AU2008350293A1 - Antibiotic tetrahydro-beta-carboline derivatives - Google Patents

Description

WO 2009/102377 PCT/US2008/084832 ANTIBIOTIC TETRAHYDRO-BETA-CARBOLINE DERIVATIVES Related Application This application claims priority to U.S. Provisional Application No. 60/991,520, 5 Attorney Docket No. NPZ-006-1, filed November 30, 2007, entitled "ANTIBIOTIC TETRAHYDRO-BETA-CARBOLINE DERIVATIVES." The contents of any patents, patent applications, and references cited throughout this specification are hereby incorporated by reference in their entireties. 10 Technical Field The present invention relates to compositions which are PPAT inhibitors and methods and uses thereof. Background of the Invention 15 In the last century, antibiotics were developed that led to significant reductions in mortality. Unfortunately, widespread use has led to the rise of antibiotic resistant bacteria, e.g., methicillin resistant Staphyloccocus aureus (MRS A), vancomycin resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonias (PRSP). Some bacteria are resistant to a range of antibiotics, e.g., strains of Mycobacterium 20 tuberculosis resist isoniazid, rifampin, ethambutol, streptomycin, ethionamide, kanamycin, and rifabutin. In addition to resistance, global travel has spread relatively unknown bacteria from isolated areas to new populations. Furthermore, there is the threat of bacteria as biological weapons. These bacteria may not be easily treated with existing antibiotics. 25 Infectious bacteria employ the coenzyme A (CoA) biosynthesis pathway, and, particularly in the penultimate step of the pathway, depend on phosphopantetheine adenyl transferase (PPAT), which transfers an adenyl moiety from adenosine triphosphate (ATP) to 4'-phosphopanthetheine, forming dephospho-CoA (dPCoA). While PPAT is present in mammalian cells, bacterial and mammalian PPAT enzymes 30 differ substantially in primary sequence (about 18% identity) and physical properties. Thus, PPAT presents a desirable, selective target for new antibiotics. Recent efforts have resulted in the identification of compounds that inhibit E. coli PPAT (Leslie, et al. "Antibacterial Anthranilates with a Novel Mode of Action"; Zhao, et al. "Inhibitors of Phosphopantetheine Adenylyltransferase"; Presented at the 1 WO 2009/102377 PCT/US2008/084832 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Diego, CA, 2002). However, these compounds are not appropriate for drug development. Furthermore, in one case, the structures are peptidic, while in the other case, representative compounds exhibited poor activity against purified PPAT. 5 Therefore, there is a need for new antibiotics that target PPAT, whereby infections from bacteria dependent on PPAT can be treated. Summary of the Invention The present invention relates to certain bicyclic PPAT inhibitors. The disclosed 10 compounds have antibiotic activity against bacteria, including drug-resistant bacteria. Thus, compounds that are PPAT inhibitors, methods of treatment with the disclosed PPAT inhibitors, and pharmaceutical compositions comprising the disclosed PPAT inhibitors are provided herein. In one aspect, the invention provides a method of treating a subject for a bacterial 15 infection, comprising administering to a subject in need of treatment for a bacterial infection an effective amount of a compound represented by structural Formula I: R6 A R5 / I N L/R 4 L-1 R3 (I) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, 20 stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof. The invention is useful for treating (therapeutically or prophylactically) bacterial infections, particularly infections caused by bacteria that depend on the CoA biosynthesis pathway, and more particularly, infections caused by bacteria that express the PPAT enzyme. Furthermore, it is useful against bacteria that have developed 25 antibiotic resistance, especially multiple drug resistant strains, because it is believed to act through a different mechanism than existing, widely used antibiotics. DETAILED DESCRIPTION OF THE INVENTION The invention is generally related to methods, compounds, and pharmaceutical compositions for treating and preventing bacterial infections. In particular, the invention 30 relates to tetrahydro-3-carboline derivatives that are PPAT inhibitors. 2 WO 2009/102377 PCT/US2008/084832 In a preferred embodiment, the compound is represented by structural Formula I: R6 A R5 / I N L/R 4 L-1 R3 (I) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, 5 stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; wherein ring A is an aryl or heteroaryl group that is optionally substituted at any substitutable ring atom; J is -0-, -S-, or -NR2-, wherein R2 is -H or optionally substituted C1-C5 alkyl; 10 or, J is -NR2'-, wherein R2' is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 cycloaliphatic, or C3-C7 cycloalkyl; R3 is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 cycloaliphatic, or C3-C7 cycloalkyl; L is -(CH 2 )-, -(CO)-, -(CS)-, -(SO)-, or -(SO 2 )-; 15 R4 is an aryl, biaryl, heteroaryl, biheteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic, C3-C7 cycloalkyl, C5-C7 cycloaliphatic, or a 3-7 membered non-aromatic heterocyclic group; wherein R4 can be substituted with halogen, -(CO)ORa, -(CO)O(CO)Ra, (CS)ORa, -(SO)ORa, SO 3 Ra, -OSO 3 Ra, -P(ORa) 2 , -(PO)(ORa) 2 , -O(PO)(ORa) 2 , -B(ORa) 2 , 20 -(CO)NR 2, -NRc(CO)Ra, -SO 2 NRb2, or -NRcSO 2 Ra; R5 is -H, -(CO)ORa, -(CO)O(CO)Ra, -(CS)ORa, -(SO)ORa, SO 3 Ra, -OSO 3 Ra _ P(ORa) 2 , -(PO)(ORa) 2 , -O(PO)(ORa) 2 , -B(ORa) 2 , -(CO)NRb2, -NRc(CO)Ra, -SO 2 NRb2, or -NRcSO 2 Ra; R6 is -H, -OH, halogen, or optionally substituted C1-C3 alkyl or alkoxy; 25 each Ra and Rc are, independently, -H, C1-C5 alkyl, aryl, or aralkyl; each Rb is, independently, -H, C1-C5 alkyl, aryl, or aralkyl, or NR b2 is a nonaromatic heterocyclic group. In one embodiment, ring A in structural Formula I is an optionally substituted heteroaryl group, for example, an optionally substituted pyrazyl, furanyl, pyrrolyl, 30 thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, or imidazolyl group. 3 WO 2009/102377 PCT/US2008/084832 Suitable optional substituents for substitutable ring atoms in Ring A are provided herein below in the section describing substituents for aryl and heteroaryl groups. More preferably, Ring A is optionally, independently, substituted at any substitutable ring atom with R1. Each R1 are, independently, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -ORd , dddd d d 5 (CO)Rd, -(CO)OR , -O(CO)Rd, -(CO)O(CO)Rd, -(CS)ORd, -(SO)OR , -SO 3 R _ CONRe 2 , -O(CO)NR 2 , -NRf(CO)NR 2 , -NRf(CO)ORd, -NRfCORd, -(SO 2 )NR 2 , NR'SO 2 R , -(CH 2 )sNR d2, or optionally substituted aryl, aralkyl or C1-C5 alkyl. In the preceding, s is from 0 to 5, each Rd and Rf are, independently, -H, aryl, aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl, and each Rc are, independently, -H, aryl, aralkyl, or C1-C5 10 alkyl, and NRe 2 is a nonaromatic heterocyclic group, for example, piperidinyl, morpholinyl, and the like. More preferably, RI is halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , ORd, -(CO)Rd, -(CO)ORd, -O(CO)Rd, -CONR2, -O(CO)NR2, -NRf(CO)ORd _ f d df-C2,Rd2 NRfCOR , -(SO 2 )NRe 2 , -NRfSO 2 Rd, -(CH 2 )sNRd 2 , or optionally substituted aryl, aralkyl or Cl-C5 alkyl. Even more preferably, RI is -H, -OH, -F, -CH 3 , -CF 3 , -OCH 3 or -OCF 3 . 15 Most preferably, RI is -H. In one embodiment, R3 in structural Formula I is an optionally substituted phenyl, pyridyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxinyl, pyrimidyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, naphthyl, quinolinyl, biphenyl, benzopyrimidyl, benzopyrazyl, benzofuranyl, indolyl, 20 benzothienyl, benzoxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, or benzimidazolyl group. Suitable optional substituents for the group represented by R3 are provided herein below. More preferably, R3 in structural Formula I is represented by one of structural formulas R3-i to R3-v: P CO ~(R1 1), (R 11), (R1 1), R3-i R3-ii R3-iii (1(R11) 1), (R 11), R3-iv R3-v 25 In structural formulas R3-i to R3-v, Y is -N-, -CH-, or -CR11-; Z is -NR'-, or -0-, wherein Rz is -H or C1-C3 alkyl, more preferably -H or methyl, or most 4 WO 2009/102377 PCT/US2008/084832 preferably -H; the variable w is 0, 1, 2, or 3; each R 11 are, independently, halogen, -CN,

-NO

2 , -CF 3 , -OCF 3 , -OR', -(CO)R', -(CO)OR', -O(CO)R', -(CO)O(CO)R', -(CS)OR', (SO)OR', -S0 3 R', -CONR" 2 , -O(CO)NR" 2 , -NR"(CO)NR" 2 , -NR"(CO)OR, NR"COR 1 , -(S0 2

)NR'

