6,11-4-carbon bridged ketolides

1. A compound represented by formula I:

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

W is selected from the group consisting of:

(a) —CH 2 —C(A)═C(B)—CH 2 —;

wherein,

A and B are independently selected from the group consisting of:

(i) hydrogen;

(ii) deuterium;

(iii) halogen;

(iv) R 1 , wherein R 1 is selected from the group consisting of:

a. C 1 -C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

b. C 2 -C 6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

c. C 2 -C 6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

(v) R 2 , wherein R 2 is selected from the group consisting of:

a. aryl;

b. heteroaryl;

c. substituted aryl; and

d. substituted heteroaryl;

(vi) —(C 1 -C 3 -alkyl)—M—(C 1 -C 3 -alkyl)—R 2 , wherein M═—O—, —NH—, —N(CH 3 )—, —NHC(O)— or —S(O) n —, wherein n═0, 1 or 2, and R 2 is as previously defined;

(vii) —(C 1 -C 3 -alkyl)—M—R 2 , wherein M and R 2 are as previously defined;

(viii) —C(O)—J—R 3 , wherein J is absent, O or S, and R 3 is H, R 1 or R 2 ; where R 1 and R 2 are as previously defined, and

(ix) —C(O)—NR 11 R 12 , wherein R 11 and R 12 are each independently selected from the group consisting of:

a. hydrogen;

b. C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

c. C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

d. C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

e. R 11 and R 12 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: —O—, —NH—, —N(C 1 -C 6 -alkyl)—, —N(R 2 )—, —S(O) n —, wherein n and R 2 are as previously defined;

(b) —CH 2 —CH(A)—C(B)═CH—, wherein A and B are as previously defined;

(c) —CH 2 —CH(E)—CH(G)—CH 2 —;

wherein E and G are independently selected from the group consisting of:

(i) A, wherein A is as previously defined;

(ii) —OH;

(iii) —OR P , wherein R P is a hydroxy protecting group;

(iv) —O—R 9 , wherein R 9 is R 1 or R 2 , and wherein R 1 and R 2 are as previously defined;

(v) —S(O) n R 9 , wherein n and R 9 are as previously defined;

(vi) —NHC(O)R 3 , wherein R 3 is as previously defined;

(vii) —NHC(O)NR 11 R 3 , wherein R 11 and R 3 are as previously defined;

(viii) —NHS(O) 2 R 9 , wherein R 9 is as previously defined;

(ix) —NHR 13 , wherein R 13 is an amino protecting group; and

(x) —NR 11 R 12 , wherein R 11 and R 12 are as previously defined;

(d)

wherein:

(i) —Q— is selected from the group consisting of: —O—; —O—C(O)—CH(R 7 )—; —N(R 7 )—; —O—C(O)—N(R 7 )—; —O—C(O)—O—; —N(R 7 )—N═N—; —C(R 7 )═N—O—; and —CH(R 7 )—N(R 8 )—O—; wherein R 7 and R 8 are independently selected from R 3 , wherein R 3 is as previously defined; or

(ii) —Q—taken together with the two carbon atoms it is attached to is selected from the group consisting of:

a. cycloalkylene;

b. cycloalkenylene; and

c. heterocycloalkylene; and

(e) —CH 2 —C(R 4 )(R 5 )—CH 2 —CH 2 —;

wherein R 4 and R 5 taken together with the carbon atom to which they are attached are selected from the group consisting of:

(i) C═O;

(ii) C(OR 1 ) 2 , wherein R 1 is as previously defined;

(iii) C(SR 1 ) 2 , wherein R 1 is as previously defined;

(iv) C[—O(CH 2 ) m ] 2 , wherein m is 2 or 3;

(v) C[—S(CH 2 ) m ] 2 , wherein m is as previously defined,

(vi) C═CHR 3 , wherein R 3 is as previously defined;

(vii) C═N—O—R 3 , wherein R 3 is as previously defined;

(viii) C═NNHR 3 , wherein R 3 is as previously defined;

(ix) C═NNHC(O)R 3 , wherein R 3 is as previously defined;

(x) C═NNHC(O)NR 11 R 3 , wherein R 11 and R 3 are as previously defined;

(xi) C═NNHS(O) 2 R 9 , wherein R 9 is as previously defined;

(xii) C═NNHR 13 , wherein R 13 is as previously defined; and

(xiii) C═NR 9 , wherein R 9 is as previously defined;

X and Y are:

(a) independently selected from the group consisting of:

(i) hydrogen;

(ii) deuterium;

(iii)—OH;

(iv)—OR P , wherein R P is as previously defined; and

(v) —NR 14 R 15 , wherein R 14 and R 15 are each independently selected from the group consisting of:

a. hydrogen;

b. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and

c. R 14 and R 15 , taken together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring optionally substituted with one or more hetero atoms selected from the group consisting of O, S and N; or

(b) taken together with the carbon atom to which they are attached are selected from the group consisting of:

