Cyclic Peptide Antiviral Agents and Methods Using Same

1 . A cyclic compound of formula (I), or a salt, solvate, enantiomer or diastereoisomer thereof:

(I)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1 ,

wherein in (I):

Xaa 1 is selected from the group consisting of absent, Glu and Arg;

Xaa 2 is selected from the group consisting of absent, Gly, Phe, Lys, Asp, Glu, Ile, Arg and Cit;

Xaa 3 is selected from the group consisting of absent, Asn, Asp, Ile, Glu, butanedioic acid, and 2-cyclohexylglycine;

Xaa 4 is selected from the group consisting of Asn and Asp;

Xaa 5 is a modified glycine of formula (III)

wherein R III is selected from the group consisting of C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl;

Xaa 6 is the modified proline of formula (IV)

wherein in (IV):

R IV is selected from the group consisting of: adamantyl substituted with 0-2 C 1 -C6 alkyl groups; —(C 0 -C 4 alkyl) phenyl, wherein the phenyl is substituted with 0-2 C 1 -C 6 alkyl groups; phenyl substituted with R 1 and with 0-2 C 1 -C 6 alkyl groups; and heteroaryl substituted with R 1 and with 0-2 C 1 -C 6 alkyl groups;

wherein each occurrence of R 1 is independently selected from the group consisting of phenyl substituted with 0-2 C 1 -C 6 alkyl groups and heteroaryl substituted with 0-2 C 1 -C 6 alkyl groups; and

wherein each occurrence of heteroaryl is independently selected from the group consisting of pyridine, pyrimidine, thiophene, furan, pyrrole, imidazole, oxazole, oxadiazole, thiazole, thiadiazolyl, isothiazole, and tetrazole;

Xaa 7 is selected from the group consisting of Trp and 3-(3-benzothienyl)-L-alanine;

Xaa 8 is selected from the group consisting of Ser, Thr, 2,4-diaminobutanoic acid, Orn and Lys;

Xaa 9 is selected from the group consisting of absent, 2,4-diaminobutanoic acid, Orn, Lys, Glu, Glu-Ala, Glu-Ala-Met, Glu-Ala-Met-Met, and 2-(2-(2-aminoethoxy)ethoxy)acetic acid;

P 1 is absent, or is a group that comprises at least one thiol group and is covalently linked through an amide bond to (i) the C-terminus of Xaa 9 if Xaa 9 is not absent, or (ii) the C-terminus of Xaa 8 if Xaa 9 is absent;

the side chain amino group of one residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9 forms an amide bond with the side chain carboxylic acid group of one residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3 , succinic acid at Xaa 3 , and Asp at Xaa 4 ; and

the C-terminus of Xaa 8 is optionally amidated if Xaa 9 and P 1 are absent, or the C-terminus of Xaa 9 is optionally amidated if P 1 is absent.

2 . The cyclic compound of claim 1 , which is selected from the group consisting of:

wherein in (Ia)-(If) ‘NH’ is derived from the side chain amino group of a residue selected from the group consisting of 2,4-diaminobutanoic acid at Xaa 8 , Orn at Xaa 8 , Lys at Xaa 8 , 2,4-diaminobutanoic acid at Xaa 9 , Orn at Xaa 9 , and Lys at Xaa 9 , and

‘C═O’ is derived from the side chain carboxylic acid group of a residue selected from the group consisting of Glu at Xaa 2 , Asp at Xaa 2 , Glu at Xaa 3 , Asp at Xaa 3 , succinic acid at Xaa 3 , and Asp at Xaa 4.

3 . The cyclic compound of claim 1 , which is the cyclic compound of formula (II):

(II)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -P 1 ,

wherein in (II):

Xaa 3 is selected from the group consisting of Asn, Asp, succinic acid, and Glu;

Xaa 4 is Asn;

Xaa 5 is Ile; and

Xaa 7 is Trp.

4 . The compound of claim 1 , wherein Xaa 5 is selected from the group consisting of Ile, Leu, norleucine (Nle), cyclopropylglycine, cyclobutylglycine, cyclopentylglycine, and cyclohexylglycine.

5 . The compound of claim 1 , wherein R III is a secondary or tertiary hydrocarbyl group.

6 . The compound of claim 5 , wherein R III is selected from the group consisting of cyclohexyl, —CH(CH 3 )(C 1 -C 4 alkyl), and —C(CH 3 ) 2 (C 1 -C 3 alkyl).

7 . The compound of claim 1 , wherein the C-terminus of Xaa 8 is not amidated if Xaa 9 and P 1 are absent, or wherein the C-terminus of Xaa 9 is not amidated if P 1 is absent.

8 . The compound of claim 1 , wherein the C-terminus of Xaa 8 is amidated if Xaa 9 and P 1 are absent, or wherein the C-terminus of Xaa 9 is amidated if P 1 is absent.

9 . The compound of claim 1 , wherein, if the carbon alpha to the carboxyl group of Xaa 8 is chiral, the stereochemistry of the alpha carbon is S.

10 . The compound of claim 1 , wherein in (IV) the heteroaryl is thiophene.