2 ), -NR"SO 2

R

1 , -(CH 2 )u 1 NR 1 2 , or optionally substituted aryl, 5 aralkyl, or C1-C5 alkyl. In the preceding, u is 0 to 5, each R and R" are, independently, -H, aryl, or aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl, and each R' is independently -H, aryl, aralkyl, or C1-C5 alkyl, or NR' 2 is a nonaromatic heterocyclic group. Even more preferably, R3 in structural Formula I is represented by one of structural formulas R3-i' to R3-v': N (R1 1), (R1 1), (R1 1), R3-F R3-i' R3-ii' -J (R 11), (R11), R3-iv' R3-v' 10 In structural formulas R3-i' to R3-v', w is 0, 1, 2, or 3, and each R11 is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF 3 , or -OCF 3 . More preferably, R 11 is represented by one of structural formulas R 11-i to R 1-xxiii: N N HN-N s-i S R11-i R11-i R11-iii R11-iv R11-v R11-vi R11-vii N N I/<N 2HN- 6 ' F R11-x R11-xi R11-xii R11-xiii R11-viii R11-ix 0 0 0 0 0 > NH > NH > NH NH OH ,O

NH

2 HN R11-xviii R11-xiv R11-xv R11-xvi R11-xvii 0 NN .L, -(PO)(OR) 2

-P(OR)

3

-O(PO)(OR)

2

-B(OR)

2 H R11-xx R11-xxi R11-xxii R11-xxiii 15 R11-xix 5 WO 2009/102377 PCT/US2008/084832 wherein R is independently -H, aryl, or aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl. Still more preferably, R3 is represented by one of structural formulas R3a to R3': ~~0 OMe R3a R3b F F CF C F OMe R3c R3 R30 R3' Ci Cl CI C Me Me CI C1 CI OH R3 R3 R3' R3 & cI OH OEt F OH F R3k R3 R3m R3" S R3 0 R3P R3q R3r 5 Most preferably, R3 is represented by structural formula R3', or R3 is perfluorinated phenyl or tretrazole. R4 in structural Formula I is optionally further substituted as described below in the section describing suitable substituents for aryl, heteroaryl, aliphatic, and 10 cycloalkyl groups. More preferably, R4 is a substituted phenyl, pyridyl, pyrimidyl, pyrazyl, naphthyl, biphenyl, phenyl-pyridyl, quinolinyl, benzopyrimidyl, benzopyrazyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, or a C2-C8 alkenyl group. 6 WO 2009/102377 PCT/US2008/084832 More preferably, R4 is represented by one of structural formulas R4-i to R4 vii: (RIO)m (R1O)m (R1O)m (CO)R8 (CO)R8 O)R8 R4- (RIO)m R4ii (R1O)m R4-vi (R10)m (R1O)m (RIO)m --- B R C (CO)R8 --- (R10)m (CO)R8 D(D )RS (D (R10). (CO)R8 R4-iii R4-iv R4-v R4-vii In structural formulas R4-i to R4-vii, each m is independently 0, 1, 2, or 3, and 5 X is -N-, -CH-, or -CR10-; Ring B is C3-C6 cycloalkyl or C3-C6 cycloalkenyl; Rings C and D are each independently aryl or heteroaryl; R8 is -ORq or -NR 2 ; R9 is -H, aryl, aralkyl, or C1-C6 aliphatic; each R10 is independently halogen, -CN, -NO 2 , CF 3 , -OCF 3 , -OR', -(CO)R', -(CO)OR', -O(CO)R', -(CO)O(CO)R', -(CS)R', -(SO)OR',

-SO

3 R, -CONR.

2 , -O(CO)NRj 2 , -NR'(CO)NRj 2 , -NR(CO)ORi, -NR'COR', 10 (SO 2 )NRj 2 , -NR'SO 2 R', -(CH 2 )tNRj 2 , or optionally substituted aryl, aralkyl or C1-C5 alkyl; the variable t is 0 to 5 and each R' and Rk are, independently, -H, aryl, aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl; each R3 and R' are, independently, -H, aryl, aralkyl, or C1 -C5 alkyl, or each NR 2 and NR' 2 are, independently, a nonaromatic heterocyclic group; and Rq is -H or optionally substituted aryl, aroyl, aralkyl, aralkanoyl, C1-C5 15 alkyl, or C1-C5 alkanoyl. Even more preferably, R4 is represented by one of structural formulas R4-i' to R4-vii': (RIO)m (R1O)' N (RIO)m (CO)R8 6 (CO)R8 (CO)R8 (RIO)m R4-i' R4-ii' R4-ii' (RIO)m (R1O)m (R1O)m R9 (CO)R8 ,(CO)R . (CO)RB (CO)RB R4-vii' R4-iv' R4-v R4-vi" 7 WO 2009/102377 PCT/US2008/084832 In structural formulas R4-i' to R4-vii', each m is independently 0, 1, 2, or 3; R8 is -OH, C1-C5 alkoxy, or C1-C5 alkanoyloxy; R9 is -H or C1-C6 aliphatic; and each RIO is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF 3 , or OCF 3 . 5 More preferably, R4 is aryl (e.g. phenyl) which is substituted by one of structural formulas RiO-i to R1O-xix: N HN-1 S 0' R10-i R10-ii R10-iii R10-iv R10-v R10-vi R10-vii F H N N NN N N F R10-x R1O-xi R10-xii R1O-xiii R10-viii R10-ix 0 0 0 0 0 > NH A NH > NH > NH H OH ,6 NH 2 HNs H R10-xiv R10-xv R1O-xvi R1O-xvii R1 O-xviii H 0 H R10-xix 8 WO 2009/102377 PCT/US2008/084832 Still more preferably, R4 is represented by one of structural formulas R4a to R4 q: (CO)R8 (CO)R8 (CO)R8 (CO)R8 Ci t-Bu CI t-Bu R4a R4b R4P R4d (CO)R8 (CO)RB (CO)R8 (CO)R8 F Me Me F R4e R41 R49 R4h (CO)R8 (CO)R8 (CO)RB N (CO)R8 R4' R4 R4k R41 (CO)R8 (CO)RB -(CO)R8 Me (CO)R8 R4" R4n R4" R4 R44 /' (CO)R8 a b 5 Most preferably, R4 is represented by structural formula R4a or R4 , or R4 is phenyl substituted with tetrazole. In R4a to R4q, R8 is -NRY 2 , -OH, C1-C5 alkoxy, or C1-C5 alkanoyloxy, wherein each RY is independently -H or C1-C3 alkyl. Even more preferably, R8 is OH or C1-C4 alkoxy, or still more preferably, -OH, -OCH 3 , or -OCH 2

CH

3 . Most 10 preferably, R8 is OCH 3 or -OCH 2

CH

3 . 9 WO 2009/102377 PCT/US2008/084832 In a preferred embodiment, R5 is: N N N HN-N S S 0 F 0 0 0 0 0 >'NH SNH NH NH N OH 6 NH 2 HN H NN H 0 H In a most preferred embodiment, R 5 is -H or -CO 2 H. In preferred embodiments, in structural Formula I, R8 is -OH, OCH 3 or 5 OCH 2

CH

3 . In structural Formula I, R3 is represented by one of structural formulas R3-i to R3-v or R4 is represented by one of structural formulas R4-i to R4-vii. More preferably, R3 is represented by one of structural formulas R3-i to R3-v and R4 is represented by one of structural formulas R4-i to R4-vii. In still another embodiment, 10 in structural Formula I, R3 is represented by one of structural formulas R3-i' to R3-v' or R4 is represented by one of structural formulas R4-i' to R4-vii'. More preferably, R3 is represented by one of structural formulas R3-i' to R3-v' and R4 is represented by one of structural formulas R4-i' to R4-vii'. In another preferred embodiment, for structural Formula I, R3 is represented by one of structural formulas R3a to R3', or R4 15 is represented by one of structural formulas R4a to R4 . Preferably, R3 is represented by one of structural formulas R3a to R3', and R4 is represented by one of structural formulas R4a to R4 . More preferably, R3 is represented by structural formula R3d R3', or R3f, or R4 is represented by structural formula R4a, R4c, or R4'. Even more preferably, R3 is represented by structural formula R3 d, R3', or R3f, and R4 is 20 represented by structural formula R4a, R4c, or R4'. In another embodiment of Formula I, ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted one or more times with halogen or tetrazole; L is (CO) 10 WO 2009/102377 PCT/US2008/084832 or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or tetrazole; and R5 is H. In another embodiment, the compound of formula I is of the formula 5: R" N -R' R3 5 5 wherein J and R 3 are the same as previously defined, A is a diazole, dioxolane, dioxane or benzene ring and R' and R" are each independently a hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or hydroxyamide. In yet another embodiment, the compound of formula I is of the formula 6: R" A R 5 A N,R R' R3 6 10 wherein J, R 3 and R 5 are the same as previously defined, Y is C=O or CH 2 , A is a diazole, dioxolane, dioxane or benzene ring and R' and R" are each independently a hydrogen, halogen, carboxylic acid, alkyl, heterocycle, nitrile or hydroxyamide. In another embodiment, the compound is of formula I, wherein ring A is an 15 aryl moiety; J is N(H); R3 is aryl optionally substituted one or more times with halogen or a heteroaryl; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H, alkyl, alkoxyl, CO 2 H or CO 2 alkyl; and R6 is H, alkyl or alkoxyl. In yet another embodiment, the compound is of formula I, wherein ring A is a 20 phenyl moiety; J is N(H); R3 is phenyl optionally substituted one or more times with halogen or tetrazole; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H or CO 2 H; and R6 is H. In another embodiment, the compound is of formula I, wherein ring A is a 25 phenyl moiety; J is N(H); R3 is phenyl optionally substituted with tetrazole; L is CH 2 ; and R4 is phenyl optionally independently substituted one or more times with halogen. 11 WO 2009/102377 PCT/US2008/084832 In other embodiments the compound, the compound of the method, and the compound of the pharmaceutical composition are each represented by the individual compounds provided in Table 1: Table 1 Compound # Structure 1 N2R HO N OHH 2 CI C N HO O N CHR 3 0 OHO N 0 H H N 4 0 -OH~ N HO HN N 5

