AU2012216678A1

AU2012216678A1 - Substituted tetracycline compounds

Info

Publication number: AU2012216678A1
Application number: AU2012216678A
Authority: AU
Inventors: Paul Abato; Haregewein Assefa; Joel Berniac; Beena Bhatia; Todd Bowser; Jackson Chen; Mark Grier; Laura Honeyman; Mohamed Y. Ismail; Ohemeng Kwasi; Mark Nelson; Jingwen Pan
Original assignee: Paratek Pharmaceuticals Inc
Current assignee: Paratek Pharmaceuticals Inc
Priority date: 2004-10-25
Filing date: 2012-09-06
Publication date: 2012-09-20

Abstract

The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.

Description

SUBSTITUTED TETRACYCLINE COMPOUNDS Related Applications This application claims priority to U.S. Provisional Patent Application No. 60/622,027, filed on October 25, 2004, and U.S. Provisional Patent Application No. 5 60/622,749, filed on October 27, 2004, the entire contents of each of which are incorporated herein by reference. Background of the Invention The development of the tetracycline antibiotics was the direct result of a 10 systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bacteriocidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the 15 analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of tetracycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972. Recently, research efforts have focused on developing new tetracycline antibiotic 20 compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Patent Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are 25 representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions. Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for 30 lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as "broad spectrum" antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for 35 both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline-resistant - 1 organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice. Summary of the Invention 5 In one embodiment, the invention pertains, at least in part, to substituted tetracycline compounds of Formula (I) - OH N(Me), 0H NH, OH 0 OH OH O O wherein 10 R 9 is substituted or unsubstituted aminocarbonylalkyl, aminoalkylcarbonylaminoalkyl, carboxylate, arylalkylaminoalkyl, alkylcarbonylaminoalkyl, dialkylaminoalkyl, N-piperazinyl alkyl substituted phenyl, alkoxy substituted phenyl, substituted furanyl, alkylaminocarbonyl and pharmaceutically acceptable salts, esters, and prodrugs thereof. 15 In another embodiment, the invention pertains, at least in part, to substituted tetracycline compounds of Formula (II): R7 N(Me), OH NH, OH OH 0 OH 0 0 (1) 20 wherein

R

7 is dimethylamino, substituted phenyl, substituted pyridinyl, alkoxycarbonylalkylaminocarbonyl, pyridinylalkylaminoalkyl, pyridinylalkylaminocarbonyl, substituted or unsubstituted arylaminoalkylcarbonyl, substituted or unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl, 25 alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl, alkoxylcarbonyl substituted alkylaminoalkylcarbonyl or arylaminoalkylcarbonyl;

R

9 is ethyl, aminomethyl, dialkylaminocarbonylalkyl, hydrogen, alkoxy substituted alkynyl, carboxylate substituted alkynyl, alkoxycarbonyl substituted alkynyl, dialkylamino substituted phenyl, cyano, acyl, substituted carboxylate aminomethyl, 30 alkylaminocarbonyl, and pharmaceutically acceptable salts, esters and prodrugs thereof. -2- In yet another embodiment, the invention pertains, at least in part, to substituted tetracycline compounds of Formula (III): N(Me)2 N(Me)2 OH R9 NH2 R9 6H OR 0 OH O(Il) 5 wherein

R

9 is R'-O-N=CR"-, R'-OC(=O)-, R 9 aR 9 bNC(=O)-, methoxycarbonyl substituted alkynyl, pyrazinyl, alkylaminocarbonyl alkyl, methoxymethyl, methoxymethyl substituted alkynyl, dimethylaminocarbonyl, cyclopropyl, methyl, amino substituted pyridinyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, pyrimidinyl, alkoxycarbonyl 10 substituted alkynyl, oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl, alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted or unsubstituted arylthiocarbonyl, cyano, deuterated alkylaminoalkyl, pyrrolidonylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted phenyl, cyano substituted pyridinyl, aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted or unsubstituted 15 thiophenyl, substituted or unsubstituted furanyl, alkylcarbonylamino substituted pyridinyl, dialkylamino substituted phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or piperazinylcarbonyl;

R

10 is hydrogen or alkenyl; R' is unsubstituted alkyl, amino substituted alkyl, methoxy substituted 20 alkyl, halogen substituted alkyl; R" is alkyl; Ra is hydrogen or alkyl; R9b is alkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, cycloalkyl or 25 aminoalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that when R 9 is halogen, then R 10 is alkenyl. -3 - In yet another embodiment, the invention also pertains, at least in part, to tetracycline compounds of Formula (IV): R7, R7b R71 R7" R7, N(Me), H, OH OH H(IV) 5 wherein R7a is methoxy, dialkylaminomethyl, substituted N-piperdinyl methyl, fluorine, or hydrogen; R7b is hydrogen;

R

7 is alkoxyalkylaminoalkyl, halogenated N-piperdinyl methyl, hydroxyl, 10 dialkylaminoalkylamino, dialkylaminomethyl, substituted N-piperidinyl methyl, substituted N-pyrrolyl methyl, or hydrogen; R7d is arylalkylaminoalkyl, arylalkyl substituted alkylaminoalkyl, substituted N-piperidinylmethyl, N-piperidinyl substituted aminomethyl, cyclopropylamino methyl, piperdinyl substituted alkyl, dialkylaminomethyl, heteroaryl 15 substituted dialkylaminomethyl, alkylaminomethyl, cycloalkylaminomethyl, alkylaminoethyl, cyano substituted dialkylaminomethyl, N-pyrrolidinyl substituted methyl, N-pyrrolyl substituted methyl, methoxy substituted dialkylaminomethyl, alkoxyalkylaminomethyl, substituted carboxylate alkylaminomethyl, hydrogen or linked with R7' by a -O-CH 2 -0- linker; 20 R 7 , is hydrogen, and pharmaceutically acceptable salts, esters and prodrugs 7a 7b 7c 7d 7' thereof, provided that each of R a, R , R', R , and R are not hydrogen. In another further embodiment, the invention pertains, at least in part, to tetracycline compound of Formula (V): 25 R7, R7hi R7 T N(Me)2 OH NH, OH O OH (V) wherein T is NH or 0; -4- R 7is dialkylaminoalkyl, N-piperidinylamino alkyl, substituted or unsubstituted N-piperdinylalkyl, N-pyrrolidinylamino alkyl, substituted or unsubstituted N-pyrrolidinylalkyl, substituted or unsubstituted N-pyrrolylalkyl, alkenenyl substituted dialkylaminoalkyl, N-decahydroisoquinolinylalkyl, alkoxyalkylaminoalkyl, or hydrogen; 5 R 7 is hydrogen; R7h is heteroaryl substituted alkylaminoalkyl, dialkylaminoalkyl, substituted N-piperidinylalkyl or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that each of R R , and R 7 h are not hydrogen. 10 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of Formula (VI): R R M OH N(Me) H OH OH OH (VI) wherein

R

7 i is fluorine or hydrogen; 15 R 7 j is trifluoromethyl, alkyloxycarbonyl, methyl, cyano, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that both of R 7 and R 7 j are not hydrogen. In yet another embodiment, the invention also pertains, at least in part, to 20 tetracycline compounds of Formula (VII):

R

7 k N N(Me)2

-

OH I NH2 OH O OH O 0 (VII) wherein p is a single or double bond;

R

7 k is alkyl, cycloalkyl, dialkylaminoalkylcarbonyl, alkoxyalkylcarbonyl, 25 halogen substituted alkyl, halogen substituted cycloalkyl, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof. -5- In yet another embodiment, the invention also pertains, at least in part, to tetracycline compounds of Formula (VIII): R7 N(Me)2 - OH NH, # ; OH OH 0 OH 0 0 (VIII) 5 wherein

R

7 is fluoro substituted N-pyrrolidinylalkyl, N-piperidinylalkylcarbonyl, dialkylaminoalkylaminocarbonyl, aminoalkyl, N-pyrroyl alkyl, dialkylamino substituted pyridinyl, phenyl substituted N-piperizinyl alkyl, alkylaminoalkyl, alkoxy substituted pyrimidinyl, 1-H-pyrimidin-2-onyl, cyano substituted pyridinyl, N-pyrrolidinyl alkyl, 10 halogen substituted pyridinyl, arylalkylamino alkyl, alkoxyalkylaminoalkyl, N imidizolylalkylcarbonyl, N-dihydroimidizolylalkylcarbonyl, imidizopyrimidinyl, imidizopyridinyl, or pyrizinyl substituted amino alkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof. 15 In yet another embodiment, the invention also pertains, at least in part, to tetracycline compounds of Formula (IX): R7 N(Me) 2 OH

R

9 cHN

NH

2 OHO OH OHOHO o (IX) wherein 20 R 7 is dialkylaminomethyl, alkoxy substituted phenyl, hydroxy, halogen substituted phenyl, halogenated alkyl substituted phenyl, naphthyl;

R

9 ' is hydrogen, fluorinated alkyl or unsubstituted alkyl and pharmaceutically acceptable salts, esters and prodrugs thereof. 25 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of the Formula (X): R 7 R 5 R 5, R 4 R 4' R8 X OH ONR ZR 2 R9r OR10 O (X) -6wherein R' is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, 5 alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or halogen, optionally linked to R2 to form a ring;

R

2 is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, or absent, optionally linked to R' to form a ring; 10 R 2 , R 2 ", R 4 a, and R 4 b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R

10 is hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; R 11 is hydroxyl, alkoxy, aryloxy, or alkylamino; 15 R4 and R4 are each independently NR 4aR 4, alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; 20 R 6 and R 6 ' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R

7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, 25 acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 )o- 3 (NR7")oiC(=W')WR71;

R

8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 )o- 3

(NR

8 :)o-iC C(=E')ER 8 a;

R

9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 30 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3

(NR

9 ')o 1 C C(=Z')ZR 9 d; 71 7m 7n 7o p7 8a 8b 8C 8d 8e 8f 9d 9e9 R1 'R"' RY" R R, 'R, 'Ra RE 'R ', R R R 'R9 R, R9f, R99, 9h 9i Rh, and R are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, 35 heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR8dRe, S, NR 8 or 0; - 7- E' is 0, NR', or S; Q is a double bond when R 2 is absent, Q is a single bond when R 2 is hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl, alkoxy, amino, alkylamino, cyano, nitro, or heterocyclic; 5 W is CR'ORP, S, NR' or 0; W' is 0, NR , or S; X is CHC(R"Y'Y), C=CR"Y, CRR', S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 10 alkylamino, or an arylalkyl; Z is CR'gRh, S, N e or 0; Z' is 0, S, or NR 9 , and pharmaceutically acceptable salts, esters and enantiomers thereof. 15 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of the Formula (XI): RIr N H H - H OH2 ONH OH O OH O O (XI) wherein 20 R 7 , is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl and pharmaceutically acceptable salts, esters and enantiomers thereof. In yet another embodiment, the invention pertains, at least in part, to tetracycline compounds of the Formula (XII):

R

7 S N O N H H OH

NH

2 25 OH 0 O-PH O O (XII) wherein W is N or CH; and -8 - Rs is substituted or unsubstituted alkyl, aryl, alkoxycarbonyl, alkylcarbonyl, cycloalkyl, or aminocarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. 5 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of Formula (XIII): NR7t'R7t" O )n N H H OH OH OH O OH O O (XIII) wherein 10 nis0,1or2;

R

7 C is hydrogen, alkyl, alkenyl or cycloalkyl;

R

7 t is unsubstituted alkyl, dialkylaminoalkyl, halogenated alkyl, alkoxyalkyl, substituted or unsubstituted arylalkyl, cycloalkyl, alkenylalkyl, heterocyclic, cyano substituted alkyl, alkoxy substituted alkyl, heteroarylalkyl, aminocarbonylalkyl, aryl, 15 hydrogen, alkylcarbonyl, aminoalkyl or alkoxycarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. In another embodiment, the invention pertains, at least in part, to tetracycline compounds of Formula (XIV): 20 RIu N H H OH NH2 OH O OH O 0 (XIV) wherein

R

7 u is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl, alkoxyaminoalkyl, alkylaminoalkyl or dipiperidinium methyl; and pharmaceutically 25 acceptable salts, esters and enantiomers thereof. In another embodiment, the invention pertains, at least in part, to tetracycline compounds of formula (XV): -9- R 7v 0 s OH NH2 OHO OHO 0 (XV) wherein

R

7 , is heterocyclic; and pharmaceutically acceptable salts, esters and enantiomers thereof. 5 In yet another embodiment, the invention pertains, at least in part, to tetracycline compounds of formula (XVI): R7 R5 R5' R4 RX OR' NR2R2' R9 OR12

OR'

0 N NR" O O (XVI) 10 wherein: R2, R2", R a, and R are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 11 12 R , R and R are each independently hydrogen, alkyl, aryl, benzyl, 15 arylalkyl, or a pro-drug moiety;

R

3 is hydroxyl, hydrogen, or a pro-drug moiety; R4 is NR 4aR4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen;

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, 20 alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R

7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 25 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR 7) 0 1 C(=W')WR7a