11 . The compound of claim 1 , wherein R IV is selected from the group consisting of:

—(C 0 -C 4 alkyl) phenyl, wherein the phenyl is substituted with 1-2 C 1 -C 6 alkyl groups, wherein one of the C 1 -C 6 alkyl groups is at the para position of the phenyl group;

wherein each occurrence of R 1 is independently C 1 -C 6 alkyl; m is 0, 1, or 2; and n is 0 or 1.

12 . The compound of claim 1 , wherein P 1 is not absent.

13 . The compound of claim 12 , wherein P 1 comprises at least one cysteine residue.

14 . The compound of claim 12 , wherein P 1 is selected from the group consisting of

βAla Gln βAla Cys-NH 2 , βAla Gln βAla Cys,

NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH,

NH 2 (CH 2 CH 2 O) 0-10 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 ,

NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)OH,

NH 2 (CH 2 ) 0-12 CH 2 C(═O)NHCH(CH 2 SH)C(═O)NH 2 ,

and

NH 2 CH 2 CH 2 OCH 2 CH 2 OC(═O)NHCH(CH 2 SH)C(═O)NH 2 .

15 . The compound of claim 1 , which is selected from the group consisting of:

29N-2 or 36 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide]

37 [also known as (3S,6S,14S,17S,20S,24S,25aS)-3-1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide]

38 [also known as (3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide]

(3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,14][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3 -triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide

(3S,6S,14S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18] hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-3-((1H-indol-3-yl)methyl)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,14S,17S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl) phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13, 18]hexaazacyclotricosine-6-carboxamide

(3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-((S)-sec-butyl)-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,14S,17S,20S,24S,25aS)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H -1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

((3S,6S,14S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-14-amino-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxo-24-(4-(4-(thiophen-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)tetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

(3S,6S,17S,20S,24S,25aS)-24-(4-([2,2′-bithiophen]-5-yl)-1H-1,2,3-triazol-1-yl)-17-(2-amino-2-oxoethyl)-3-(benzo[b]thiophen-3-ylmethyl)-20-cyclohexyl-1,4,12,15,18,21-hexaoxotetracosahydro-1H-pyrrolo[2,1-f][1,4,7,10,13,18]hexaazacyclotricosine-6-carboxamide

or a salt or solvate thereof.

16 . The compound of claim 1 , which is a compound of formula (V):

wherein:

R a is NH 2 or H;

R b is cyclohexyl or sec-butyl;

R c is selected from the group consisting of:

R d is NH or S;

or a salt or solvate thereof.

17 . The compound of claim 1 , wherein P 1 is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

18 . The compound of claim 17 , wherein the at least one nanoparticle has an average diameter of about 20 nm.

19 . A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one cyclic compound of claim 1 .

20 . The composition of claim 19 , wherein P 1 in (I) is not absent and wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

21 . The composition of claim 19 , further comprising at least one additional compound useful for treating viral infections.

22 . The composition of claim 21 , wherein the at least one additional compound is selected from the group consisting of antiviral combination drugs, entry and fusion inhibitors, integrase inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, protease inhibitors, and any combinations thereof.

23 . The composition of claim 19 , wherein the peptide is encapsulated in a hydrogel and/or liposome.

24 . A method of treating, reducing or preventing HIV-1 infection in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1 .

25 . The method of claim 24 , wherein the compound is at least one compound of claim 15 or 16 , or a salt or solvate thereof.

26 . The method of claim 24 , wherein P 1 is not absent.

27 . The method of claim 26 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

28 . The method of claim 24 , wherein the mammal is further administered at least one additional compound useful for treating viral infections.

29 . The method of claim 24 , wherein the mammal is human.

30 . A method of reducing the risk of HIV-1 infection in a mammal at risk of HIV-1 exposure, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1 .

31 . The method of claim 30 , wherein the compound is at least one compound of claim 15 or 16, or a salt or solvate thereof.

32 . The method of claim 30 , wherein P 1 is not absent.

33 . The method of claim 32 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

34 . The method of claim 30 , wherein the mammal is further administered at least one additional compound useful for treating viral infections.

35 . The method of claim 30 , wherein the mammal is human.

36 . A method of promoting virolysis of a virus, the method comprising contacting the virus with an effective amount of at least one cyclic compound of claim 1 , wherein P 1 is not absent.

37 . The method of claim 36 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

38 . The method of claim 36 , wherein the virus comprises HIV-1.

39 . A method of reducing the rate of or preventing entry of a virus into a cell of a mammal, the method comprising administering to the mammal a therapeutically effective amount of at least one cyclic compound of claim 1 .

40 . The method of claim 39 , wherein the compound is at least one compound of claim 15 or 16 , or a salt or solvate thereof.

41 . The method of claim 39 , wherein P 1 is not absent.

42 . The method of claim 41 , wherein (I) is complexed through the at least one thiol group with at least one gold nanoparticle.

43 . The method of claim 39 , wherein the virus comprises HIV-1.

44 . The method of claim 39 , wherein the mammal is human.

45 . A method of preparing a derivatized gold nanoparticle, the method comprising contacting the nanoparticle with at least one cyclic compound of claim 1 to generate a reaction system; and isolating the derivatized gold nanoparticle from the reaction system.