Peptidomimetics for the treatment of coronavirus and picornavirus infections

Patent metadata

Field	Value
Publication number	US-2022273753-A1
Application number	US-202117544438-A
Country	US
Kind code	A1
Filing date	Dec 7, 2021
Priority date	Jun 5, 2019
Publication date	Sep 1, 2022
Grant date	—

Abstract

Compounds, compositions and methods for preventing, treating or curing a coronavirus, picornavirus, and/or hepeviridae virus infection in human subjects or other animal hosts. Specific viruses that can be treated include enteroviruses. In one embodiment, the compounds can be used to treat an infection with a severe acute respiratory syndrome virus, such as human coronavirus 229E, SARS, MERS, SARS-CoV-1 (OC43), and SARS-CoV-2. In another embodiment, the methods are used to treat a patient co-infected with two or more of these viruses, or a combination of one or more of these viruses and norovirus.

First claim

1 - 30 . (anceled)

31 . A method for treating a host infected with a coronavirus, picornavirus or hepeviridae virus, preventing a coronavirus, picornavirus or hepeviridae virus infection, curing an a coronavirus, picornavirus or hepeviridae virus infection, or reducing the biological activity of an infection with a coronavirus, picornavirus or hepeviridae virus in a host, comprising administering an effective amount of a compound of any of Formulas I-II, IV and VI to a patient in need of treatment thereof:

or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
R 1 is optionally substituted aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarlalkoxy,
R 3 is an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, arylalkyl, alkylaryl, heteroarylalkyl, or alkylheteroaryl, specifically including —CH 2 -napthyl, —CH 2 -(hydroxy)phenyl, such as —CH 2 -(4-hydroxy)phenyl, and —CH 2 -(halo)phenyl, such as —CH 2 -(4-halo)phenyl, including —CH 2 -(fluoro)phenyl, specifically, —CH 2 -(4-fluoro)phenyl.
R 4 is an optionally substituted C 1-6 alkyl,
R 5 is —C(O)H, CH═C(CN)C(O)NH 2 , —C(O)CF 3 , —CH(OH)CF 3 , —C(OH)SO 3 -(and an associated cation, such as Na + ), or an optionally-substituted epoxide ring, and is preferably —C(O)H,
R 2 , R 2 ′, R 10 and R 10 ′ are, independently, hydrogen, CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, or C 2-6 alkenyl,
X is, independently, a bond, O or NH,
m, n and p are, independently, 0, 1, 2, or 3;
R 6 and R 6 ′ are, independently, hydrogen, halogen, CF 3 , hydroxy, N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, C 2-6 alkenyl, cyano, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxyalkyl; or R 6 and R 6 ′, together with the carbon to which they are attached, form a carbonyl,
each R′ is, independently, H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl,
the R′ groups can optionally be substituted with one or more substituents, which substituents are, independently, halo, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, or phosphonate;
two R′ residing on the same carbon or nitrogen atom can come together to form a C 3-6 ring optionally containing a N, O, or S heteroatom;
R 6 and R 6 ′ can come together to form an optionally substituted double bond or a C 3-6 ring optionally containing a N, O, or S heteroatom;
R 7 and R 7 ′ are, independently, hydrogen, CF 3 , N(R′)S(O) 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , C 1-6 alkoxy, C 2-6 alkenyl, cyano, C 2-6 alkynyl, C 3-6 alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxyalkyl; and
R 7 and R T ′ can come together to form an optionally substituted double bond or a C 3-6 ring optionally containing a N, O, or S heteroatom;

or a pharmaceutically acceptable salt or prodrug thereof,
wherein p, X, R 1 , R 2 , R 2 ′, R 3 , R 4 and R 5 are as defined above with respect to Formula I;

or a pharmaceutically acceptable salt or prodrug thereof,
wherein R 4 , R 5 , R 7 , R 7 ′, R 10 , and R 10 ′ are as defined above with respect to Formula I, and R 1 is an optionally-substituted C 6-12 cycloalkyl, or an optionally-substituted five or six membered ring heteroaryl;
and

or a pharmaceutically-acceptable salt or prodrug thereof,
wherein Cbz=carbobenzoxy, and R 3 , R 4 , R 5 , R 6 , R 6 ′, R 7 , R 7 ′, R 10 , R 10 ′, m and n are as defined above with respect to Formula I.

32 . The method of claim 31 , wherein R 5 is C(O)H.

33 . The method of claim 31 , wherein R 3 is alkylaryl or alkylheteroaryl.

34 . The method of claim 31 , wherein R 1 is

35 . The method of claim 31 , wherein R 1 is thiophene.

36 . The method of claim 31 , wherein X is O, R 2 and R 2 ′ are H, and R 1 is an optionally substituted phenyl.

37 . The method of claim 31 , wherein X=a covalent bond, p=0, and R 1 is an optionally substituted aryl or heteroaryl.

38 . The method of claim 24 , wherein the heteroaryl ring is a pyrazine, thiophene, isoxazole, or oxazole ring.

39 . The method of claim 31 , wherein R 3 is phenyl, halo-substituted phenyl, or naphthyl.

40 . The method of claim 31 , wherein the Hepeviridae virus is the hepatitis E virus.

41 . The method of claim 31 , wherein the picornavirus is an enterovirus.

42 . The method of claim 31 , wherein the virus is a causative agent for multiple sclerosis, SARS, MERS, or COVID-19.

43 . The method of claim 31 , wherein the virus is a causative agent for a respiratory infection.

44 . The method of claim 31 , wherein the method further comprising administering another anti-coronavirus or picornavirus virus agent in combination or alternation with the compound of any of Formulas I-VI.

45 . The method of claim 31 , wherein the patient is co-infected with norovirus, and the compound is also effective at treating the norovirus co-infection.

46 . A method for treating a coronavirus, picornavirus, and/or Hepeviridae virus infection, preventing a coronavirus, picornavirus, or Hepeviridae virus infection, or reducing the biological activity of an infection with a coronavirus, picornavirus, or Hepeviridae virus, comprising administering an effective amount of a compound of any of Formulas VII-X to a patient in need of treatment or prevention thereof:

or a pharmaceutically acceptable salt or prodrug thereof,
wherein:
R 1 is optionally substituted C 1-10 alkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarlalkoxy,
R 3 is an optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, arylalkyl, alkylaryl, heteroarylalkyl, or alkylheteroaryl, —CH 2 -(hydroxy)phenyl, and —CH 2 -(halo)phenyl,
R 4 is an optionally substituted C 1-6 alkyl,
R 5 is —(CH 2 ) q —SH,

—CH(OH)CF 3 , —CH(OH)CN,

R 8 is independently H, an optionally substituted C 1-10 alkyl, C 2-10 alkene, C 2 - io alkyne, aryl, heteroaryl, arylalkyl, alkylaryl, heteroarylalkyl, or a

Assignees

• Univ Emory

Inventors

• Schinazi Raymond F
• Zandi Keivan
• Amblard Franck

Classifications

• A61K38/05

  Dipeptides · CPC title

• A61P31/14 Primary

  for RNA viruses · CPC title

• C07K5/0819

  with the first amino acid being acidic · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/06034

  the side chain containing 2 to 4 carbon atoms · CPC title