R

8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR c)o-i (=E')ER8a - 10 -

R

9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR9c)o 1 C(=Z')ZR9a 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R I, R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 5 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 10 E is CR8dRe, S, NR 8 or 0; E' is 0, NR', or S; 7d 7e 7b WisCR R , S, NR or 0; W' is 0, NR 7 f, or S; X is CHC(R Y'Y), C=CR Y, CRR', S, NR6, or 0; 15 Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; Z is CR9dR**, S, NR9b or 0; Z' is 0, S, or NR 9 , and pharmaceutically acceptable salts, esters and 20 enantiomers thereof. In yet another embodiment, the invention pertains, at least in part, to tetracycline compounds of formula (XVII): R7 R5 R5' R4 RaX OR H R9 N Ra (XVII) wherein: R2a is alkyl or aryl; R4a and R are each independently hydrogen, alkyl, alkenyl, alkynyl, 30 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 11 12 R , R and R are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; - 11 -

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, 5 alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkylcarbonyloxy, or arylcarbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R

7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 10 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR 7) 0

_

1 C(=W')WR7a

R

)

0

-

3 (NR c)o 1 C(=E')ER8a 15 R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR9c)o 1 C(=Z')ZR9a 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R I, R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, 20 alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR8dRe, S, NR 8 or 0; 25 E' is 0, NR', or S; 7d 7e 7b WisCR R , S, NR or 0; W' is 0, NR 7 f, or S; X is CHC(R Y'Y), C=CR Y, CR6'R6, S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, 30 sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; Z is CR 9R**, S, NR9b or 0; Z' is 0, S, or NR 9 , and pharmaceutically acceptable salts, esters and enantiomers thereof. 35 In another further embodiment, the invention pertains, at least in part, to methods for treating subjects for tetracycline responsive states by administering to them an effective amount of a tetracycline compound of the invention, e.g., a compound of - 12 - Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or a tetracycline compound otherwise described herein. In another further embodiment, the invention pertains, at least in part, to to pharmaceutical compositions which comprise an effective amount of a tetracycline 5 compound of the invention, e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or a tetracycline compound otherwise described herein, and a pharmaceutically acceptable carrier. Detailed Description of the Invention 10 The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression. 15 The term "tetracycline compound" includes many compounds with a similar ring structure to tetracycline. Examples of tetracycline compounds include: chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, chelocardin, rolitetracycline, lymecycline, apicycline; clomocycline, guamecycline, meglucycline, mepylcycline, penimepicycline, pipacycline, etamocycline, penimocycline, etc. Other derivatives and 20 analogues comprising a similar four ring structure are also included (See Rogalski, "Chemical Modifications of Tetracyclines," the entire contents of which are hereby incorporated herein by reference). Table 1 depicts tetracycline and several known other tetracycline derivatives. Table 1 H3C OH OH N(Me)2 c H OH N(Me), N(Me)2 N(Me)2 OH OH O CONH2 CONH, OH ONH2 OH 0 OH 0 OH 0 OH 0 OH 0 OH 0 Oxytetracycline Demeclocycline Minocycline CH2 OH N(Me)2 C113 Oil OHMO N(e OH Oil i2 CONH2 ol NHN ONH2 O H 0 O H 0 Oil 0 Oil 0 O 0 0H 0 Methacycline Doxycycline Chlortetracycline

H

3 C OH N(Me) 2 N(Me)2 N(Me)2 OH O H OH OH CONH2 HC OCH3 H H 0 OH 0 O H 0 O H O H 0 0 H TetracycHne Sancycline Chelocardin 25 -13 - Other tetracycline compounds which may be modified using the methods of the invention include, but are not limited to, 6-demethyl-6-deoxy-4 dedimethylaminotetracycline; tetracyclino-pyrazole; 7-chloro-4 dedimethylaminotetracycline; 4-hydroxy-4-dedimethylaminotetracycline; 12a-deoxy-4 5 dedimethylaminotetracycline; 5-hydroxy-6a-deoxy-4-dedimethylaminotetracycline; 4 dedimethylamino-12a-deoxyanhydrotetracycline; 7-dimethylamino-6-demethyl-6-deoxy 4-dedimethylaminotetracycline; tetracyclinonitrile; 4-oxo-4-dedimethylaminotetracycline 4,6-hemiketal; 4-oxo- 11 a Cl-4-dedimethylaminotetracycline-4,6-hemiketal; 5 a,6-anhydro 4-hydrazon-4-dedimethylamino tetracycline; 4-hydroxyimino-4-dedimethylamino 10 tetracyclines; 4-hydroxyimino-4-dedimethylamino 5a,6-anhydrotetracyclines; 4-amino-4 dedimethylamino-5a, 6 anhydrotetracycline; 4-methylamino-4-dedimethylamino tetracycline; 4-hydrazono- 11 a-chloro-6-deoxy-6-demethyl-6-methylene-4 dedimethylamino tetracycline; tetracycline quaternary ammonium compounds; anhydrotetracycline betaines; 4-hydroxy-6-methyl pretetramides; 4-keto tetracyclines; 5 15 keto tetracyclines; 5a, 11 a dehydro tetracyclines; 11 a Cl-6, 12 hemiketal tetracyclines; 11 a Cl-6-methylene tetracyclines; 6, 13 diol tetracyclines; 6-benzylthiomethylene tetracyclines; 7, 11 a -dichloro-6-fluoro-methyl-6-deoxy tetracyclines; 6-fluoro (c)-6 demethyl-6-deoxy tetracyclines; 6-fluoro (p)-6-demethyl-6-deoxy tetracyclines;6-a acetoxy-6-demethyl tetracyclines; 6-P acetoxy-6-demethyl tetracyclines; 7, 13 20 epithiotetracyclines; oxytetracyclines; pyrazolotetracyclines; 11 a halogens of tetracyclines; 12a formyl and other esters of tetracyclines; 5, 12a esters of tetracyclines; 10, 12a- diesters of tetracyclines; isotetracycline; 12-a-deoxyanhydro tetracyclines; 6-demethyl-12a-deoxy 7-chloroanhydrotetracyclines; B-nortetracyclines; 7-methoxy-6-demethyl-6 deoxytetracyclines; 6-demethyl-6-deoxy-5a-epitetracyclines; 8-hydroxy-6-demethyl-6 25 deoxy tetracyclines; monardene; chromocycline; 5a methyl-6-demethyl-6-deoxy tetracyclines; 6-oxa tetracyclines, and 6 thia tetracyclines. In one embodiment, the invention pertains, at least in part, to substituted tetracycline compounds of Formula (I): 30 - OH N(Me), NH, OH OH 0 OH O () wherein

R

9 is substituted or unsubstituted aminocarbonylalkyl, aminoalkylcarbonylaminoalkyl, carboxylate, arylalkylaminoalkyl, 35 alkylcarbonylaminoalkyl, dialkylaminoalkyl, N-piperazinyl alkyl substituted phenyl, - 14 alkoxy substituted phenyl, substituted furanyl, alkylaminocarbonyl and pharmaceutically acceptable salts, esters, and prodrugs thereof. In one embodiment, R 9 is substituted aminocarbonylalkyl (e.g., t-butyl substituted aminoalkylcarbonyl). In another embodiment, R9 is dialkylaminoalkyl, such as 5 dimethylaminoalkyl. In yet another embodiment R9 is arylalkylaminoalkyl, such as phenylalkylaminoalkyl. In another embodiment, R 9 is alkoxy substituted phenyl which is further substituted by a pyrrolidinyl alkyl moiety. In yet another embodiment, R 9 is substituted furanyl, such as carbonyl substituted furanyl, dialkylaminoalkyl (e.g., dimethylaminoalkyl) substituted furanyl and pyrrolidinylalkyl substituted furanyl. 10 Examples of substituted tetracycline compounds of Formula (I) include: OH"N -1 N NH HC)H - H H O OH 0 O HOO O HHO HHO O H O O NH2 HNH OH H- O NH2 NHN N-C OOH OH 0 OH 0 0 H OH NH2OH NH2CFOsC. NH2 H!'; F) H H OH - OH-O H-lj OH OH NH2NH2 NHH OH OHO0 OHO0 0 OHO0 OHO 0 OHI OF N -CF, H CH, HC~ CH, H CH ,OH 'N CH H ' HHN OH OH OH R 9 -

NH

2 OHO OH O OH 0 HC, ~ OH 0 OH -H0 0 N 0H 60 OHO 01 0' 0 1 -OH"N .1 OH'N" OH H O

NH

2

-NH

2 -50 OHO0 0? 0 NOOH O 0 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of Formula (11): R7 N(Me), NiH, # 06H H00 O 0 0 (I 15 wherein R 7 is dimethylamino, substituted phenyl, substituted pyridinyl, alkoxycarbonylalkylamino carbonyl, pyridinylalkylaminoalkyl, pyridinylalkylamino carbonyl, substituted or unsubstituted arylaminoalkylcarbonyl, substituted or unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl, - 15 alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl, alkoxylcarbonyl substituted alkylaminoalkylcarbonyl or arylaminoalkylcarbonyl;

R

9 is ethyl, aminomethyl, dialkylaminocarbonylalkyl, hydrogen, alkoxy substituted alkynyl, carboxylate substituted alkynyl, alkoxycarbonyl substituted alkynyl, 5 dialkylamino substituted phenyl, cyano, acyl, substituted carboxylate aminomethyl, alkylaminocarbonyl, and pharmaceutically acceptable salts, esters and prodrugs thereof. In one embodiment, R 7 is dimethylamino. In another embodiment, R 9 is ethyl, dialkylaminocarbonylalkyl (e.g., dimethylaminocarbonylalkyl) alkyoxysubstituted alkynyl (e.g., methoxysubstituted alkynyl), carboxylate substituted alkynyl, alkoxycarbonyl 10 substituted alkynyl (e.g methoxycarbonyl substituted alkynyl), dialkylamino substituted phenyl (e.g. dimethylamino substituted phenyl), cyano, acyl, substituted carboxylate aminomethyl or alkylaminocarbonyl (e.g., n-propylaminocarbonyl or t butylaminocarbonyl). In another embodiment, R 9 is hydrogen. In yet another embodiment, R 7 is 15 substituted pyridinyl (e.g., methyl substituted pyridinyl), alkoxycarbonylalkylaminocarbonyl (e.g., methyoxycarbonylalkylaminocarbonyl), pyridinylalkylaminoalkyl, substituted or unsubstituted arylaminoalkylcarbonyl (e.g., phenylaminoalkylcarbonyl), substituted or unsubstituted tetrahydropyridinyl (e.g., isopropyl substituted tetrahydropyridinyl or dimethylaminoalkylcarbonyl substituted 20 tetrahydropyridinyl), cycloalkylaminoalkylcarbonyl (e.g., cyclohexylaminoalkylcarbonyl or morpholinoaminoalkylcarbonyl), alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl (e.g., pyrimidinylaminoalkylcarbonyl) or alkoxylcarbonyl substituted alkylaminoalkylcarbonyl. In yet another embodiment, R 9 is aminomethyl. In another embodiment, R 7 is 25 substituted phenyl such as dichloro substituted phenyl. Examples of tetracycline compounds of Formula (I) include: CI C1 NN N" N N O N OH N~I N01- O H, HHH OH

,NH

2 HN NH2 0 OHO OH OHO OH 0 OHO OHO 0 N N N N N N H HH H H H OH- OH - - OH Ir , - 1 OHNH N INN NH - 2 H N 2 0H OH 0~ H OHOHO 0 0 OHO 0Ho OMe OH - 16 - N "HIN NN N N" N O O H H NH H HOH OH OH OH N NHOHN NH 2 OH OHO ON O N OH 0 OH O HeO 0 NHN HNH OH O OOH2NH HN HN H H' H NH H NN H H N OH H O OH K-I N 2 H OH K NI NH 2 NH2 NH 2 NH2 OHO 4 O O OH O OH O O NN N OH HN' HN N NN OHH HN2OHH HN H ON N NH N H N NH 2 OHO O O OHO Or OH OHOO OH O H II N HN O N O0 N N NH2 O OH O O .

