Bifunctional heterocyclic compounds and methods of making and using same

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof;

wherein

A at each occurrene is carbon;

B is selected from the group consisting of O, NR 2 , S(O) r , C═O, C═S, and C═NOR 3 ,

p is 0;

q, at each occurrence, independently is 0 or 1;

r is 0, 1 or 2;

R 2 , at each occurrence, independently is selected from the group consisting of:

a) hydrogen, b) S(O) r R 4 , c) formyl, d) C 1-8 alkyl, e) C 2-8 alkenyl, f) C 2-8 alkynyl, g) C 1-8 alkoxy, h) C 1-8 alkylthio, i) C 1-8 acyl, j) saturated, unsaturated, or aromatic C 3-8 carbocycle, and k) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of d)–k) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —S(O) r R 4 , —S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , and —OC(O)NR 3 R 3 ;

alternatively, two R 2 groups, taken together with the atom to which they are bonded, form i) 5–8 membered saturated or unsaturated carbocycle, or ii) 5–8 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein i)–ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —S(O) r R 4 , —S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 , C 1-6 acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 3 , at each occurrence, independently is selected from the group consisting of:

a) hydrogen, b) C 1-8 alkyl, c) C 2-8 alkenyl, d) C 2-8 alkynyl, e) C 1-8 acyl, f) saturated, unsaturated, or aromatic C 3-8 carbocycle, and g) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of b)–h) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 6 R 6 , —OR 6 , —S(O) r R 6 , —S(O) r NR 6 R 6 , —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —C(O)NR 6 R 6 , —OC(O)NR 6 R 6 , C 1-6 acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

alternatively, two R 3 groups, taken together with the atom to which they are bonded, form i) a 5–7 membered saturated or unsaturated carbocycle, or ii) a 5–7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein i)–ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 6 R 6 , —OR 6 , —S(O) r R 6 , —S(O) r NR 6 R 6 , —C(O)R 6 , —C(O)OR 6 , OC(O)R 6 , —C(O)NR 6 R 6 , —OC(O)NR 6 R 6 , C 1-6 acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 4 is selected from the group consisting of:

a) hydrogen, b) —NR 3 R 3 , c) —NR 3 OR 3 , d) —NR 3 NR 3 R 3 e) —NHC(O)R 3 , f) —C(O)NR 3 R 3 , g) —N 3 , h) C 1-8 alkyl, i) C 2-8 alkenyl, j) C 2-8 alkynyl, k) saturated, unsaturated, or aromatic C 3-8 carbocycle, and l) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of h)–l) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —SR 3 , —S(O) r R 5 , —S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 5 is selected from the group consisting of:

a) hydrogen, b) —NR 3 R 3 , c) —NR 3 OR 3 , d) —NR 3 NR 3 R 3 e) —NHC(O)R 3 , f) —C(O)NR 3 R 3 , g) —N 3 , h) C 1-8 alkyl, i) C 2-8 alkenyl,j) C 2-8 alkynyl, k) saturated, unsaturated, or aromatic C 3-8 carbocycle, and l) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of h)–l) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —SR 3 —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 6 , at each occurrence, independently is selected from the group consisting of:

hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;

alternatively, two R 6 groups taken together are —(CH 2 ) s —,

wherein s is 1, 2, 3, 4, or 5;

D-E is

E is selected from the group consisting of:

d) 5–10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13 groups; and

e) C 5-10 aromatic carbocycle, optionally substituted with one or more R 13 groups;

R 7 selected from the group consisting of:

a) hydrogen, b) carbonyl, c) formyl, d) F, e) Cl, f) Br, g) I, h) CN, i) NO 2 , j) OR 3 , k) —S(O) r R 5 , l) —S(O) i N═R 2 , m) —C(O)R 2 , n) —C(O)OR 3 , o) —OC(O)R 2 , p) —C(O)NR 2 R 2 , q) —OC(O)NR 2 R 2 , r) —C(═NR 12 )R 2 , s) —C(R 2 )(R 2 )OR 3 , t) —C(R 2 )(R 2 )OC(O)R 2 , u) —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 , v) —NR 2 R 2 , w) —NR 2 OR 3 , x) —N(R 2 )C(O)R 2 , y) —N(R 2 )C(O)OR 3 , z) —N(R 2 )C(O)NR 2 R 2 , aa) —N(R 2 )S(O) r R 5 , bb) —C(OR 6 )(OR 6 )R 2 , cc) —C(R 2 )(R 3 )NR 2 R 2 , dd) —C(R 2 )(R 3 )NR 2 R 12 , ee) ═NR 12 , ff) —C(S)NR 2 R 2 , gg) —N(R 2 )C(S)R 2 , hh) —OC(S)NR 2 R 2 , ii) —N(R 2 )C(S)OR 3 , jj) —N(R 2 )C(S)NR 2 R 2 , kk) —SC(O)R 2, ll) C 1-8 alkyl, mm) C 2-8 alkenyl, nn) C 2-8 alkynyl, oo) C 1-8 alkoxy, pp) C 1-8 alkylthio, qq) C 1-8 acyl, rr) saturated, unsaturated, or aromatic C 5-10 carbocycle, and ss) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of ll)–ss) optionally is substituted with one or more moieties selected from the group consisting of:

carbonyl; formyl; F; Cl; Br; I; CN; NO 2 ; OR 3 ; —S(O) r R 5 ; —S(O) r N═R 2 , —C(O)R 2 ; —C(O)OR 3 ; —OC(O)R 2 ; —C(O)NR 2 R 2 ; —OC(O)NR 2 R 2 ; —C(═NR 10 )R 2 ; —C(R 2 )(R 2 )OR 3 ; —C(R 2 )(R 2 )OC(O)R 2 ; —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 ; —NR 2 R 2 ; —NR 2 OR 3 ; —NR 2 C(O)R 2 ; —NR 2 C(O)OR 3 ; —NR 2 C(O)NR 2 R 2 ; —NR 2 S(O) r R 5 ; —C(OR 6 )(OR 6 )R 2 ; —C(R 2 )(R 3 )NR 2 R 2 ; —C(R 2 )(R 3 )NR 2 R 12 ; ═NR 12 ; —C(S)NR 2 R 2 ; —NR 2 C(S)R 2 ; —OC(S)NR 2 R 2 ; —NR 2 C(S)OR 3 ; —NR 2 C(S)NR 2 R 2 ; —SC(O)R 2 ; C 2-5 alkenyl; C 2-5 alkynyl; C 1-8 alkoxy; C 1-8 alkylthio; C 1-8 acyl; saturated, unsaturated, or aromatic C 5-10 carbocycle, optionally substituted with one or more R 8 groups; and saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 8 groups;

R 8 is selected from the group consisting of:

hydrogen; F; Cl; Br; I; CN; NO 2 ; OR 6 ; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C 1-6 alkyl, optionally substituted with one or more moieties selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO 2 , and OR 6 ;

alternatively, R 7 and R 8 taken together are —O(CH 2 ) r O—;

R 9 , at each occurrence, independently is selected from the group consisting of: hydrogen, F, Cl, Br, I, CN, OR 3 , NO 2 , —NR 2 R 2 , C 1-6 alkyl, C 1-6 acyl, and C 1-6 alkoxy;

R 10 selected from the group consisting of:

a) saturated, unsaturated, or aromatic C 5-10 carbocycle, b) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) -X-C 1-6 alkyl-saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, d) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, e) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and f) R 9 ,

wherein

any of a)–e) optionally is substituted with one or more R 13 groups,

and

X is 0 or NR 3 ;

alternatively, R 10 and one R 9 group, taken together with the atoms to which they are bonded, form a 5–7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 13 groups; or a 5–7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13 groups;

R 11 at each occurrence, independently is selected from the group consisting of:

hydrogen; an electron-withdrawing group; aryl; substituted aryl;

heteroaryl; substituted heteroaryl; and C 1-6 alkyl, optionally substituted with F, Cl, or Br;

alternatively, any R 11 and R 8 , taken together with the atoms to which they are bonded, form a 5–7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 13 groups; or a 5–7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13 groups;

R 12 is selected from the group consisting of:

—NR 2 R 2 , —OR 3 , —OC(O)R 2 , —OC(O)OR 3 , —NR 2 C(O)R 2 , —NR 2 C(O)NR 2 R 2 , —NR 2 C(S)NR 2 R 2 , and —NR 2 C(═NR 2 )NR 2 R 2 ;

R 13 , at each occurrence, independently is selected from the group consisting of:

a) hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h) CN, i) NO 2 , j) OR 3 , k) —S(O) r R 5 , l) —S(O) r N═R 3 , m) —C(O)R 2 , n) —C(O)OR 3 , o) —OC(O)R 2 , p) —C(O)NR 2 R 2 , q) —OC(O)NR 2 R 2 , r) —C(═NR 12 )R 2 , s) —C(R 2 )(R 2 )OR 3 , t) —C(R 2 )(R 2 )OC(O)R 2 , u) —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 , v) —NR 2 R 2 , w) —NR 2 OR 3 , x) —N(R 2 )C(O)R 2 , y) —N(R 2 )C(O)OR 3 , z) —N(R 2 )C(O)NR 2 R 2 , aa) —N(R 2 )S(O) r R 5 , bb) —C(OR 6 )(OR 6 )R 2 , cc) —C(R 2 )(R 3 )NR 2 R 2 , dd) —C(R 2 )(R 3 )NR 12 R 2 , ee) ═NR 12 , ff) —C(S)NR 2 R 2 , gg) —N(R 2 )C(S)R 2 , hh) —OC(S)NR 2 R 2 , ii) —N(R 2 )C(S)OR 3 , jj) —N(R 2 )C(S)NR 2 R 2 , kk) —SC(O)R 2 , ll) C 1-8 alkyl, mm) C 2-8 alkenyl, nn) C 2-8 alkynyl, oo) C 1-8 alkoxy, pp) C 1-8 alkylthio, qq) C 1-8 acyl, rr) saturated, unsaturated or aromatic C 5-10 carbocycle, ss) saturated, unsaturated, or aromatic 5–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, tt) saturated, uusaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and uu) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

