Peptidomimetics for the treatment of norovirus infection

Patent metadata

Field	Value
Publication number	US-11021513-B2
Application number	US-201716301168-A
Country	US
Kind code	B2
Filing date	May 15, 2017
Priority date	May 13, 2016
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The present invention is directed to compounds, compositions and methods for preventing, treating or curing Norovirus infection in human subjects or other animal hosts.

First claim

We claim:

1. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 5 is selected from

R 2 , R 2 ′, R 10 , R 10 ′, R 11 and R 11 ′ are, independently, hydrogen, CF 3 , C 1-6 alkyl, C 1-6 haloalkyl, or C 2-6 alkenyl,
R 12 , R 12 ′ are, independently, C 1-6 alkyl, C 1-6 haloalkyl, or C 2-6 alkenyl,
R 12 and R 12 can come together to form an optionally substituted C 3-7 ring, optionally containing an N, O, or S;
R 8 is, independently, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, aryl, or arylalkyl;
m, n, p and r are independently 0, 1, 2, 3, 4 or 5;
q is 1, 2, 3, 4 or 5,
X is a bond,
Y is independently CI, F, I or Br,
R 12 is hydrogen, CF 3 , CO 2 R′, S(O) 2 R′, S(O) 2 N(R′) 2 , P(O)(OR′) 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 alkoxyalkyl, C 1-6 alkyl, arylalkoxycarbonyl, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 hydroxy alkyl;
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, and other optionally substituted 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, hydrazine, 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 an N, O, or S;
R 6 and R 6 can come together to form an optionally substituted double bond, a C 3-6 ring optionally containing an N, O, or S;
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;
R 7 and R 7′ can come together to form an optionally substituted double bond or a C 3-6 ring optionally containing an N, O, or S;
R 4 and R 3 are, independently, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, arylalkyl, heteroarylalkyl, or —CH 2 —R 4′ ,
R 4′ is a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, which are independently N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S, or a three membered ring; and
R 1 is optionally substituted aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarylalkoxy.

2. A compound of the following formula:

or a pharmaceutically acceptable salt thereof, wherein:
R 5 is

ketoamides, bisulfite salts,

or
R 9 is, independently, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl,
R 4 and R 3 are, independently, optionally substituted C 1-6 alkyl, C 1-6 haloalkyl, C 2 -8 alkoxyalkyl, arylalkyl, heteroarylalkyl, or —CH 2 —R 4′ ,
R 4′ is a six-membered ring or a six-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, which are independently N, O, or S, a seven-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S, a five-membered ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S; a four-membered ring containing zero, one, or two heteroatoms, which are, independently, N, O, or S, or a three membered ring;
R 1 is optionally substituted aryl, heteroaryl, aryloxy, heteroaryloxy, arylalkoxy, or heteroarlalkoxy,
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, 3, 4 or 5;
when n and m are not 1;
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, hydrazine, 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 hydroxy alkyl;
R 7 and R 7′ can come together to form an optionally substituted double bond or a C 3 -6 ring optionally containing a N, O, or S heteroatom; and
when n and m are 1, at least one or R 2 , R 6 , R 6′ , R 7 and R 7′ is not hydrogen.

3. A compound of the following formula:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R 5 is

Assignees

• Univ Emory

Inventors

• Schinazi Raymond F
• Amblard Franck
• Kovari Ladislau
• Liu Peng
• Zhou Shaoman
• Kuiper Benjamin D
• Keusch Bradley J

Classifications

• A61K38/05

  Dipeptides · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/4015 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title