OH

N'H

2 NN NNH OHOHO OHO0 OHO oOHO 0 2 H 0 OHO 0

J

0 N N HNHN-CN 0 HN N N H - H H HH' OH H H IOH NH' H OH I HI H OH OH o OHO OHO 0 OH0 OHP 0 N- N O-- N" N" H HH H' OH N N' N' NH 2 I NH OHIfl: N N' N'N' N NH 2 0 OH 0 OHM 1 t 0 OHO P OHO 0 OHO 0H 0 N' N' H H F H N N' N' NH 2 0 O OH0 OHO 00 In another further embodiment, the invention pertains to tetracycline compounds of Formula (III): N(Me)2 N(Me)2 OH R9 NH2 R9 6H OR H O (III) 5 wherein

R

10 is hydrogen or alkenyl; R' is unsubstituted alkyl, amino substituted alkyl, methoxy substituted 20 alkyl, halogen substituted alkyl; R" is alkyl; Ra is hydrogen or alkyl; R9b is alkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, cycloalkyl or 25 aminoalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that when R 9 is halogen, then R 10 is alkenyl. In one embodiment, R 10 is alkenyl. In another embodiment R9 is halogen, for example, iodine. In another embodiment, R 10 is hydrogen. In a further embodiment, R 9 is R'-O 30 N=CR"-, wherein R" is alkyl, such as methyl and R' is unsubstituted alkyl, for example, methyl. In yet another embodiment, R 10 is hydrogen and R9 is R'-OC(=O)-. In one embodiment R' is unsubstituted alkyl (e.g., ethyl or isopropyl), amino substituted alkyl - 18 - (e.g., dialkylamino substituted alkyl, such as dimethylamino substituted alkyl), halogen substituted alkyl (such as trifluoromethyl substituted alkyl) or methoxy substituted alkyl. In another embodiment, R 10 is hydrogen and R 9 is R 9 aR"bNC(=O)-. In one embodiment, R9a and R are each alkyl, such as, for example methyl or ethyl. In one 5 embodiment, R9a is alkyl (e.g., methyl) and R is alkoxyalkyl, such as methoxyalkyl. In yet another embodiment, R9a is ethyl and R is n-propyl. In a further embodiment, R9a is hydrogen and R 9 b is hydrogen, hydroxy, alkoxy (e.g., methoxy, ethoxy or t-butyloxy), hydroxyalkyl, alkyl (e.g., methyl-t-butyl, n-propyl, ethyl, t-butyl or n-butyl), cycloalkyl (such as cyclopropyl), alkylcarbonylaminoalkyl (e.g., methylcarbonylaminoalkyl), 10 alkoxycarbonylalkyl (e.g., methoxycarbonylalkyl), aryl (e.g., phenyl)or aminoalkyl. In another embodiment, R 10 is hydrogen and R 9 is methoxycarbonyl substituted alkynyl, pyrazinyl, methoxymethyl, cyclopropyl, methyl, methoxymethyl substituted alkynyl, amino substituted pyridinyl, alkylcarbonyl (e.g., ethylcarbonyl or isopropylcarbonyl.), arylcarbonyl (e.g., phenylcarbonyl), pyrimidinyl, oxazolyl, pyrazolyl, 15 carboxylate, pyridinyl, thiazolyl, substituted or unsubstituted thiophenyl (e.g., carboxylate substituted thiophenyl), piperidinylcarbonyl, dialkylaminomethyl (e.g., di-n butylaminomethyl), cyano, substituted or unsubstituted arylthiocarbonyl (e.g., p methylphenylthiocarbonyl), deuterated alkylaminoalkyl, substituted furanyl (e.g., methoxyalkylaminomethyl substituted furanyl, alkylaminomethyl substituted furanyl or 20 halogenated alkylaminomethyl substituted furanyl, such as fluoroalkylaminomethyl substituted furanyl), isoxolazolyl, cyano substituted pyridinyl, alkylcarbonylamino substituted pyridinyl (such as acylamino substituted pyridinyl), dialkylamino substituted phenyl (e.g., para-dimethylamino substituted phenyl), pyrrolidonylcarbonyl, azepanylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted phenyl (e.g., meta-acyl 25 substituted phenyl), aminocarbonyl substituted phenyl (e.g., is para-aminocarbonyl substituted phenyl or meta-aminocarbonyl substituted phenyl), carboxylate substituted phenyl (e.g., meta-carboxylate substituted phenyl)or piperazinylcarbonyl. Examples of tetracycline compounds of Formula (III) include: N H NN OHO OHHO OH H O O 0 OHOO OH N N H H OH N N O HO HO N OH OOH O OF O OH0 OH 0 OH OO O N" N N H H N H Hr OOH OH OH-I O O NH 2

NH

2 N O NH2 O H 0 OH 0 OH 0 O0 OH 0 OHF O N-1 OH 0 OH 09 N 'N" N H H - O H H- O I - ~ NH, ~ NH - ' . NH OHOH OH O F 0 OHO OH 0 HN-JN N H OFPHO 0 H 0 OHO0 OHO 0 - 19 - - OH H OH F- -NH, F~- 0

~H

2 NH 2 OH FO 6Hol OH0 OFHO o 0 OHO0 OHO 0 OHO0 OHO N" N" N" N" H H H H H H H - OH - - OH FOH .- ~ .NH, .- - NH, N . NH, OH(OH KN 0HO 0H 0 0 0 OHO0 OHF 0 0 OHO 0H 0 NN"N" N' N" N H OH H Hr H H O - - H- OH H NH, 0 O OH~ NH0 H H OH OHO 0 H HN:7 0 O H OMe ' NOHO OH 0 H H N N OH H H Hr OH H H HH NF H" N H OH OH OHP OHIf0 HH IOHI

NH

2 N ,-NH 2 - NH 2 MeO 0 OHO0OOH 0 OH 0 Wi- 0 04H 0 N N1N N NN "N" N H H H H- H H - O - - OH OH

NNH

2 . NH 2 N NH 2 OHO0 OFi-N 0 V-S OHO0 OHO 00 H H-N H N ~ H H r OHOH OH OHI 'S NH 2

NH

2

NH

2 OH ~~~~o 00 HH OH OO 0 N O OH 0 H 0 0OH 0 OHP 0 0 H H~ N = OH N H N ~ N H

NH

2 OH OH H HO o- oNN -NH 2

/NH

2 D KN' OHO0 OF? S' OHO oF? o' H- H -H * OH 7 OH 0 ~- .- NH 2 0 - NH 2 MGNO 0 /'-N OHO 0 ... / 0 OHO OF? 0 H H -N"N H H = = HH H OH OH

NH

2 0 - NNH 2

-~NH

2 N OHH0 HH OH 0OF 0 H NNN H OHH H - H OH H~ OHOH OH NH OH JH 0OH 0 6HH 0 NH2 N -NH 2 N~ H H F N OH 0 0 o H NNN'N N H HT H HN -N H H OH OH = r OH H Hj

NH

2 HO' N ~.NH 2 MeO' N - ~ NH 2 H N- N OH 0OH 0 OHO ? o OHO 0? 4 HH - OH" H N" 'N~ H HN - -- -OH H OH ,-H- -,Ny4 NH 2 N O0 & 00 OHO 0 0, o 0 OH 0O o - 20 - N 11 H N N "N N" 1 N" H H N N H H N H HN

-

OH- OH OH OH N NH 2 HO NH 2 Meo N 4 0 NH 2 O OHO O O 0 OHO OFO 0 0 OH O O 0 N N N H N N H HN OH O HH OH N NH2 ,KN N H HNH2 NH 2 MeONH 2 0 OH 2N- 0 0 OHO 0 OHO N 0 H H N H HN H H - OH HOH N- OH H O - HI ~N N NNH 2

H

2 N N NH 2 O OHO O 0 OOHOO 0 O OHO O 0 H 4NH H H OHH OH 0 OH

'---NNH

2 L0'2 KN X NH 2

NH

2 O O 01 0 0 OHO 0~ o F OHO 0? 00 N H HN NH H OOH H HN O OH OH

NH

2 H OH T NH 2 O0 OHO O?& 0 >r N r NH 2 0=S OH0 OF? 0a

NH

2 OH N H N NN H H'~ H 0 OH O OH ( H

H

2 N R s NH 2 HOi m e NH 2 N-p y NH 2 SOH0 oi-P 0 OHO 01-? 0 0 OHO 0 0 0 RN is hydrgen N"H HN N H HN -N H HN OH = - H NO H HYNCN NH ON NH R i ak2 h t NH 2 m l hy 2 0 0H OF? 0 0o OH 0OP oi 0 0 OHO 0 0& YU OH

-,,,NNH

2 0 OHO 0 -P o In another embodiment, the invention pertains to tetracycline compounds of Formula (IV): OH 0 OH O 0 0(IV) wherein 5 R 7 , is methoxy, dialkylaminomethyl, substituted N-piperdinyl methyl, fluorine, or hydrogen; *R7 is hydrogen;

*R

7 , is alkoxyalkylaminoalkyl, halogenated N-piperdinyl methyl, hydroxyl, dialkylaminoalkylamino, dialkylaminomethyl, substituted N-piperidinyl methyl, 10 substituted N-pyrrolyl methyl, or hydrogen; -21- R7d is arylalkylaminoalkyl, arylalkyl substituted alkylaminoalkyl, substituted N-piperidinylmethyl, N-piperidinyl substituted aminomethyl, cyclopropylamino methyl, piperdinyl substituted alkyl, dialkylaminomethyl, heteroaryl substituted dialkylaminomethyl, alkylaminomethyl, cycloalkylaminomethyl, 5 alkylaminoethyl, cyano substituted dialkylaminomethyl, N-pyrrolidinyl substituted methyl, N-pyrrolyl substituted methyl, methoxy substituted dialkylaminomethyl, alkoxyalkylaminomethyl, substituted carboxylate alkylaminomethyl, hydrogen or linked with R7' by a -O-CH 2 -0- linker; R 7 is hydrogen, and pharmaceutically acceptable salts, esters and prodrugs 10 thereof, provided that each of R a, R , R , R , and R are not hydrogen. In one embodiment, R is hydrogen and R and R are each hydrogen. In a further embodiment, R 7 a is methoxy and R 7 d is substituted N-piperidinylmethyl, R 7 a is halogen (e.g., fluorine) and R is substituted N-piperidinylmethyl or R 7 a is methoxy and R7d is arylalkyl substituted alkylaminoalkyl, such as phenylmethyl substituted 15 alkylaminoalkyl In another embodiment, R and R 7, R and R are each hydrogen. In a further embodiment, R7d is dialkylaminomethyl, for example, methylisopropylaminomethyl, methylcyclohexylaminomethyl, methylethylaminomethyl, methylpropylaminomethyl, methylisobutylaminomethyl, propylisopropylaminomethyl, ethylisopropylaminomethyl, 20 propylcyclopropylmethylaminomethyl, cyano-substituted ethylmethylaminomethyl, methoxy-substituted ethylaminomethyl, t-butoxy substituted ethylmethylaminomethyl or pyridine substituted methymethylaminomethyl. In another embodiment, R is substituted N-piperidinylmethyl, such as dimethyl substituted N-piperidinylmethyl, trifluoromethyl substituted N-piperidinylmethyl or halogen (e.g., fluorine) substituted N 25 piperidinylmethyl, cycloalkylaminomethyl (e.g., cyclopropylaminomethyl, dimethylpyrrolidinylaminomethyl or dimethylpyrrolylaminomethyl) or alkylaminomethyl (e.g., t-butylmethylaminomethyl). In yet another embodiment, R and R 7, R and R7d are each hydrogen. In a further embodiment, R 7 c is alkoxyalkylaminoalkyl (e.g., methoxyalkylaminoalkyl), hydroxy, 30 dialkylaminoalkylamino (e.g., diisopropylaminomethyl), dialkylaminomethyl, substituted N-piperidinylmethyl, substituted N-pyrrolyl or substituted carboxylate alkylaminomethyl, 7e 7b 7c 7d In another embodiment, R and R , R and R are each hydrogen. In a further embodiment, R 7 a is dialkylaminomethyl, such as dimethylaminomethyl. In yet another embodiment, R and R are each hydrogen and R 7 a is substituted 35 N-piperidinylmethyl and R7d is linked with R 7 c by a -O-CH 2 -0- linker. Examples of tetracycline compounds of Formula (IV) include: - 22 - N NHN N OOFN N OH O H r OH NH2I r OH NH H SNH ,O H 2 NH 2 NH 2 OH 0 OH 00O OH 0 OH 0 O OH 0 OH O OH O OH o N N N NN H H N" - OH H H= N - OH H H OH - NH 2 r H OH N NH 2 NH2 OH O OH 0 0 OH O OH O 0 :N NN N N ~H H O H H N - OH -O H H I OH

NH

2 NH 2

NH

2 OH O OHO 0 OHO OHO 0 OH 0 OH 0 0 NN N N N" H H- H H= N OOH H H Hr OH NH,

NH

2 NH2 OH OH OH OH O OHO O OHO OHO O OH0 OHO 0 HNN NI N H H H N H H r OHOH H H OH OH 1 OHI NH, NH 2 NH2 OHHOO 0O OH 0 OHP 0 0 OHO OHO O OHO OHO 0 F53 F F N HN N N N HH= H H= OH - OH r r OH I

NH

2

NH

2 - NH 2 H 0 OH OH O OH 0 OH O OH O 0 OH 0 OH 0 0 N N NN N H H N H H OH H HF OH O H OH

NH

2

NH

2 _ NH 2 yOH OH OH O OH O 0 OHO OH O 0 OH O OH O 0 -23 - N NNF N H F N SH OH- OH NH NH2 NH 2 OHO OHO 0 OH O OH O 0 OHO OHO 0 OH -- \ N, OHN N N 0 H Hr HF H OH OH H H

