),6.77(dd,J＝ 8.4,2.7Hz,1H),6.69(d,J＝2.7Hz,1H),6.62(s,1H),3.47(dq,J＝11.9,2.6Hz,1H),3.39(dt,J＝11.9,2.7Hz, 1H),3.12(dd,J＝10.5,3.1Hz,1H),3.02(dt,J＝11.4,2.6Hz,1H),2.92(td,J＝11.8,2.9Hz,1H),2.69(dd,J＝ 11.9,10.5Hz,1H),2.44(td,J＝11.6,3.1Hz,1H),2.08(s,3H),2.07(s,3H),1.54(q,J＝4.9Hz,2H),1.39–1.34 (m,2H).MS(ESI,m/z):C32H33N3O,[M+H]+476.26.
example 62:
THU62: 1 H NMR(400MHz,Chloroform-d)δ8.45(d,J＝8.4Hz,1H),7.94(dd,J＝7.1,1.2Hz,1H),7.91– 7.85(m,1H),7.80(d,J＝8.2Hz,1H),7.57(ddd,J＝8.4,6.8,1.4Hz,1H),7.53–7.42(m,2H),6.98(d,J＝8.4Hz, 1H),6.79(dd,J＝8.4,2.7Hz,1H),6.68(d,J＝2.7Hz,1H),6.50(s,1H),3.29(dt,J＝11.7,2.0Hz,1H),3.17(dt,J ＝11.6,3.8Hz,1H),2.99–2.83(m,2H),2.78(ddd,J＝11.7,5.0,3.1Hz,1H),2.69–2.58(m,2H),2.53(dd,J＝ 11.9,7.6Hz,1H),2.45(ddd,J＝12.0,8.9,3.3Hz,1H),2.36(s,3H),2.06(s,3H),1.56(t,J＝3.4Hz,2H),1.42– 1.35(m,4H).MS(ESI,m/z):C28H30N4O,[M+H]+439.24.
example 63:
THU63: 1 H NMR(400MHz,Methanol-d 4 )δ8.60(d,J＝8.5Hz,1H),7.95–7.90(m,1H),7.88(dd,J＝7.1, 1.2Hz,1H),7.83(d,J＝8.2Hz,1H),7.61(ddd,J＝8.4,6.8,1.4Hz,1H),7.53(ddd,J＝8.0,6.8,1.2Hz,1H),7.46 (dd,J＝8.3,7.1Hz,1H),6.99(s,1H),6.54(s,1H),3.82(d,J＝4.9Hz,2H),3.38(d,J＝12.1Hz,2H),3.24(dd,J＝ 12.4,2.3Hz,2H),2.30(s,3H),2.06(s,3H),1.99(dd,J＝9.6,5.0Hz,1H),1.94–1.86(m,1H),1.46(q,J＝4.8Hz, 2H),1.35–1.30(m,2H).MS(ESI,m/z):C28H31N3O,[M+H]+426.25.
example 64:
THU64: 1 H NMR(400MHz,MeOD)δ8.63–8.56(m,1H),7.95–7.87(m,2H),7.83(d,J＝8.2Hz,1H), 7.59(ddd,J＝8.4,6.8,1.5Hz,1H),7.55–7.42(m,2H),6.78(dd,J＝12.4,2.5Hz,1H),6.54(d,J＝2.5Hz,1H), 3.31(s,8H),1.87(d,J＝2.0Hz,3H),1.49–1.45(m,2H),1.34–1.30(m,2H). 13 C NMR(101MHz,MeOD)δ 170.77,162.78,160.36,149.16(d,J＝10.4Hz),139.47,136.60,134.17,132.04,128.42,127.94,125.64,125.14, 124.72,124.42,113.80,110.27,104.23(d,J＝27.4Hz),45.84,43.09,34.23,13.51,9.00(d,J＝4.1Hz).MS(ESI, m/z):C25H26FN3O,[M+H]+404.21.