N

N H 6 CI CI Iq 0 HO N 12 WO 2009/102377 PCT/US2008/084832 7 N F N K H N 8

N

N H N\ N Np NU NN CH 10 N N 0 H HO0 N H0 -N HO 0 12 HO 0 c c N N H 13 cI 0000 HO 0 13 WO 2009/102377 PCT/US2008/084832 14 N N H 15 0 N N H 16/ 0 / C H H) 17 CI CI N K N0 OH 18N 0 Y0 HO 0 190 KO~N N ':0 OH 20 - OH N H 14 WO 2009/102377 PCT/US2008/084832 21 \/N - N N H \N 22 N H N 23 N H \N 24 0 -\ N OH N H 25 cI cI N - 0 0- 0 HO 26C 0 C N 0 0 OH 27 / c N OOH H 0 0N 15 WO 2009/102377 PCT/US2008/084832 28 N N N H N 29 30 / HN NN CN N H 30I 31 HO O // \ - N N N 32 H HN 32 / \ 0 N _N N-N cl 0 NI N CI 16 WO 2009/102377 PCT/US2008/084832 34 -0 N -N N N 36 N H 0 c3 N ci 35 N-N F\ NN NN N 17H H F 36 -0 0 N- N/ H N H F"Q- F 370 0 NN H HN N CXe N 38 HO 0 NN H N HN N 390 OH HN N F Fi j F N 17 WO 2009/102377 PCT/US2008/084832 40 HO N N N / \ 41 N N CI 0 N N CI 42 N O N .NH NN N N N 43 I Ny N O N- NH O 0 44 N H HO N 0 4 5 H N - Nk N F HN N F OH 0 18 WO 2009/102377 PCT/US2008/084832 46 HN- N N N 47 F HN N N

N

NH 48 N- N NN C I H N N N CIq N N H 50 H4 NY N cl t c)/ N SN NH CI 51 H 0 HN COH CIl 0 0 OH HN F 19 WO 2009/102377 PCT/US2008/084832 52 |~ N OH N F 53 N~ NKa C N F N 54 N FN HN F 55 F NN N H H F N 56 NN N NN H NH 20 0 9HN CN N\ \ N C I ::C NNH 20 WO 2009/102377 PCT/US2008/084832 58 0/c, 0CI N O N OH N H 59 CI N H 59 ci CI, 60 HN N H N N H 61 N HN N N N H 62 N H N N N \\.. N N N H 621 WO 2009/102377 PCT/US2008/084832 63 HN N N NH 64 N_ HN N NH 65 HN N KN N N H 66 H2N 0 HN N N c NNH 22 WO 2009/102377 PCT/US2008/084832 67 HN N C 67 c HN H 68 HN N N HN N N 69 H N N N N KN N I N H 70 N 0 HN N N N N H 23 WO 2009/102377 PCT/US2008/084832 71 HO ~0 0 HN N F 0 . HO 0 F 72 HO HO O 73 o HN N NN N N HN 73 H N N N 24 N H 744 WO 2009/102377 PCT/US2008/084832 75 HN N H N N 76 N HN N N N H 77 N HN KN N N H 78 N HN N N N H 25 WO 2009/102377 PCT/US2008/084832 79 HN HNN CI CIl 80 NH N H HO 0 81 NH N H o o 82 N N ci H NIC N 26 WO 2009/102377 PCT/US2008/084832 83 N OH H 0 N 84 N H N 85 0 NN FC 86 N HN7 27 WO 2009/102377 PCT/US2008/084832 87 HN N NN 88F N N 89 N 90 o/ FF H N 89 -0o) HN N "' c I N~H/ 90 0 I NH N H F F 28 WO 2009/102377 PCT/US2008/084832 91 O 9 I NH 0 N H F 92 HN N CI <NH 93 HO CI NNNH 94