NH

2

NH

2 - - CH OHO OHO 0 OH O OHO O NH 2 CHo0 0 OMe OMe N Y O O< N O O N' 0 0 0 0 H HN N OH H H- H H 0 OH -: OH NH2 S NNH 2

NH

2 OHO 0OF? 0 0 - 0 OH O 0 OH O O O OMe N N N O O O O N N N H OH H H- H H- O NH C OH OH 2NH 2

NH

2 OHO OI- O O OH O O O OH 06F? 0 In another embodiment, the invention pertains to tetracycline compounds of Formula (V): R7, R7h, R7 T N(Me)2 OH NH, OH O OH O 0(V) 5 wherein T is NH or 0; R is dialkylaminoalkyl, N-piperidinylamino alkyl, substituted or unsubstituted N-piperdinylalkyl, N-pyrrolidinylamino alkyl, substituted or unsubstituted N-pyrrolidinylalkyl, substituted or unsubstituted N-pyrrolylalkyl, alkenenyl substituted 10 dialkylaminoalkyl, N-decahydroisoquinolinylalkyl, alkoxyalkylaminoalkyl, or hydrogen; R7 is hydrogen; - 24 - R h is heteroaryl substituted alkylaminoalkyl, dialkylaminoalkyl, substituted N-piperidinylalkyl or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that each of R 7 ', R , and R 7 h are not hydrogen. In one embodiment, T is NH and R 7 f and R 7 are each hydrogen. In a further 5 embodiment, R7h is dialkylaminoalkyl (e.g., dimethylaminomethyl) or substituted N piperidinylalkyl (e.g., methyl substituted N-piperidinylmethyl). In another embodiment ,T is 0 and R 7 f and R 7 are each hydrogen. In a further embodiment, R 7 h is heteroaryl substituted alkylaminoalkyl, such as, for example, pyridinyl substituted methylaminomethyl or methyl substituted 10 isoxazolylmethylaminomethyl. In yet another embodiment ,T is 0 and R 7 and R 7 h are each hydrogen. In a further embodiment, R 7 f is dialkylaminoalkyl (e.g., methylisopropylaminomethyl or allylmethylaminomethyl), substituted N-piperidinylalkyl (e.g., methyl substituted N piperidinylmethyl or halogen substituted N-piperidinylmethyl, such as fluorine substituted 15 N-piperidinylmethyl) substituted N-pyrrolylalkyl (e.g., methyl substituted N pyrrolylmethyl), substituted N-pyrrolidinylalkyl (e.g., methyl substituted N pyrrolidinylmethyl), N-decahydroisoquinolinylalkyl or alkoxyalkylaminoalkyl (e.g., methoxyalkylaminomethyl). Examples of tetracycline compounds of Formula (V) include: N N N N 0 H HH N" N H N H HN H H OH OH OH

NH

2 K I NH 2

NH

2 OH O OH O H OHO OHOO 0 OH 0 oH o F ON - N N O HN H H N N HO N OH OH OH NHNH2 - NH 2

NH

2 OHO OHO 0 OH OH OH O OHO o OH O OH O 0 F F F-0 N N H H OH O H N NH 2

NH

2 NH, OHO OH O OH OH O OH O O OH 0 OHO0 OHO0 0 H H N/ O H OH OH OH NH2 ,NH 2

NH

2 OH 0 OH 00 OH O 0 OHO - o - 25 - H N MeOX'\N N 0 N H H - OH H HI U I N N NH2 OH NH2 OH 0 OH 0 0 In another embodiment, the invention pertains to tetracycline compounds of Formula (VI): R'3 N N(Me)7 OH NH, OH H OH0 (VI) wherein 5 R' is fluorine or hydrogen;

R

7 3 is trifluoromethyl, alkyloxycarbonyl, methyl, cyano, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that both of R 7 i and R 7 j are not hydrogen. In one embodiment, R is hydrogen. In a further embodiment, R 7 j is methyl, cyano, 10 trifluoromethyl, or alkyloxycarbonyl, such as, for example, methoxycarbonyl. In another embodiment, R 7 'is fluorine and R 7 j is hydrogen. Examples of tetracycline compounds of Formula (VI) include: F CN N r Na "N N N CN N N HH Hz - OH HNH2

HNH

2 OH HNH 2 OH O OHO 0 OHO OHO O OHO OH O 0 O F F 0 F' N/N N N H H Hr OH- OH

HNH

2

HNH

2 OH O 0 I OH O OH O O OHO 0 - 26 - In another embodiment, the invention pertains to tetracycline compounds of Formula (VII):

R

7 k N N(Me)2

-

OH I NH2 OH O OH O 0 (VII) wherein 5 p is a single or double bond;

R

7 k is alkyl, cycloalkyl, dialkylaminoalkylcarbonyl, alkoxyalkylcarbonyl, halogen substituted alkyl, halogen substituted cycloalkyl, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof. In one embodiment, p is a single bond and R 7 k is alkyl, such as isopropyl, or 10 hydrogen. In another embodiment, p is a double bond. In a further embodiment, R 7 k is hydrogen, alkyl (e.g., isopropyl), cycloalkyl (e.g., cyclohexyl or cyclopropylmethyl) , halogen substituted alkyl (e.g., trifluoromethyl substituted propyl), halogen substituted cycloalkyl (e.g., trifluoromethyl substituted cyclohexyl), alkoxyalkylcarbonyl (e.g., 15 methoxymethylcarbonyl) or dialkylaminoalkylcarbonyl (e.g., dimethylaminomethylcarbonyl). Examples of tetracycline compounds of Formula (VII) include: H N N N H H 7 H H OH N H N" N 2 OH OH

NH

2 OH O NH 2

NH

2 OHO0 OHO0 0 2 O OH O OH 0 OHO OHO F F0N N N NN H H H HH H OHH OH H H H H OHOH - - OH OH- NH NH2-

NH

2 OH 0 OH 00 O OH O OH O OH O O OH 0 OH 0 0 F- 7 F F H 7 N N NN SH H -- OH H Hr H H~ NH OH H NH2 z NH 2 OHO0 OHP 0 H 0H OHO0 0 OHO0 OHO 0 _ 27 - O OMe N N H H OH

NH

2 OHO O? O In another embodiment, the invention pertains to tetracycline compounds of Formula (VIII): R 7 N(Me)2 -- OH NH, OH OH 0 OH 0 0 (VIII) 5 wherein

R

7 is fluoro substituted N-pyrrolidinylalkyl, N-piperidinylalkylcarbonyl, dialkylaminoalkylaminocarbonyl, aminoalkyl, N-pyrroyl alkyl, dialkylamino substituted pyridinyl, substituted or unsubtituted phenyl substituted N-piperizinyl alkyl, 10 alkylaminoalkyl, alkoxy substituted pyrimidinyl, 1-H-pyrimidin-2-onyl, cyano substituted pyridinyl, substituted or unsubstituted N-pyrrolidinyl alkyl, halogen substituted pyridinyl, substituted or unsubstituted arylalkylamino alkyl, alkoxyalkylaminoalkyl, N imidizolylalkylcarbonyl, N-dihydroimidizolylalkylcarbonyl, alkylaminoalkyl, imidizopyrimidinyl, substituted or unsubstituted imidizopyridinyl, or substituted or 15 unsubstituted pyrizinyl substituted alkylaminoalkyl, alkoxyalkylcarbonyl; and pharmaceutically acceptable salts, esters and prodrugs thereof In one embodiment, the fluoro substituted N-pyrrolidinylalkyl is difluoro substituted N-pyrrolidinylmethyl. In another embodiment, the aminoalkyl is aminomethyl. 20 In yet another embodiment, the N-pyrroyl alkyl is N-pyrroyl methyl. In another embodiment, the dialkylamino substituted pyridinyl is dimethylamino substituted pyridinyl. In a further embodiment, the substituted phenyl substituted N-piperizinyl alkyl is para-fluorophenyl substituted phenyl N-piperizinyl methyl. 25 In one embodiment, the alkoxy substituted pyrimidinyl is methoxy substituted pyrimidinyl. In another embodiment, the substituted N-pyrrolidinyl alkyl is dimethyl substituted N-pyrrolidinyl methyl. In yet another embodiment, the halogen substituted pyridiyl is fluorine substituted 30 pyridinyl. In another embodiment, the arylalkylamino alkyl is phenylmethylaminomethyl. - 28 - In one embodiment, the alkoxyalkylaminoalkyl is methoxyalkylaminomethyl. In another embodiment, the alkylaminoalkyl is methylaminomethyl. In yet another embodiment, the substituted arylalkylamino alkyl is hydroxy substituted phenylmethylamino methyl. 5 In another embodiment, the substituted pyrizinyl substituted amino alkyl is methyl pyrizinyl substituted methylaminomethyl. In yet another embodiment, the substituted imidizopyridinyl is halogen substituted imidizopyridinyl, for example, fluorine substituted imidizopyridinyl. In one embodiment, the alkoxyalkylcarbonyl is methoxymethylcarbonyl. 10 Examples of tetracycline compounds of Formula (VIII) include: F F

HNH

2 O HF N NHr , sN N H -H OH H H: - OH H - - O

-

OHNH NH2 IH OH 0 OH 0 0 OH 0 OH 0 0 N N N N N S N N N HHH HH H 2 H HNH OH O O OH OO O OH O O O OH NH 2

NH

2

NH

2 OH OHO HI OH OO Oe OH 0 OH 0 OMe 0 Q N NN H N HN N2N ONN NN N H H0 H H H H OH N :: OH H H: OH

NH

2 NH 2 NH 2 OH 0 O 0 OH 0 0 0 OH 0 O 0 N I I /-< NN NN F N N H H- OH H OH H H- N

H

2 OO i- NH 2

NH

2 NHOH OOH 0 H OHO00F 0 OMe HN N HN N H H:O NN H N NA H - O N :: OH NOH IH -NH2

NH

2 H NH2 OH 0OF 0 V OH 0 OF? P 0 OHO 0 -P o QNN OHHN N"N Ny N HN N H H:O H H O OH : U HHH OH

KNH

2 1 - INH 2 N NH 2 OH 0 0 1 -Po 0' OH 0 (M-F O H - 29 - OMe NH H N Hy H H NH N OH H H H H OH - N OH N. OHI - - HNH 2 NH 2 o OH O OH O 0 OH O OHO 0 OHO0 OHo 0 In yet another embodiment, the invention pertains to tetracycline compounds of Formula (IX): R 7 N(Me) 2 - OH

R

9 CHN - NH 2 OHO OH7 OH O OHO o (IX) 5 wherein R' is dialkylaminomethyl, alkoxy substituted phenyl, hydroxy, halogen substituted phenyl, halogenated alkyl substituted phenyl, naphthyl;

R

9 ' is hydrogen, fluorinated alkyl or unsubstituted alkyl and pharmaceutically acceptable salts, esters and prodrugs thereof 10 In one embodiment, R 9 ' is hydrogen. In a further embodiment is dialkylaminomethyl (e.g., dimethylaminomethyl ), alkoxy substituted phenyl (e.g., para trifluoromethoxy substituted phenyl) or halogen substituted phenyl (e.g., chlorine substituted phenyl or trifluoro substituted phenyl). In one embodiment, the chlorine substituted phenyl is further substituted with trifluoromethyl. In yet another embodiment, 15 R 7 is halogenated alkyl substituted phenyl such as, for example, di-triflouoromethyl substituted phenyl. In another embodiment, R 9 ' is fluorinated alkyl and R 7 is halogen substituted phenyl such as, for example, difluoro substituted phenyl. In yet another embodiment, R 9 ' is unsubstituted alkyl and R 7 is hydroxy. 20 - 30 - Examples of tetracycline compounds of Formula (IX) include: F F_ CI F 0 FF HH H N OH OH

H

2 N NH 2 U OH OH2 OHO 0 H 2 N - NH NH S OH OH O OH O 0 OH 0 OH 0 F F F FtNF - F F FN H H N H H OH - - OH HN H 2 N NH 2 N NH2

H

2 - ~ . - NH, OH HN OH 0 OH HO OHO OH 0 O OH0OH 0 0 OH0OH 0 0 F OH N F N- OH F H OH N

NH

2 F H N NH F.<~ I- -0 H OH 0 01-P F OH O OHO 0 In another embodiment, the invention includes tetracycline compounds of the Formula (X): R 8 X 0 OH Z R9 NR2 oR10 o 0'' (X) 5 wherein

R

1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or halogen, optionally linked to R2 to 10 form a ring; R2 is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, or absent, optionally linked to R1 to form a ring; R2', R2", R4a , and R4b are each independently hydrogen, alkyl, alkenyl, 15 alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety;

R

10 is hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; R 11 is hydroxyl, alkoxy, aryloxy, or alkylamino; R and R are each independently NR 4aR 4, alkyl, alkenyl, alkynyl, 20 hydroxyl, halogen, or hydrogen; -31-

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, 5 halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R

7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 )o- 3 (NR7")oiC(=W')WR 7 1; 10 R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR c)o 1 C(=E')ER8a