(i) C═O;

(ii) C═NR 3 , wherein R 3 is as previously defined;

(iii) C═NC(O)R 3 , wherein R 3 is as previously defined;

(iv) C═N—OR 6 , wherein R 6 is selected from the group consisting of:

a. hydrogen;

b. —CH 2 O(CH 2 ) 2 OCH 3 ;

c. —CH 2 O(CH 2 O) n CH 3 , wherein n is as previously defined;

d. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

e. C 3 -C 12 cycloalkyl;

f. C(O)—C 1 -C 12 alkyl;

g. C(O)—C 3 -C 12 cycloalkyl;

h. C(O)—R 2 , wherein R 2 is as previously defined; and

i. —Si(R a )(R b )(R c ), wherein R a , R b and R c are each independently selected from the group consisting of C 1 -C 12 alkyl, aryl and substituted aryl;

(v) C═N—O—C(R 16 )(R 17 )—O—R 18 , wherein R 16 and R 17 taken together with the carbon atom to which they are attached form a C 3 to C 12 cycloalkyl group or each independently is selected from the group consisting of: hydrogen, and C 1 -C 12 alkyl; and R 18 is selected from the group consisting of:

a. hydrogen;

b. —CH 2 O(CH 2 ) 2 OCH 3 ;

c. —CH 2 O(CH 2 O) n CH 3 , wherein n is as previously defined;

d. C 1 -C 12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;

e. C 3 -C 12 cycloalkyl; and

f. —Si(R a )(R b )(R c ), wherein R a , R b and R c are as previously defined;

L is selected from the group consisting of:

(a) —CH(OH)CH 3 ;

(b) C 1 -C 6 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

(c) C 2 -C 6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

(d) C 2 -C 6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

Z is selected from the group consisting of:

(a) hydrogen;

(b) methyl; and

(c) halogen; and

R x is hydrogen or R P , wherein R P is as previously defined.

2. A compound according to claim 1 , wherein: X and Y taken together with the carbon atom to which they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 ; L is CH 2 CH 3 ; Z is hydrogen and R x is hydrogen, where R 3 , R 6 , R 16 , R 17 and R 18 are as defined in claim 1 .

3. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, X, Y, Z and R x are as defined in claim 1 .

4. A compound according to claim 3 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

5. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, X, Y, Z and R x are as defined in claim 1 .

6. A compound according to claim 5 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

7. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, X, Y, Z and R x are as defined in claim 1 .

8. A compound according to claim 7 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

9. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein E, G, X, Y, Z and R x are as defined in claim 1 .

10. A compound according to claim 9 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

11. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Q, X, Y, Z and R x are as defined in claim 1 .

12. A compound according to claim 11 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═N—C(O)—R 3 , C═N—O—R 6 and C═N—R 3 .

13. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X, Y, Z, R x , R 4 and R 5 are as previously defined.

14. A compound according to claim 13 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

15. A compound according to claim 1 which is represented by the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X, Y, Z, R x , R 4 and R 5 are as defined in claim 1 .

16. A compound according to claim 15 or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein X and Y taken together with the carbon atom they are attached to are selected from the group consisting of: C═O, C═NR 3 , C═N—O—R 6 , C═N—C(O)R 3 and C═N—O—C(R 16 )(R 17 )—O—R 18 .

17. A compound according to claim 1 which is selected from the group consisting of:

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═NH; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═N—OCH 2 OCH 3 ; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═N—OH; L═CH 2 CH 3 ; Z═H and R x ═C(O)C 6 H 5 ;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═N—O—CH 2 —OCH 3 ; L═CH 2 CH 3 ; Z═H and R x ═C(O)C 6 H 5 ;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═O; L═CH 2 CH 3 ; Z═H and R x ═C(O)CH 3 ;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═O; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (I): W═—CH 2 —CH(3-quinolyl)—CH═CH—; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (III a): A═3-quinolyl; B═H; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; Z═H and R x ═H;

Compound of Formula (V): Q═—C(C 6 H 5 )═N—O—; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; Z═H and R x ═H;

Compound of Formula (V): Q═—O—C(O)—O—; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; Z═H and R x ═H;

Compound of Formula (I): W═—CH 2 CH═CHCH 2 —; X and Y taken together with the carbon atom they are attached are C═N—C(O)CH 2 OCH 3 ; L═CH 2 CH 3 ; Z═H and R x ═H;

Compound of Formula (V): Q═—O—; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; Z═H and R x ═H; and

Compound of Formula (I): W═—CH 2 —C(CH═CH—C 6 H 5 )═CH—CH 2 —; X and Y taken together with the carbon atom they are attached are C═NC(O)CH 3 ; L═CH 2 CH 3 ; Z═H and R x ═H.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.

19. A method for controlling a bacterial infection in an animal comprising administering to an animal a therapeutically effective amount of a pharmaceutical composition according to claim 18 .