Antiviral compounds and methods using same
The present invention includes compounds that are useful in preventing or treating viral infections, such as viral infections caused by a filovirus, arenavirus, rhabdovirus, paramyxovirus, and/or retrovirus. The present invention further includes compositions comprising such compounds, and methods of treating a viral infection in a subject using such compounds.
1. A compound of formula (II):
wherein:
ring a is fused with ring b to form bicyclic core ab, wherein ring a is selected from the group consisting of benzene and, pyridine
wherein a is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, nitro, cyano, halogen, hydroxy, C 1 -C 4 alkoxy optionally substituted with one or more fluoro atoms, C 1 -C 4 thioalkoxy optionally substituted with one or more fluoro atoms, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR, and —C(═O)NRR;
Q is S, S(═O), S(═O) 2 , O or NR;
each occurrence of R is independently H or C 1 -C 4 alkyl;
R 1 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR, and —C(═O)NRR;
R 2 is selected from the group consisting of —C(═O)N(R)C(═O)NR 3 R 4 and —C(═O)N(R)C(═O)OR 3 ;
R 3 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR and —C(═O)NRR;
R 4 is H or C 1 -C 4 alkyl, or R 3 and R 4 are taken together with the N atom to which both groups are bound to form a four- to seven-membered optionally substituted heterocyclic or heteroaromatic ring;
R 5 is selected from the group consisting of H and C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halo, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR and —C(═O)NRR;
wherein the compound is not selected from the group consisting of 2-((3-methylquinoxalin-2-yl)thio)-N-((2,2,2-trifluoroethyl)carbamoyl) acetamide (3); 2-((3-methylquinoxalin-2-yl)thio)-N-(phenylcarbamoyl)acetamide (5); 2-((3-methylquinoxalin-2-yl)thio)-N-((thiophen-2-ylmethyl)carbamoyl)acetamide (3i); N-[(cyclopentylamino)carbonyl]-2-[(3-methyl-2-quinoxalinyl)thio]-acetamide; N-[(ethylamino)carbonyl]-2-[(3-methyl-2-quinoxalinyl)thio]-propanamide; N-[(methylamino)carbonyl]-2-[(3-methyl-2-quinoxalinyl) thio]-propanamide; N-[aminocarbonyl]-2-[(3-methyl-2-quinoxalinyl)thio]-3-methyl-butanamide; N-[(methylamino)carbonyl]-2-(2-quinoxalinylthio)-propanamide; N-[(ethylamino)carbonyl]-2-(2-quinoxalinylthio)-propanamide; N-[[(1-methylethyl)amino]carbonyl]-2-(2-quinoxalinylthio)-propanamide; N-[[(phenylmethyl)amino]carbonyl]-2-(2-quinoxalinyloxy)-acetamide; N-[[(1-methylethyl)amino]carbonyl]-2-(2-quinoxalinyloxy)-acetamide; and ethyl (2-((3-methylquinoxalin-2-yl)thio)acetyl)carbamate (3y).
2. The compound of claim 1 , which is at least one selected from the group consisting of:
N-(ethylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3f)
N-(cyclopropylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3g)
N-(benzylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3o)
2-((3-methylquinoxalin-2-yl)thio)-N-(pyridin-2-ylcarbamoyl)acetamide (3p)
2-((3-methylquinoxalin-2-yl)thio)-N-(pyridin-3-ylcarbamoyl)acetamide (3q)
N-((1H-pyrazol-3-yl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3r)
N-(3,5-dimethyl-1H-pyrazol-4-yl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3s)
2-((3-methylquinoxalin-2-yl)thio)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)carbamoyl)acetamide (3t)
N-((2-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3u)
N-((3-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3v)
N-((4-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3w)
1-[2-(3-methyl-quinoxalin-2-yloxy)-acetyl]-3-phenyl-urea (3x)
1-Methyl-3-[2-(3-methyl-quinoxalin-2-ylsulfanyl)-acetyl]-1-phenyl-urea (3aa)
1-[2-(3-Benzyl-quinoxalin-2-ylsulfanyl)-acetyl]-3-(3,5-dimethyl-1H-pyrazol-4-yl)-urea (3ab)
2-((3-benzylquinoxalin-2-yl)thio)-N41,3,5-trimethyl-1H-pyrazol-4-yl)carbamoyl)acetamide (3ac)
and,
2-((3-benzylquinoxalin-2-yl)thio)-N-((4-fluorophenyl)carbamoyl)acetamide (3ad)
3. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and
a compound of formula (II):
wherein
ring a is fused with ring b to form bicyclic core ab, wherein ring a is selected from the group consisting of benzene and pyridine,
wherein a is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, nitro, cyano, halogen, hydroxy, C 1 -C 4 alkoxy optionally substituted with one or more fluoro atoms, C 1 -C 4 thioalkoxy optionally substituted with one or more fluoro atoms, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR, and —C(═O)NRR;
Q is S, S(═O), S(═ 0 ) 2 , O or NR;
each occurrence of R is independently H or C 1 -C 4 alkyl;
R 1 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR, and —C(═O)NRR;
R 2 is selected from the group consisting of —C(═O)N(R)C(═O)NR 3 R 4 and —C(═O)N(R)C(═O)OR 3 ;
R 3 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR and —C(═O)NRR;
R 4 is H or C 1 -C 4 alkyl, or R 3 and R 4 are taken together with the N atom to which both groups are bound to form a four- to seven-membered optionally substituted heterocyclic or heteroaromatic ring; and,
R 5 is selected from the group consisting of H and C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halo, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR and —C(═O)NRR.
4. The pharmaceutical composition of claim 3 , further comprising at least one additional antiviral agent.
5. The pharmaceutical composition of claim 4 , wherein the compound and the at least one additional agent are coformulated in the composition.
6. The pharmaceutical composition of claim 3 , wherein the at least one compound is selected from the group consisting of:
2-((3-methylquinoxalin-2-yl)thio)-N-((2,2,2-trifluoroethyl)carbamoyl) acetamide (3);
N-(ethylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3f);
N-(cyclopropylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3g);
2-((3-methylquinoxalin-2-yl)thio)-N-(phenylcarbamoyl)acetamide (5);
2-((3-methylquinoxalin-2-yl)thio)-N-((thiophen-2-ylmethyl)carbamoyl)acetamide (3i);
6-(3-Methyl-quinoxalin-2-ylsulfanylmethyl)-1H-pyrimidine-2,4-dione (3n);
N-(benzylcarbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3o);
2-((3-methylquinoxalin-2-yl)thio)-N-(pyridin-2-ylcarbamoyl)acetamide (3p);
2-((3-methylquinoxalin-2-yl)thio)-N-(pyridin-3-ylcarbamoyl)acetamide (3q);
N-((1H-pyrazol-3-yl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3r);
N4(3,5-dimethyl-1H-pyrazol-4-yl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3s);
243-methylquinoxalin-2-yl)thio)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)carbamoyl)acetamide (3t);
N4(2-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3u);
N4(3-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3v);
N4(4-fluorophenyl)carbamoyl)-2-((3-methylquinoxalin-2-yl)thio)acetamide (3w);
1-[2-(3-Methyl-quinoxalin-2-yloxy)-acetyl]-3-phenyl-urea (3x);
ethyl (2-((3-methylquinoxalin-2-yl)thio)acetyl)carbamate (3y);
1-Methyl-3-[2-(3-methyl-quinoxalin-2-ylsulfanyl)-acetyl]-1-phenyl-urea (3aa);
1-[2-(3-Benzyl-quinoxalin-2-ylsulfanyl)-acetyl]-3-(3,5-dimethyl-1H-pyrazol-4-yl)-urea (3ab);
243-benzylquinoxalin-2-yl)thio)-N41,3,5-trimethyl-1H-pyrazol-4-yl)carbamoyl)acetamide (3ac); and,
2-((3-benzylquinoxalin-2-yl)thio)-N-((4-fluorophenyl)carbamoyl)acetamide (3ad).
7. A kit comprising
a compound of formula (II)
wherein:
ring a is fused with ring b to form bicyclic core ab, wherein ring a is selected from the group consisting of benzene and pyridine
wherein a is optionally substituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, nitro, cyano, halogen, hydroxy, C 1 -C 4 alkoxy optionally substituted with one or more fluoro atoms, C 1 -C 4 thioalkoxy optionally substituted with one or more fluoro atoms, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR, and —C(═O)NRR;
Q is S, S(═O), S(═O) 2 , O or NR;
each occurrence of R is independently H or C 1 -C 4 alkyl;
R 1 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR, and —C(═O)NRR;
R 2 is selected from the group consisting of —C(═O)N(R)C(═O)NR 3 R 4 and —C(═O)N(R)C(═O)OR 3 ;
R 3 is selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with one or more fluoro atoms, C 3 -C 6 cycloalkyl optionally substituted with one or more fluoro atoms, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyl, substituted heteroalkyl, —C(═O)OR and —C(═O)NRR;
R 4 is H or C 1 -C 4 alkyl, or R 3 and R 4 are taken together with the N atom to which both groups are bound to form a four- to seven-membered optionally substituted heterocyclic or heteroaromatic ring;
R 5 is selected from the group consisting of H and C 1 -C 4 alkyl optionally substituted with at least one substituent selected from the group consisting of halo, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 thioalkoxy, —SO 2 (C 1 -C 4 alkyl), —C(═O)OR, —NRR and —C(═O)NRR;
wherein the kit further comprises instructional material comprising instructions for using the at least one compound to treat or prevent a viral infection in a subject.
8. The kit of claim 7 , wherein the viral infection is caused by at least one virus selected from the group consisting of a filovirus, arenavirus, rhabdovirus, paramyxovirus, and retrovirus.