HIV-1 fusion inhibitors and methods
A new series of HIV-1 fusion inhibitors and methods of use are disclosed. The compounds are based on a substituted indole, benzimidazole, indoline or isoindoline fragment. The compounds find use in inhibiting or preventing HIV fusion from occurring, thus inhibiting or preventing entry of viral RNA into host cells. The compounds may be useful towards other biological targets involving protein-protein interactions.
1. A compound, according to formula Va:
wherein:
Z 3 is —(CH 2 ) 0-3 CO 2 R a or H;
each R a is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl;
each R 2a is independently optionally substituted C 1-6 alkyl, halo, —OC 1-6 alkyl, —OH —N(C 1-6 alkyl) 2 , —N(H)C 1-6 alkyl, —CN, —NO 2 , —C(O)C 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —C(O)N(H)C 1-6 alkyl or —C(O)N(C 1-6 alkyl) 2 ;
each of R 3 and R 4 are, independently, —H, halo, optionally substituted C 1-6 alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted C 4-11 cycloalkylalkyl, optionally substituted C 6-10 aryl, optionally substituted C 7-16 arylalkyl, optionally substituted 3-10 membered heteroalicyclyl, optionally substituted 4-11 membered heteroalicyclylalkyl, optionally substituted 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; and
where each R 40 is independently C 1-6 alkyl, halo, —OC 1-6 alkyl, —OH, —N(R 80a ) 2 , perhaloalkyl, —CN, —NO 2 , —CO 2 C 1-6 alkyl or —C(O)NR 80a R 80a , where each R 80a is independently H or C 1-6 alkyl; and at least one of R 40 is —OC 1-6 alkyl.
2. A compound, or pharmaceutically acceptable salt thereof, which is
3-((1H-indol-6-yl)methyl)benzoic acid (I-1);
3-((1-(4-methoxybenzyl)-1H-indol-6-yl)methyl)benzoic acid (I-2);
3-((3-(carboxycarbonyl)-1H-indol-6-yl)methyl)benzoic acid (I-3);
3-((1-(3-(carboxy)benzyl)-1H-indol-6-yl)methyl)benzoic acid (I-4);
3,3′-(1,1′-methylenebis(1H-indole-6,1-diyl))bis(methylene)dibenzoic acid (I-5);
3-(6-(3-carboxybenzyl)-1H-indol-1-yl)benzoic acid (I-6);
3-((1-(3-methoxyphenyl)-1H-indol-6-yl)methyl)benzoic acid (I-7);
3-((3-formyl-1H-indol-6-yl)methyl)benzoic acid (I-8);
3-((1H-indol-5-yl)methyl)benzoic acid (I-9);
3-((1-(3-carboxybenzyl)-1H-indol-5-yl)methyl)benzoic acid (I-10);
3-((6-(3-methoxyphenyl)-1H-indol-1-yl)methyl)benzoic acid (I-11);
3-(1H-indol-6-yl)benzoic acid (I-12);
3-(1-(3-carboxybenzyl)-1H-indol-5-yl)benzoic acid (I-13);
3-((6-(3-hydroxyphenyl)-1H-indol-1-yl)methyl)benzoic acid (I-14);
6-(3-nitrobenzyl)-1H-indole (I-15);
3-((1H-indol-6-yl)methyl)-4-nitrobenzoic acid (I-16);
3-((1H-indol-6-yl)methyl)-4-methoxybenzoic acid (I-17);
3-((1H-indol-6-yl)methyl)-5-hydroxybenzoic acid (I-18);
3-((1H-indol-6-yl)methyl)-4-hydroxybenzoic acid (I-19);
3-((1H-indol-6-yl)methyl)-5-methoxybenzoic acid (I-20);
3-((3-(1-(3-carboxybenzyl)-1H-indol-6-yl)phenoxy)methyl)benzoic acid (I-21);
3-((3-((6-(3-(4-methoxybenzyloxy)phenyl)-1H-indol-1-yl)methyl)benzoyloxy)methyl)benzoic acid (I-22);
3-((6-(6-chloroquinolin-2-yl)-1H-indol-1-yl)methyl)benzoic acid (II-1);
3-((5-(6-chloroquinolin-2-yl)-1H-indol-1-yl)methyl)benzoic acid (II-2) or
3-((1′-(4-methoxybenzyl)-1H,1′H-6,6′-biindol-1-yl)methyl)benzoic acid (II-3).
3. A pharmaceutical composition comprising the compound according to claim 2 and a pharmaceutically acceptable carrier.
4. A unit dosage formulation comprising the pharmaceutical composition of claim 3 .
5. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.
6. A unit dosage formulation comprising the pharmaceutical composition of claim 5 .