%I

HN N NNH 29 WO 2009/102377 PCT/US2008/084832 95 N H \ N F F 96 N HN N N-/ NH cI 97 :I NH 0 N H 98 HNN HNN N NH 30 WO 2009/102377 PCT/US2008/084832 99 HN N N NH F F 100 HN N N NH 101 HN NN N NH N* 102 N N -O N ONH 31 WO 2009/102377 PCT/US2008/084832 103 F 104 HN N FN N yHO 0 F:) 104 HN N N N-NH 105 HN N HNN NH 106 /0 HNN HO 0 F 32 WO 2009/102377 PCT/US2008/084832 107 HN N N N NH In a particular embodiment, the compounds of Table 1 can be used to treat a bacterial infection in a subject in need thereof. In another embodiment, compounds 4, 13, 22, 32, 49, 67, 71 and 72 can be 5 used to treat a bacterial infection in a subject in need thereof. As used herein, a "subject" includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, aquarium fish, reptiles, and the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, farm-raised fish and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, aquarium fish, reptiles, and the like). 10 Alternatively, the subject is a warm-blooded animal. More preferably, the subject is a mammal. Most preferably, the subject is human. A subject in need of treatment has a bacterial infection (or has been exposed to an infectious environment where bacteria are present, e.g., in a hospital) the symptoms of which may be alleviated by administering an effective amount of the 15 disclosed bicyclic derivatives. For example, a subject in need of treatment can have an infection for which the disclosed bicyclic derivatives can be administered as a treatment. In another example, a subject in need of treatment can have an open wound or burn injury, or can have a compromised immune system, for which the disclosed PPAT inhibitors can be administered as a prophylactic. Thus, a subject can 20 be treated therapeutically or prophylactically. More preferably, a subject is treated therapeutically. Typically, the subject is treated for a bacterial infection caused by a bacteria of a genus selected from Allochromatium, Acinetobacter, Bacillus, Campylobacter, Chlamydia, Chlamydophila, Clostridium, Citrobacter, Escherichia, Enterobacter, 25 Enterococcus, Francisella, Haemophilus, Helicobacter, Klebsiella, Listeria, Moraxella, Mycobacterium, Neisseria, Proteus, Pseudomonas, Salmonella, erratia, 33 WO 2009/102377 PCT/US2008/084832 Shigella, Stenotrophomonas, Staphyloccocus, Streptococcus, Synechococcus, Vibrio, and Yersina. More preferably, the subject is treated for a bacterial infection from Allochromatium vinosum, Acinetobacter baumanii, Bacillus anthracis, 5 Campylobacterjejuni, Chlamydia trachomatis, Chlamydia pneumoniae, Clostridium spp., Citrobacter spp., Escherichia coli, Enterobacter spp., Enterococcusfaecalis., Enterococcus faecium, Francisella tularensis, Haemophilus influenzas, Helicobacterpylori, Klebsiella spp., Listeria moiwcytogenes, Moraxella catarrhalis, Mycobacterium tuberculosis, Neisseria meningitidis, Neisseria gonorrhoeae, Proteus 10 mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella spp., Serratia spp., Shigella spp., Stenotrophomonas maltophilia, Staphyloccocus aureus, Staphyloccocus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Yersinapestis, and Yersina enterocolitica, and the like. Preferably, the subject is treated for a bacterial infection caused by a 15 bacterium that expresses a PPAT protein. As used herein, a PPAT protein is a phosphopantetheine adenytransferase enzyme, i.e., systematic name ATP:pantetheine 4'-phosphate adenylyltransferase, IUBMB systematic classification EC 2.7.7.3, (see International Union of Biochemistry and Molecular Biology, www.chem.qmul.ac.uk/iubmb/). 20 In one embodiment, a subject is also concurrently treated for a fungal infection, for example, a fungal infection caused by a pathogenic dermatophyte, e.g., a species of the genera Trichophyton, Tinea, Microspormn, Epidermophyton and the like; or a pathogenic filamentous fungus, e.g., a species of genera such as Aspergillus, Histoplasma, Cryptococcus, Microspormn, and the like; or a pathogenic non 25 filamentous fungus, e.g., a yeast, for example, a species of the genera Candida, Malassezia, Trichosporon, Rhodotorula, Torulopsis, Blastomyces, Paracoccidioides, Coccidioides, and the like. Preferably, the subject is concurrently treated for a fungal infection resulting from a species of the genera Aspergillus or Trichophyton. Species of Trichophyton include, for example, T. mentagrophytes, T. rubrum, T. schoenleinii, 30 T. tonsurans, T. verrucosum, and T. violaceum. Species of Aspergillus include, for example, A. fumigatus, A.flavus, A. niger, A. amstelodami, A. candidus, A. carneus, A. nidulans, A oryzae, A. restrictus, A. sydowi, A. terreus, A. ustus, A. versicolor, A. caesiellus, A. clavatus, A. avenaceus, and A. deflectus. More preferably, the subject is concurrently treated therapeutically for a fungal infection caused by a species of the 34 WO 2009/102377 PCT/US2008/084832 genus Aspergillus selected from A. fumigatus, A. flavits, A. niger, A. canstelodami, A. candidus, A. carneus, A. nidulans, A oryzae, A. restrictus, A. sydowi, A. terreus, A. ustus, A. versicolor, A. caesiellus, A. clavatus, A. avenaceus, and. A. deflectus. Even more preferably the subject is concurrently treated therapeutically for a fungal 5 infection caused by Aspergillus fumigatus or A spergillus niger, and most preferably, Aspergillus fumigatus. An "effective amount" of a compound of the disclosed invention is the quantity that, when administered to a subject in need of treatment, improves the prognosis of the subject, e.g., delays the onset of and/or reduces the severity of one or 10 more of the subject's symptoms associated with a bacterial infection. The amount of the disclosed compound to be administered to a subject will depend on the particular disease, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled artisan will be able to 15 determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 0.01 mg/kg per day and about 100 mg/kg per day, and preferably between 0.1 mg/kg per day and about 10 mg/kg/day. Techniques for administration of the disclosed compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 1 9 h 20 edition, Mack Publishing Co., Easton, PA (1995), the entire teachings of which are incorporated herein by reference. A "pharmaceutically acceptable salt" of the disclosed compound is a product of the disclosed compound that contains an ionic bond, and is typically produced by reacting the disclosed compound with either an acid or a base, suitable for 25 administering to a subject. For example, an acid salt of a compound containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, such as hydrogen chloride, hydrogen bromide, acetic acid, perchloric acid and the like. Compounds with a quaternary ammonium group also contain a counteranion 30 such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)-tartrates, (-)-tartrates or mixtures thereof including racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid. 35 WO 2009/102377 PCT/US2008/084832 Salts of compounds containing a carboxylic acid or other acidic functional groups can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline 5 earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N, N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2 hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, N 10 benzyl-3-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acid such as lysine and arginine. Certain compounds and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures 15 thereof. As used herein, a "pharmaceutical composition" is a formulation containing the disclosed compounds in a form suitable for administration to a subject. The pharmaceutical composition can be in bulk or in unit dosage form. The unit dosage form can be in any of a variety of forms, including, for example, a capsule, an IV bag, 20 a tablet, a single pump on an aerosol inhaler, or a vial. The quantity of active ingredient (i.e., a formulation of the disclosed compound or salts thereof) in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It is appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. 25 The dosage will also depend on the route of administration. A variety of routes are contemplated, including topical, oral, pulmonary, rectal, vaginal, parenternal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal. The compounds described herein, and the pharmaceutically acceptable salts thereof, can be used in pharmaceutical preparations in combination with a 30 pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. 36 WO 2009/102377 PCT/US2008/084832 Techniques for formulation and administration of the disclosed compounds of the Invention can be found in Remington: the Science and Practice of Pharmacy, above. For oral administration, the disclosed compounds or salts thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, 5 pills, powders, syrups, solutions, suspensions and the like. The tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium 10 stearate; and/or a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or 15 both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like. For parental administration of the disclosed compounds, or salts, solvates, or hydrates thereof, can be combined with sterile aqueous or organic media to form 20 injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a 25 preservative to prevent the growth of microorganisms. In addition to the formulations previously described, the compounds may also be formulated as a depot preparation. Suitable formulations of this type include biocompatible and biodegradable polymeric hydrogel formulations using crosslinked or water insoluble polysaccharide formulations, polymerizable polyethylene oxide 30 formulations, impregnated membranes, and the like. Such long acting formulations may be administered by implantation or transcutaneous delivery (for example subcutaneously or intramuscularly), intramuscular injection or a transdermal patch. Preferably, they are implanted in, or applied to, the microenvironment of an affected organ or tissue, for example, a membrane impregnated with the disclosed compound 37 WO 2009/102377 PCT/US2008/084832 can be applied to an open wound or burn injury. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials, for example, as an emulsion in acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. 5 For topical administration, suitable formulations may include biocompatible oil, wax, gel, powder, polymer, or other liquid or solid carriers. Such formulations may be administered by applying directly to affected tissues, for example, a liquid formulation to treat infection of conjunctival tissue can be administered dropwise to the subject's eye, a cream formulation can be administer to a wound site, or a bandage 10 may be impregnated with a formulation, and the like. For rectal administration, suitable pharmaceutical compositions are, for example, topical preparations, suppositories or enemas. For vaginal administration, suitable pharmaceutical compositions are, for example, topical preparations, pessaries, tampons, creams, gels, pastes, foams or 15 sprays. In addition, the compounds may also be formulated to deliver the active agent by pulmonary administration, e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler. Suitable formulations of this type can also include 20 other agents, such as antistatic agents, to maintain the disclosed compounds as effective aerosols. The term "pulmonary" as used herein refers to any part, tissue or organ whose primary function is gas exchange with the external environment, i.e., 0 2 /CO2 exchange, within a patient. "Pulmonary" typically refers to the tissues of the 25 respiratory tract. Thus, the phrase "pulmonary administration" refers to administering the formulations described herein to any part, tissue or organ whose primary function is gas exchange with the external environment (e.g., mouth, nose, pharynx, oropharynx, laryngopharynx, larynx, trachea, carina, bronchi, bronchioles, alveoli). For purposes of the present invention, "pulmonary" is also meant to include a tissue 30 or cavity that is contingent to the respiratory tract, in particular, the sinuses. A drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery. The canister in the drug delivery device has a head space representing 38 WO 2009/102377 PCT/US2008/084832 greater than about 15% of the total volume of the canister. Often, the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve. 5 For nasal administration, either a solid or a liquid carrier can be used. The solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages. Where the liquid carrier is used, the formulation may be administered as a nasal spray or drops and may include oil or 10 aqueous solutions of the active ingredients. In addition to the formulations described above, a formulation can optionally include, or be co-administered with one or more additional drugs, e.g., other antibiotics, anti-inflammatories, antirungals, antivirals, immunomodulators, antiprotozoals, steroids, decongestants, bronchodialators, and the like. For example, 15 the disclosed compound can be co-administered with drugs such as such as ibuprofen, prednisone (corticosteroid) pentoxifylline, Amphotericin B, Fluconazole, Ketoconazol, Itraconazol, penicillin, ampicillin, amoxicillin, and the like. The formulation may also contain preserving agents, solubilizing agents, chemical buffers, surfactants, emulsifiers, colorants, odorants and sweeteners. 20 The term "derivative," e.g., in the term "bicyclic derivatives," refers to compounds that have a common core structure, and are substituted with various groups as described herein. For example, all of the compounds represented by structural Formula I are tetrahydro-j-carboline derivatives, and have structural Formula I as a common core. 25 In the structural formulas depicted herein, a dashed line indicates a bond by which the depicted or moiety or group is connected to the remainder of the molecule. For example, the dashed line in R4-i indicates the bond that connects the depicted group to another structural formula. A dashed or solid line across a bond in a ring, for example, the solid line from R 11 in R4-i, indicates that the represented bond can be 30 connected to any substitutable atom in the ring. A zig-zag line indicates either cis or trans arrangement of the respective substituents with respect to the bond represented by the dashed line. The term "aryl" group refers to carbocyclic aromatic groups such as phenyl, naphthyl, and anthracyl. The term "heteroaryl" group refers to heteroaromatic groups 39 WO 2009/102377 PCT/US2008/084832 such as imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, 1,2,3 triazolyl, 1,2,4-triazolyl, and tetrazolyl. As used herein, a "heteroaryl" group is a 5 membered carbocyclic ring containing at least one N, S, or 0 atom and two double 5 bonds, or a 6 membered carbocyclic ring containing at least one N, S, or 0 atom and three double bonds. The term "nonaromatic heterocyclic" refers to non-aromatic ring systems typically having four to eight members, preferably five to six, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, 0, 10 or S. Examples of non-aromatic heterocyclic rings include 3-tetrahydrofuranyl, 2 tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3] dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2 morpholinyl, 3-morpholinyl, 4-raorpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4 thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrorolidinyl, 1-piperazinyl, 2 15 piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, 5-diazolonyl, N-substituted diazolonyl, and 1-pthalimidinyl. The disclosed compounds can contain one or more chiral centers. The presence of chiral centers in a molecule gives rise to stereoisomers. For example, a pair of optical isomers, referred to as "enantiomers", exist for every chiral center in a 20 molecule. A pair of diastereomers exists for every chiral center in a compound having two or more chiral centers. Where the structural formulas do not explicitly depict stereochemistry, for example in structural Formula I, it is to be understood that these formulas encompass enantiomers free from the corresponding optical isomer, racemic mixtures, mixtures enriched in one enantiomer relative to its corresponding 25 optical isomer, a diastereomer free of other diastereomers, a pair of diastereomers free from other diasteromeric pairs, mixtures of diasteromers, mixtures of diasteromeric pairs, mixtures of diasteromers in which one diastereomer is enriched relative to the other diastereomer(s) and mixtures of diasteromeric pairs in which one diastereomeric pair is enriched relative to the other diastereomeric pair(s). 30 The term "alkyl" used alone or as part of a larger moiety (e.g., aralkyl, alkoxy, alkylamino, alkylaminocarbonyl, haloalkyl), is a straight or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight or branched alkyl group has from 1 to about 10 carbon atoms, preferably from 1 to about 5 if not otherwise specified. Examples of suitable straight or branched alkyl groups include 40 WO 2009/102377 PCT/US2008/084832 methyl, ethyl, n-propyl, 2-propyl, w-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl. A Ci-C1O straight or branched alkyl group or a C3-C8 cyclic alkyl group can also be referred to as a "lower alkyl" group. An "alkoxy" group refers to an alkyl group that is connected through an intervening oxygen atom, e.g., methoxy, ethoxy, 2 5 propyloxy, tert-butoxy, 2-butyloxy, 3-pentyloxy, and the like. The terms "optionally halogenated alkyl" and "optionally halogenated alkoxy", as used herein, includes the respective group substituted with one or more of -F, -Cl, -Br, or-I. The terms "alkanoyl," "aroyl," and the like, as used herein, indicates the 10 respective group connected through an intervening carbonyl, for example, (CO)CH 2

