Antimicrobial compounds and methods of making and using the same

1. A compound having the formula:

wherein -G-H-J is

wherein each H and J is independently selected, or -G-H-J is

wherein R x is selected from CH 2 , NH, N(C 1-8 alkyl), S, and O; R y and R z are C or CH each independently substituted with one or more F, CH 3 , CF 3 , OH, and OCH 3 ; or R x , R y , and R z are each independently selected from CH 2 and CR a R b wherein R a and R b are taken together to form a C 1-5 carbocycle;

J′ is selected from NH 2 , NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , NHC(═O)CH 3 , NHC(═O)NH 2 , NHC(═NH)NH 2 , and NHC(═NH)H;

wherein n is 0, 1, or 2;

alternatively, -G-H-J is

wherein R x is selected from CH 2 , NH, N(C 1-8 alkyl), S, and O; R z is a C or CH, substituted with one or more CH 3 or R z is CR a R b wherein R a and R b are taken together to form a C 1-5 carbocycle, wherein m is 1, 2, or 3;

J′ is selected from NH 2 , NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , NHC(═O)CH 3 , NHC(═O)NH 2 , NHC(═NH)NH 2 , and NHC(═NH)H;

C-B-A-, -D-E-F, and -G-H-J are chemical moieties, wherein

D and G are independently selected from the group consisting of:

(a) a single bond, (b) —(C 1-8 alkyl)-, (c) —(C 2-8 alkenyl)-, (d) —(C 2-8 alkynyl)-, wherein

i) 0-4 carbon atoms in any of (b)-(d) immediately above optionally is replaced by a moiety selected from the group consisting of —O—, —S(O) p —, —NR 6 —, —(C═O)—, —S(O) p NR 6 —, —NR 6 S(O) p —, and —NR 6 S(O) p NR 6 —,

ii) any of (b)-(d) immediately above optionally is substituted with one or more R 5 groups, and

iii) any of (b)-(d) immediately above optionally is substituted with —(C 1-8 alkyl) -R 5 groups;

(e) —O—, (f) —NR 6 —, (g) —S(O) p —, (h) —C(O)—, (i) —C(O)O—, (j) —OC(O)—, k) —OC(O)O—, (l) —C(O)NR 6 —, (m) —NR 6 CO—, (n) —NR 6 C(O)NR 6 —, (o) —C(═NR 6 )—, (p) —C(═NR 6 )O—, (q) —OC(═NR 6 )—, (r) —C(═NR 6 )NR 6 —, (s) —NR 6 C(═NR 6 )—, (t) —C(═S)—, (u) —C(═S)NR 6 —, (v) —NR 6 C(═S)—, (w) —C(O)S—, (x) —SC(O)—, (y) —OC(═S)—, (z) —C(═S)O—, (aa) —NR 6 (CNR 6 )NR 6 —, (bb) —CR 6 R 6 C(O)—, (cc) —C(O)NR 6 (CR 6 R 6 ) t —, (dd) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (ee) a 3-14 member saturated, unsaturated, or aromatic carbocycle, and (ff) —(CR 6 R 6 ) t —,

wherein (dd) or (ee) is optionally substituted with one or more R 5 groups;

E, and H are independently selected from the group consisting of:

(a) a single bond,

(b) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,

(c) a 3-14 member saturated, unsaturated, or aromatic carbocycle,

wherein (b) or (c) is optionally substituted with one or more R 5 groups;

(d) —(C 1-8 alkyl)-, (e) —(C 2-8 alkenyl)-, (f) —(C 2-8 alkynyl)-, wherein

i) 0-4 carbon atoms in any of (d)-(f) immediately above optionally is replaced by a moiety selected from the group consisting of —O—, —S(O) p —, —NR 6 —, —(C═O)—, —C(═NR 6 )—, —S(O) p NR 6 —, —NR 6 S(O) p —, and —NR 6 S(O) p NR 6 —,

ii) any of (d)-(f) immediately above optionally is substituted with one or more R 5 groups, and

iii) any of (d)-(f) immediately above optionally is substituted with —(C 1-8 alkyl) -R 5 groups;

and (g) —(CR 6 R 6 ) t —,

F, and J are independently selected from the group consisting of:

(a) hydrogen, (c) F, (d) Cl, (e) Br, (f) I, (g) —CF 3 , (h) —CN, (i) —N 3 (j) —NO 2 , (k) —NR 6 (CR 6 R 6 ) t R 8 , (l) —OR 8 , (m) —S(O) p (CR 6 R 6 ) t R 8 , (n) —C(O)(CR 6 R 6 ) t R 8 , (o) —OC(O)(CR 6 R 6 ) t R 8 , (p) —SC(O)(CR 6 R 6 ) t R 8 , (q) —C(O)O(CR 6 R 6 ) t R 8 , (r) —NR 6 C(O)(CR 6 R 6 ) t R 8 , (s) —C(O)NR 6 (CR 6 R 6 ) t R 8 , (t) —C(═NR 6 )(CR 6 R 6 ) t R 8 , (u) —C(═NNR 6 R 6 )(CR 6 R 6 ) t R 8 , (v) —C(═NNR 6 C(O )R 6 )(CR 6 R 6 ) t R 8 , (w) —C(═NOR 8 )(CR 6 R 6 ) t R 8 , (x) —NR 6 C(O)O(CR 6 R 6 ) t R 8 , (y) —OC(O)NR 6 (CR 6 R 6 ) t R 8 , (z) —NR 6 C(O)NR 6 (CR 6 R 6 ) t R 8 , (aa) —NR 6 S(O) p (CR 6 R 6 ) t R 8 , (bb) —S(O) p NR 6 (CR 6 R 6 ) t R 8 , (cc) —NR 6 S(O) p NR 6 (CR 6 R 6 ) t R 8 , (dd) —NR 6 R 8 , (ee) —NR 6 (CR 6 R 6 )R 8 , (ff) —OH, (gg) —NR 8 R 8 , (hh) —OCH 3 , (ii) —S(O) p R 8 , (jj) —NC(O)R 8 , (kk) —NR 6 C(NR 6 )NR 6 R 8 , (ll) a C 1-8 alkyl group, (mm) a C 2-8 alkenyl group, (nn) a C 2-8 alkynyl group, (oo) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (pp) a 3-14 member saturated, unsaturated, or aromatic carbocycle, (qq) —(CR 6 R 6 ) t NR 6 (CR 6 R 6 ) t R 8 , (rr) —N[(CR 6 R 6 ) t R 8 ][C═O(CR 6 R 6 )R 8 ], (ss) —(CR 6 R 6 ) t N[(CR 6 R 6 ) t R 8 ][(CR 6 R 6 ) t R 8 ], (tt) —(CR 6 R 6 ) t NR 6 (C═O)(CR 6 R 6 ) t R 8 , (uu) -haloalkyl, (vv) —C(O)(CR 6 )[(CR 6 R 6 ) t R 8 ]R 8 , (ww) —(CR 6 R 6 ) t C(O)NR 8 R 8 , (xx) —(CR 6 R 6 ) t C(O)O(CR 6 R 6 ) t R 8 , (yy) —NR 6 C(O)CR 8 R 8 R 8 , (zz) —N[(CR 6 R 6 ) t R 8 ]C(O)R 8 , and (aaa) —S(O) p NR 8 R 8 ;

wherein (ll) through (pp) is optionally substituted with one or more R 7 groups;

C—B-A- is selected from the group consisting of:

R 5 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF 3 , (g) —CN, (h) —N 3 (i) —NO 2 , (j) —NR 6 R 6 , (k) —OR 8 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8 alkyl, (n) —C 1-8 alkenyl, (o) —C 1-8 alkynyl, (p) —(C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) —(C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s) -SR 6 , (t) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic carbocycle; alternatively, two R 5 groups are taken together to form a carbocycle;

wherein (m) through (r) and (t) through (u) is optionally substituted with one or more R 8 ;

