Antimicrobial compounds and methods of making and using the same

1. A compound of Formula (I)

or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer wherein:

R 1 is H or F, wherein when R 1 is H, then R 2 is CF 3 , OCF 3 , SCF 3 , SOCF 3 or halo and R 3 is H; and when R 1 is F, then (i) R 2 is Cl or OCF 3 and R 3 is H; or (ii) R 2 is H and R 3 is C 1 -C 6 alkyl; or (iii) R 2 is C 1 -C 6 alkyl optionally substituted with one or more halo and R 3 is halo;

R 4 is H, OH, NH 2 , or C 1 -C 6 alkoxyl, or when X is O or CHR 17 , R 4 and R 5 together with the two atoms to which they are attached and the atom connecting said two atoms form a 5- to 8-membered heterocycloalkyl ring having 1 to 2 heteroatoms; or when X is a bond, R 4 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form a 5- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms;

R 5 is H, CH 2 OH or CH 2 OC 1 -C 6 alkyl, or when X is O or CHR 17 , R 4 and R 5 together with the two atoms to which they are attached and the atom connecting said two atoms form a 5- to 8-membered heterocycloalkyl ring having 1 to 2 heteroatoms;

R 6 is C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, OH, azido, amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkylthio, C 2 -C 3 alkenyl, OCOR a , CH 2 OCOR a , and —OP(O)(OR a ) 2 , in which R a is C 1 -C 6 alkyl, amino, or phenyl, and R a is optionally substituted with COOH, COOC 1 -C 6 alkyl, OCOC 1 -C 6 alkyl, phenyl, or C 7 -C 12 arylalkyl; or R 6 and R 7 together with the two atoms to which they are attached, form a 5- to 12-membered heterocycloalkyl ring having 0 to 1 additional heteroatom optionally substituted with an oxo group; or R 6 and R 17 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form a 5- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms; or when X is a bond, R 4 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form a 5- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms;

R 7 is H, C(═NH)NH 2 , or COR b in which R b is C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxyl or amino; or R 6 and R 7 together with the two atoms to which they are attached, form a 5- to 12-membered heterocycloalkyl ring having 0 to 1 additional heteroatom optionally substituted with an oxo group;

R 11 is Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with one or more halo or hydroxyl, and T 1 is H, halo, OH, COOH, cyano, azido, C 1 -C 3 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 2 -C 6 haloalkenyl, C 1 -C 6 alkylthio, COOC 1 -C 6 alkyl, —NHC(O)CH 2 NH 2 , NHS(O)C 1 -C 3 alkyl, SO 2 C 1 -C 6 alkyl, or R c , in which R c is amino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, —O-heteroaryl, —NH-heteroaryl, —S-heteroaryl, or C(O)NR d R e , each of R d and R e independently being H or C 1 -C 6 alkyl, or R d and R e together with the nitrogen atom to which they are attached forming a 5- to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms; and R c is optionally substituted with -Q 2 -T 2 , in which Q 2 is a bond or C 1 -C 3 alkyl and T 2 is H, halo, C 1 -C 3 alkyl, amino, 5- or 6-membered heteroaryl or C 6 -C 10 aryl wherein the aryl and heteroaryl are optionally substituted with C 1 -C 6 alkoxyl or C 1 -C 4 aminoalkyl;

R 8 and R 10 , together with the two carbon atoms to which they are attached and the Z atom connecting said two carbon atoms, form a 5- to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms optionally substituted with one more substituents independently selected from C 1 -C 6 alkyl or —C(═N)NH 2 ;

R 8′ is H

R 12 is H or C 1 -C 6 alkyl, or R 12 and R 11 together with the carbon atom to which they are attached form a 4- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms optionally substituted with C(═NH)NH 2

each of R 9 and R 13 independently is H, C 1 -C 3 alkyl, C 2 -C 4 alkenyl or —C(O)H, or R 9 and R 13 , when Z is NR 9 , together with the two nitrogen atoms to which they are attached and the carbon atoms connecting said two nitrogen atoms, form a 7- to 12-membered saturated heterocycloalkyl ring having 0 to 1 additional heteroatom, or R 9 and A, when Z is NR 9 and A is NR 13 R 14 , together with the two atoms to which they are attached and the atoms connecting said atoms form a 5- to 8-membered heterocycloalkyl ring having 2 to 3 heteroatoms optionally substituted with an oxo or an imino group;

R 11 and R 13 , when A is NR 13 R 14 , together with the atoms to which they are attached form a 5- to 8-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms optionally substituted with oxo;

R 14 is H, C(O)C 1 -C 3 alkyl, C(O)NH 2 , C(CH═NO 2 )NHCH 3 , C(═NH)H, C(═NH)C 1 -C 3 alkyl, 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, 5 or 6-membered heterocycloalkyl having 1 to 3 heteroatoms, C 1 -C 6 alkyl optionally substituted with one or more substituents independently selected from 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, C 3 -C 8 cycloalkyl, and 5 or 6-membered heterocycloalkyl having 1 to 3 heteroatoms, or C(═NR 16 )NH 2 , in which R 16 is H, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 3 -C 8 cycloalkyl, or 4- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms, or R 16 and R 11 together with the two atoms to which they are attached and the atoms connecting said two carbon atoms, form a 5- to 12-membered heterocycloalkyl ring having 0 to 1 additional heteroatom;

