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CN-114957110-B - Antiviral compound and preparation method and application thereof

CN114957110BCN 114957110 BCN114957110 BCN 114957110BCN-114957110-B

Abstract

The invention discloses an antiviral compound and a preparation method and application thereof, in particular an anti-coronavirus compound which can be used as PLPro inhibitor and a preparation method and application thereof. The compound has a structure shown in a general formula I, has high inhibition activity, can be used for broad-spectrum antivirus, in particular coronaviruses (such as SARS-CoV, MERS-CoV and SARS-CoV-2), and has very good potential application prospect in the field of medicines.

Inventors

  • HE WEI
  • WANG MEIJING
  • LIU LEI
  • LI BIN
  • XU LIQIAN
  • LI HAOXIANG
  • ZHENG JIQING
  • Wan Shizhang
  • WU CAI
  • WANG TIAN

Assignees

  • 清华大学
  • 清华大学

Dates

Publication Date
20260421
Application Date
20220223
Priority Date
20210226

Claims (15)

  1. 1. A compound, or a pharmaceutically acceptable salt thereof, having the structure: (I) Wherein, the Ar is naphthyl, wherein the hydrogen atom in the naphthyl is optionally substituted with C 1 -C 6 alkyl, -NH 2 、-OH、-OC 1 -C 6 alkyl, -CH 2 X、-CHX 2 、-CX 3 ; L 1 is-CO-or-SO 2 -; A 1 、A 2 、A 3 、A 4 and A 5 are independently selected from C or N, and when A 1 、A 2 、A 3 、A 4 or A 5 is an N atom, R 1 、R 2 、R 3 、R 4 or R 5 which are connected with the A 1 、A 2 、A 3 、A 4 or the A 5 are not present, and the number of N atoms in A 1 、A 2 、A 3 、A 4 and A 5 is 0-2; R 1 、R 2 、R 3 、R 4 and R 5 are independently selected from H, C 1 -C 6 alkyl, -L 2 -NR 9 R 10 、-OH、-OC 1 -C 6 alkyl, -CN, -X, -CH 2 X、-CHX 2 、-CX 3 ; L 2 is selected from single bond, C 1 -C 6 alkylene, -CO-, -SO 2 -、-NHCO-、-NH-SO 2 -; R 9 and R 10 are independently selected from H, C 1 -C 6 alkyl, -CH 2 X、-CHX 2 、-SO 2 (C 1 -C 6 alkyl), -CX 3 、-L 3 -NR 11 R 12 , 、 、 Wherein R 13 is selected from H, C 1 -C 6 alkyl; L 3 is selected from the group consisting of C 1 -C 6 alkylene, -CO-, -SO 2 -、-NHCO-、-NH-SO 2 -, phenylene, 、 ; R 11 and R 12 are independently selected from H, C 1 -C 6 alkyl, -CO (C 1 -C 6 alkyl); x is selected from F, cl, br, I; R 6 is selected from H, C 1 -C 6 alkyl; W 1 is C, W 2 is C; R 7 and R 8 are independently selected from H, (=O), C1-3 alkyl, -CF 3 , hydroxy.
  2. 2. The compound of claim 1, wherein Ar is 1-naphthyl.
  3. 3. The compound of claim 1, wherein A 1 、A 2 、A 3 、A 4 and A 5 are both C, or, A 1 is N, A 2 、A 3 、A 4 and A 5 are C, or, A 2 is N, A 1 、A 3 、A 4 and A 5 are C, or, A 3 is N, A 1 、A 2 、A 4 and A 5 are C, or, A 4 is N, A 1 、A 2 、A 3 and A 5 are C, or, A 5 is N, A 1 、A 2 、A 3 and A 4 are C, or, A 1 and A 2 are N, A 3 、A 4 and A 5 are C, or, A 1 and A 3 are N, A 2 、A 4 and A 5 are C, or, A 1 and A 4 are N, A 2 、A 3 and A 5 are C, or, A 1 and A 5 are N, A 2 、A 3 and A 4 are C, or, A 2 and A 3 are N, A 1 、A 4 and A 5 are C, or, A 2 and A 4 are N, A 1 、A 3 and A 5 are C, or, A 2 and A 5 are N, A 1 、A 3 and A 4 are C, or, A 3 and A 4 are N, A 1 、A 2 and A 5 are C, or, A 3 and A 5 are N, A 1 、A 2 and A 4 are C, or, A 4 and A 5 are N, and A 1 、A 2 and A 3 are C.
  4. 4. The compound of claim 1, wherein R 7 and R 8 are both H.
  5. 5. The compound of claim 1, wherein the compound has the structure: Or (b) 。
  6. 6. The compound of claim 1, wherein R 6 is selected from the group consisting of H, -CH 3 、-CH 2 CH 3 .
  7. 7. A compound according to any one of claims 1 to 6, wherein L 2 is selected from the group consisting of a single bond, -CH 2 -、-SO 2 -、-NHCO-、-NH-SO 2 -, and/or, R 9 and R 10 are independently selected from H、-CH 3 、-CH 2 CH 3 、-C(CH 3 ) 3 、-SO 2 CH 3 、-L 3 -NR 11 R 12 、 、 、 。
  8. 8. The compound of claim 1, wherein L 3 is selected from the group consisting of-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CO-、-SO 2 -, 、 、 And/or, R 11 and R 12 are independently selected from H, -CH 3 、-CH 2 CH 3 、-COCH 3 、-COCH 2 CH 3 .
  9. 9. The compound of claim 1, wherein R 1 、R 2 、R 3 、R 4 and R 5 are independently selected from the group consisting of H, -CH 3 、-OCH 3 、-CF 3 、-L 2 -NR 9 R 10 .
  10. 10. The compound of claim 1, wherein-L 2 -NR 9 R 10 is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。
  11. 11. The compound of claim 1, wherein the compound has the structure: Or (b) 。
  12. 12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  13. 13. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 12, for the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition caused by or associated with a viral infection, said virus being a coronavirus.
  14. 14. The use according to claim 13, wherein the virus is selected from the group consisting of HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU, SARS-CoV, MERS-CoV, SARS-CoV-2.
  15. 15. The use according to claim 13, wherein the disease or condition is COVID-19, SARS or MERS.