R 6 is selected from (a) hydrogen, (b) —C 1-8 alkyl or alternatively two R 6 groups are taken together to form a carbocycle, (c) -haloalkyl, (d) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e) -3-14 member saturated, unsaturated, or aromatic carbocycle;

wherein (b) through (e) is optionally substituted with one or more R 8 ;

R 7 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF 3 , (g) —CN, (h) —N 3 (i) —NO 2 , (j) —NR 6 R 6 , (k) —OR 6 , (1) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8 alkyl, (n) —C 1-8 alkenyl, (o) —C 1 -8 alkynyl, (p) —(C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) —(C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s) —NR 6 R 8 , (t) —OR 8 , (u) —(CR 6 R 6 ) t NR 6 R 8 , (v) -CR 6 R 8 R 8 , (w) —SR 6 , (x) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (y) -3-14 member saturated, unsaturated, or aromatic carbocycle, (z) —(CR 6 R 6 ) t C(O)NR 8 R 8 , (aa) —S(O) p R 8 , (bb) —NR 6 C(O)NR 6 R 6 , (cc) —NR 6 C(O)R 6 , and (dd) —C(═NR 6 )NR 6 R 6 ;

wherein (m) through (q) and (x) through (y) are optionally substituted with one or more R 9 ;

R 8 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF 3 , (g) -CN, (h) —N 3 (i) —NO 2 , (j) —NR 6 R 9 , (k) —OR 9 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8 alkyl, (n) —C 1-8 alkenyl, (o) —C 1-8 alkynyl, (p) -(C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (q) - (C 1 - 8 alkyl)-(3-14 member saturated, unsaturated, or aromatic carbocycle), (r) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (s) -3-14 member saturated, unsaturated, or aromatic carbocycle, (t) -haloalkyl, (u) —C(O)(CR 6 R 6 ) t R 9 , (v) —SR 6 , (w) —OC(O)(CR 6 R 6 ) t R 9 , (x) —NR 6 C(O)NR 6 R 9 , (y)—NR 6 C(O)R 9 , (z) —NR 6 (CNR 9 )(NR 6 R 6 ), (aa) —ONR 6 (CNR 6 )NR 6 R 6 , (bb) —C(═NR 9 )NR 6 R 6 , (cc) —S(O) p R 9 , (dd) —(CR 6 R 6 ) t C(O)NR 6 R 9 , (ee) —(CR 6 R 6 ) t OR 9 , and (ff) (—CR 6 R 6 ) t NR 6 R 9 ;

wherein (m) through (s) is optionally substituted with one or more R 9 ;

R 9 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF 3 , (g) —CN, (h) —N 3 (i) —NO 2 , (j) —NR 6 R 10 , (k) —OR 6 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C(O)(CR 6 R 6 ) t NR 6 R 6 , (n) —C 1-8 alkyl, (o) —C 1-8 alkenyl, (p) —C 1-8 alkynyl, (q) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 member saturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t) (—CR 6 R 6 ) t OR 6 , (u) O(CR 6 R 6 ) t NR 6 R 10 , (v) —C(O)R 6 , (w) —SR 6 , (x) —C(O)OR 10 , (y) —S(O) p R 6 , (z) (—C 1-8 alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) -(C 1-8 alkyl) -(3-14 member saturated, unsaturated, or aromatic carbocycle), (bb) —O(CR 6 R 6 ) t OR 6 , (cc) —C(═NR 6 )NR 6 R 6 , (dd) —ONR 6 R 6 , (ee) —NR 6 C(O)NR 6 R 6 , (ff) —O(CR 6 R 6 ) t OR 6 , (gg) —NR 6 C(O)R 6 , and (hh) —(CR 6 R 6 ) t NR 6 R 10 ;

wherein (n) through (r) and (z) through (aa) is optionally substituted with one or more R 10 ;

