Chromane monobactam compounds for the treatment of bacterial infections

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

T, U and V are each CH;

W is O;

Q is CR 3 ;

X is CH 2 ;

Y is O or CH 2 ,

Z is O or CH n ,

A is

1) —C(═NH)—NH,

2) AryC, or

3) HetC,

wherein A is unsubstituted or substituted with one to four R i ;

AryC is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to four R i , wherein AryC is optionally fused to a 4- to 7-membered heterocycloalkyl ring containing one to two heteroatoms selected from O, S and —NR g ;

HetC is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to four R i ;

L is

1) absent,

2) R 4 ,

3) —NHR 4 ,

4) —N(R 4 ) 2 ,

5) —OR 4 ,

6) —(CH 2 ) n R 4 ,

7) —C(O)R 4 ,

8) —C(NH)R 4 , or

9) —S(O) m R 4 ,

wherein L is unsubstituted or substituted with 1-4 substituents selected from R e ;

M is

1) R 5 ,

2) —NHR 5 ,

3) —N(R 5 ) 2 ,

4) —OR 5 ,

5) —(CH 2 ) u R 5 ,

6) —C(O)R 5 ,

7) —C(NH)R 5 , or

8) —S(O) v R 5 ,

wherein M is unsubstituted or substituted with 1-4 substituents selected from R 6 ;

R 1 and R 2 are independently selected from:

1) hydrogen,

2) —C 1 -C 8 alkyl, and

3) —C(O)OR e ,

wherein —C 1 -C 8 alkyl is unsubstituted or substituted with one to three R a ,

provided that if R 1 is —C(O)OR e , then R 2 is not —C(O)OR e ,

R 3 is hydrogen;

each occurrence of R 4 is independently:

1) hydrogen,

2) —C 1 -C 10 alkyl,

3) —C 2 -C 8 alkenyl,

4) —(CH 2 ) n OR e ,

5) —S(O) m R e ,

6) —S(O) m NR c R d ,

7) —(CH 2 ) n NR c R d ,

8) —OC(O)R e ,

9) —C(O)OR e ,

10) —CN,

11) —C(O)NR c R d ,

12) —NR c (O)R e ,

13) —NR c C(O)OR e ,

14) —NR c (O)NR c R d ,

15) —NR c S(O) m R e ,

16) ═NR 11 ,

17) —C 3 -C 7 cycloalkyl,

18) —O—C 3 -C 6 cycloalkyl,

19) —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl,

20) —O—C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl,

21) HetB,

22) —O-HetB,

23) —C 1 -C 10 alkylene-HetB,

24) —O—C 1 -C 10 alkylene-HetB,

25) AryB,

26) —O-AryB,

27) —C 1 -C 10 alkylene-AryB, or

28) —O—C 1 -C 10 alkylene-AryB,

wherein R 4 is unsubstituted or substituted with one to four R 6 ;

AryB is a 5- to 6-membered monocyclic aromatic ring with 0, 1, 2, or 3 ring atoms independently selected from N, O and S, unsubstituted or substituted with one to four W;

HetB is a 4- to 7-membered saturated or monounsaturated monocyclic ring with 1, 2, or 3 heteroatom ring atoms independently selected from N, N as a quaternary salt, O and S, unsubstituted or substituted with one to three R a ;

R 5 is

1) hydrogen,

2) C 1 -C 10 alkyl,

3) —C 2 -C 8 alkenyl,

4) —(CH 2 ) u OR e ,

5) —S(O) v R e ,

6) —S(O) v NR c R d ,

7) —(CH 2 ) u NR c R d ,

8) —OC(O)R e ,

9) —C(O)OR e ,

10) —CN,

11) —C(O)NR e R d ,

12) —NR c C(O)R e ,

13) —NR c C(O)OR e ,

14) —NR c C(O)NR c R d ,

15) —NR c S(O) v R e ,

16) ═NR 11 ,

17) —C 3 -C 7 cycloalkyl,

18) —O—C 3 -C 6 cycloalkyl,

19) —C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl,

20) —O—C 1 -C 10 alkylene-C 3 -C 6 cycloalkyl,

21) HetB,

22) —O-HetB,

23) —C 1 -C 10 alkylene-HetB,

24) —O—C 1 -C 10 alkylene-HetB,

25) AryB,

26) —O-AryB,

27) —C 1 -C 10 alkylene-AryB, or

28) —O—C 1 -C 10 alkylene-AryB,

wherein R 5 is unsubstituted or substituted with one to four R 6 ;

each occurrence of R 6 is independently:

1) halogen,

2) —C 1 -C 6 alkyl,

3) —OR e ,

4) —S(O) v R e ,

5) —S(O) v NR c R d ,

6) —C(O)R e ,

7) —OC(O)R e ,

8) —C(O)OR e ,

9) —CN,

10) —C(O)NR c R d ,

11) —C(NH)NR c R d ,

12) —(CH 2 ) u NR c R d ,

13) —(CH 2 ) u NR c R d ,

14) —N(R c )(C(O)R e ),

15) —N(R c )(C(O)OR e ),

16) —N(R c )(C(O)NR c R d ),

17) —N(R c )(S(O) v R e ), or

18) HetB;

R 7 is

1) hydrogen,

2) C 1 -C 3 alkyl, or

3) C 3 -C 7 cycloalkyl,

wherein C 1 -C 3 alkyl and C 3 -C 7 cycloalkyl are unsubstituted or substituted with one to three R a ;

R 8 is

1) hydrogen,

2) C 1 -C 4 alkyl, or

3) C 3 -C 7 cycloalkyl;

R 9 is

1) hydrogen,

2) C 1 -C 4 alkyl, or

3) C 3 -C 7 cycloalkyl;

R 10 is

1) hydrogen,

2) C 1 -C 4 alkyl, or

3) C 3 -C 7 cycloalkyl;

R 11 is

1) hydrogen,

2) C 1 -C 4 alkyl, or

3) C 3 -C 7 cycloalkyl;

R 12 and R 13 are independently C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is unsubstituted or substituted with one to seven fluorines,

or alternatively R 12 and R 13 together with the carbon to which they are attached form a monocyclic C 4 -C 6 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;

each occurrence of R a is independently:

1) hydrogen,

2) halogen,

3) C 1 -C 3 alkyl,

4) —NR c R d , or

5) —OR e ;

each occurrence of R b is independently:

1) hydrogen,

2) —C 1 -C 6 alkyl,

3) —OC 1 -C 6 alkyl,

4) OH,

5) N(R 9 ) 2 , or

6) halogen,

wherein —C 1 -C 3 alkyl is unsubstituted or substituted with one to three R a ;

R c and R d are independently selected from:

1) hydrogen,

2) —C1-C10 alkyl, and

3) —C2-C10 alkenyl,

wherein each Rc and Rd is unsubstituted or substituted with one to three Rf;

each occurrence of R e is independently hydrogen, or —C 1 -C 10 alkyl, wherein each R e is unsubstituted or substituted with one to three R h ;

each occurrence of R f is independently:

1) halogen,

2) —C 1 -C 10 alkyl,

3) —OH,

4) —OC 1 -C 4 alkyl,

5) —S(O) m C 1 -C 4 alkyl,

6) —CN,

7) —CF 3 ,

8) —OCHF 2 ,

9) —OCF 3 , or

10) NH 2 ,

wherein —C 1 -C 10 alkyl is unsubstituted or substituted with one to three substituents independently

selected from —OH, halogen, cyano, and —S(O) 2 CH 3 ;

each occurrence of R g is independently:

1) hydrogen,

2) —C(O)R e , or

3) —C 1 -C 10 alkyl,

wherein —C 1 -C 10 alkyl is unsubstituted or substituted with one to five fluorines;

each occurrence of R h is independently:

1) halogen,

2) —C 1 -C 10 alkyl,

3) —OH,

4) —OC 1 -C 4 alkyl,

5) —S(O) m C 1 -C 4 alkyl,

6) —CN,

7) —CF 3 ,

8) —OCHF 2 , or

9) —OCF 3 ,

wherein —C 1 -C 10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, or —S(O) 2 CH 3 ;

each occurrence of R i is independently:

1) —C 1 -C 8 alkyl,

2) —C 2 -C 8 alkenyl,

3) —C 2 -C 8 alkynyl,

4) halogen,

5) —OR e ,

6) —S(O) m R e ,

7) —S(O) m NR c R d ,

8) —C(O)R e ,

9) —OC(O)R e ,

10) —C(O)OR e ,

11) —CN,

12) —C(O)NR c R d ,

13) —NR c R d ,

14) —(CH 2 ) n NR c R d ,

15) —NR c C(O)R e ,

16) —NR c C(O)OR e ,

17) —NR c C(O)NR c R d ,

18) —NR c S(O) m R e ,

19) ═NH,

20) —CF 3 ,

21) —OCF 3 , or

22) —OCHF 2 ;

each occurrence of R j is independently:

1) hydrogen,

2) C 1 -C 3 alkyl,

3) OR 10 ,

4) ═NR 10 ,

5) N(R 10 ) 2 , or

6) halogen,

wherein C 1 -C 3 alkyl unsubstituted or substituted with one to three R b ;

each n is independently 0, 1, 2, 3, 4, 5 or 6;

each m is independently 0, 1 or 2;

each p is independently 1 or 2;

each q is independently 0, 1, 2, 3, 4, 5 or 6;

each s is independently 0, 1, 2 or 3;

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

each u is independently 0, 1, 2, 3, 4, 5 or 6; and

each v is independently 0, 1, or 2.

2. The compound of claim 1 wherein

Y is CH 2 ; and

Z is O;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein

R 1 and R 2 are independently selected from

1) —C 1 -C 8 alkyl, and

2) —C(O)OR e ,

provided if R 1 is —C(O)OR e , then R 2 is —C 1 -C 8 alkyl, and if R 2 is —C(O)OR e , then R 1 is —C 1 -C 8 alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein A is

1) AryC, or

2) HetC,

wherein A is unsubstituted or substituted with one to four R i ;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein

A is —C(═NH)—NH, wherein A is unsubstituted or substituted with one to four R i ;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein

A is AryC, wherein A is unsubstituted or substituted with one to four R i ;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein

L is

1) absent, or

2) R 4 ,

wherein L is unsubstituted or substituted with 1-4 substituents selected from R e ; and

each occurrence of R 4 is independently:

1) hydrogen,

2) —C 1 -C 10 alkyl,

3) —(CH 2 ) n OR e ,

4) —(CH 2 ) n NR c R d , or

5) —C 1 -C 10 alkylene-HetB,

wherein R 4 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5 wherein

each occurrence of R 4 is independently:

1) —C 1 -C 10 alkyl,

2) —(CH 2 ) n NR c R d , or

3) —C 1 -C 10 alkylene-HetB,

wherein R 4 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 wherein

M is

1) R 5 , or

2) —NHR 5 ,

wherein M is unsubstituted or substituted with 1-4 substituents selected from R 6 ; and

R 5 is

1) hydrogen,

2) C 1 -C 6 alkyl,

3) —C 1 -C 4 alkyl-(NR c R d ) 2 ,

4) —(CH 2 ) u NR c R d , or

5) —C 1 -C 10 alkylene-HetB,

wherein R 5 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 7 wherein

R 5 is

1) —C 1 -C 4 alkyl-(NR c R d ) 2 , or

2) —(CH 2 ) u NR c R d ,

wherein R 5 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein

T, U and V are CH;

W is O;

Q is CR 3 ;

X is CH 2 ;

Y is O or CH 2 ;

Z is O or CH 2 ;

R 1 and R 2 are independently selected from:

1) hydrogen,

2) —C 1 -C 8 alkyl, and

3) —C(O)OR e ,

wherein —C 1 -C 8 alkyl is unsubstituted or substituted with one to three R a , provided that if R 1 is —C(O)OR e , then R 2 is independently selected from hydrogen and —C 1 -C 8 alkyl;

R 3 is hydrogen;

R 12 and R 13 are independently C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is unsubstituted or substituted with one to seven fluorines,

or alternatively R 12 and R 13 together with the carbon to which they are attached form a monocyclic C 4 -C 6 cycloalkyl unsubstituted or substituted with one to three substituents independently selected from —F, —OH and —OC 1 -C 3 alkyl;

A is

1) —C(═NH)—NH,

2) AryC, or

3) HetC,

wherein A is unsubstituted or substituted with one to four R i ;

L is

1) absent, or

2) R 4 ,

wherein L is unsubstituted or substituted with 1-4 substituents selected from R e ;

each occurrence of R 4 is independently:

1) hydrogen,

2) —C 1 -C 10 alkyl,

3) —(CH 2 ) n OR e ,

4) —(CH 2 ) n NR c R d , or

5) —C 1 -C 10 alkylene-HetB,

wherein R 4 is unsubstituted or substituted with one to four R 6 ;

M is

1) R 5 , or

2) —NHR 5 ,

wherein M is unsubstituted or substituted with 1-4 substituents selected from R 6 ; and

R 5 is

1) hydrogen,

2) —C 1 -C 6 alkyl,

3) —C 1 -C 4 alkyl-(NR c R d ) 2 ,

4) —(CH 2 ) u NR c R d , or

5) —C 1 -C 10 alkylene-HetB,

wherein R 5 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 wherein

T, U and V are CH;

W is O;

Q is CR 3 ;

R 3 is hydrogen;

X is CH 2 ;

Y is CH 2 ;

Z is O;

R 1 and R 2 are independently selected from

1) —C 1 -C 6 alkyl, and

2) —C(O)OR e ,

wherein —C 1 -C 6 alkyl is unsubstituted or substituted with one to three R a , provided that if R 1 is —C(O)OR e , then R 2 is —C 1 -C 6 alkyl;

R 12 and R 13 are independently C 1 -C 3 alkyl, wherein C 1 -C 3 alkyl is unsubstituted or substituted with one to seven fluorines;

A is

1) AryC, or

2) HetC,

wherein A is unsubstituted or substituted with one to four R i ;

L is

1) absent, or

2) R 4 ,

wherein L is unsubstituted or substituted with 1-4 substituents selected from R e ;

each occurrence of R 4 is independently:

1) —C 1 -C 10 alkyl,

2) —(CH 2 ) n NR c R d , or

3) —C 1 -C 10 alkylene-HetB,

wherein R 4 is unsubstituted or substituted with one to four R 6 ;

M is

1) R 5 , or

2) —NHR 5 ,

wherein M is unsubstituted or substituted with 1-4 substituents selected from R 6 ;

R 5 is

1) —C 1 -C 4 alkyl-(NR c R d ) 2 , or

2) —(CH 2 ) u NR c R d ,

wherein R 5 is unsubstituted or substituted with one to four R 6 ;

or a pharmaceutically acceptable salt thereof.

13. A compound selected from:

or a pharmaceutically acceptable salt thereof.

14. A compound which is:

or a pharmaceutically acceptable salt thereof.

15. A compound which is:

or a pharmaceutically acceptable salt thereof.

16. A compound which is:

or a pharmaceutically acceptable salt thereof.

17. A compound which is:

or a pharmaceutically acceptable salt thereof.

18. A compound which is:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

20. A pharmaceutical composition according to claim 19 , which further comprises a therapeutically effective amount of a beta-lactamase inhibitor compound.

21. A pharmaceutical composition according to claim 20 , wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam, tazobactam, clavulanic acid, sulbactam, and avibactam.