CH

3 , benzoyl, and the like. The terms "alkanoyloxy", "aroyloxy", and the like, as used herein, indicates the respective group connected through an intervening carboxylate, for example, -O(CO)CH 2

CH

3 , -O(CO)C 6

H

5 , and the like. The term "cycloalkyl group" is a cyclic alkyl group has from 3 to about 10 15 carbon atoms, preferably from 3 to about 7. Examples of suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. A "cycloalkoxy" group refers to a cycloalkyl group that is connected through an intervening oxygen atom, e.g., cyclopentyloxy, cyclohexyloxy, and the like. The term "aliphatic" includes branched and linear alkyl groups that contain 20 one or more units of carbon-carbon unsaturation, i.e., carbon-carbon double or triple bonds. A cycloaliphatic group is a cyclic aliphatic group, for example, cyclohexenyl or cyclopentenyl. The terms "aralkyl," "heteroaralkyl," "cycloalkylalkyl," "cycloaliphaticalkyl," and "nonaromatic heterocycloalkyl" refer to aryl, heteroaryl, cycloalkyl, 25 cycloaliphatic, and nonaromatic heterocyclic groups, respectively, that are connected through an alkyl chain, e.g., benzyl, -CH 2

-CH

2 - pyridine, (3-cyclohexyl)propyl, and the like. The terms biaryl, biheteroaryl, aryl-heteroaryl and heteroaryl-aryl, as used herein, indicate two aryl groups connected by a single covalent bond, two heteroaryl 30 groups connected by a single covalent bond, an aryl and heteroaryl group connected by single covalent bond, and a heteroaryl and aryl group connected by a single covalent bond, respectively. Examples of biaryl, biheteroaryl, heteroaryl-aryl and aryl-heteroaryl groups include biphenyl, bipyridyl, pyrimidyl-phenyl, and phenyl pyridyl, respectively. When a biaryl, biheteroaryl, heteroaryl-aryl or aryl-heteroaryl 41 WO 2009/102377 PCT/US2008/084832 group is a substituent, as in the definition of R4 for structural Formula I, the first recited group is bonded to the remainder of the molecule, i.e., "L" in structural Formula I. For example, when R4 in structural Formula I is a phenyl-pyridyl group, the phenyl of the phenyl-pyridyl group is bonded to L. 5 An "acyclic" group is a substituent that does not contain a ring. A "monocyclic" group contains only a single ring, for example, a phenyl ring that is not fused to another ring. A "polycyclic" group is a group that contains multiple fused rings, for example, naphthyl. A "substitutable atom" is any atom such as nitrogen or carbon that is bonded 10 through a single covalent bond to a hydrogen atom, wherein the hydrogen atom can be replaced with another group. A "substitutable ring atom" in an aromatic ring is any ring atom, e.g., a carbon or nitrogen, which is bonded by a single covalent bond to a hydrogen atom, wherein the hydrogen atom can be replaced with another group. Suitable substituents are those that do not substantially interfere with the 15 pharmaceutical activity of the disclosed compound. A compound or group can have one or more substituents, which can be identical or different. Examples of suitable substituents for a substitutable carbon atom in an alkyl, aliphatic, cycloalkyl, cycloaliphatic, non-aromatic heterocyclic, aryl, or heteroaryl group include -OH, halogen (-Br, -Cl, -I and -F), -R, -OR, -CH 2 R, - CH 2

CH

2 R, -OCH 2 R, -CH 2 OR, 20 CH 2

CH

2 OR, -CH 2 0C(O)R, -O-COR, -COR, -SR, -SCH 2 R, - CH 2 SR, -SOR, -SO 2 R, CN, -NO 2 , -COOH, -SO 3 H, -NH 2 , -NHR, -N(R) 2 , -COOR, -CH 2 COOR, CH 2

CH

2 COOR, -CHO, -CONH 2 , -CONHR, -CON(R) 2 , -NHCOR, -NRCOR, NHCONH 2 , -NHCONRH, -NHCON(R) 2 , -NRCONH 2 , -NRCONRH, -NRCON(R) 2 , C(=NH)-NH 2 , -C(=NH)-NHR, -C(=NH)-N(R) 2 , -C(=NR)-NH 2 , -C(=NR)-NHR, 25 C(=NR)-N(R) 2 , -NH-C(=NH)-NH 2 , -NH-C(=NH)-NHR, -NH-C(=NH)-N(R) 2 , -NH

C(=NR)-NH

2 , -NH-C(=NR)-NHR, -NH-C(=NR)-N(R) 2 , -NRH-C(=NH)-NH 2 , -NR C(=NH)-NHR, -NR-C(=NH)-N(R) 2 , -NR-C(=NR)-NH 2 , -NR-C(=NR)-NHR, -NR

C(=NR)-N(R)

2 , -SO 2

NH

2 , -SO 2 NHR, -SO 2

NR

2 , -SH, -SOkR (k is 0,1 or 2) and -NH

C(=NH)-NH

2 . Each R is independently an alkyl, cycloalkyl, benzyl, aromatic, 30 heteroaromatic, or N-anilinyl group that is optionally substituted. Preferably, R is unsubstituted. In addition, -N(R) 2 , taken together, can also form a substituted or unsubstituted heterocyclic group, such as pyrrolidinyl, piperidinyl, morpholinyl and thiomorpholinyl. Examples of substituents on group represented by R include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, 42 WO 2009/102377 PCT/US2008/084832 dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Suitable substituents on the nitrogen of a heterocyclic group or heteroaromatic group include -R', -N(R') 2 , -C(O)R', -CO 2 R, -C(O)C(O)R', -C(O)CH 2 C(O)R', 5 SO 2 R', -S02 N(R') 2 , -C(=S)N(R') 2 , -C(=NH)-N(R') 2 , and -NR'SO 2 R', wherein R' is hydrogen, an alkyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, phenoxy, benzyl, benzyloxy, heteroaromatic, or heterocyclic group that is optionally substituted. Examples of substituents on the groups represented by R' include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, 10 dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl. Preferably, R' is unsubstituted. Advantageously, the present invention also provides kits for use by a consumer for treating disease. The kits comprise a) a pharmaceutical composition comprising an antibiotic and a pharmaceutically acceptable carrier, vehicle or diluent; 15 and, optionally, b) instructions describing a method of using the pharmaceutical composition for treating the specific disease. The instructions may also indicate that the kit is for treating disease while substantially reducing the concomitant liability of adverse effects associated with antibiotic administration. A "kit" as used in the instant application includes a container for containing 20 the separate unit dosage forms such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for 25 pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained 30 within a box. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a 43 WO 2009/102377 PCT/US2008/084832 preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the 5 recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed 10 from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. It may be desirable to provide a written memory aid, where the written memory aid is of the type containing information and/or instructions for the 15 physician, pharmacist or subject, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested or a card which contains the same type of information. Another example of such a memory aid is a calendar printed on the card e.g., as follows "First Week, Monday, Tuesday," . . . etc. . . . "Second Week, 20 Monday, Tuesday, ... "etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. Another specific embodiment of a kit is a dispenser designed to dispense the daily doses one at a time. Preferably, the dispenser is equipped with a memory-aid, so 25 as to further facilitate compliance with the regimen. An example of such a memory aid is a mechanical counter, which indicates the number of daily doses that, has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one 30 when the next dose is to be taken. 44 WO 2009/102377 PCT/US2008/084832 EXEMPLIFICATION Example 1: Synthesis of PPAT inhibitors of structural Formula I: H O A 0H

NH

2 H R 3 2 R3 4R R" R" A N R'

R

3 5 R' and R" are, e.g. each indepently a hydrogen, carboxylic acid, halogen, alkyl, heterocycle, nitrile or hydroxyamide; R 3 is, e.g. an optionally substituted aryl. To a stirred solution of amine 1 in CH 2 Cl 2 is added aldehyde 2 followed by 5 TFA. The resulting solution is heated at reflux overnight. After concentration, a formed solid is filtered, washed with hexane, and dried to give 3. 3 is stirred at ambient temperature in a vial with DMF, benzaldehdye 4, and AcOH followed by addition of NaBH(OAc) 3 . The resulting solution is heated at 50 C overnight. Excess benzaldehyde may be added to drive the reaction to completion. The reaction mixture 10 is taken up in EtOAc and washed with saturated NaHCO 3 , brine, and dried (Na 2

SO

4 ) to obtain 5 that is further purified by flash chromatography. Example 2: Synthesis of PPAT inhibitor 2-(4-(2H-tetrazol-5-yl)benzyl)-1-(2,3 dichlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole: C N -H N--N a NHb CN N N ~N NN N~ NH H CI CI C CI CI 2 CI 3 1C Reagents and Conditions: a) 2,3-dichlorobenzaldehyde, TFA, DCE, heat. b) 3-cyanobenzaldehdye, AcOH, 15 DCE, then NaBH(OAc) 3 . c) NaN 3 , ZnBr 2 , heat. To a stirred solution of tryptamine (3.2g, 20 mmol) in dichloroethane (100 mL) was added 2,3-dichlorobenzaldehdye (3.5g, 20mmol), followed by TFA (0.5mL). The resulting solution was heated at reflux overnight. After concentration, a formed 45 WO 2009/102377 PCT/US2008/084832 solid was filtered, washed with hexane, and dried to give 1 as a pale yellow solid in quantitative yield. To a screw-capped 15 mL vial 1 (316 mg, 1.0 mmol), DMF (5 mL), 4 cyanobenzaldehdye (300mg, 2.3 mmol), and AcOH (200 tL) was added at ambient 5 temperature. To this solution was added NaBH(OAc) 3 (640 mg, 3 mmol). The resulting solution was heated at 50 C overnight. To the solution was added additional 4-cyanobenzaldehdye (200mg, 1.5 mmol) and NaBH(OAc) 3 (210 mg, Immol). After heating at 50 C overnight, the solution was taken up into with EtOAc (50 mL). The organic solution was washed with saturated NaHCO 3 (25 mL), brine 10 (10 mL), and dried (Na 2

SO

4 ) to obtain 3 (260mg, 60%) as a white solid after purification by flash chromatography (acetone : hexane = 20: 80). 'H NMR (400MHz, CDCl 3 ) 8 2.70 (m, 1H), 2.83 (m, 2H), 3.05 (dt, 1H), 3.60 and 3.86 (two d, 2H, J = 14Hz), 5.37 (s, 1H), 7.1-7.6 (set of m, 11H); LC/MS ES- 430 (M-1); >95% pure 15 To a 15 mL screw-capped vial was placed 2 (140mg, 0.32 mmol), followed by MeOH (5 mL). To this was added NaN 3 (150mg, 2.5 mmol), followed by ZnBr 2 (225mg, 1 mmol). The suspension was heated at 100 C overnight. Additional NaN 3 (150mg, 2.5 mmol) was added followed by heating at 100 C overnight. After concentration, the residue was triturated with IN HCl, followed by CHCl 3 , and dried 20 to provide a solid, which was purified by flash chromatography (EtOAc) to obtain 3 (100mg, 70%) as a yellow solid. 1H NMR (400MHz, DMSO-d 6 ) 8 2.61 and 2.85 (two m, 2H + 2H), 3.64 and 3.80 (two d, 2H J = 13.6Hz), 5.31 (s, 1H), 6.9-8.0 (set of m, 11H): LC/MS ES- 473 (M-1), ES+ 475 (M+1), >95% pure 25 Example 3: Synthesis of PPAT inhibitor 1-(3-(1H-tetrazol-5-yl)phenyl)-2-(2,3 dichlorobenzyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole CI C I NH c a\ NH c --- \ N NH2 - \ NH--b N N N H H H NO 1 CN N-N 3 N-N Reagents and Conditions: a) 3-cyanobenzaldehdye, TFA, DCE, heat. b) NaN 3 , ZnBr 2 , heat. c) 2,3-dichlorobenzaldehyde, AcOH, DCE, then NaBH(OAc) 3 46 WO 2009/102377 PCT/US2008/084832 To a stirred solution of tryptamine (1.60g, 10 mmol) in dichloroethane (50 mL) was added 3-cyanobenzaldehdye (1.31g, 10mmol), followed by TFA (0.25mL). The resulting solution was heated at reflux overnight. After concentration, the solid 5 was isolated on a filter, washed with hexane, and dried to give 1 as a pale yellow solid in quantitative yield. 'H NMR (400MHz, DMSO-d 6 ) 8 2.87 (m, 2H), 3.17 (m, 2H), 5.52 (s, 1H), 7.0-7.7 (set of m, 8H), 10.65 (s, 1H); LC/MS; ES+ 274 (M+1), >95% pure. To three screw-capped 15 mL vials were placed 1 (450mg/each, 1.7 10 mmol/each), followed by n-BuOH/H 2 0 (3 m/3 mL each). To this was added NaN 3 (130mg, 2.0 mmol), followed by ZnBr 2 (450mg, 2 mmol). The suspension was heated at 130 C overnight. After addition of H 2 0 and hexane, the solid was was isolated on filter and dried to provide 2 (1.50g total, 95%) as white solid. 1H NMR (400MHz, DMSO-d 6 ) 8 0.83 (t, 1H, J = 7.2Hz), 1.27 (m, 1H), 2.80 (m, 2H), 3.18 (m, 15 2H), 5.45 (s, 1H), 6.9-8.0 (set of m, 8H), 10. 60 (s, 1H); ES+ 317 (M+1), ES- 315 (M 1), >95% pure. To a screw-capped 15 mL vial was placed 2 (160 mg, 0.5 mmol), followed by DMF/DCM (2 mL/6 mL), 2,3-dichlorobenzaldehdye (153mg, 0.9 mmol), and AcOH (200 [IL) at ambient temperature. To this solution was added NaBH(OAc) 3 (250 mg, 20 1.2 mmol). The resulting solution was heated at 40'C overnight. The solution was poured into H 2 0 (20 mL) to form a solid, which was collected, washed with hexane, and dried to obtain 3 (130mg, 55%) as a yellow solid, after purification by chromatography (DCM: MeOH = 95:5). 1H NMR (400MHz, CD 3 0D) 8 3.16 (m, 2H), 3.35 and 3.60 (two m, 2H), 4.33 (ABq, 2H, J = 14.4Hz), 5.63 (s, 1H), 7.0-8.1 (set 25 of m, 11H); LC/MS ES+ 475 (M+1) ES- 473 (M-1) >95% pure Example 4: Bacteria are dependent on PPAT, a general target for antibiotics The gene for PPAT, named coaD (alternatively, kdtE), has been identified: see Geerlof, et al., "Purification and characterization of Phosphopantetheine 30 Adenylyltransferase from E. Coli" J. Biol. Chem., 1999, 274(38), pp. 27105-11, the entire teachings of which are incorporated herein by reference. The gene sequence has been searched in a range of bacteria and in mammals using BLAST@ (Basic 47 WO 2009/102377 PCT/US2008/084832 Local Alignment Search Tool, available online at http://www.ncbi.nkri.nih.gov/BLAST/). The results are provided in Table 2. Table 2: Conservation of PPAT gene (coaD) among range of bacterial species 5 Bacteria Gram p/n P(N) % Identity % Similarity Klebsiella pneumoniae negative 1.4E-72 85 91 Pseudomonas aeruginosa negative 7.20E-49 61 81 Neisseria meningitidis negative 4.80E-27 35 62 Enterococcusfaecium positive 4.20E-36 46 67 Staphylococcus aureus positive 2.10E-36 46 69 Staphylococcus positive 1.1OE-35 44 67 Streptococcus positive 2.60E-26 36 61 (mammalian) NA - 18 PPAT is seen to be highly conserved across a range of bacterial pathogens. Thus, PPAT is a general target for antibiotics. Furthermore, although PPAT is present in mammalian cells, the mammalian sequence is sufficiently different to indicate that 10 the disclosed PPAT inhibitors can be selective for bacterial PPAT. The gene for PPAT, coaD, is disrupted from a range of bacteria by allelic exchange; see, for example, Geerlof, et al., above, and Freiberg, et al. 2001. "Identification of novel essential Escherichia coli genes conserved among pathogenic bacteria" J Mol Microbiol Biotechnol 2001, 3, pp 483-9, the entire teachings of which 15 are incorporated herein by reference. The survival of Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Streptococcus pneumoniae in complex growth media is studied. The inability of the modified bacteria to survive without the coaD gene indicates that PPAT is necessary for bacterial survival and is thus a potential antibiotic target. 20 An additional experiment can test the survival of Escherichia coli in media containing exogenous dePhospho-CoA and/or CoA. Mammalian, including human cells, can make CoA from pantothenate (vitamin B 5 ) scavenged from the environment. Thus, it is possible that in a human subject, human cells/tissues could supply CoA to a bacterium that is unable to synthesize CoA. The inability of modified 25 Escherichia coli to survive in media containing exogenous dePhospho- CoA and/or CoA further indicates that PPAT can be an antibacterial target. 48 WO 2009/102377 PCT/US2008/084832 Example 5: Kinetic assay of PPAT inhibition The IC 50 (Inhibition Concentration at 50 percent) values for the disclosed compounds against PPAT can be determined with various concentrations of the compounds in a range of 0.003 ~ 200 tg/ml. Compounds with IC 5 o values >200 can 5 have a measurable IC50 using a different assay method. These inhibition assays can be performed in 96-well assay plates, using a similar method to the screening assay above. The reaction buffer should contain 20mM Hepes (pH 7.5), 100mM NaCl, 1mM MgCl 2 , 0.5mM DTT, 0.006% Brij 35, 10% Glycerol, 25tM PPT, 0.5mM ATP, 0.2 Unit of pyrophosphatase, 200ng of PPAT in a total volume of 100[tl. The reaction 10 is performed for 2 minutes, and then stopped with 150ml Malachite Green reagent. Absorption at 650nm is measured after 10 minutes of color development. The IC 5 o's are determined with fitting data to the four-parameter method using XLfit (ID Business Solutions Inc., Cambridge, MA). The IC 50 value is derived from the curve as the compound concentration that gives 50% inhibition of the enzymatic reaction. 15 In order to perform the IC 50 assays, purified PPAT is needed. The E. coli PPAT gene is cloned into the pET28a expression vector (Novagen, Inc., Madison, WT) and expressed in E. coli BL21(DE3) cells. A chromatographic purification procedure employs Q-sepharose, gel filtration, and MonoQ chromatography, as follows. The methods are described in detailed in Geerlof, et al., above. 20 Each cell pellet is suspended in a 4 fold-volume of lysis buffer (50mM