wherein any of ll)–uu) optionally is substituted with one or more moieties selected from the group consisting of:

carbonyl; formyl; F; Cl; Br; I; CN; NO 2 ; OR 3 ; —S(O) r R 5 ; —S(O) r N═R 2 , —C(O)R 2 ; —C(O)OR 3 ; —OC(O)R 2 ; —C(O)NR 2 R 2 ; —OC(O)NR 2 R 2 ; —C(═NR 12 )R 2 ; —C(R 2 )(R 2 )OR 3 ; —C(R 2 )(R 2 )OC(O)R 2 ; —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 ; —NR 2 R 2 ; —NR 2 OR 3 ; —NR 2 C(O)R 2 ; —NR 2 C(O)OR 3 ; —NR 2 C(O)NR 2 R 2 ; —NR 2 S(O) r R 5 ; —C(OR 6 )(OR 6 )R 2 ; —C(R 2 )(R 3 )NR 2 R 2 ; —C(R 2 )(R 3 )NR 2 R 12 ; ═NR 12 ; —C(S)NR 2 R 2 ; —NR 2 C(S)R 2 ; —OC(S)NR 2 R 2 ; —NR 2 C(S)OR 3 ; —NR 2 C(S)NR 2 R 2 ; —SC(O)R 2 ; C 1-8 alkyl, C 2-8 alkenyl; C 2-8 alkynyl; C 1-8 alkoxy; C 1-8 alkylthio; C 1-8 acyl; saturated, unsaturated, or aromatic C 3-10 carbocycle optionally substituted with one or more R 7 groups; and saturated, unsaturated, or aromatic 3–10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitregen, oxygen, and sulfur, and substituted with one or more R 7 groups;

G is selected from the group consisting of:

t, at each occurrence, independently is 0, 1, 2, or 3;

R 14 is selected from the group consisting of:

a) hydrogen, b) C 1-6 -alkyl, c) C 2-6 alkenyl , d) C 2-6 alkynyl, e) —C(O)—R 3 , f) —C(O)—C 1-6 alkyl-R 3 , g) —C(O)—C 2-6 alkenyl-R 3 , h) —C(O)—C 2-6 alkynyl-R 3 , i) —C 1-6 alkyl-J-R 3 , j) —C 2-6 alkenyl-J-R 3 ; and k) —C 2-6 alkynyl-J-R 3 ;

wherein

(i) any of b)–d) optionally is substituted with one or more substituents selected from the group consisting of:

F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —OR 3 , —O—C 1-6 alkyl-R 2 , —O—C 2-6 alkenyl-R 2 , —O—C 2-6 alkynyl-R 2 , and —NR 2 R 2 ; and

(ii) J is selected from the group consisting of:

—OC(O)—, —OC(O)O—, —OC(O)NR 2 —, —C(O)NR 2 —, —NR 2 C(O)—, —NR 2 C(O)O—, —NR 2 C(O)NR 2 — —NR 2 C(NH)NR 2 —, and S(O) r ; and

R 15 is selected from the group consisting of:

hydrogen; C 1-10 alkyl, optionally substituted with one or more R 13 groups; C 1-6 acyl, optionally substituted with one or more R 13 groups; aryl; substituted aryl; heteroaryl; substituted heteroaryl; arylalkyl; substituted arylalkyl; and a macrolide.

2. The compound according to claim 1 , having the formula:

wherein A, E, and G are as defined in claim 1 .

3. The compound according to claim 1 , wherein E has the formula:

wherein R 9 and R 10 , at each occurrence, are as defined in claim 1 .

4. The compound according to claim 1 , wherein E has the formula:

wherein R 10 is as defined in claim 1 .

5. The compound according to claim 3 , wherein R 10 has the formula:

wherein

K is selected from the group consisting of O, NR 2 , and S(O) r , and

x is 0, 1 , 2, or 3.