R

9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, 15 acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR9)o 1 C(=Z')ZR9a 71 7m 7n 7o p7 8a 8b 8C 8d 8e 8f 9a 9 C R 1, R ", R ", R' , R P, R 4, R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 20 R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR8dRe, S, NR 8 or 0; E' is 0, NR', or S; Q is a double bond when R 2 is absent, Q is a single bond when R 2 is 25 hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl, alkoxy, amino, alkylamino, cyano, nitro, or heterocyclic; W is CR ORP, S, NR or 0; Wis 0, NR , or S; X is CHC(R Y'Y), C=CR Y, CR6'R6, S, NR6, or 0; 30 Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; Z is CR 9R**, S, NR9b or 0; Z' is 0, S, or NR 9 , and pharmaceutically acceptable salts, esters and 35 enantiomers thereof. - 32 - In a further embodiment, the tetracycline compound of Formula (X) is: H C N CH 3 CH, OH C'N CH, CH, L H OH HNH NH I N 2 HO H 0 0 OHH OH 0 O O O 0 o HC CH, HC In another embodiment, the invention includes tetracycline compounds of the Formula (XI): O RIr N H H OH NH2 5 OH O H O O (XI) wherein

R

7 , is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl and pharmaceutically acceptable salts, esters and enantiomers thereof. In one embodiment, dialkylaminoalkyl is dimethylaminomethyl. In another 10 embodiment, the substituted N-piperidinylalkyl is methyl substituted N-piperidinylmethyl. Examples of the tetracycline compounds of Formula (XI) are: 10 ..-N 11 .1NN0 N H H N N H H: - OH H H OH - OH NH2 NH 2

NH

2 OHO OH 0 OHO O OH 0 OFP 01 In another embodiment, the invention includes tetracycline compounds of the Formula (XII): RIS N O NN" H H OH NH2 OH O OH O O (XII) 15 wherein W is N or CH; and R s is substituted or unsubstituted alkyl, aryl, alkoxycarbonyl, alkylcarbonyl, cycloalkyl, or aminocarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. - 33 - In one embodiment, W is CH. In a further embodiment, R 7 , is unsubstituted alkyl such as, for example, methyl. In another embodiment, W is N. In a further embodiment, is alkoxycarbonyl (e.g., ethoxycarbonyl), alkylcarbonyl (e.g., acyl), cycloalkyl (e.g., cyclohexyl), aryl (e.g., 5 phenyl), alkyl (e.g., isopropyl), or aminocarbonyl. Examples of the tetracycline compounds of Formula (XII) are: N N NN H HN OH H H OH OH - OH H NH2 NH2

NH

2 OHO OH 0H 0O OH O 0O 0 N N) (N) (N) N O HNNN H N OH H OH - OH

NH

2 _ NH 2

NH

2 OH 0 O 0 OH 0 01 0 OH O 0H O O NH2 N N H H - OH

NH

2 OHO O ? 0 In another embodiment, the invention includes tetracycline compounds of Formula XIII: 10 NR 7t'R 7t" O )n N H H OH OH OH O OH O O (XIII) wherein n is 0, 1 or2;

R

7 t is hydrogen, alkyl, alkenyl or cycloalkyl; 15 R 7 t" is unsubstituted alkyl, dialkylaminoalkyl, halogenated alkyl, alkoxyalkyl, substituted or unsubstituted arylalkyl, cycloalkyl, alkenylalkyl, heterocyclic, cyano substituted alkyl, alkoxy substituted alkyl, heteroarylalkyl, aminocarbonylalkyl, - 34 aryl, hydrogen, alkylcarbonyl, aminoalkyl or alkoxycarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. In one embodiment, n is 0. In a further embodiment, R"' is hydrogen. In yet another embodiment, R 7 " is dialkylaminoalkyl. 5 In another embodiment , n is 1. In a further embodiment, R 7 " is alkoxyalkyl, such as, for example, methoxyethyl. In another embodiment, R 7 " is alkyl such as, for example, isopropyl. In yet a further embodiment R 7 ' is alkyl such as, for example, methyl. In another embodiment, R 7 ' is alkenyl. In a further embodiment, R 7 " is alkoxycarbonyl such as, for example, methoxycarbonyl In another embodiment, R 7 " is 10 alkylcarbonyl such as, for example, acyl. Ina further embodiment, R 7 ' is cycloalkyl, such as cyclpropyl. In another embodiment, n is 1. In a further embodiment, R 7 ' is hydrogen. In another embodiment, R 7 " is halogenated alkyl (e.g., fluoroethyl, difluoroethyl or trifluoroethyl), unsubstituted alkyl (e.g., methyl, ethyl, t-butylmethyl, t-butyl or 15 diethylmethyl), cycloalkyl (e.g., cyclohexyl, cyclopropyl, morpholino, cyclobutyl, bicyclo[2.2. 1]heptenyl, cyclopentyl), arylalkyl (e.g., phenylmethyl), alkenylalkyl, cyano substituted alkyl, heteroarylalkyl (e.g., pyridinylmethyl, furanylmethyl or N methylpyrrolylmethyl), aminocarbonylalkyl (e.g., aminocarbonylmethyl), alkoxy substituted alkyl (e.g., methoxy substituted alkyl), aryl (e.g., pyridinyl or phenyl), 20 aminoalkyl (e.g., aminomethyl) or substituted arylalkyl (e.g., difluorophenyl). In yet another embodiment, n is 2. In a further embodiment, R 7 ' is hydrogen. In yet a further embodiment, R 7 " is alkyl, such as for example, methyl. In another embodiment, R 7 " is alkylcarbonyl, such as, for example, acyl. Examples of the tetracycline compounds of Formula (XIII) are: F F N HN HN N ON H H OH H Hr OH HN 0 N NH H H OH

NH

2 OH O O H O O NH2 OHO O? 0 OH 0 OH 0 F 00 HN O HN O N OH H H OH OH

NH

2

NH

2

NH

2 OH 0 O 0 OH O 0H 0 OH 0 oFP o -35 - HN N H HN O H N H H OH H N- H H OH

NH

2 - OH NH 2 OH 0 o o OH O 0 ONH OH O OF 0 F F HNA H N'CH3 HN N CH3 H ' H OH H HHHO H- H H OHN OH OH

NH

2

NH

2

NH

2 OH 0 OF? o OH 0 OF? o OH 0 O o NH Z " kN H2N HN ' H N O 0 N HN H HH H H OH OH H H OH

NH

2 NH 2 NH 2 OHO OHO o OH O OH OHO O o CN N -- H 2 N 0H NH H -N H - H H H - OH

NH

2

NH

2

NH

2 NH2 NH2 .0O O0 - ol OHH O0- 0 0H F MeO( N O HHNNH) H N O 0 O N H H H H H H H OH OH - - - OH

NH

2

NH

2

NH

2 OH 0 o O OHO 0 O o OH 0 OF? O INH 0? -6 NN HN HN H H: 0 N 0 NI NH NH 2 NH NH 2 H HN OH 0 OH N Nr NH

NH

N : OHH H- N" O N H- OHO NI NH 2 NH NH 2 NI NH 2 OH0 o o OH 0F 0 H o OHO0 oF? o 0OMe 0 NH N '- N -- 0O" N N" H N H H- H Hr N : OH N - : OH NOH NH H 2

NH

2 UOH FO On 0 0 OH 0 OH- 0 0 - 36 - N O HNC O NHO H NHN 0N H 0 - OH OH OH NH2

NH

2

NH

2

NH

2 OHHO OH 0 OFH O OH 0 OH 0 0 OH 0 OH 0 0 NH NH F F 0 0 NH NH HH OH O N OH N HN OHNH2

NH

2 HNH 2 &H HO 0 OH OHOHO OHO OH O OHO OH 0 FP 00 OH0 HF 0 In another embodiment, the invention includes tetracycline compounds of Formula XIV: R 7u OH NH2 OH O OH O 0 (XIV) wherein 5 R 7 u is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl, alkoxyaminoalkyl, alkylaminoalkyl or dipiperidinium methyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. In one embodiment, R 7 u is substituted N-piperidinylalkyl, such as, for example, methyl substituted N-piperidinylalkyl or halogen substituted N-piperidinylalkyl. 10 In another embodiment, the halogen substituted N-piperidinylalkyl is, includes, for example, fluorine substituted N-piperidinylalkyl. In yet another embodiment, R 7 u is dialkylaminoalkyl, including, for example, dimethylaminomethyl. In another embodiment, R 7 u is alkylaminomethyl is methylaminomethyl. 15 In yet another embodiment, R 7 u is alkoxyaminoalkyl is methoxyaminoalkyl. - 37 - Examples of the tetracycline compounds of Formula (XIV) are: N N N N H N H H H H H' N OH OH - OH

NH

2 - NH 2

NH

2 OH 0 O- O OH 0 O? 0 OH 0 O 0 F DOCH 3 N N N H H H H - N HOH OH H H: OH N - - OH- O- O

NH

2

NH

2 H OH 0 OH 0 OH 0 OF? 0 NH OHO OF? 0 HN N H OH I NH 2 OHO OF? 0 In another embodiment, the invention pertains, at least in part, to tetracycline compounds of formula (XV): R 7v 0 N H H OH I0 | NH2 5 OH O OH O 0 (XV) wherein

R

7 v is heteroaryl; and pharmaceutically acceptable salts, esters and enantiomers thereof. In one embodiment, the said heteroryl is imidizolyl, methyl imidizolyl, 10 imidizolidinyl or methyl imidizolidinyl. Examples of tetracycline compounds of formula (XV) are: fUN -N 5,1 N N NN O sN" N 0N H H H H H OH OH

NH

2

NH

2

NH

2 OHO O? OH 0 0 OH 0 O O [-N N N O'N~ N H HOHHH :: OH -OH

K-NH

2 1 - NH 2 OHO O O OHO O O - 38 - In another embodiment, the invention pertains, at least in part, to tetracycline compounds of formula (XVI): R7 R 5 R5' R 4 R8 X OR' R9 X:NR2R" 5 OR' 0 N NR" O O (XVI) wherein: 2' 2" a 4b R , R2", R , and R are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 R 1 , R" and R 12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety;

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, 15 aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 20 R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR 7)oiC(=W')WR7a

R

8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, 25 acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR c)o 1 C(=E')ER8a

R

)

0

-

3 (NR9c)o-IC(=Z')ZR9a 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R , R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 30 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; - 39 - R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR"Re, S, NR" or 0; E' is 0, NR', or S; 5 W is CR "R', S, NR" or 0; W' is 0, NR 7 f, or S; X is CHC(R Y'Y), C=CR Y, CRR', S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 10 alkylamino, or an arylalkyl; Z is CR "R*, S, NR9' or 0; Z' is 0, S, or NR 9 , and pharmaceutically acceptable salts, esters and enantiomers thereof. 15 In a further embodiment, R2, R , Ro, R , and R12 are each hydrogen or a prodrug moiety; X is CR R6'; and R 2", R , R , R6, and R6' are each hydrogen. Alternatively, R and R are hydrogen and X is CR R 6 ', wherein R 6 is methyl and

R

6 ' is hydroxy. Alternatively, when R 5 is hydroxyl; X is CR 6

R

6 '; R 6 is methyl; and R 5 ' and R6' are hydrogen. In yet another embodiment, X is CR R 6'; R , R , R and R' are 20 hydrogen atoms and R 7 is dimethylamino. In one embodiment, R9 is hydrogen. In another embodiment, R9 is substituted or unsubstituted aryl (e.g., phenyl or heteroaryl). In another embodiment, R 9 is substituted or unsubstituted alkyl. In a further embodiment, R 9 is aminoalkyl, e.g., aminomethyl (e.g., 9n 9M 9n

CH

2 -N R m wherein R 9 " is hydrogen or a prodrug and Rom is hydrogen or lower alkyl). 25 In another embodiment, R 7 is hydrogen. In yet another embodiment, R 7 is substituted or unsubstituted aryl, e.g., phenyl or heteroaryl (e.g., pyridinyl, pyrrolyl, pyrazinyl, etc.). In another embodiment, R 7 is substituted or unsubstituted amino (e.g., dimethylamino), nitro or halogen. In another embodiment, R 8 is hydrogen. In another further embodiment, R 11 is hydrogen. 30 In a further embodiment, the tetracycline compound is:

H

3 C'N CH 3

H

3 C N'CH 3 H H2 - - OH - NH 2 OH N-NH 0O - 40 - In another embodiment, the invention pertains to tetracycline compounds substituted at the 2 position such as compounds of formula (XVII): R7 R 5 R5' R 4 RX OR'H2 R9 N Ra

OR'

0 0 OR" 0 0 0 (XVII) wherein: 5 R 2 a is alkyl or aryl; R4a and R are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 11 12 R , R and R are each independently hydrogen, alkyl, aryl, benzyl, 10 arylalkyl, or a pro-drug moiety;

R

5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, 15 alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;

R

7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 20 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR 7) 0

_

1 C(=W')WR7a

R

)

0

-

3 (NR 7) 0

_

1 C(=E')ER8a 25 R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2

)