KH

2

PO

4 pH 8.0, 100mM NaCl, 2mM EGTA, and 10% glycerol. Cells are broken by passage through a Microfluidics cell disrupter 4 times, and the cell lysate should be centrifuged at 3,000 g for 20 minutes. The supernatant is then applied to a pre equilibrated Q-sepharose column (10mM Tris-HCl pH 8.0, 0.1mM EGTA, 1mM 25 PMSF, 100mM NaCl, 10% glycerol, 0.1% p-mercaptoethanol, and 0.02% Brij 35). PPAT is eluted with NaCl gradient (0.1~IM) in the equilibrium buffer. The major peak fractions are pooled and concentrated, then applied to a Sephacryl S200 HR column (10mM Tris-HCl pH 7.5, 150mM NaCl, 0.1mM EGTA, 0.1mM PMSF, 10% glycerol, 0.1% -mercaptoethanol, and 0.02% Brij 35). PPAT is eluted with the same 30 buffer. The major peak fractions are pooled and loaded on a pre-equilibrated MonoQ column (10mM Tris-HCl, pH 7.0, 0.1mM EGTA, 0.1mM PMSF, 10% glycerol, 0.1% -mercaptoethanol, and 0.02% Brij 35). PPAT should be eluted with a gradient of NaCl from 100mM up to 1000mM. The peak fractions are pooled and dialyzed in the 49 WO 2009/102377 PCT/US2008/084832 storing buffer (10mM MOPS pH7.0,150mM NaCl, 0.1mM EGTA, 50% glycerol, 0.02% Brij 35), then stored at -20'C. Data for these experiments for the compounds of the invention are shown in Table 3. Table 3: IC 5 o data for PPat inhibitors of formula I Compound PPAT E coli (pM) 1 >200 2 >200 3 75-150 4 1-10 5 >200 6 >200 7 NA 8 NA 9 NA 10 >200 11 75-100 12 40-120 13 30-50 14 20-40 15 25-75 16 30-70 17 20-40 18 50-80 19 30-50 20 20-40 21 30-60 22 5-15 23 110-180 24 20-40 25 90-120 26 70-90 27 60-110 28 >200 29 >200 30 20-50 31 140-180 32 5-10 33 50-80 34 30-50 35 30-50 36 90-100 37 120-170 38 75-160 39 80-110 40 >200 41 90-130 50 WO 2009/102377 PCT/US2008/084832 42 125-160 43 >200 44 110-160 45 >200 46 110-140 47 >200 48 20-40 49 20-30 50 20-30 51 40-60 52 80-110 53 30-50 54 >200 55 120-150 56 140-160 57 110-130 58 >200 59 >200 60 30-50 61 30-50 62 40-60 63 30-50 64 30-50 65 120-140 66 50-70 67 30-50 68 200 69 30-50 70 40-60 71 <1 72 1-10 73 >200 74 40-60 75 70-90 76 50-70 77 100-120 78 60-80 79 >200 80 30-50 81 30-50 82 >200 83 >200 84 >200 85 >200 86 >200 87 >200 88 >200 89 110-130 51 WO 2009/102377 PCT/US2008/084832 90 >200 91 >200 92 20-40 93 40-60 94 100-120 95 >200 96 50-70 97 >200 98 40-60 99 >200 100 >200 101 110-130 102 90-110 103 >200 104 90-110 105 >200 106 >200 107 >200 Example 6: Measuring disclosed PPAT inhibitors' antibiotic activity against drug-resistant bacteria Potency, spectrum, target specificity and serum effect is evaluated by 5 measuring the MIC (Minimum Inhibitory Concentration). This is the lowest concentration, in [tg/mL, in a series of 2-fold dilutions of the compound that completely inhibits growth, for a panel of pathogenic bacteria. The strains comprising the bacterial panel are either obtained from American Type Culture Collection (ATCC, Manassas, VA), or genetically engineered to express varying levels of PPAT. 10 The ATCC strains include the following: Escherichia coli (ATCC 35218), Staphylococcus aureus (ATCC 700699), and Enterococcusfaeciim (ATCC 700221). Other strains include Staphylococcus aureus RN4220, Escherichia coli WO-0159, Escherichia coli WO-0153, and Bacillus subtilis BD170 with endogenous PPAT disrupted and complemented with PPAT under the regulation of inducible promoter, 15 Pspace. The MIC assays are performed essentially as described in the NCCLS recommendations, the entire teachings of which are incorporated herein by reference (National Center for Clinical Laboratory Standards, 1997, (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria the Grow Aerobically), 4th ed.; 20 approved standard. NCCLS document M7-A4. NCCLS, Wayne, PA.), with the following exceptions: both Tryptic Soy broth, and Mueller Hinton broth with and 52 WO 2009/102377 PCT/US2008/084832 without the presence of serum are used as the growth medium. The concentration range tested is from 200 to 0.39 mcg/ml. Concentrations of 50-fold the desired final concentration are made by 2-fold serial dilutions in 96-well microtiter plates, after which 2 [tL are transferred to the assay plates. Cells are grown up in the appropriate 5 culture media and diluted back to final OD 600 of 0.001, after which 98 [tL is inoculated into the assay plates. The final volume in each assay well is 100 uL. After an overnight incubation at 37'C, the assay plates are read. The MIC is determined as the minimal concentration that results in >80% inhibition of growth. 10 GOVERNMENT SUPPORT This invention was made with government support from the National Institutes of Health. The government has certain rights in the invention. 15 53

Claims (19)

1. A compound of structural Formula I: R6 A R 5 J N'L/R4 R3 5 (I) and pharmaceutically acceptable salts, solvates, hydrates, enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof; wherein ring A is an aryl or heteroaryl group that is optionally substituted at any 10 substitutable ring atom; J is -0-, -S-, or -NR2-, wherein R2 is -H or optionally substituted C1-C5 alkyl; or, J is -NR2'-, wherein R2' is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 cycloaliphatic, or C3-C7 cycloalkyl; R3 is optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl, C3-C7 15 cycloaliphatic, or C3-C7 cycloalkyl; L is -(CH 2 )-, -(CO)-, -(CS)-, -(SO)-, or -(SO 2 )-; R4 is an aryl, biaryl, heteroaryl, biheteroaryl, heteroaryl-aryl, aryl-heteroaryl, aralkyl, heteroaralkyl, C1-C8 aliphatic, C3-C7 cycloalkyl, C5-C7 cycloaliphatic, or a

3-7 membered non-aromatic heterocyclic group; 20 wherein R4 can be substituted with halogen, -(CO)ORa, -(CO)O(CO)Ra, (CS)ORa, -(SO)ORa, SO 3 Ra, -OSO 3 Ra, -P(ORa) 2 , -(PO)(ORa) 2 , -O(PO)(ORa) 2 , B(ORa) 2 , -(CO)NR2, -NRc(CO)Ra, -SO 2 NRb2, or -NRcSO 2 Ra; R5 is -H, -(CO)ORa, -(CO)O(CO)Ra, -(CS)ORa, -(SO)ORa, SO 3 Ra, -OSO 3 Ra, -P(ORa) 2 , -(PO)(ORa) 2 , -O(PO)(ORa) 2 , -B(ORa) 2 , -(CO)NRb2, -NRc(CO)Ra, 25 SO 2 NRb2, or -NRcSO 2 Ra; R6 is -H, -OH, halogen, or optionally substituted C1-C3 alkyl or alkoxy; each Ra and Rc are, independently, -H, C1-C5 alkyl, aryl, or aralkyl; each R is, independently, -H, C1-C5 alkyl, aryl, or aralkyl, or NR b2 is a nonaromatic heterocyclic group. 30 54 WO 2009/102377 PCT/US2008/084832 2. The compound of claim 1, wherein Ring A is optionally substituted at any substitutable ring atom with RI, wherein each RI is independently halogen, -CN, NO 2 , -ORd, -(CO)Rd, -(CO)ORd, -O(CO)Rd, -(CO)O(CO)Rd, -(CS)ORd, -(SO)ORd _ d d d SO 3 R , -CONR 2, -O(CO)NRe 2 , -NR (CO)NRe 2 , -NRf(CO)ORd, -NR COR _ df d(H)N d 2 C 5 (S0 2 )NRe 2 , -NR'SO 2 Rd, -(CH 2 )sNRd2, or optionally substituted aryl, aralkyl or C1-C5 alkyl; wherein: each Rd and Rf are, independently,-H, aryl, aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl; and 10 each Re is independently -H, aryl, aralkyl, or C1-C5 alkyl, or NRe2 is a nonaromatic heterocyclic group, and s is 0 to 5. 3. The compound of claim 2 wherein Ring A is an optionally substituted phenyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, 15 isothiazolyl, or imidazolyl group.

4. The compound of claim 1, wherein R3 is an optionally substituted phenyl, pyridyl, benzo[1,3]dioxolyl, 2,3-dihydro-benzo[1,4]dioxine, pyrimidyl, pyrazyl, furanyl, pyrrolyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, 20 naphthyl, quinolinyl, biphenyl, benzopyrimidyl, benzopyrazyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzoisooxazolyl, benzothiazolyl, benzoisothiazolyl, or benzimidazolyl group.