6. The compound according to claim 5 , wherein K is oxygen.

7. The compound according to claim 5 , wherein x is 1.

8. The compound according to claim 1 , wherein G has the formula:

and R 15 is a macrolide.

9. The compound according to claim 1 , wherein G has the formula:

and R 15 is a macrolide.

10. The compound according to claim 1 , wherein R 15 is selected from the group consisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein

R 17 is selected from the group consisting of:

hydrogen, hydroxy protecting group, R 3 , and -V-W-R 13 ,

wherein

V is —C(O), —C(O)O—, —C(O)NR 2 , or absent, and

W is C 1-6 alkyl, or absent;

alternatively R 17 and R 14 , taken together with the atoms to which they are bonded, form:

Q is selected from the group consisting of:

—NR 2 CH 2 —, —CH 2 —NR 2 —, —C(O)—, —C(═NR 2 )—, —C(═NOR 3 )—, —C(═N—NR 2 R 2 )—, —CH(OR 3 )—, and —CH(NR 2 R 2 )—;

R 18 is selected from the group consisting of:

i) C 1-6 alkyl, ii) C 2-6 alkenyl, and iii) C 2-6 alkynyl;

wherein any of i)–iii) optionally is substituted with one or more moieties selected from the group consisting of —OR 3 , aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R 19 is selected from the group consisting of:

a) OR 17 , b) C 1-6 alkyl, c) C 2-6 alkenyl, d) C 2-6 alkynyl, e) —NR 2 R 2 , f) —C(O)R 3 , g) —C(O)—C 1-6 alkyl-R 13 , h) —C(O)—C 2-6 alkenyl-R 3 , and i) —C(O)—C 2-6 alkynyl-R 13 ,

wherein any of b)–d) optionally is substituted with one or more R 13 groups;

alternatively, R 14 and R 19 , taken together with the atoms to which they are bonded, form:

wherein

L is CH or N, and

R 23 is —OR 3 , or R 3 ;

R 20 is —OR 17 ;

alternatively, R 19 and R 20 , taken together with the atoms to which they are bonded, form a 5-membered ring by attachment to each other through a linker selected from the group consisting of:

—OC(R 2 )(R 2 )O—, —OC(O)O—, —OC(O)NR 2 —, —NR 2 C(O)O—, —OC(O))NOR 3 —, —N(OR 3 )C(O)O—, —OC(O)N—NR 2 R 2 —, —N(NR 2 R 2 )C(O)O—, —OC(O)CHR 2 —, —CHR 2 C(O)O—, —OC(S)O—, —OC(S)NR 2 —, —NR 2 C(S)O—, —OC(S)NOR 3 —, —N(OR 3 )C(S)O—, —OC(S)N—NR 2 R 2 —, —N(NR 2 R 2 )C(S)O—, —OC(S)CHR 2 —, and —CHR 2 C(S)O—;

alternatively, Q, R 19 , and R 20 , taken together with the atoms to which they are bonded, form:

wherein

M is O or NR 2 ;

R 21 is selected from the group consisting of:

hydrogen, F, Cl, Br, and C 1-6 alkyl;

R 22 , at each occurrence, independently is selected from the group consisting of:

hydrogen, —OR 3 , —O-hydroxy protecting group, —O—C 1-6 alkyl-J-R 13 , —O—C 2-6 alkenyl-J-R 13 , —O—C 1-6 alkynyl-J-R 13 , and —NR 2 R 2 ;

alternatively, two R 22 groups taken together are ═O, ═N—OR 3 , or ═N—NR 2 R 2 ; and

R 2 , R 3 , R 13 , R 14 , and J are as described in claim 1 .

11. The compound according to claim 1 , wherein G has the formula selected from the group consisting of:

and R 15 has the formula selected from the group consisting of:

12. The compound according to claim 1 , wherein G has the formula:

wherein n=1, 2, 3, or 4.

13. The compound according to claim 1 , wherein G has the formula:

wherein n=1, 2, 3, or 4.

14. The compound according to claim 1 , wherein G has the formula selected from the group consisting of:

15. A compound having the structure corresponding to any of the structures listed below:

Compound Number

Structure

145

146

147

148

149

150

151

152

153

175

176

177

178

179

180

181

182

183

184

185

203

204

205

206

207

208

209

210

211

212

213

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

or a pharmaceutically acceptable salt, ester, or prodrug thereof.

16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

17. A method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 .

18. The method according to claim 17 wherein the compound is administered orally, parentally, or topically.

19. A pharmaceutical composition comprising a compound according to claim 15 and a pharmaceutically acceptable carrier.

20. The compound according to claim 1 , wherein G has the formula:

and R 15 is a macrolide.

21. A pharmaceutical composition comprising a compound according to claim 8 and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising a compound according to claim 20 and a pharmaceutically acceptable carrier.