preparation of the compound:
(1) preparation of cyclopropylamine intermediate (1- (naphthalen-1-yl) cyclopropylamine) the synthetic route is as follows:
the specific operation is as follows:
1-Naphthalenecarbonitrile (1, 5mmol,1.0e.q.) was placed in a round bottom flask, 10mL of dried tetrahydrofuran was added as a solvent, followed by tetraisopropyl titanate (5.5mmol, 1.0e.q.), the reaction was cooled to-78 deg.C, and then Ethyl Grignard reagent (11mmol, 2.2e.q.) was slowly added dropwise to the reaction. After the completion of the dropwise addition, the reaction system was warmed to room temperature to react for 1.5 hours. Boron trifluoride diethyl etherate (10mmol, 2.0e.q.) was then added dropwise to the reaction system, and the reaction was stirred at room temperature for three hours after completion of the dropwise addition. After the reaction, 20mL of 2N hydrochloric acid was added dropwise to the reaction system, and the mixture was quenched with stirring for 20 minutes, followed by addition of an excess of saturated sodium hydroxide solution. Adding ethyl acetate for extraction, collecting the organic phase, and separating by silica gel column chromatography after spin drying to obtain the intermediate 2 of the cyclopropylamine.
(2) The compounds of examples 32 and 34 were prepared by the following synthetic route:
the specific operation is as follows:
synthesis of the compound of example 34, THU 34:
methyl 2-methyl-5-bromobenzoate (3, 2mmol, 1.0e.q.) was placed in a 50mL sealed tube and N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid (2mmol, 1.0e.q.), tris (dibenzylideneacetone) dipalladium (0.04mmol, 0.02e.q.), X-PHOS ligand (0.08mmol, 0.04e.q.) and cesium carbonate (4mmol, 2.0e.q.) were added. Then dioxane solvent (10mL) was added, the reaction was protected with argon, the tube was sealed and the reaction was stirred overnight at 100 ℃. And after TLC detection of substrate conversion, spin-drying the organic solvent and separating and purifying by column chromatography to obtain an intermediate 4.
Intermediate 4(1.0e.q.) was placed in a round bottom flask and tetrahydrofuran: methanol: water 3:1:1 as solvent, then adding lithium hydroxide (4.0e.q.) into the reaction system, stirring and reacting for 6 hours at 45 ℃, then spin-drying the solvent, acidifying the reaction system with 2N hydrochloric acid, adding ethyl acetate for extraction, recrystallizing to obtain white solid, and drying to obtain the intermediate 5.
Adding 5 and the previously obtained ternary cyclic amine intermediate 2 into DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 45 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with pure water and saturated ammonium chloride solution for three times, spin-drying the organic phase, and purifying by silica gel column chromatography to obtain a product 6.
Putting 6 into a 25mL round-bottom flask, taking DCM as a solvent, adding a dioxane solution (4M, 4.0e.q.) of hydrochloric acid, stirring for 6 hours at room temperature, spin-drying the solvent, recrystallizing to obtain a light yellow solid, and drying to obtain the final product THU 34.
Synthesis of the compound of example 32, THU 32:
putting the intermediate 5 into a 50mL round-bottom flask, adding 20mL of methanol and Pd/C (0.2e.q.) as solvents, fully introducing hydrogen into the reaction system, and stirring at normal temperature for 12 h. And after TLC detection of substrate conversion, spin-drying the organic solvent and separating and purifying by column chromatography to obtain an intermediate 7.
Adding 7 and the previously obtained tricyclic amine intermediate 2 into a DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 45 ℃ for 12h, extracting a reaction solution by ethyl acetate, washing with pure water and a saturated ammonium chloride solution for three times, and after an organic phase is dried by rotation, carrying out silica gel column chromatography and purification to obtain an intermediate 8.
Putting 8 into a 25mL round-bottom flask, taking DCM as a solvent, adding a dioxane solution (4M, 4.0e.q.) of hydrochloric acid, stirring for 6 hours at room temperature, spin-drying the solvent, recrystallizing to obtain a light yellow solid, and drying to obtain the final product THU 32.