5. The compound of claim 1, wherein R4 is a substituted phenyl, pyridyl, 25 pyrimidyl, pyrazyl, naphthyl, biphenyl, phenyl-pyridyl, bipyridyl, quinolinyl, benzopyrimidyl, benzopyrazyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, or C2-C8 alkenyl group. 30 55 WO 2009/102377 PCT/US2008/084832

6. The compound of claim 5, wherein R4 is represented by one of structural formulas R4-i to R4-vii: A(R1O)m (R10)m (R10)M (CO)R8 (CO)R8 R4-i (RIO)m R4-i (RIO)m R4-vi (RIO)m (RIO)m (RIO)m R9 - - -- C -- -- --B (CO)R8 (R1O)m (CO)R8 D D (CO)R8 (R1O)m (CO)R8 R4-ii R4-iv R4-v R4-vii 5 wherein: each m is independently 0, 1, 2, or 3; X is -N-, -CH-, or -CR10-; Ring B is C3-C6 cycloalkyl or C3-C6 cycloalkenyl; Rings C and D are each independently aryl or heteroaryl; 10 R8 is-OR q or -NRW2; R9 is -H, aryl, aralkyl, or C1-C6 aliphatic; each RIO is independently halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR', -(CO)R', (CO)OR', -O(CO)R', -(CO)O(CO)R', -(CS)OR', -(SO)OR', -SO 3 R', -CONRj 2 , O(CO)NR 2 , -NRk(CO)NRj 2 , -NRk(CO)ORi, -NRkCOR', -(SO 2 )NR' 2 , -NR SO 2 R', 15 (CH 2 )tNRj 2 , or optionally substituted aryl, aralkyl or Cl-C5 alkyl; each R and Rk are, independently,-H, aryl, aralkyl, Cl-C5 alkyl, or Cl-C5 haloalkyl; each Ri and R are, independently, -H, aryl, aralkyl, or Cl-C5 alkyl, or each NR1 2 and NRr 2 are, independently, a nonaromatic heterocyclic group; 20 Rq is -H or optionally substituted aryl, aroyl, aralkyl, aralkanoyl, Cl-C5 alkyl, or Cl-C5 alkanoyl; and t is 0 to 5. 56 WO 2009/102377 PCT/US2008/084832

7. The compound of claim 6, wherein R4 is represented by one of structural formulas R4-i' to R4-vii': (R10) (R1O)m (R1O)m (CO)R8 O (CO)R8 (CO)RB (RIO)m R4- R4-ii' R4-1111 (R10)m (RIO)m (R1O)m R9 (CO)R8C)R8 (CO)R(CO)RB (CO)RO R4-vii' R4-iv' R4-v' R4-vi' wherein: 5 each m is independently 0, 1, 2, or 3; R8 is -OH, C1-C5 alkoxy, or C1-C5 alkanoyloxy; R9 is -H or C1-C6 aliphatic; and each RIO is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, C1-C4 alkoxy, -CF 3 , or -OCF 3 . 10

8. The compound of claim 4, wherein R3 is represented by one of structural formulas R3-I to R3-v: (R1 1), (R 11), (R 11), R3-i R3-ii R3-iii C z(R1 1), (R 11), (Ri i1), (R1 1)" R3-iv R3-v wherein 15 Y is -N-, -CH-, or -CR11-; Z is-NRz-, -S-, or -0-, wherein Rz is -H or C1-C3 alkyl; the variable w is 0, 1, 2, or 3; each R 11 are, independently, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , -OR , (CO)R 1 , -(CO)OR, -O(CO)Rl, -(CO)O(CO)Rl, -(CS)OR, -(SO)OR, -S0 3 R 1 , 20 CONR m 2 , -O(CO)NR m 2 , -NR"(CO)NR m 2 , -NR"(CO)OR 1, -NR"COR 1 , -(S0 2 )NR m 2 ) NR"SO 2 R 1 , -(CH 2 )uNRI 2 , or optionally substituted aryl, aralkyl, or C1-C5 alkyl; 57 WO 2009/102377 PCT/US2008/084832 u is 0 to 5, each RI and R" are, independently, -H, aryl, or aralkyl, C1-C5 alkyl, or C1-C5 haloalkyl; and each R' is independently -H, aryl, aralkyl, or C1-C5 alkyl, or NR' 2 is a nonaromatic heterocyclic group. 5

9. The compound of claim 8, wherein R3 is represented by one of structural formulas R3-i' to R3-v': 0 N (R11), (R11), (R1 1), R3-4 R3-ji' R3-ii' SSJ (R11)) (R1 1), R3-iv' R3-v' wherein: 10 w is 0, 1, 2, or 3; and each R11 is independently -OH, -NO 2 , -F, -Cl, -Br, C1-C4 alkyl, Cl-C4 alkoxy, -CF 3 , or -OCF 3 .

10. The compound of claim 5, wherein R4 is phenyl substituted by one of 15 structural formulas ROi - RIOxix: HN H-N s 0' R10-i R10-ii R10-iii R10-iv R10-v R1O-vi R10-vii F H NN N N N F R10-x R10-xi R10-xii R10-xiii R10-viii R10-ix 0 0 0 0 0ON) ) NH > NH > NH NH OH 10 NH 2 HNN H R10-xiv R10-xv R10-xvi R10-xvii R10-xv111 H R10-xix 58 WO 2009/102377 PCT/US2008/084832

11. The compound of claim 8, wherein R 11 is represented by one of structural formulas R11-i to R11-xxiii; /N '-) > HN-N 8 0' R11-i R11-i R11-iii R11-iv R11-v R11-vi R11-vii FN N N N-N-N L F R11-x R11-xi R11-xii R11-xiii R11-viii R11-ix 0 0 0 0 0 > NH > NH > NH > NH H OH $ NH 2 HNN RHh-xviii R11-xiv R11-xv R11-xvi R11-xvii 0 N (PO)(OR) 2 -P(OR) 3 -O(PO)(OR) 2 -B(OR) 2 H R11-xx R11-xxi R11-xxii R11-xxiii R11-xix wherein R is independently -H, aryl, or aralkyl, C1-C5 alkyl, or C1-C5 5 haloalkyl. 10 15 20 59 WO 2009/102377 PCT/US2008/084832

12. The compound of claim 1, wherein: R3 is represented by one of structural formulas R3a to R3r: OMe R3a R3b F F F CI F OMe R3C R3d R30 R3r CI C1 Cl Me Me CI CI CI OH R39 R3h R3 R3 CI OH OEt F OH F R3k R3 R3" R3" N CS R3 0 R3P R3q R3r 5 10 60 WO 2009/102377 PCT/US2008/084832

13. The compound of claim 1, wherein R4 is represented by one of structural formulas R4a to R4q: (CO)R8 (CO)R8 (CO)R8 (CO)R8 CI t-Bu CI t-Bu R4a R4b R4 R4d (CO)R8 (CO)R8 (CO)R8 (CO)R8 F Me Me F R49 R41 R49 R4h (CO)R8 (CO)R8 (CO)R8 (CO)RS NN R4' R41 R4k R4' (CO)R8 (CO)R8 I (CO)R8 Me (CO)R8 R4 m R4" R4 0 R4P R44 /3(CO)R8 5 wherein R4a to R4 R8 is -NRY 2 , -OH, C1-C5 alkoxy, or C1-C5 alkanoyloxy, wherein each RY is independently -H or C1-C3 alkyl.

14. The compound of claim 1 wherein: R3 is represented by one of structural formulas R3a to R3'; and 10 R4 is represented by one of structural formulas R4a to R4 . 61 WO 2009/102377 PCT/US2008/084832

15. The compound of claim 1, wherein R5 is N N N // \ i> 0 HN-N 8 SS 0 Fb N 0 0 0 0 0 > NH > NH > NH NH OH 6 NH 2 HNs H H 0 H

16. The compound of claim 1, wherein ring A is an aryl moiety; J is N(H); R3 is 5 aryl optionally substituted one or more times with halogen or a heteroaryl; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H, alkyl, alkoxyl, CO 2 H or CO 2 alkyl; and R6 is H, alkyl oralkoxyl. 10 17. The compound of claim 1, wherein ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted one or more times with halogen or tetrazole; L is (CO) or (CH 2 ); R4 is phenyl optionally independently substituted one or more times with halogen, CO 2 H, or a heteroaryl; R5 is H or CO 2 H or CO 2 alkyl; and R6 is H. 15 18. The compound of claim 1, wherein ring A is a phenyl moiety; J is N(H); R3 is phenyl optionally substituted with tetrazole; L is CH 2 ; R4 is phenyl optionally independently substituted one or more times with halogen.

19. The compound of claim 1, wherein the compound of Formula I is selected 20 from the group consisting of the individual compounds provided in Table 1. 62 WO 2009/102377 PCT/US2008/084832

20. A method of treating a subject for a bacterial infection, comprising administering to a subject in need of treatment for a bacterial infection an effective amount of a compound of claim 1. 5 21. The method of claim 20, wherein the compound of claim 1 is selected from the group consisting of the individual compounds provided in Table 1.

22. The method of claim 20, wherein the subject is a human. 10 23. The method of claim 20, wherein the infection is caused by a bacterium that expresses phosphopantetheine adenylytransferase.

24. The method of claim 20, wherein the infection is caused by a bacteria of a genus selected from Acinetobacter, Bacillus, Campylobacter, Chlamydia, 15 Chlamydophila, Clostridium, Citrobacter, Escherichia, Enterobacter, Enterococcus, Francisella, Haemophilus, Helicobacter, Klebsiella, Listeria, Moraxella, Mycobacterium, Neisseria, Proteus, Pseudomonas, Salmonella, Serratia, Shigella, Stenotrophomonas, Staphyloccocus, Streptococcus, and Yersina. 20 25. A pharmaceutical composition comprising a compound of claim 1. 63