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 occurrence, 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 1) 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 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) 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 is 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 O 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 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, 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, unsaturated, 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 nitrogen, 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 G has the formula:

and R 15 is a macrolide.

11. 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 13 , 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 —, —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 .

12. 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:

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:

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

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

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

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

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

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

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

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