Peptidomimetics for the treatment of coronavirus and picorna virus infections
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.
1. A compound of Formulas III or V:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted aryl, 5-membered ring heteroaryl, aryloxy, heteroaryloxy, or heteroarylalkoxy,
R 3 is an optionally substituted 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═C(CN)C(O)NH 2 , —C(O)CF 3 , —CH(OH)CF 3 , —C(OH)SO 3 − (and an associated cation), or an optionally-substituted epoxide ring,
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 or NH,
n and p are, independently, 0, 1, 2, or 3;
m is 2,
p is 0;
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 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;
wherein, with respect to Formula V, m is 1.
2. The compound of claim 1 , wherein R 3 is alkylaryl or alkylheteroaryl, and R 1 is
3. A compound having one of the following formulas:
4. A compound of claim 3 having the formula: