Tricyclic gyrase inhibitors

1. A compound having the structure of Formula I

or a pharmaceutically suitable salt, or an ester thereof,

wherein

L is O or S;

wherein when L is O, R 8 is H or an interacting substituent, and when L is S, R 8 is an interacting substituent,

wherein the interacting substituent is selected from the group consisting of Cl, F, Br, OH, NH 2 , 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH 3 , OCH 2 CH 3 , cyclopropyl, CH 2 cyclopropyl, CH 2 Cl, CHCl 2 , CCl 3 , CH 2 CH 2 Cl, CH 2 Br, CHBr 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , NHNH 2 , NHOH, NHNHCH 3 , NHOCH 3 , NHCD 3 , SCH 3 , and NHCOH;

X, Y and Z are CR X , CR Y , and CR Z , respectively,

wherein R X is H, CH 3 , Cl, Br, or F;

wherein R Y is H, CH 3 , CHF 2 , CF 3 , CN, CH 2 CH 3 , Cl, Br, or F;

wherein R Z is H, CH 3 , Cl, Br, or F;

R 2 is a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein 2 adjacent noninterfering substituents on R 2 may form one or more fused rings with the 6-membered aryl or heteroaryl ring;

wherein the noninterfering substituents for R 2 are selected from the group consisting of OH, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, SO 2 NH 2 , SO 2 CH 3 , SOCH 3 , NHOH, NHOCH 3 , NO 2 and an optionally substituted C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms, wherein the C1-15 hydrocarbyl residue is optionally substituted with OH, CN, ═O, NH 2 , NHOH, ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 ;

wherein the 6-membered aryl or heteroaryl ring of R 2 has a CH at the positions immediately adjacent the position where R 2 attaches to L;

R 4 is:

H;

an optionally substituted OR a ;

an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N; or

an optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms;

wherein the optional substituent is 0-3 noninterfering substituents;

wherein R a is a 5-6 membered aryl or heteroaryl containing 0-3 O, S, or N heteroatoms optionally substituted with 0-3 noninterfering substituents;

wherein the noninterfering substituents for R 4 are selected from the group consisting of OH, NO, CO 2 H, CN, NH 2 , Br, Cl, F, SO 3 H, NO 2 , and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms, wherein the C1-15 hydrocarbyl residue is optionally substituted with OH, CN, ═O, NH 2 , ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 ;

wherein the R 4 substituent does not project greater than about 3 Å below the plane of the A, B and C Rings toward the GyrB/ParE binding pocket floor in the bound conformation; and

wherein R 4 does not sterically interfere with R 2 or Z when the compound is in the bound conformation.

2. The compound of claim 1 wherein L is O.

3. The compound of claim 1 wherein L is S.

4. The compound of claim 1 wherein R 8 is H, CH 3 , CH 2 CH 3 , Cl, OCH 3 , NHCD 3 , NHCH 3 , NHCH 2 CH 3 , or NH 2 .

5. The compound of claim 4 wherein R 8 is NHCH 3 .

6. The compound of claim 1 wherein R 2 is a 6-membered heteroaryl ring substituted with C1-15 hydrocarbyl residue, wherein the C1-15 hydrocarbyl residue contains 0-5 O, S, or N heteroatoms and is optionally substituted with OH, CN, ═O, NH 2 , ═NOH, ═NNH 2 , ═NOCH 3 , Br, F, Cl, SO 3 H, or NO 2 .

7. The compound of claim 1 wherein 2 adjacent noninterfering substituents on R 2 form one or more fused rings, and

wherein the combination of the one or more fused rings with the 6-membered aryl or heteroaryl ring of R 2 contains 5-15 members, and 0-5 O, S, or N heteroatoms, optionally substituted with OH, ═O, CN, NH 2 , Br, F, or Cl.