0

-

3 (NR 7) 0

_

1 C(=Z')ZR9a 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R , R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, 30 alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; -41- E is CR"Re, S, NR l or 0; E' is 0, NR', or S; W is CR "R', S, NR l or 0; W' is 0, NR 7 f, or S; 5 X is CHC(R"Y'Y), C=CR"Y, CRR', S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; Z is CR "R*, S, NR9b or 0; 10 Z' is 0, S, or NR , and pharmaceutically acceptable salts, esters and enantiomers thereof. In a further embodiment, R , Ro, R", and R12 are each hydrogen or a prodrug moiety; X is CR R6'; and R , R , R , and R6' are each hydrogen. 15 Alternatively, R and R are hydrogen and X is CR R 6 ', wherein R 6 is methyl and

R

6 ' is hydroxy. Alternatively, when R 5 is hydroxyl; X is CR 6

R

6 '; R 6 is methyl; and R 5 ' and R6' are hydrogen. In yet another embodiment, X is CR R 6'; R , R , R and R' are hydrogen atoms and R 7 is dimethylamino. In one embodiment, R9 is hydrogen. In another embodiment, R9 is substituted or 20 unsubstituted aryl (e.g., phenyl or heteroaryl). In another embodiment, R 9 is substituted or unsubstituted alkyl. In a further embodiment, R 9 is aminoalkyl, e.g., aminomethyl (e.g., 9n 9M 9n

CH

2 -N R m wherein R 9 " is hydrogen or a prodrug and Rom is hydrogen or lower alkyl). In another embodiment, R 7 is hydrogen. In yet another embodiment, R 7 is substituted or unsubstituted aryl, e.g., phenyl or heteroaryl (e.g., pyridinyl, pyrrolyl, 25 pyrazinyl, etc.). In another embodiment, R 7 is substituted or unsubstituted amino (e.g., dimethylamino), nitro or halogen. In another embodiment, R 8 is hydrogen. In a further embodiment, R2a is alkyl, e.g., methyl, ethyl or propyl. In another further embodiment, the tetracycline compound is:

H

3 C' N CH 3

H

3 C 'N'CH 3

H

3 C'N, CH 3

H

3

C'NCH

3 ' H Hr H Hr - ~ - - O C 3 rrOH OH HCCH H N CH N CH H N CH 3H H3 Y H 3 C H OHO OH 0 0F YHH 0OHFP1OFH OH 0 H

CH

3 OH 0 OH 0 0 CH 3 3 30 In one embodiment, the tetracycline compounds of the invention do not include those described in U.S.S.N. 09/660,598, 09/823,884, 09/852,908, 10/819,343, 10/820,456, 09/894,805, 09/895,796, 09/895,812, 09/895,797, 09/895,857, 10/097,634, 10/759,484, 10/337,914, 10/636,437, 10/752,378, or 10/740,961. The entire contents of each of these applications are hereby incorporated herein in their entirety. 35 - 42 - Methods for Synthesizing Tetracycline Compounds of the Invention The tetracycline compounds of this invention can be synthesized using the methods described in the Schemes and/or by other techniques known to those of ordinary skill in the art. 5 The substituted tetracycline compounds of the invention can be synthesized using the methods described in the following schemes and by using art recognized techniques. All novel substituted tetracycline compounds described herein are included in the invention as compounds. 10 9- and 7- substituted tetracyclines can be synthesized by the method shown in Scheme 1. As shown in Scheme 1, 9- and 7-substituted tetracycline compounds can be synthesized by treating a tetracycline compound (e.g., doxycycline, 1A), with sulfuric acid and sodium nitrate. The resulting product is a mixture of the 7-nitro and 9-nitro isomers (lB and IC, respectively). The 7-nitro (IB) and 9- nitro (IC) derivatives are treated by 15 hydrogenation using hydrogen gas and a platinum catalyst to yield amines ID and 1E. The isomers are separated at this time by conventional methods. To synthesize 7- or 9 substituted alkenyl derivatives, the 7- or 9-amino tetracycline compound (1 E and 1F, respectively) is treated with HONO, to yield the diazonium salt (IG and 1H). The salt (1 G and 1 H) is treated with an appropriate reactive reagent to yield the desired 20 compound(e.g., in Scheme 1, 7-cyclopent-1-enyl doxycycline (1H) and 9-cyclopent-1-enyl doxycycline (11)). H3C >CH 3 H3C CH 3 -H H _-CCH 3 CH, OH NO CHa H NOH H O H O O NH2 H2N NH2 OH O H EH 0 OH 0 0 O H 0 OH 0 0 OH 0 O H 0 0 1C lA P H, C H H H3CN CH 3 NCH3 '~ NIN H,

CH

3 OH N OH N2+OH N H H H H 1F H3CN CH 3

CH

3 OH3 CN H3

CH

3 OH OHN N H H OH NH2 NH2 H H OH 0 0

CH

3

H

3 % >CH 3 H3 C H3 CH 3 OH

QH

3 OH OHN H1H' NH2 8HNN~ OH H OH 0 OH OH 0 OH 0 0 1 H 11 SCHEME 1 - 43 - As shown in Scheme 2, tetracycline compounds of the invention wherein R is a carbamate or a urea derivative can be synthesized using the following protocol. Sancycline (2A) is treated with NaNO 2 under acidic conditions forming 7-nitro sancycline (2B) in a mixture of positional isomers. 7-nitrosancycline (2B) is then treated with H 2 gas 5 and a platinum catalyst to form the 7-amino sancycline derivative (2C). To form the urea derivative (2E), isocyanate (2D) is reacted with the 7-amino sancycline derivative (2C). To form the carbamate (2G), the appropriate acid chloride ester (2F) is reacted with 2C. N (M e NH 2 N(M OH NOH H,SQ NaNO, H R"O NH (Me) NNH2 RO C OH 0 OH 0 0 OH 0 OH 0 0 Ossoni cee3 ercciecmonso the~ inetoweri ri R"HN' NH LN(Me) 2 NH (Me) 2 OH OHC NH2 2DNH OH 0 OH 0 0 OH 0 OH 0 0 o 2L ' heterocylkeon (iE haoe) uc izl substituted amnogouamibesnthsizedycling theF). v S

H

3 C NC3H 3 CNCH

H

2 NH2 FmocHN H2 O O OHOOO 1) - F moc H2N H H3C ocCH3 2 r3 R 3 H OHH 2 N 2 OH o HH OHO0 O O O O H O OH 0 10 3F2SCH EM 1)- s i S e 3 t ie os 4 n heterocycli Hi 2 N NHiaoe susiue 0mn Oru a esnteie sn hebv H3,C3D SCHEME N CH H2N N mocHN3 OH 44 OH 7- alkenyl tetracycline compounds, such as 7-alkynyl sancycline (4A) and 7 alkenyl sancycline (4B), can be hydrogenated to form 7-alkyl substituted tetracycline compounds (e.g., 7-alkyl sancycline, 4C). Scheme 4 depicts the selective hydrogenation 5 of the 7- position double or triple bond, in saturated methanol and hydrochloric acid solution with a palladium/carbon catalyst under pressure, to yield the product. R R R

N(CH

3 )2 N(CH 3 ), N(CH 3 ), OH OH OH )H NH, or NH, Pd/C OH NH, OH 0 OH 0 0 OH 0 OH 0 0 OH 0 OH 0 0 4A 4B 4C SCHEME 4 10 In Scheme 5, a general synthetic scheme for synthesizing 7-position aryl derivatives is shown. A Suzuki coupling of an aryl boronic acid with an iodosancycline compound is shown. An iodo sancycline compound (5B) can be synthesized from sancycline by treating sancycline (5A) with at least one equivalent N-iodosuccinimide 15 (NIS) under acidic conditions. The reaction is quenched, and the resulting 7-iodo sancycline (5B) can then be purified using standard techniques known in the art. To form the aryl derivative, 7-iodo sancycline (5B) is treated with an aqueous base (e.g., Na 2

CO

3 ) and an appropriate boronic acid (5C) and under an inert atmosphere. The reaction is catalyzed with a palladium catalyst (e.g., Pd(OAc) 2 ). The product (5D) can be purified by 20 methods known in the art (such as HPLC). Other 7-aryl, alkenyl, and alkynyl tetracycline compounds can be synthesized using similar protocols NMe 2 NMe 2 N-iodosuccinimide OH

NH

2 H

NH

2 OH HH OH 0 OH 0 0 OH 0 OH OH0 0 5A 5B Pd(OAc) 2 , Na 2

CO

3 , MeOH N OH X - OH xBOH o,11 NH2 5C OH O OHO HO O 5D SCHEME 5 25 - 45 - The 7-substituted tetracycline compounds of the invention can also be synthesized using Stille cross couplings. Stille cross couplings can be performed using an appropriate tin reagent (e.g., R-SnBu 3 ) and a halogenated tetracycline compound, (e.g., 7 iodosancycline). The tin reagent and the iodosancycline compound can be treated with a 5 palladium catalyst (e.g., Pd(PPh 3

)

2 Cl 2 or Pd(AsPh 3

)

2 Cl 2 ) and, optionally, with an additional copper salt, e.g., Cul. The resulting compound can then be purified using techniques known in the art. The compounds of the invention can also be synthesized using Heck-type cross 10 coupling reactions. As shown in Scheme 6, Heck-type cross-couplings can be performed by suspending a halogenated tetracycline compound (e.g., 7-iodosancycline, 6A) and an appropriate palladium or other transition metal catalyst (e.g., Pd(OAc) 2 and Cul) in an appropriate solvent (e.g., degassed acetonitrile). The substrate, a reactive alkene (6B) or alkyne (6D), and triethylamine are then added and the mixture is heated for several hours, 15 before being cooled to room temperature. The resulting 7-substituted alkenyl (6C) or 7 substituted alkynyl (6E) tetracycline compound can then be purified using techniques known in the art. R' N (CH 3 )2 6B OH

CONH

2 Transition Metal OH OO caayt OH 0 OH 0 N (C H3)2 Phosphine Ligand 6C OH

CONH

2 OH O OH O Transition Metal R' 6A Ph ire Ligand N(CH I I N(C 3

)

2 'K OH 6D

CONH

2 OH60H OH OHO 20 6E SCHEME 6 - 46 - To prepare 7-(2'-Chloro-alkenyl)-tetracycline compounds, the appropriate 7 (alkynyl)-sancycline (7A) is dissolved in saturated methanol and hydrochloric acid and stirred. The solvent is then removed to yield the product (7B). R

N(CH

3

)

2 CI N(CH3)2 OH MeOH/HCI OH

NH

2 NH2 OH 0 OH 0 O OH OH O O 5 7A 7B SCHEME 7 As depicted in Scheme 8, 5-esters of 9- substituted tetracycline compounds can be formed by dissolving the 9- substituted compounds (8A) in strong acid (e.g. HF, methanesulphonic acid, and trifluoromethanesulfonic acid) and adding the appropriate 10 carboxylic acid to yield the corresponding esters (8B). 0 H Rj__ H 3 C.N ,CH 3

H

3 C, ,CH 3 H0 N

CH

3 OHCN CH 3 C CN OH i carboxylic acid OH

NH

2 anhydrous

NH

2 OH 0 OH 0 0 0 8A 8B SCHEME 8 As shown in Scheme 9 below, 7 and 9-aminomethyl tetracyclines may be synthesized using reagents such as hydroxymethyl-carbamic acid benzyl ester.

