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CN-121974913-A - Compounds and methods for treating viral infections

CN121974913ACN 121974913 ACN121974913 ACN 121974913ACN-121974913-A

Abstract

Disclosed are compounds and methods of using the compounds, alone or in combination with additional agents, and salts, crystalline forms, pharmaceutical compositions of the compounds for treating viral infections.

Inventors

  • E. Ban Yang
  • Quan Bingkuan
  • K. E. Denpas
  • XU HANZHONG
  • R V Cara
  • R.L. McMann

Assignees

  • 吉利德科学公司

Dates

Publication Date
20260505
Application Date
20210826
Priority Date
20200827

Claims (10)

  1. 1. A compound of formula I: I is a kind of Or a pharmaceutically acceptable salt thereof, wherein: R 1 is OH, OCOR 4 OR OC (O) OR 4 ;R 2 is OH, OCOR 5 OR OC (O) OR 5 , OR R 1 and R 2 together form-OC (O) O-or-OCHR 6 O-, where R 6 is H, C 1 -C 6 alkyl or C 6 -C 10 aryl; R 3 is H, COR 7 or COOR 7 ; R 4 、R 5 and R 7 are each independently C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 carbocyclyl, C 6 -C 10 aryl, or a 5 to 6 membered heteroaryl containing 1,2, or 3 heteroatoms selected from N, O and S; Wherein R 4 、R 5 and R 7 are each independently optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano, -N 3 、-OR 8 、-NR 9 R 10 and phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of halo, cyano and C 1 -C 6 alkyl, and Each R 8 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cycloalkyl; Each R 9 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cycloalkyl; Each R 10 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 6 cycloalkyl, and The base is 、 Or (b) Wherein R 11 is C 1 -C 6 alkyl substituted with-OP (O) (OH) 2 ; provided that when R 3 is H, then R 1 is OCOR 4 OR OC (O) OR 4 , OR R 2 is OCOR 5 OR OC (O) OR 5 , OR R 1 and R 2 together form-OC (O) O-or-OCHR 6 O-.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 is COR 7 or COOR 7 .
  3. 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the base is Or (b) 。
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the base is 。
  5. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the base is 。
  6. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the base is 。
  7. 7. The compound according to any one of claims 1 to 6, OR a pharmaceutically acceptable salt thereof, wherein R 1 is OH, OCOR 4 OR OC (O) OR 4 and R 2 is OH, OCOR 5 OR OC (O) OR 5 .
  8. 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 1 is OH.
  9. 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 is OH.
  10. 10. The compound according to any one of claims 1 to 7, OR a pharmaceutically acceptable salt thereof, wherein R 1 is OCOR 4 OR OC (O) OR 4 .

Description

Compounds and methods for treating viral infections The application is a divisional application of China patent application (application day: 2021, 8, 26, title of application: compounds and methods for treating viral infections) with application number 202180051956.2. Cross reference The present application claims priority from U.S. provisional application 63/071,134, filed on 8.27, 2021, 3.17, and 2021, U.S. provisional application 63/215,310, each of which is incorporated herein in its entirety for all purposes. Background There is a need for compounds and methods for treating viral infections such as paramyxoviridae (paramyxoviridae), pneumoviridae (pneumoviridae), picornaviridae (picornaviridae), flaviviridae (FLAVIVIRIDAE), filoviridae (filoviridae), arenaviridae (ARENAVIRIDAE), orthomyxoviridae (orthomyxovirus), and coronaviridae (coronaviridae) infections. The present disclosure addresses the above and other needs. Disclosure of Invention The present disclosure provides compounds of formula I: I is a kind of Or a pharmaceutically acceptable salt thereof, wherein: R 1 is OH, OCOR 4 OR OC (O) OR 4;R2 is OH, OCOR 5 OR OC (O) OR 5, OR R 1 and R 2 together form-OC (O) O-or-OCHR 6 O-, where R 6 is H, C 1-C6 alkyl or C 6-C10 aryl; R 3 is H, COR 7 or COOR 7; R 4、R5 and R 7 are each independently C 1-C8 alkyl, C 2-C8 alkenyl, C 2-C8 alkynyl, C 3-C8 carbocyclyl, C 6-C10 aryl, or a 5 to 6 membered heteroaryl containing 1,2, or 3 heteroatoms selected from N, O and S; Wherein R 4、R5 and R 7 are each independently optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, cyano, -N 3、-OR8、-NR9R10 and phenyl optionally substituted with one, two or three substituents independently selected from the group consisting of halo, cyano and C 1-C6 alkyl, and Each R 8 is independently H, C 1-C6 alkyl, C 1-C6 haloalkyl, and C 3-C6 cycloalkyl; Each R 9 is independently H, C 1-C6 alkyl, C 1-C6 haloalkyl, and C 3-C6 cycloalkyl; Each R 10 is independently H, C 1-C6 alkyl, C 1-C6 haloalkyl, and C 3-C6 cycloalkyl, and The base is、Or (b)Wherein R 11 is C 1-C6 alkyl substituted with-OP (O) (OH) 2; provided that when R 3 is H, then R 1 is OCOR 4 OR OC (O) OR 4, OR R 2 is OCOR 5 OR OC (O) OR 5, OR R 1 and R 2 together form-OC (O) O-or-OCHR 6 O-. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof. The present disclosure also provides a method of treating or preventing a viral infection in a human in need thereof, wherein the method comprises administering to the human a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure also provides a method of preparing a medicament for treating or preventing a viral infection in a human in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof. The present disclosure also provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a viral infection in a human in need thereof. Drawings Figure 1 shows the antiviral efficacy of compound 1.1 a-b viral yield reduction by compound 1 (a) and reference compound A (b) representing the A, B.1.351, B.1.1.7 and P.1 lineages, respectively, for SARS-CoV-2 clinical isolates WA1/2020, SA/2020, CA/2020 and BZ/2021 on VeroE6 cells. EC 50 concentrations are specified. 1c-d in vitro cytotoxicity profiles of Compound 1 (c) and reference Compound A (d) on VeroE6, HEp-2, BHK-21, HCT-8 and a set of primary HAE cells ("F2", "F3", "M2", "M6", "DF 2") from independent donors. In (a-d), the symbols represent a single biological repeat (n=3), the error bars show the standard deviation, and the lines depict a nonlinear regression model. 1e in vitro cytotoxicity profile of Rede-Sivir (remdesivir) on VeroE6, HEp-2, BHK-21, HCT-8 and the set of primary HAE cells ("F2", "F3", "M2", "M6", "DF 2"). The symbols represent a single biological repeat (n=3), the error bars show standard deviation, and the lines depict a nonlinear regression model. Figure 2 shows the prophylactic efficacy of orally administered compound 1. Schematic of the design of the preventive efficacy study. 2b viral titer from nasal lavage fluid, loD, limit of detection. 2c, collecting temperature measurement values once a day. Body weight was measured once daily. Infection titres of SARS-CoV-2 in turbinates harvested four days post infection. 2f SARS-CoV-2 RNA copies present in nasal lavage fluid. 2g SARS-CoV-2 RNA copies detected in the turbinate. 2h-2i SARS-CoV-2 infectious particles in the lung four days after infection (h) and SARS-CoV-2 RNA copies (i). The number of independent biological replicates (individual animals) is shown in each sub-graph, the symbols represent the independent biological replicates, the lines (b, c, d, f) and bar grap