8. The compound of claim 1 wherein R 2 is selected from the group consisting of an optionally substituted pyrimidinyl, phenyl, and pyridyl; or

wherein the optionally substituted 6-membered aryl or heteroaryl ring of R 2 in combination with the one or more fused rings is present and is selected from the group consisting of optionally substituted indolyl, azaindolyl, pyrimidopyridyl, quinazolinyl, quinoxalinyl, naphthyridinyl, purinyl, imidizopyridinyl, furopyridinyl, isoindolylinyl, benzodioxinyl, dihydrobenzodioxinyl, benzothiazolyl, pyrrolopyridinyl, dihydropyrrolopyridinyl, benzoimidazolyl, imidazopyridinyl, dihydroimidazopyridinyl, tetrahydroisoindolyl, chromenyl, benzthiophene, benztriazolyl, benzfuranyl, benzoxadiazolyl, indazolyl, quinolinyl, isoquinolinyl, indoline, azaindolinyl, and

9. The compound of claim 8 wherein R 2 is pyrimidinyl or pyridinyl optionally substituted with CH(OH)CH 3 , C(OH)(CH 3 ) 2 , OCH 3 , CN, CH 3 , CH 2 CH 3 , O-cyclopropyl, SCH 3 , Br, Cl, F, or NH 2 .

10. The compound of claim 1 wherein R 2 is selected from the group consisting of:

11. The compound of claim 1 wherein R 4 is the optionally substituted OR a and R a is an optionally substituted pyrimidinyl or pyridinyl.

12. The compound of claim 11 wherein R a is unsubstituted pyrimidinyl or pyrimidinyl substituted with CH 3 or NH 2 .

13. The compound of claim 1 wherein R 4 is the optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N, further comprising a primary or secondary amine, wherein the primary or secondary amine is not directly attached to the C Ring;

wherein the primary or secondary amine not directly attached to the C Ring is positioned in the compound in the bound conformation wherein:

the distance between the C or N atom of Y and the primary or secondary amine N is about 7 Å to about 10.5 Å;

the distance between the C atom to which R 8 is attached and the primary or secondary amine N is about 6 Å to about 9 Å;

the distance between the C atom to which R 4 is attached and the primary or secondary amine N is about 3.5 Å to about 6 Å; and

the distance between the C atom to which R 2 is attached and the primary or secondary amine N is about 5 Å to about 7.5 Å.

14. The compound of claim 1

wherein R 4 is an optionally substituted 4-14 membered saturated cycloheteroaliphatic tertiary amine ring system containing 1-3 N atoms, 0-3 O atoms and 0-1 S atoms; and

wherein the optionally substituted 4-14 membered saturated cycloheteroaliphatic ring system is an optionally substituted single ring, a fused ring system, a bridge ring system, or a spiro ring system.

15. The compound of claim 1 wherein R 4 is the optionally substituted tertiary amine attached to the C ring through the tertiary amine N, wherein the optionally substituted tertiary amine contains at least one additional N separated from the tertiary amine N by 2-3 atoms.

16. The compound of claim 1 wherein R 4 is a noncyclic secondary or tertiary amine substituted with 1-2 noninterfering substituents.

17. The compound of claim 1 wherein R 4 is selected from the group consisting of optionally substituted pyrazolyl, phenyl, piperazinyl, pyridinyl, and tetrahydropyridinyl.

18. The compound of claim 1 wherein R 4 is the optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms comprises 0-2 optional substituents selected from the group consisting of CH 3 , NH 2 , F, Cl, and CH 2 NH 2 .

19. The compound of claim 1 wherein R 4 is H or a substituent selected from the group consisting of:

20. The compound of claim 1 wherein

L is O;

R 8 is NHCH 3 ;

X, Y and Z are CR X , CR Y , or CR Z respectively and wherein R X is H or F; R Y is H, F, Cl, or CF 3 ; and R Z is H, CH 3 or F;

R 2 is selected from the group consisting of

and

R 4 is selected from the group consisting of

21. The compound of claim 1 selected from the group consisting of

22. The compound of claim 1 selected from the group consisting of

23. A process of making the compound of claim 1 , wherein R 4 is an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N, comprising:

with HR 4 to make the compound of Formula I;

optionally further comprising, before the treating step, protecting R 8 with a protecting group, or protecting an amine in R 4 which is not the secondary or tertiary amine N, if present, with a protecting group; and

optionally removing of the protecting group after the treating step.