Description

Antiviral compound and preparation method and application thereof Technical Field The invention relates to the technical field of pharmaceutical chemistry, in particular to an antiviral compound and a preparation method and application thereof, and especially relates to an anti-coronavirus compound capable of serving as PLPro inhibitor and a preparation method and application thereof. Background Many important infectious diseases that humans suffer from 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 often fatal, others such as rubella and cytomegalovirus can cause congenital malformations. Coronaviruses are a large family of viruses, the genome of which is the largest among the currently known positive-strand RNA viruses. Coronaviruses can be classified into four classes, alpha, beta, gamma and delta, depending on the host, serotype gene sequence and structure. Of these four classes, the α, β and delta species only infect mammals, the γ and delta species mainly infect birds, the α genus coronavirus includes human coronavirus (HCoV-229E, HCoV-NL 63), long wing hepialus coronavirus (HKU 1, HKU 8), canine coronavirus (CCoV) and feline coronavirus (FCoV) and the like, the β genus coronavirus includes human coronavirus (HCoV-OC 43, HCoV-HKU 1), novel coronavirus (SARS-CoV-2), SARS coronavirus (SARS-CoV), middle east respiratory syndrome coronavirus (MERS-CoV), murine coronavirus, fruit hepialus coronavirus (HKU 9) and the like, the γ genus coronavirus mainly includes avian coronavirus such as avian Infectious Bronchitis Virus (IBV), the δ genus coronavirus includes night coronavirus (BuCoV HKU), peyronie coronavirus (WECoV), wild duck coronavirus (WiCoV), black water coronavirus (CMCoV) and the like. Papain (papain-like protease, PLPro) is a hydrolase expressed on the 5' -terminal genome nsp3 of coronavirus and has the main function of cleaving the specific tetrapeptide structure LXGG between nsp1-2, nsp2-3, nsp3-4 on polyprotein pp1a, which needs to be hydrolyzed to become a mature functional protein, and thus is a key protein for coronavirus proliferation, and importantly, PLpro can cleave the ubiquitin unit of the key immunity protein of host cells, thereby protecting coronaviruses from immune attack by host cells. Therefore, the PLPro protein for inhibiting coronavirus can inhibit the proliferation of coronavirus, and can also enhance the monitoring of host cell immune system on coronavirus, thereby reducing cytokine storm. PLPro is critical 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 remains to be further improved. Disclosure of Invention The present invention provides a compound having the structure: Wherein, the Ar is selected from naphthyl, quinolinyl, isoquinolinyl or quinazolinyl, wherein the hydrogen atom in the naphthyl, quinolinyl, isoquinolinyl or quinazolinyl group may be optionally substituted with C 1-C6 alkyl, -NH 2、-OH、-OC1-C6 alkyl, -CH 2X、-CHX2、-CX3; L 1 is selected from C 1-C6 alkylene, -CO-, -SO 2 -; A 1、A2、A3、A4 and a 5 are independently selected from C or N, and when a 1、A2、A3、A4 or a 5 is an N atom, R 1、R2、R3、R4 or R 5 attached thereto is absent; R 1、R2、R3、R4 and R 5 are independently selected from H, C 1-C6 alkyl, -L 2-NR9R10、-L2-OH、-L2-OC1-C6 alkyl, -CN, -X, -CH 2X、-CHX2、-CX3, or two of R 1、R2、R3、R4 and R 5 together with the atoms to which they are attached form a heterocyclic group; L 2 is selected from single bond, C 1-C6 alkylene, -CO-, -SO 2-、-NHCO-、-NH-SO2 -; R 9 and R 10 are independently selected from H, C 1-C6 alkyl, -CH 2X、-CHX2、-SO2(C1-C6 alkyl), -CX 3、-L3-NR11R12, nitrogen-containing heterocyclyl; L 3 is selected from the group consisting of C 1-C6 alkylene, -CO-, -SO 2-、-NHCO-、-NH-SO2 -, phenylene, R 11 and R 12 are independently selected from H, C 1-C6 alkyl, -CH 2X、-CHX2、-SO2(C1-C6 alkyl), -CX 3、-CO(C1-C6 alkyl; x is selected from F, cl, br, I; R 6 is selected from H, C 1-C6 alkyl; W 1 and W 2 are independently selected from C, N, O, and when W 1 or W 2 is O, the corresponding R 7 or R 8 is absent; R 7 and R 8 are independently selected from H, (=O), C 1-C6 alkyl, -X, -CH 2X、-CHX2、-CX3, hydroxy, -OC 1-C6 alkyl. In an embodiment of the present invention, the above-mentioned compoundIs that Specifically, the above naphthyl group may be a 1-naphthyl group or a 2-naphthyl group. Specifically, the above-mentioned quinolinyl group may be a 2-quinolinyl group, a 3-quinolinyl group, a 4-quinolinyl group, a 5-quinolinyl group, a 6-quinolinyl group, a 7-quinolinyl group or an 8-quinolinyl group. Specifically, the above-mentioned isoquinolinyl may be 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl