Compositions and methods for inhibiting viral infection

1. A compound having the structure of Formula (I) or (III)

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,

wherein:

X is O;

W is —YR A , wherein Y is O or NH, and R A is H, or (C 1 -C 8 )alkyl optionally substituted with a OH, O(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;

A has the structure of formula (IV);

wherein formula (IV) is

 wherein;

A 1 is N or CR 10 , wherein R 10 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;

A 2 is N or CR 11 , wherein R 11 H, halogen, (C 1 -C 8 )haloalkyl, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;

A 3 is N or CR 12 , wherein R 12 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl; or A 2 is CR 11 and A 3 is CR 12 , and wherein R 11 and R 12 form the ring structure:

A 4 is N or CR 13 , wherein R 13 is H, halogen, or OR O , and wherein R O is H or (C 1 -C 8 )alkyl;

R 2 is phenyl or a 6-membered heteroaryl having a N atom, and where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , CN, or SMe;

R 3 is H, phenyl, (C 1 -C 8 )alkyl, 5-6 membered heteroaryl comprising a heteroatom selected from N, O and S, (C 2 -C 8 )alkenyl, (C 1 -C 8 )haloalkyl, —C(O)NH 2 , —C(O)NMe 2 or —CO 2 H, where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with a OH, O(C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; and wherein when R 3 is not H; R 3 is syn to R 2 or R 3 is trans to R 2 ;

R 4 is H, (C 1 -C 8 )alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from the group consisting of N, O and S, (C 1 -C 8 )haloalkyl, C 3 -C 8 cycloalkyl, NH(aryl), NH(CN), CO 2 (alkyl), or NH(C 1 -C 8 alkyl), where the phenyl can be optionally substituted with a halogen, OH, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with halogen, O(C 1 -C 8 )alkyl, C(O)-lower alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl;

Z is O, NH, Se, N(alkyl), N(CN), CN or CR C R F ; wherein R C and R F independently are H, (C 1 -C 8 )alkyl or CN;

R 5 is H, (C 1 -C 8 )alkyl or phenyl, where the (C 1 -C 8 )alkyl can be optionally substituted with 1 or 2 halogen, OH or O(C 1 -C 8 )alkyl;

D is a 5-6 membered heteroaryl comprising 1 or 2 heteroatoms selected from N, O and S;

or D is a 5-6 membered heterocyclyl comprising 1 or 2 heteroatoms selected from N, O and S; and

provided that the compound is not (−)-6, (+)-6, (−)-6-OH, racemates of (−)-6 or (+)-6, structural isomers of (−)-6-OH or enantiomers of (−)-6-OH,

2. The compound according to claim 1 , wherein at least one of R 10 , R 11 , R 12 or R 13 is a (C 1 -C 8 )alkoxy.

3. The compound according to claim 1 , wherein:

the compound has the structure of formula (I);

W is OH;

X is O;

Z is O;

R 2 is a phenyl optionally substituted with a halogen, O(C 1 -C 8 )alkyl, NH 2 , N[(C 1 -C 4 )alkyl] 2 , or CN;

R 3 is a phenyl;

R 2 is syn relative to R 3 ;

R 5 is H or (C 1 -C 8 )alkyl; and

R 4 is (C 1 -C 8 )alkyl or phenyl, where the phenyl can be optionally substituted with a halogen, OH, (C 1 -C 8 )alkyl, O(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 , and the (C 1 -C 8 )alkyl can be optionally substituted with halogen, O(C 1 -C 8 )alkyl, C(O)-lower alkyl or (C 2 -C 8 )alkenyl.

4. The compound according to claim 1 , wherein the compound is of Formula (I).

5. The compound according to claim 1 , wherein;

the compound has the structure of formula (I);

W is OH;

X is O;

Z is O;

R 2 is

R 3 is a phenyl;

R 2 is syn relative to R 3 ;

R 5 is H or (C 1 -C 8 )alkyl; and

R 4 is (C 1 -C 8 )alkyl,

6. The compound according to claim 1 , wherein R 3 is syn to R 2 .

7. A compound selected from the following compounds;

8. A composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or excipient.

9. The compound of claim 1 , wherein ring A is

10. The compound of claim 1 , wherein

W is OH;

X is O;

Z is O;

R 2 is a phenyl optionally substituted with a halogen, O(C 1 -C 8 )alkyl, NH 2 , N[(C 1 -C 4 )alkyl] 2 , or CN; and

R 3 is phenyl or 5-6 membered heteroaryl comprising a heteroatom selected from N, O and S, where the phenyl can be optionally substituted with a halogen, OH, O(C 1 -C 8 )alkyl, NH 2 , NH(C 1 -C 4 )alkyl or N[(C 1 -C 4 )alkyl] 2 .

11. The compound of claim 1 , where the compound has the structure of Formula (I);

A has the structure of formula (IV) and,

A 1 is N or CR 10 , wherein R 10 is H, OMe or F;

A 2 is N, or CR 11 , wherein CR 11 is H, F, OMe or CF 3 , and A 3 is N or CR 12 , wherein CR 12 is H, F, Cl, Br or OMe, or

A 2 is CR 11 and A 3 is CR 12 , wherein R 11 and R 12 form the ring structure

 and

A 4 is N or CR 13 , wherein CR 13 is H, F, or Br;

W is OH, —NH 2 , OMe, —NH(CH 2 CH 2 )OMe, or —O—CH 2 C≡CH;

X is O;

Z is O, Se, ═NH, ═N(CN), or ═C(CN) 2 ;

R 2 is

R 3 is an H, phenyl, methyl, —CH 2 CH═CH 2 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —C≡CCH 3 , C(O)NMe 2 ,

R 5 is H, phenyl, methyl or —CH 2 CH 2 CH 2 C(OMe) 2 ;

and R 4 is H, Me, —NH 2 , —CH 2 Cl, —CH 2 CH═CH2, —CH 2 OMe, —CH 2 C(O)OEt, —CH 2 C(O)OMe, —CH(CH 3 ) 2 , -cyclopropyl, -cyclohexyl, phenyl, benzyl, —NHC(O)CH═CH 2 , —NHCH 2 C≡CH,

12. The compound of claim 1 , wherein the compound has the structure of Formula (III);

A 1 is CR 10 , wherein R 10 is H or OMe;

A 2 is CR 11 , wherein CR 11 is H;

A 3 is CR 12 , wherein CR 12 is H or OMe;

A 4 is CR 13 , wherein CR 13 is H;

W is OH;

X is O;

Z is O;

R 2 is

R 3 is phenyl;

D is

and

wherein the compound is not (−)-6, (+)-6, (−)-6-OH, racemates of (−)-6 or (+)-6, or structural isomers or enantiomers of (−)-6-OH and (+)-6-OH.

13. A method for preparing a compound having formula (I) or (II), wherein:

or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof,

wherein:

A has the structure of formula (IV) and,

A 1 is N or CR 10 , wherein R 10 is H, OMe or F;

A 2 is N, or CR 11 , wherein CR 11 is H, F, OMe or CF 3 ;

A 3 is N or CR 12 , wherein CR 12 is H, F, Cl, Br or OMe; or

A 2 is CR 11 and A 3 is CR 12 , wherein R 11 and R 12 form the ring structure

A 4 is N or CR 13 , wherein CR 13 is H, F, or Br;

W is OH, —NH 2 , OMe, —NH(CH 2 CH 2 )OMe, or —O—CH 2 C≡CH;

X is O;

Z is O;

Z′ is a OH;

R 2 is

R 3 is an H, phenyl, methyl, —CH 2 CH═CH 2 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —C≡CCH 3 , C(O)NMe 2 ,

 and

wherein the second compound has the structure of (VIII) wherein R 5 is H, phenyl, methyl or —CH 2 CH 2 CH 2 C(OMe) 2 , and R 4 is H, Me, —NH 2 , —CH 2 Cl, —CH 2 CH═CH 2 , —CH 2 OMe, —CH 2 C(O)OEt, —CH 2 C(O)OMe, —CH(CH 3 ) 2 ,-cyclopropyl,-cyclohexyl, phenyl, benzyl, —NHC(O)CH═CH 2 , —NHCH 2 C≡CH,

the method comprising:

reacting a compound of structure (VI) or (VII) or a salt thereof with a compound of structure (VIII) or a salt thereof, wherein the structures of (VI), (VII) and (VIII) are

wherein Q is OR G or NR H R I , wherein R G , R H and R I are independently H or an alkyl, and wherein L is a leaving group.