(3) Preparation of the compound of example 47, the synthetic route is as follows:
adding anhydrous cerium trichloride (15mmol,3.0e.q.) into 30mL of dry tetrahydrofuran at 0 ℃, stirring at room temperature for 2 hours under the protection of argon, cooling the reaction system to-78 ℃, slowly adding methyllithium (15mmol,3.0e.q.), stirring for 30 minutes, adding 1-naphthacenitrile (1, 5mmol,1.0e.q.), returning the reaction system to room temperature, stirring for 2 hours, cooling to-78 ℃, adding excessive ammonia water, adding ethyl acetate for extraction, collecting an organic phase, spin-drying, and separating by silica gel column chromatography to obtain a dimethylamine intermediate 9 for subsequent reaction.
Methyl 2-methyl-5-bromobenzoate (3, 2mmol, 1.0e.q.) was placed in a 50mL stopcock and tert-butyl piperazine-1-carboxylate (3mmol, 1.5e.q.), tris (dibenzylideneacetone) dipalladium (0.04mmol, 0.02e.q.), X-PHOS ligand (0.08mmol, 0.04e.q.) and cesium carbonate (4mmol, 2.0e.q.) were added. Toluene solvent (10mL) was then added, the reaction was purged with argon, and the tube was sealed and heated to 110 ℃ and the reaction stirred overnight. And (3) after the point plate detection is carried out to complete the conversion of the substrate, the organic solvent is dried in a spinning way, and the intermediate 10 is obtained by column chromatography separation and purification.
Intermediate 10(1.0e.q.) was placed in a round bottom flask and tetrahydrofuran: and (2) taking water as a solvent, then adding lithium hydroxide (4.0e.q.) into the reaction system, stirring at 60 ℃ for reaction for 6 hours, acidifying the reaction system by using 2N hydrochloric acid, adding ethyl acetate to precipitate a white solid, and filtering the solid by suction and drying to obtain an intermediate 11.
Adding the intermediate 11 and the intermediate 9 into DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 70 ℃ for 12h, extracting reaction liquid with ethyl acetate, washing with saturated ammonium chloride solution for three times, spin-drying an organic phase, and purifying by silica gel column chromatography to obtain the final product THU 47.
(4) Preparation of the compound of example 22, THU22, the synthetic route is as follows:
methyl 4-bromothiophene-2-carboxylate (12, 10.0mmol, 1.0e.q.), N-methylpiperazine (10.0mmol, 1.0e.q.), tris (dibenzylideneacetone) dipalladium (0.2mmol, 0.02e.q.), 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl (0.8mmol, 0.08e.q.), cesium carbonate (20.0mmol, 2.0e.q.) were placed in a sealed tube, 50mL of toluene was added as a solvent, and the reaction was continued for 24h under argon protection at 110 ℃. After the reaction is finished, transferring the reaction solution into a round-bottom flask, spin-drying the solvent, adding ethyl acetate and water for extraction, washing an organic phase once by using a saturated ammonium chloride solution and a saturated saline solution respectively, spin-drying the organic phase, and purifying by silica gel column chromatography to obtain an intermediate 13.
Intermediate 13 was placed in a round bottom flask and mixed solvent (THF: MeOH: H) was added 2 O ═ 3:1:1)45mL, lithium hydroxide (40.0mmol, 4.0e.q.) was added, and the reaction was stirred at 45 ℃ for 12 h. And after the reaction is finished, spin-drying the solvent, dropwise adding 2N hydrochloric acid solution to adjust the pH value to be about 3, and spin-drying the solvent again to obtain a crude product of the carboxylic acid product 14.
Adding 14 and the previously obtained ternary cyclic amine intermediate 2 into DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 45 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with pure water and saturated ammonium chloride solution for three times, spin-drying the organic phase, and purifying by silica gel column chromatography to obtain the final product THU 22.
(5) Preparation of the compounds of examples 24 and 25, the synthetic route is as follows:
methyl 2-methyl-4-bromobenzoate (15, 2mmol, 1.0e.q.) was placed in a 50mL stopcock, and the nitrogen-hydrogen containing amine compound 16(3mmol, 1.5e.q.), tris (dibenzylideneacetone) dipalladium (0.04mmol, 0.02e.q.), X-PHOS ligand (0.08mmol, 0.04e.q.) and cesium carbonate (4mmol, 2.0e.q.) were added. Toluene solvent (10mL) was then added, the reaction was purged with argon, and the tube was sealed and heated to 110 ℃ and the reaction stirred overnight. And (3) after the point plate detection is carried out to complete the conversion of the substrate, the organic solvent is dried in a spinning way, and the intermediate 17 is obtained by column chromatography separation and purification.
Intermediate 17(1.0e.q.) was placed in a round bottom flask and tetrahydrofuran: using water as a solvent, adding lithium hydroxide (4.0e.q.) into the reaction system, stirring at 60 ℃ for 6 hours, acidifying the reaction system with 2N hydrochloric acid, adding ethyl acetate to precipitate a white solid, filtering the solid by suction, and drying to obtain an intermediate 18.
Adding 18 and the previously obtained tricyclic amine intermediate 2 into DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 70 ℃ for 12h, extracting the reaction solution with ethyl acetate, washing with saturated ammonium chloride solution three times, spin-drying the organic phase, and purifying by silica gel column chromatography to obtain a product 19.
When Boc (tert-butyloxycarbonyl) protection is present in the amine compound 16, the final product is obtained after the last removal of the tert-butyloxycarbonyl group from compound 19 by means of hydrochloric acid.
(6) The synthetic routes for other example compounds are as follows:
examples of other example Compounds are shown above (wherein R is 1 、R 2 、R 3 、R 4 、Y 1 、Y 2 Selected according to the structure of a specific compound), the specific operation is as follows:
reactant M1(2mmol, 1.0e.q.) was placed in a 50mL stopcock, and N-hydrogen containing amine compound M2(3mmol, 1.5e.q.), tris (dibenzylideneacetone) dipalladium (0.04mmol, 0.02e.q.), X-PHOS ligand (0.08mmol, 0.04e.q.) and cesium carbonate (4mmol, 2.0e.q.) were added. Toluene solvent (10mL) was then added, the reaction was purged with argon, and the tube was sealed and heated to 110 ℃ and the reaction stirred overnight. And (3) after the point plate detection shows that the substrate conversion is finished, spin-drying the organic solvent and separating and purifying by column chromatography to obtain an intermediate M3.
Intermediate M3(1.0e.q.) was placed in a round bottom flask and tetrahydrofuran: using water as a solvent, adding lithium hydroxide (4.0e.q.) into the reaction system, stirring at 60 ℃ for 6 hours, acidifying the reaction system with 2N hydrochloric acid, adding ethyl acetate to precipitate a white solid, filtering the solid by suction, and drying to obtain an intermediate M4.
Adding the intermediate M4 and the previously obtained tricyclic amine intermediate 2 into a DMF solvent according to one-to-one equivalent, adding HATU (1.5e.q.) and DIPEA (2.0e.q.), reacting at 70 ℃ for 12h, extracting a reaction solution with ethyl acetate, washing with a saturated ammonium chloride solution for three times, spin-drying an organic phase, and purifying by silica gel column chromatography to obtain a product P.
When Boc (tert-butyloxycarbonyl) protection is present in the amine compound M2, the final product is obtained after the last removal of the tert-butyloxycarbonyl group by means of hydrochloric acid of compound P. Experimental example 1: the compounds prepared in the above examples were tested for PLpro inhibitory activity
Biological test conditions:
1、Reaction buffer:20mM HEPEs,pH 7.5,100mM NaCl,1mM TCEP
2. preparing a mother solution:
(1)20 μ M Ub-AMC (Ub-AMC dry powder is directly dissolved by reaction buffer, and used after removing the precipitate by centrifugation);
(2)400nM PLpro (molecular sieves purified, frozen to-80 ℃, thawed on ice before use, diluted with interaction buffer);
(3)40 μ M test compound (dry test compound powder dissolved in DMSO to 40 mM; diluted to 400 μ M in 50% DMSO; and then diluted to 40 μ M in interaction buffer);
3. for the single point inhibition test reaction system: 10 μ M Ub-AMC,100nM PLpro,1 μ M test compound, total volume 20 μ L, 384 well plate reaction;
add 5. mu.L PLpro mother liquor + 5. mu.L test compound mother liquor to 384 well plate, incubate 30min at 4 ℃;
adding 10 μ L Ub-AMC mother liquor into 384 well plate, reacting at 37 deg.C for 30min, and measuring AMC fluorescence intensity (excitation:360 nm; emission:460 nm);
4. + Control, DMSO at the corresponding dilution times substituted the test compound;
reaction buffer to replace PLpro;
5. data processing: subtracting a Blank value from the measured value, and normalizing by taking a DMSO value as a reference;
6、IC 50 and (3) determination:
test compound concentration gradient (nM): 10000, 5000, 1000, 500, 250, 125, 62.5, 31.25, 15.625,10,5,2,1,0.5, 0.1,0.01
Reacting for 15min to measure fluorescence value (the enzyme reaction rate is in a linear interval and 30min non-linear interval around 15 min);
7. and (3) fitting data: the data were normalized and then processed with Sigmaplot (fitting equation: Logistic,3 Parameter).
The results are shown in the following table.
TABLE 1 results of the experiment
Among them, GRL0617 is a positive reference, which is a representative of a class of molecules reported in the literature to have the strongest inhibitory activity on PLpro (Ghosh et al, 2009; Ghosh et al, 2010; Ratia et al, 2008).
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and the like that are within the spirit and principle of the present invention are included in the present invention.
The foregoing embodiments and methods described in this disclosure may vary based on the abilities, experience, and preferences of those skilled in the art.
The mere order in which the steps of a method are listed in the present invention does not constitute any limitation on the order of the steps of the method.
Claims (27)
1. A compound, or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, the compound having the structure:
wherein the content of the first and second substances,
Ar 1 is aryl or heteroaryl, which may be optionally substituted;
Ar 2 is aryl or heteroaryl, which may be optionally substituted;
b is heterocyclyl, which may be optionally substituted;
R 1 and R 2 Independently selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted; or, R 1 And R 2 Forms, with the carbon atom to which they are attached, a cycloalkyl or heterocyclyl group, which may be optionally substituted;
L 1 selected from: -NR 3 C(O)-、-NR 3 S(O) t -、-C(O)-、-C(O)O-、-NR 3 -、-C(O)NR 3 -、-S(O) t NR 3 -；
R 3 Selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy; or, R 3 And the nitrogen atom to which it is attached to L 2 Or L 3 Together form a heterocyclyl, which may be optionally substituted;
L 2 selected from: a single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, which may be optionally substituted;
L 3 selected from the group consisting of: a single bond, alkylene, heteroalkylene, which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted.
2. The compound of claim 1, wherein Ar is Ar 1 Has the following structure:
wherein, X 1 -X 7 Independently selected from: C. n;
R 5 represents one or more independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted;
preferably, X 1 -X 7 Are all C; or, X 1 -X 7 At least one of which is N;
more preferably, Ar 1 Is naphthyl, quinolyl, isoquinolyl or pteridinyl, R 5 Is Ar 1 One or more independent substituents on the ring;
further preferably, Ar 1 Is composed of
Or
3. The compound of claim 2, wherein R is 5 Represents Ar 1 One or more independent substituents on the ring selected from: H. alkyl, halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl).
4. A compound according to any one of claims 1 to 3 wherein R is 1 Is H or C1-6 alkyl, R 2 Is C1-6 alkyl.
5. A compound according to any one of claims 1 to 3 wherein R is 1 And R 2 Together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl group, particularly a C3-6 cycloalkyl group, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxypropyl, aziridinyl, which may be optionally substituted.