R 10 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) -CF 3 , (g) —CN, (h) —N 3 (i) —NO 2 , (j) —NR 6 R 6 , (k) —OR 6 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C(O)(CR 6 R 6 ) t NR 6 R 6 , (n) —C 1-8 alkyl, (o) —C 1-8 alkenyl, (p) —C 1-8 alkynyl, (q) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (r) -3-14 member saturated, unsaturated, or aromatic carbocycle, (s) -haloalkyl, (t) —(CR 6 R 6 ) t OR 6 , (u) —O(CR 6 R 6 ) t NR 6 R 6 , (v) —C(O)R 6 , (w) —SR 6 , (x) —C(O)OR 6 , (y) —S(O) p R 6 , (z) —(C 1-8 alkyl )-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (aa) —(C 1-8 alkyl) -(3-14 member saturated, unsaturated, or aromatic carbocycle), (bb) —O(CR 6 R 6 ) t OR 6 , (cc) —C(=NR 6 )NR 6 R 6 , (dd) —ONR 6 R 6 , (ee) —NR 6 C(0)NR 6 R 6 , (ff) —O(CR 6 R 6 ) t OR 6 , (gg) —NR 6 C(O)R 6 , and (hh) —(CR 6 R 6 ) t NR 6 R 6 ;

wherein either the group -D-E-F or the group -G-H-J is absent, but both -D-E-F and -G-H-J are not simultaneously absent;

p is 0, 1, or 2, and

t is 1, 2, or 3,

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

2. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

3. The compound according to claim 1 having the formula:

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

4. The compound according to claim 1 , wherein G is selected from

(a) a single bond, (b) —(C 1-8 alkyl)-, (c) —(C 2-8 alkenyl)-, (d) —(C 2-8 alkynyl)-, wherein

i) 0-4 carbon atoms in any of (b)-(d) immediately above optionally is replaced by a moiety selected from the group consisting of —O—, —S(O) p —, —NR 6 ——(C═O)—, —C(═NR 6 )-, —S(O) p NR 6 -, —NR 6 S(O) p —, and —NR 6 S(O) p NR 6 -,

ii) any of (b)-(d) immediately above optionally is substituted with one or more R 5 groups, and

iii) any of (b)-(d) immediately above optionally is substituted with —(C 1-8 alkyl) - R 5 groups;

(e) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and

(f) a 3-14 member saturated, unsaturated, or aromatic carbocycle,

wherein (e) or (f) is optionally substituted with one or more R 5 groups;

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

5. The compound according to claim 1 , wherein R 5 is selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF 3 , (g) —CN, (h) —N 3 (i) —NO 2 , (j) —NH 2 , (k) OR 6 , (l) —NHC(═NH)NH 2 , (m) —C 1-8 alkyl, (n) —C 1-8 alkenyl, (o) —C 1-8 alkynyl, (p) —(C 1-8 alkyl) -(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms slected from the group consisting of nitrogen, oxygen, and sulfur), (q) —(C 1-8 -alkyl)(3-14 member saturated, unsaturated, or aromatic carbocycle), (r) -haloalkyl, (s) —SR 6 , (t) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (u) -3-14 member saturated, unsaturated, or aromatic carbocycle; alternatively, two R 5 groups are taken together to form a carbocycle; or a pharmaceutically acceptable salt, ester, or tautomer thereof.

6. The compound according to claim 1 , wherein R 6 is selected from (a) hydrogen, (b) —C 1-8 alkyl or alternatively two R 6 groups are taken together to form a carbocycle, (c) -haloalkyl, (d) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (e) -3-14 member saturated, unsaturated, or aromatic carbocycle; or a pharmaceutically acceptable salt, ester, or tautomer thereof.

7. The compound according to claim 1 , wherein G is selected from (a) a single bond, (b) —(C 1-8 alkyl)—, (c) —(C 2-8 alkenyl)-, (d) —(C 2-8 alkynyl)-, wherein

i) 0-4 carbon atoms in any of (b)-(d) immediately above optionally is replaced by a moiety selected from the group consisting of —O—, —S(O) p —,—NR 6 , —(C═O)—, —C(═NR 6 )-, —S(O) p NR 6 -, —NR 6 S(O) p —, and —NR 6 S(O) p NR 6 -,

ii) any of (b)-(d) immediately above optionally is substituted with one or more R 5 groups, and

iii) any of (b)-(d) immediately above optionally is substituted with —(C 1-8 alkyl) - R 5 groups;

wherein p is 0, 1, or 2,

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

8. The compound according to claim 5 , wherein

is selected from:

or -G-H-J is

wherein R x is selected from CH 2 , NH, N(C 1-8 alkyl), S, and O; R y and R z are C or CH each independently substituted with one or more F, CH 3 , CF 3 , OH, and OCH 3 ; or R x , R y , and R z are each independently selected from CH 2 and CR a R b wherein R a and R b are taken together to form a C 1-5 carbocycle;

J′ is selected from NH 2 , NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , NHC(═O)CH 3 , NHC(═O)NH 2 , NHC(═NH)NH 2 , and NHC(═NH)H;

wherein n is 0, 1, or 2;

alternatively, -G-H-J is

wherein R x is selected from CH 2 , NH, N(C 1-8 alkyl), S, and O; R z is a C or CH, substituted with one or more CH 3 or R z is CR a R b wherein R a and R b are taken together to form a C 1-5 carbocycle,

wherein m is 1, 2, or 3;

J′ is selected from NH 2 , NH(C 1-8 alkyl), N(C 1-8 alkyl) 2 , NHC(═O)CH 3 , NHC(═O)NH 2 , NHC(═NH)NH 2 , and NHC(═NH)H; or a pharmaceutically acceptable salt, ester, or tautomer thereof.

9. A compound selected from,

Comp.

No.

Structure

392

393

396

400

402

440

442

460

528

529

543

544

557

558

575

576

578

579

592

595

598

603

604

606

614

615

627

638

639

641

642

643

651

656

657

658

659

660

664

667

669

671

672

674

675

676

681

685

686

689

690

691

694

695

696

707

708

714

715

718

729

730

731

732

733

738

740

741

748

749

750

751

752

753

754

763

765

774

776

777

781

782

783

792

793

794

795

798

811

812

818

832

833

858

859

868

869

870

888

889

890

891

903

904

908

909

916

917

919

920

921

938

941

942

950

953

954

955

956

972

973

976

993

1006

1007

1008

1014

1016

1025

1026

1030

1031

1032

1033

1041

1042

1055

1056

1058

1070

1071

1072

1073

1082

1083

1084

1086

1096

1133

1134

1135

1145

1146

1147

1192

1193

1197

1198

1212

1213

1234

1235

1236

1237

1238

1244

1269

1270

1271

1368

1369

1370

1421

1426

1427

1441

1449

1450

1464

1465

1466

1467

4000c

4001c

4002c

4003c

4004c

4005c

4006c

4007c

4008c

or a pharmaceutically acceptable salt, ester, or tautomer thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or tautomer thereof, and a pharmaceutically acceptable carrier.

11. A method of treating a microbial infection in a human or animal comprising administering to the human or animal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or tautomer thereof.

12. A method of treating or reducing the risk of a microbial infection in a human or animal comprising administering to the human or animal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or tautomer thereof, wherein the microbial infection is selected from the group consisting of:

a skin infection, a Gram positive infection, a Gram negative infection, nosocomial pneumonia, community acquired pneumonia, post-viral pneumonia, hospital acquired pneumonia/ventilator associated pneumonia, a respiratory tract infection, acute pelvic infection, a complicated skin and skin structure infection, a skin and soft tissue infection (SSTI) including uncomplicated skin and soft tissue infections (uSSTI)s and complicated skin and soft tissue infections, an abdominal infection, a complicated intra-abdominal infection, a urinary tract infection, bacteremia, septicemia, endocarditis, an atrio-ventricular shunt infection, a vascular access infection, meningitis, surgical prophylaxis, a peritoneal infection, a bone infection, a joint infection, a methicillin-resistant Staphylococcus aureus infection, a vancomycin-resistant Enterococci infection, a linezolid-resistant organism infection, a Bacillus anthracis infection, a Francisella tularensis infection, a Yersinia pestis infection, and tuberculosis.

13. The method according to claim 12 , wherein the compound, or a pharmaceutically acceptable salt, ester, or tautomer thereof, is administered otically, ophthalmically, nasally, orally, parenterally, intravenously, or topically.