H

2 N

N(CH

3

)

2 0 OH

N(CH

3

)

2

OHNH

2 OH C H H TFA OHO O O o

NH

2 1 +

N(CH

3

)

2 OH 0 O 24 hr., 25C OH

H

2 N NH 2 15 H SCHEME 9 The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), 20 branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted - 47 cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its 5 backbone (e.g., C 1

-C

6 for straight chain, C 3

-C

6 for branched chain), and more preferably 4 or fewer. Likewise, preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C 1

-C

6 includes alkyl groups containing 1 to 6 carbon atoms. Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted 10 alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 15 alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an 20 aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "arylalkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids. The term "aryl" includes groups, including 5- and 6-membered single-ring 25 aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, 30 benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, 35 halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, - 48 phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, 5 trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin). The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double 10 bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted 15 cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2

-C

6 for straight chain, C 3

-C

6 for branched chain). 20 Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C 2

-C

6 includes alkenyl groups containing 2 to 6 carbon atoms. Moreover, the term alkenyl includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a 25 hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including 30 alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. 35 The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. -49 - For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur 5 or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2

-C

6 for straight chain, C 3

-C

6 for branched chain). The term C 2

-C

6 includes alkynyl groups containing 2 to 6 carbon atoms. Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted 10 alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, 15 alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an 20 aromatic or heteroaromatic moiety. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for example, 2-5 carbon atoms. 25 The term "acyl" includes compounds and moieties which contain the acyl radical

(CH

3 CO-) or a carbonyl group. It includes substituted acyl moieties. The term "substituted acyl" includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, 30 alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, 35 alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. - 50 - The term "acylamino" includes moieties wherein an acyl moiety is bonded to an amino group. For example, the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups. The term "aroyl" includes compounds and moieties with an aryl or heteroaromatic 5 moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc. The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or 10 sulfur atoms. The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be 15 substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino 20 (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 25 chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term includes "alkyl amino" which comprises groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term "dialkyl amino" includes groups wherein the nitrogen 30 atom is bound to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a 35 nitrogen atom which is also bound to an alkyl group. The term "amide," "amido" or "aminocarbonyl" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarbonyl" or "alkylaminocarbonyl" -51 groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl and arylcarbonylamino groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarbonyl," 5 "alkenylaminocarbonyl," "alkynylaminocarbonyl," "arylaminocarbonyl," "alkylcarbonylamino," "alkenylcarbonylamino," "alkynylcarbonylamino," and "arylcarbonylamino" are included in term "amide." Amides also include urea groups (aminocarbonylamino) and carbamates (oxycarbonylamino). The term "carbonyl" or "carboxy" includes compounds and moieties which 10 contain a carbon connected with a double bond to an oxygen atom. The carbonyl can be further substituted with any moiety which allows the compounds of the invention to perform its intended function. For example, carbonyl moieties may be substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos, etc. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. 15 The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an 20 oxygen atom which is covalently bonded to another alkyl group. The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, 25 alkenyl, or alkynyl groups are as defined above. The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a 30 sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -0-. The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term 35 "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms. The terms "polycyclyl" or "polycyclic radical" refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two - 52 or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, 5 aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amido, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, 10 arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "heteroatom" includes atoms of any element other than carbon or 15 hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. The term "prodrug moiety" includes moieties which can be metabolized in vivo to a hydroxyl group and moieties which may advantageously remain esterified in vivo. Preferably, the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups. Examples of prodrugs and 20 their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties 25 include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy 30 substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Preferred prodrug moieties are propionoic acid esters and acyl esters. It will be noted that the structure of some of the tetracycline compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the 35 isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by - 53 stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof Methods for Treating Tetracycline Responsive States 5 The invention also pertains to methods for treating a tetracycline responsive states in subjects, by administering to a subject an effective amount of a tetracycline compound of the invention (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or otherwise described herein), such that the tetracycline responsive state is treated. 10 The term "treating" includes curing as well as ameliorating at least one symptom of the state, disease or disorder, e.g., the tetracycline compound responsive state. The language "tetracycline compound responsive state" or "tetracycline responsive state" includes states which can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the invention. Tetracycline compound 15 responsive states include bacterial, viral, and fungal infections (including those which are resistant to other tetracycline compounds), cancer (e.g., prostate, breast, colon, lung melanoma and lymph cancers and other disorders characterized by unwanted cellular proliferation, including, but not limited to, those described in U.S. 6,100,248), arthritis, osteoporosis, diabetes, and other states for which tetracycline compounds have been found 20 to be active (see, for example, U.S. Patent Nos. 5,789,395; 5,834,450; 6,277,061 and 5,532,227, each of which is expressly incorporated herein by reference). Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infection, mastitis and the like. In addition, 25 methods for treating neoplasms using tetracycline compounds of the invention are also included (van der Bozert et al., Cancer Res., 48:6686-6690 (1988)). In a further embodiment, the tetracycline responsive state is not a bacterial infection. In another embodiment, the tetracycline compounds of the invention are essentially non-antibacterial. For example, non-antibacterial tetracycline compounds of the invention may have MIC 30 values greater than about 4 gg/ml (as measured by assays known in the art and/or the assay given in Example 2). Tetracycline compound responsive states also include inflammatory process associated states (IPAS). The term "inflammatory process associated state" includes states in which inflammation or inflammatory factors (e.g., matrix metalloproteinases 35 (MMPs), nitric oxide (NO), TNF, interleukins, plasma proteins, cellular defense systems, cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc.) are involved or are present in an area in aberrant amounts, e.g., in amounts which may be advantageous to alter, e.g., to benefit the subject. The inflammatory process is the - 54 response of living tissue to damage. The cause of inflammation may be due to physical damage, chemical substances, micro-organisms, tissue necrosis, cancer or other agents. Acute inflammation is short-lasting, lasting only a few days. If it is longer lasting however, then it may be referred to as chronic inflammation. 5 IPAF's include inflammatory disorders. Inflammatory disorders are generally characterized by heat, redness, swelling, pain and loss of function. Examples of causes of inflammatory disorders include, but are not limited to, microbial infections (e.g., bacterial and fungal infections), physical agents (e.g., burns, radiation, and trauma), chemical agents (e.g., toxins and caustic substances), tissue necrosis and various types of 10 immunologic reactions. Examples of inflammatory disorders include, but are not limited to, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal, including diphtheria and pertussis); acute and chronic bronchitis, sinusitis, and upper respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute 15 and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis); uremic pericarditis; acute and chronic cholecystis; acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (thermal, chemical, and electrical); and sunburn. 20 Tetracycline compound responsive states also include NO associated states. The term "NO associated state" includes states which involve or are associated with nitric oxide (NO) or inducible nitric oxide synthase (iNOS). NO associated state includes states which are characterized by aberrant amounts of NO and/or iNOS. Preferably, the NO associated state can be treated by administering tetracycline compounds of the invention. 25 The disorders, diseases and states described in U.S. Patents Nos. 6,231,894; 6,015,804; 5,919,774; and 5,789,395 are also included as NO associated states. The entire contents of each of these patents are hereby incorporated herein by reference. Other examples of NO associated states include, but are not limited to, malaria, senescence, diabetes, vascular stroke, neurodegenerative disorders (Alzheimer's disease & 30 Huntington's disease), cardiac disease ( reperfusion-associated injury following infarction), juvenile diabetes, inflammatory disorders, osteoarthritis, rheumatoid arthritis, acute, recurrent and chronic infections (bacterial, viral and fungal); acute and chronic bronchitis, sinusitis, and respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and 35 chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendonitis); uremic pericarditis; acute and chronic cholecystis; cystic fibrosis, acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (thermal, chemical, and electrical); and sunburn. - 55 - The term "inflammatory process associated state" also includes, in one embodiment, matrix metalloproteinase associated states (MMPAS). MMPAS include states characterized by abberrant amounts of MMPs or MMP activity. These are also include as tetracycline compound responsive states which may be treated using 5 compounds of the invention. Examples of matrix metalloproteinase associated states ("MMPAS's") include, but are not limited to, arteriosclerosis, corneal ulceration, emphysema, osteoarthritis, multiple sclerosis(Liedtke et al., Ann. Neurol. 1998, 44:35-46; Chandler et al., J Neuroimmunol. 1997, 72:155-71), osteosarcoma, osteomyelitis, bronchiectasis, chronic 10 pulmonary obstructive disease, skin and eye diseases, periodontitis, osteoporosis, rheumatoid arthritis, ulcerative colitis, inflammatory disorders, tumor growth and invasion (Stetler-Stevenson et al., Annu. Rev. Cell Biol. 1993, 9:541-73; Tryggvason et al., Biochim. Biophys. Acta 1987, 907:191-217; Li et al., Mol. Carcinog. 1998, 22:84 89)),metastasis, acute lung injury, stroke, ischemia, diabetes, aortic or vascular aneurysms, 15 skin tissue wounds, dry eye, bone and cartilage degradation (Greenwald et al., Bone 1998, 22:33-38; Ryan et al., Curr. Op. Rheumatol. 1996, 8;238-247). Other MMPAS include those described in U.S. Pat. Nos. 5,459,135; 5,321,017; 5,308,839; 5,258,371; 4,935,412; 4,704,383, 4,666,897, and RE 34,656, incorporated herein by reference in their entirety. In another embodiment, the tetracycline compound responsive state is cancer. 20 Examples of cancers which the tetracycline compounds of the invention may be useful to treat include all solid tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas. Adenocarcinomas are carcinomas derived from glandular tissue or in which the tumor cells form recognizable glandular structures. Sarcomas broadly include tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective 25 tissue. Examples of carcinomas which may be treated using the methods of the invention include, but are not limited to, carcinomas of the prostate, breast, ovary, testis, lung, colon, and breast. The methods of the invention are not limited to the treatment of these tumor types, but extend to any solid tumor derived from any organ system. Examples of treatable cancers include, but are not limited to, colon cancer, bladder cancer, breast 30 cancer, melanoma, ovarian carcinoma, prostatic carcinoma, lung cancer, and a variety of other cancers as well. The methods of the invention also cause the inhibition of cancer growth in adenocarcinomas, such as, for example, those of the prostate, breast, kidney, ovary, testes, and colon. In an embodiment, the tetracycline responsive state of the invention is cancer. The 35 invention pertains to a method for treating a subject suffering or at risk of suffering from cancer, by administering an effective amount of a substituted tetracycline compound, such that inhibition cancer cell growth occurs, i.e., cellular proliferation, invasiveness, metastasis, or tumor incidence is decreased, slowed, or stopped. The inhibition may result - 56 from inhibition of an inflammatory process, down-regulation of an inflammatory process, some other mechanism, or a combination of mechanisms. Alternatively, the tetracycline compounds may be useful for preventing cancer recurrence, for example, to treat residual cancer following surgical resection or radiation therapy. The tetracycline compounds 5 useful according to the invention are especially advantageous as they are substantially non-toxic compared to other cancer treatments. In a further embodiment, the compounds of the invention are administered in combination with standard cancer therapy, such as, but not limited to, chemotherapy. Examples of tetracycline responsive states also include neurological disorders 10 which include both neuropsychiatric and neurodegenerative disorders, but are not limited to, such as Alzheimer's disease, dementias related to Alzheimer's disease (such as Pick's disease), Parkinson's and other Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amylotrophic lateral sclerosis (ALS), progressive supranuclear palsy, epilepsy, and Creutzfeldt-Jakob disease; 15 autonomic function disorders such as hypertension and sleep disorders, and neuropsychiatric disorders, such as depression, schizophrenia, schizoaffective disorder, Korsakoff's psychosis, mania, anxiety disorders, or phobic disorders; learning or memory disorders, e.g., amnesia or age-related memory loss, attention deficit disorder, dysthymic disorder, major depressive disorder, mania, obsessive-compulsive disorder, psychoactive 20 substance use disorders, anxiety, phobias, panic disorder, as well as bipolar affective disorder, e.g., severe bipolar affective (mood) disorder (BP-1), bipolar affective neurological disorders, e.g., migraine and obesity. Further neurological disorders include, for example, those listed in the American Psychiatric Association's Diagnostic and Statistical manual of Mental Disorders (DSM), the most current version of which is 25 incorporated herein by reference in its entirety. Other examples of tetracycline compound responsive states are described in WO 03/005971A2 and U.S. Patent Application Publication No. 20040214800, each of which is incorporated herein by reference. The language "in combination with" another therapeutic agent or treatment 30 includes co-administration of the tetracycline compound, (e.g., inhibitor) and with the other therapeutic agent or treatment, administration of the tetracycline compound first, followed by the other therapeutic agent or treatment and administration of the other therapeutic agent or treatment first, followed by the tetracycline compound. The other therapeutic agent may be any agent which is known in the art to treat, prevent, or reduce 35 the symptoms of an IPAS. Furthermore, the other therapeutic agent may be any agent of benefit to the patient when administered in combination with the administration of an tetracycline compound. In one embodiment, the cancers treated by methods of the - 57 invention include those described in U.S. Patent Nos. 6,100,248; 5,843,925; 5,837,696; or 5,668,122, incorporated herein by reference in their entirety. In another embodiment, the tetracycline compound responsive state is diabetes, e.g., juvenile diabetes, diabetes mellitus, diabetes type I, or diabetes type II. In a further 5 embodiment, protein glycosylation is not affected by the administration of the tetracycline compounds of the invention. In another embodiment, the tetracycline compound of the invention is administered in combination with standard diabetic therapies, such as, but not limited to insulin therapy. In a further embodiment, the IPAS includes disorders described in U.S. Patents Nos. 5,929,055; and 5,532,227, incorporated herein by reference in their 10 entirety. In another embodiment, the tetracycline compound responsive state is a bone mass disorder. Bone mass disorders include disorders where a subjects bones are disorders and states where the formation, repair or remodeling of bone is advantageous. For examples bone mass disorders include osteoporosis (e.g., a decrease in bone strength and density), 15 bone fractures, bone formation associated with surgical procedures (e.g., facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism. Bone mass disorders include all states in which the formation, repair or remodeling of bone is 20 advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the tetracycline compounds of the invention. In a further embodiment, the bone mass disorders include those described in U.S. Patents Nos. 5,459,135; 5,231,017; 5,998,390; 5,770,588; RE 34,656; 5,308,839; 4,925,833; 3,304,227; and 4,666,897, each of which is hereby incorporated herein by 25 reference in its entirety. In another embodiment, the tetracycline compound responsive state is acute lung injury. Acute lung injuries include adult respiratory distress syndrome (ARDS), post pump syndrome (PPS), and trauma. Trauma includes any injury to living tissue caused by an extrinsic agent or event. Examples of trauma include, but are not limited to, crush 30 injuries, contact with a hard surface, or cutting or other damage to the lungs. The invention also pertains to a method for treating acute lung injury by administering a substituted tetracycline compound of the invention. The tetracycline responsive states of the invention also include chronic lung disorders. The invention pertains to methods for treating chronic lung disorders by 35 administering a tetracycline compound, such as those described herein. The method includes administering to a subject an effective amount of a substituted tetracycline compound such that the chronic lung disorder is treated. Examples of chronic lung disorders include, but are not limited, to asthma, cystic fibrosis, and emphesema. In a - 58 further embodiment, the tetracycline compounds of the invention used to treat acute and/or chronic lung disorders such as those described in U.S. Patents No. 5,977,091; 6,043,231; 5,523,297; and 5,773,430, each of which is hereby incorporated herein by reference in its entirety. 5 In yet another embodiment, the tetracycline compound responsive state is ischemia, stroke, or ischemic stroke. The invention also pertains to a method for treating ischemia, stroke, or ischemic stroke by administering an effective amount of a substituted tetracycline compound of the invention. In a further embodiment, the tetracycline compounds of the invention are used to treat such disorders as described in U.S. Patents 10 No. 6,231,894; 5,773,430; 5,919,775 or 5,789,395, incorporated herein by reference. In another embodiment, the tetracycline compound responsive state is a skin wound. The invention also pertains, at least in part, to a method for improving the healing response of the epithelialized tissue (e.g., skin, mucusae) to acute traumatic injury (e.g., cut, burn, scrape, etc.). The method may include using a tetracycline compound of the 15 invention (which may or may not have antibacterial activity) to improve the capacity of the epithelialized tissue to heal acute wounds. The method may increase the rate of collagen accumulation of the healing tissue. The method may also decrease the proteolytic activity in the epthithelialized tissue by decreasing the collagenolytic and/or gellatinolytic activity of MMPs. In a further embodiment, the tetracycline compound of 20 the invention is administered to the surface of the skin (e.g., topically). In a further embodiment, the tetracycline compound of the invention used to treat a skin wound, and other such disorders as described in, for example, U.S. Patent Nos. 5,827,840; 4,704,383; 4,935,412; 5,258,371; 5,308,8391 5,459,135; 5,532,227; and 6,015,804; each of which is incorporated herein by reference in its entirety. 25 In yet another embodiment, the tetracycline compound responsive state is an aortic or vascular aneurysm in vascular tissue of a subject (e.g., a subject having or at risk of having an aortic or vascular aneurysm, etc.). The tetracycline compound may by effective to reduce the size of the vascular aneurysm or it may be administered to the subject prior to the onset of the vascular aneurysm such that the aneurysm is prevented. In one 30 embodiment, the vascular tissue is an artery, e.g., the aorta, e.g., the abdominal aorta. In a further embodiment, the tetracycline compounds of the invention are used to treat disorders described in U.S. Patent Nos. 6,043,225 and 5,834,449, incorporated herein by reference in their entirety. Bacterial infections may be caused by a wide variety of gram positive and gram 35 negative bacteria. The compounds of the invention are useful as antibiotics against organisms which are resistant to other tetracycline compounds. The antibiotic activity of the tetracycline compounds of the invention may be determined using the method discussed in Example 2, or by using the in vitro standard broth dilution method described - 59 in Waitz, J.A., National Commission for Clinical Laboratory Standards, Document M7 A2, vol. 10, no. 8, pp. 13-20, 2"d edition, Villanova, PA (1990). The tetracycline compounds may also be used to treat infections traditionally treated with tetracycline compounds such as, for example, rickettsiae; a number of gram 5 positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, psittacosis. The tetracycline compounds may be used to treat infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus or E. faecalis. In one embodiment, the tetracycline compound is used to treat a bacterial infection that is 10 resistant to other tetracycline antibiotic compounds. The tetracycline compound of the invention may be administered with a pharmaceutically acceptable carrier. The language "effective amount" of the compound is that amount necessary or sufficient to treat or prevent a tetracycline compound responsive state. The effective amount can vary depending on such factors as the size and weight of the subject, the type 15 of illness, or the particular tetracycline compound. For example, the choice of the tetracycline compound can affect what constitutes an "effective amount". One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the tetracycline compound without undue experimentation. 20 The invention also pertains to methods of treatment against microorganism infections and associated diseases. The methods include administration of an effective amount of one or more tetracycline compounds to a subject. The subject can be either a plant or, advantageously, an animal, e.g., a mammal, e.g., a human. In the therapeutic methods of the invention, one or more tetracycline compounds 25 of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient 30 thereof. -60- Pharmaceutical Compositions of the Invention The invention also pertains to pharmaceutical compositions comprising a therapeutically effective amount of a tetracycline compound (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or any other 5 compound described herein) and, optionally, a pharmaceutically acceptable carrier. The language "pharmaceutically acceptable carrier" includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g., treat or prevent a tetracycline responsive state. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, 10 alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for 15 influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention. The tetracycline compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of the tetracycline 20 compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, 25 glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 1,1 '-methylene-bis-(2-hydroxy-3 naphthoate)] salts. Although such salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal, it is often desirable in practice to initially isolate a tetracycline compound of the invention from the reaction mixture as a 30 pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous 35 solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The preparation of other tetracycline compounds of the invention not specifically described in - 61 the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art. The preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations 5 of the reactions described above that will be apparent to those skilled in the art. The tetracycline compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those tetracycline compounds of the invention that are acidic in nature are those that form non-toxic base salts with such 10 compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic 15 amines. The pharmaceutically acceptable base addition salts of tetracycline compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods. Thus, these salts may be readily prepared by treating the tetracycline compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, 20 preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the tetracycline compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness. The preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations 25 of the reactions described above that will be apparent to those skilled in the art. The tetracycline compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of 30 administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. The pharmaceutical compositions of the invention may be administered alone or in 35 combination with other known compositions for treating tetracycline responsive states in a subject, e.g., a mammal. Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas). The language "in combination with" - 62 a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the 5 therapeutically composition known in the art for treating tetracycline responsive states can be used in the methods of the invention. The tetracycline compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple 10 doses. For example, the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays (e.g., aerosols, etc.), creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable 15 solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. 20 For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, 25 lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active 30 ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. The compositions of the invention may be formulated such that the tetracycline compositions are released over a period of time after administration. 35 For parenteral administration (including intraperitoneal, subcutaneous, intravenous, intradermal or intramuscular injection), solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater - 63 than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard 5 pharmaceutical techniques well known to those skilled in the art. For parenteral application, examples of suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories. Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% 10 saline dextrose solutions commonly used with injectables. Additionally, it is also possible to administer the compounds of the present invention topically when treating inflammatory conditions of the skin. Examples of methods of topical administration include transdermal, buccal or sublingual application. For topical applications, therapeutic compounds can be suitably admixed in a 15 pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream. Such topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils. Other possible topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate 5% in water, sodium lauryl sulfate 5% in water, and the like. In addition, 20 materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired. For enteral application, particularly suitable are tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or the like can be used wherein a 25 sweetened vehicle is employed. Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. In addition to treatment of human subjects, the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock 30 such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats. Also, the compounds of the invention may be used to treat non-animal subjects, such as plants. It will be appreciated that the actual preferred amounts of active compounds used in a given therapy will vary according to the specific compound being utilized, the 35 particular compositions formulated, the mode of application, the particular site of administration, etc. Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art using conventional dosage determination tests conducted with regard to the foregoing guidelines. - 64 - In general, compounds of the invention for treatment can be administered to a subject in dosages used in prior tetracycline therapies. See, for example, the Physicians' Desk Reference. For example, a suitable effective dose of one or more compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of body weight 5 of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day. The desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule. 10 It will also be understood that normal, conventionally known precautions will be taken regarding the administration of tetracyclines generally to ensure their efficacy under normal use circumstances. Especially when employed for therapeutic treatment of humans and animals in vivo, the practitioner should take all sensible precautions to avoid conventionally known contradictions and toxic effects. Thus, the conventionally 15 recognized adverse reactions of gastrointestinal distress and inflammations, the renal toxicity, hypersensitivity reactions, changes in blood, and impairment of absorption through aluminum, calcium, and magnesium ions should be duly considered in the conventional manner. Furthermore, the invention also pertains to the use of a tetracycline compound of 20 formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI or XVII or any other compound described herein, for the preparation of a medicament. The medicament may include a pharmaceutically acceptable carrier and the tetracycline compound is an effective amount, e.g., an effective amount to treat a tetracycline responsive state. 25 EXEMPLIFICATION OF THE INVENTION Example 1: Preparation of 7-(1,2,3,6-tetrahydro-pyridin-4-y)-sancycline Boc N H I H HN Pd(OAc), N OH NaCO N H H - TEA am NH2 Boc OH T H H H OH 0 OHOH O N NH 2 5H NH 2 OH 0 OH OH 0 OH O OHOOH O