6. A compound according to any one of claims 1 to 3, having the structure:
wherein, W 1 And W 2 Independently selected from: C. n, O, respectively; and when W 1 Or W 2 When is O, the corresponding R 6 Or R 7 Is absent;
R 6 and R 7 Independently selected from: H. (═ O), alkyl, halogen, haloalkyl, hydroxy, alkoxy;
preferably, W 1 Is C, W 2 Is C; or, W 1 Is C, W 2 Is N; or, W 1 Is C, W 2 Is O.
Preferably, R 6 And R 7 Independently selected from: H. (═ O), C1-3 alkyl, -CF 3 And a hydroxyl group.
7. A compound according to any one of claims 1 to 6 wherein L is 2 Is a single bond or alkylene; and/or the presence of a gas in the gas,
L 3 is a single bond or alkylene.
8. The compound of any one of claims 1-7, wherein L is 1 is-NR 3 C (O) -or-NR 3 S(O) 2 -。
9. The compound of claim 8, wherein R is 3 Is H or C1-6 alkyl.
10. A compound according to any one of claims 1 to 9, characterised in that Ar is Ar 2 Has the following structure:
wherein the content of the first and second substances,
n is 0 or 1;
Y 1 -Y 6 independently selected from: C. n, O, S;
R 8 represents one or more independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted;
preferably, Ar 2 Has the following structure:
wherein Y is 1 -Y 5 Independently selected from: C. n;
more preferably, Y 1 -Y 5 Are all C, or, Y 1 -Y 5 At least one of which is N.
11. The compound of any one of claims 1-9, wherein the compound has the structure:
wherein the content of the first and second substances,
Y 2 and Y 5 Independently selected from: C. n;
R 9 independently selected from: H. alkyl, cycloalkyl, or a salt thereof,Cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
R 10 represents one or two independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, which may be optionally substituted;
preferably, Y 2 Is N, Y 5 Is C; or, Y 2 Is C, Y 5 Is N; y is 2 Is C, Y 5 Is C.
12. The compound of claim 11, wherein R is 9 Selected from: H. alkyl, halo, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl), cycloalkyl;
preferably, R 9 Selected from: c1-6 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, -NH 2 NH (C1-3 alkyl), -N (C1-3 alkyl) (C1-3 alkyl);
more preferably, R 9 Is methyl or-NH 2 。
13. The compound of claim 11, wherein R is 10 Selected from: H. alkyl, halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl);
preferably, R 10 Selected from: H. c1-6 alkyl, F, Cl, Br, I, -CF 3 、-OH、-OCH 3 、-NH 2 、
More preferably, R 10 Selected from: H. methyl group, F, Cl.
14. The compound of claim 10, wherein Ar is Ar 2 Has the following structure:
wherein Y is 1 Selected from: C. n, O, S, respectively;
Y 2 -Y 4 independently selected from: C. and N is added.
15. The compound of any one of claims 1-9, wherein the compound has the structure:
wherein, Y 1 Selected from: C. n, O, S, respectively;
R 11 represents one or two independent substituents on the ring selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、-R L -CH＝NR'、-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted;
preferably, Y 1 Is O or S.
16. The compound of claim 15, wherein R is 11 Selected from: H. an alkyl group,Halogen, haloalkyl, hydroxy, alkoxy, amino, -NH (alkyl), -N (alkyl); preferably, R 11 Is H.
17. The compound of any one of claims 1-16, wherein B has the structure:
wherein Z is 2 -Z 6 Independently selected from: C. n, O, S;
Z 1 selected from: C. n;
Z 7 absent or selected from: a single bond, C, N, O, S;
m1-m4 are independently selected from integers from 0-5;
R 12 represents one or more independent substituents on the ring selected from: H. (═ O), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、
-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
r' "is selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen,
t is 1 or 2;
R L selected from: single bond, alkyleneRadical, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted.