24. The process of claim 23 , wherein before the treating step, the process further comprises:

with R 2 LH under basic conditions,

wherein

G 1 and G 2 are leaving groups independently selected from the group consisting of Cl, Br, F, I, SR, SOR, SO 2 R, OSO 2 R, and OBt,

R is C1-8 alkyl, aryl, or heteroaryl containing 0-5 O, S, or N atoms optionally substituted with C1-4 alkyl, C1-4 alkyloxy, Cl, Br, F, I, or NO 2 ; and

Bt is benzotriazole;

to make the compound having the structure

25. A process of making the compound of claim 1 , wherein R 4 is an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N, comprising:

with R 2 LH under basic conditions, wherein G 2 is a leaving group selected from the group consisting of Cl, Br, F, and I; and

optionally further comprising, before the treating step, protecting R 8 with a protecting group, or protecting an amine in R 4 which is not the secondary or tertiary amine N, if present, with a protecting group; and deprotecting R 8 and R 4 after the treating step.

26. The process of claim 25 , wherein before the treating step, the process further comprises:

with HR 4 to make

wherein G 1 is a leaving group selected from the group consisting of Cl, Br, F, and I.

27. A process of making the compound of claim 1 , wherein R 4 is an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N, comprising:

wherein G 1 is a leaving group derived from SO 2 halide, bis(2-oxo-3-oxazolidinyl)phosphine (BOP), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (pyBOP),

with HR 4 to make the compound of Formula I;

optionally further comprising, before the treating step, protecting R 8 with a protecting group, or protecting an amine in R 4 which is not the secondary or tertiary amine N, if present, with a protecting group; and deprotecting R 8 and R 4 after the treating step.

28. The process of claim 27 , wherein before the treating step, the process further comprises:

with G 1 X 1 to provide

wherein G 1 X 1 is SO 2 halide, bis(2-oxo-3-oxazolidinyl)phosphine (BOP), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (pyBOP).

29. The process of claim 27 , wherein before the treating step, the process further comprises:

reacting

with R 2 X 2 wherein X 2 is Br or I to form

30. The compound of claim 1 ,

wherein

L is O;

R 8 is NHCH 3 ;

X, Y and Z are CR X , CR Y , or CR Z respectively;

R x is H; and

R Y and R z are each H or F.

31. The compound of claim 30 ,

wherein R 2 is pyrimidinyl or pyridinyl optionally substituted with CH(OH)CH 3 , C(OH)(CH 3 ) 2 , OCH 3 , CN, CH 3 , CH 2 CH 3 , O-cyclopropyl, SCH 3 , Br, Cl, F, or NH 2 .

32. The compound of claim 31 ,

wherein R 2 is pyrimidinyl substituted with CH(OH)CH 3 .

33. The compound of claim 24 , wherein R 2 is

34. The compound of claim 30 , wherein R 2 is

35. The compound of claim 32 , wherein R 2 is

36. The compound of claim 24 , wherein R 4 is

37. The compound of claim 30 , wherein R 4 is

38. The compound of claim 35 , wherein R 4 is

39. The compound of claim 3 wherein R 8 is NHCH 3 .

40. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is

41. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is

42. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is

43. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is

44. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is

45. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is selected from the group consisting of

46. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is selected from the group consisting of

47. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is selected from the group consisting of

48. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is selected from the group consisting of

49. The compound or a pharmaceutically suitable salt or an ester thereof of claim 1 , wherein the compound is selected from the group consisting of