R 14 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl having 1 to 3 additional heteroatoms optionally substituted with oxo; or R 14 and R 13 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl having 1 to 3 additional heteroatoms optionally substituted with oxo;

R 15 is H or halo;

A is C(O)NH 2 , NR 13 R 14 , C(O)NHC 1 -C 3 alkyl, C(O)OH, OH, CN, C 3 -C 8 cycloalkyl, —OP(O)(OR b ) 2 , in which R b is C 1 -C 6 alkyl, amino, or phenyl, 5 or 6-membered heterocycloalkyl having 1 to 3 heteroatoms optionally substituted with oxo, or 5- or 6-membered heteroaryl having 1 to 4 heteroatoms optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkylenyl-aryl, NO 2 , or amino, wherein the alkyl, alkylenyl, and aryl are optionally substituted with one or more substituents independently selected from C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 1 -C 3 alkoxy, or halo; or R 9 and A, when Z is NR 9 and A is NR 13 R 14 , together with the two carbon atoms to which they are attached and the atoms connecting said carbon atoms form a 5- to 8-membered heterocycloalkyl ring having 2 to 3 heteroatoms optionally substituted with an oxo or an imino group;

W is CH or C; or W and Y, when W is C, together with the atoms to which they are attached, form a 5- to 12-membered heterocycloalkyl ring having 0 to 1 additional heteroatom;

X is a bond, O, or CHR 17 , in which R 17 is H, or R 17 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form a 5- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms; or when X is a bond, R 4 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form a 5- to 12-membered saturated heterocycloalkyl ring having 1 to 2 heteroatoms;

Y is NH; or Y and W together with the atoms to which they are attached, form a 5- to 12-membered heterocycloalkyl ring having 0 to 1 additional heteroatom;

Z is a bond, O, NR 9 , NH, CH, or CH 2 ; or R 11 and Z, when Z is NH or CH, together with the atoms to which they are attached and the atoms connecting said two atoms form a 5- to 8-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms;

each m and o is independently 0 or 1;

and p is 0, 1, or 2; and

provided that for a compound of Formula (I)

(c) when R 14 is C(═NR 16 )NH 2 , X is CH 2 , and R 6 is CH 2 OCH 3 , then at least one of R 4 , R 5 , R 7 , R 8 , R 10 , R 11 , R 12 , or R 15 is not H.

2. The compound of claim 1 having Formula (Ia):

or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, provided that

(c) when X is CH 2 , R 6 is CH 2 OCH 3 , then at least one of R 4 , R 5 , R 7 , R 8 , R 10 , R 11 , R 12 , or R 15 is not H.

3. The compound of claim 1 having Formula (Ib), (Ic), or (Id):

or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer.

4. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein each of R 1 and R 3 is H and R 2 is CF 3 , OCF 3 , SCF 3 , SOCF 3 or Cl.

5. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 1 is F, R 3 is H and R 2 is OCF 3 or Cl.

6. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein each of R 1 and R 3 is F, and R 2 is CF 3 or ethyl.

7. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 1 is F, R 2 is H, and R 3 is methyl.

8. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 6 is methyl, ethyl, CH 2 OH, CH 2 CH 2 OH, CH 2 F, CH 2 OCH 3 , CH 2 SCH 3 , CH(OH)CH 2 OH, CH 2 NH 2 , CH 2 OCOCH 3 , CH 2 OCOC 6 H 5 , CH 2 OCONHCH 2 C 6 H 5 , CH 2 OCOCH 2 CH 2 COOH, CH 2 OCOC 6 H 4 OCOCH 3 , CH 2 OCOCH 2 C 6 H 4 , CH 2 OP(O)(OH) 2 , or CH 2 OP(O)(OPh) 2 .

9. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 7 is H, C(═NH)NH 2 , COOCH 2 CH 3 , COCH 2 NH 2 , or COCH 3 .

10. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 6 and R 7 together with the atoms to which they are attached, form

11. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein X is a bond, and R 4 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form

with carbon 1 connected to phenyl and carbon 2 connected to NHR 7 .

12. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein each of R 4 and R 5 is H, X is CHR 17 , in which R 17 and R 6 together with the two carbon atoms to which they are attached and the carbon atom connecting said two carbon atoms, form

with carbon 1 connected to phenyl and carbon 2 connected to NHR 7 .

13. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein X is O.

14. The compound of claim 13 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 5 is H and R 6 is methyl, ethyl, CH 2 OH, CH 2 CH 2 OH, CH 2 F, CH 2 OCH 3 , CH 2 SCH 3 , CH(OH)CH 2 OH, CH 2 NH 2 , CH 2 OCOCH 3 , CH 2 OCOC 6 H 5 , CH 2 OCONHCH 2 C 6 H 5 , CH 2 OCOCH 2 CH 2 COOH, CH 2 OCOC 6 H 4 OCOCH 3 , CH 2 OCOCH 2 C 6 H 4 , CH 2 OP(O)(OH) 2 , or CH 2 OP(O)(OPh) 2 .

15. The compound of claim 13 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein R 5 is H and R 6 is CH 2 OH.

16. The compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer, wherein each of R 11 and R 12 is H or CH 3 , or R 11 and R 12 together with the carbon atom to which they are attached form

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, or ester of said compound or tautomer.