18. The compound of any one of claims 1-16, wherein B has the structure:
wherein, Z 1 And Z 4 Independently selected from: C. n, O, S, and when Z 4 When is O or S, R 9 Is absent;
Z 7 absent or selected from: a single bond, C, N, O, S;
m1 and m2 are independently selected from integers from 0 to 5;
R 13 selected from: H. (═ O), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、
-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-R L -N(S(O) t R')(S(O) t R”)、-NR'-R L -NR”R”'、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
R 14 represents one or more independent substituents on the ring selected from: H. (═ O), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, -R L -COR'、-R L -C(O)OR'、-R L -C(O)NR'R”、
-R L -CN、-R L -OR'、-R L -OC(O)R'、-R L -S(O) t -NR'R”、-R L -S(O) t -R'、-R L -NR'R”、-R L -NR'C(O)R”、-R L -NR'S(O) t R”、-NR'-R L -NR'R”、-R L -NO 2 、-R L -N ═ CR' R ", which may be optionally substituted;
r' "is selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen,
t is 1 or 2;
R L selected from: single bond, alkylene, heteroalkylene, cycloalkylene, heterocyclylene, -NR 4 C(O)-、-NR 4 S(O) t -、-C(O)-、-C(O)O-、-NR 4 -、-C(O)NR 4 -、-S(O) t NR 4 -, which may be optionally substituted;
R 4 selected from: H. alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy;
r' and R "are independently selected from: H. amino, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halo, which may be optionally substituted.
19. The compound of claim 1, wherein B has the structure:
preferably, B has the structure:
wherein R is 15 Is H or C1-6 alkyl.
20. The compound of claim 18 or 19, wherein R is 14 Is H or C1-6 alkyl.
21. The compound of claim 18 or 19, wherein R is 13 Selected from the following structures: -H, (═ O), F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF 3 、-OH、
22. The compound of claim 1, wherein the compound is selected from the structures:
23. the compound of claim 1, wherein the stereoisomer is selected from the following structures:
24. a pharmaceutical composition comprising a compound of any one of claims 1-23, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.
25. Use of a compound of any one of claims 1-23, or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds thereof, or a pharmaceutical composition of claim 24, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition caused by or associated with a viral infection.
26. The use of claim 25, wherein the virus is a coronavirus, e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2.
27. The use of claim 26, wherein the disease or condition is selected from the group consisting of: COVID-19, SARS, MERS.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023064493A1 (en) * | 2021-10-13 | 2023-04-20 | Clear Creek Bio, Inc. | Compounds and methods for treating coronaviruses |
| WO2023208171A1 (en) * | 2022-04-29 | 2023-11-02 | 清华大学 | Plpro protein inhibitor, and preparation method and application thereof |
| WO2023208170A1 (en) * | 2022-04-29 | 2023-11-02 | 清华大学 | Protease inhibitor, method for preparing same, and use thereof |
| WO2024040496A1 (en) * | 2022-08-25 | 2024-02-29 | 清华大学 | Antiviral compound, and preparation method therefor and use thereof |
| WO2024040497A1 (en) * | 2022-08-25 | 2024-02-29 | 清华大学 | Antiviral compound, preparation method therefor and use thereof |
| WO2024121779A1 (en) | 2022-12-09 | 2024-06-13 | Pfizer Inc. | Papain-like protease (plpro) inhibitors |
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2022
- 2022-02-23 CN CN202210168271.2A patent/CN114957165A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023064493A1 (en) * | 2021-10-13 | 2023-04-20 | Clear Creek Bio, Inc. | Compounds and methods for treating coronaviruses |
| WO2023208171A1 (en) * | 2022-04-29 | 2023-11-02 | 清华大学 | Plpro protein inhibitor, and preparation method and application thereof |
| WO2023208170A1 (en) * | 2022-04-29 | 2023-11-02 | 清华大学 | Protease inhibitor, method for preparing same, and use thereof |
| WO2024040496A1 (en) * | 2022-08-25 | 2024-02-29 | 清华大学 | Antiviral compound, and preparation method therefor and use thereof |
| WO2024040497A1 (en) * | 2022-08-25 | 2024-02-29 | 清华大学 | Antiviral compound, preparation method therefor and use thereof |
| WO2024121779A1 (en) | 2022-12-09 | 2024-06-13 | Pfizer Inc. | Papain-like protease (plpro) inhibitors |
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