B(OH)

2 In a 500 mL two-neck round bottom flask, 7-iodo-sancycline TFA salt (654 mg, 1 30 mmol) and Pd(OAc) 2 (22 mg, 0.1 mmol) were taken in 100 mL of MeOH. The reaction mixture was then heated to 70 0 C under argon. After 5 minutes, Na 2

CO

3 (420 mg, 4 mmol, a saturated solution in 10 mL of water) was added. A yellow precipitate was obtained which was further heated at 70 0 C for 10 minutes. To this solution, 4-N,N dimethylamino-3-pyridinyl-boronic acid (248 mg, 1.5 mmol, dissolved in 10 mL of DMF) - 65 was added and the reaction mixture was heated for another 2 hours. Progress of the reaction was monitored by HPLC and LC/MS. The reaction was completed in 2 hours. Reaction mixture was filtered through celite to remove the catalyst. Solvent was then evaporated to dryness and the crude material was precipitated using MeOH/diethyl ether 5 (20/200 mL). Brown-yellow precipitate was filtered and dried under vacuum. The solid obtained was taken in 20 mL of TFA and stirred at room temperature for 5 minutes. TFA was removed and purification was done on a C-18 Luna column using a 5-25 % organic gradient (CH 3 CN/0.1% TFA and Water/0.1% TFA). Fractions collected were dried in vacuo and the solid obtained was converted to its HCl salt using a saturated solution of 10 methanol-HCl (20mL). Compound was dried overnight over P 2 0 5 to yield the product as a yellow powder. MS: (m/z) 496.2391. 'H NMR (300MHz, CD 3 0D): 6 7.32 (d, 1H), 6.75 (d, 1H), 5.51 (s, 1H), 3.95 (s, 1H), 3.71 (s, 2H), 3.35 (m, 2H), 2.94-2.76 (m, 8H), 2.52 2.39 (m, 1H), 2.36-2.31(m, 1H), 2.05 (m, 1H), 1.48-1.47 (m, 1H). 15 Example 2: Preparation of 7-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-sancycline H NN N / Na(OAc) 3 BH, DMF H Hr 0 H H OH H- OH

NH

2 NH2 OH 0 OH HOH 0 OH O OHOHO In 40 mL glass vial, 7-(1,2,3,6-tetrahydro-pyridin-4 yl)-sancycline (495 mg, 1 mmol) and InCl 3 (11 mg, 0.1 mmol) were taken in DMF (20 mL) under an argon atmosphere. Isobutyraldehyde (144 [tL, 2 mmol) was added to the reaction mixture and it 20 was further stirred at room temperature for 20 minutes. To this sodium cyanoborohydride (186 mg, 3 mmol) was added, and the reaction solution was stirred at room temperature for another 4 hours. Completion of the reaction was confirmed by HPLC and LC-MS. Solvent was then evaporated to dryness, redissolved in water/0. 1 %TFA and purified using a C-18 Luna column using a 7-35% organic gradient (CH 3 CN/0.1% TFA and water/0.1% 25 TFA). The Fractions collected were dried in vacuo and the solid obtained was converted to its HCl salt using a saturated solution of Methanol-HCl (20mL). The compound was then dried overnight over P 2 0 5 to yield the product as a yellow powder. MS: (m/z) 552.3212. 'H NMR (300MHz, CD 3 0D): 6 7.26-7.23 (m, 1H), 6.74-6.72 (m, 1H), 5.50 5.46 (m, 1H), 4.02(s, 1H), 3.92-3.88 (m, 1H), 3.65-3.60 (m, 2H), 3.03-2.76 (m, 11H), 30 2.33-2.28 (m, 1H), 2.20-2.15 (m, 3H), 1.18-1.04 (m, 1H), 1.04-0.99 (m, 6H). - 66 - Example 3: Preparation of 7-imidazo-[1,2-a]-pyrimidin-2-yl-sancycline Br HNH HOAc OHNH NN H-N _r N K2CO3 N' H H OH OH OH O OHO to prevent oxidation of products) were taken in acetic acid (4 mL) and water (1 mL). The 5 reaction mixture was stirred until contents dissolved (5 minutes) under argon atmosphere. To this solution, HBr (33 wt% solution in HOAc, 3 mL, 0.02 mmol) was slowly added. Dropwise addition of bromine (0. 15 mL, 1.21 mmol) gave an exothermic reaction. The reaction was monitored by HPLC and LC-MS and completion of the reaction was observed within 15 minutes. HPLC/LC-MS indicates the formation of mono and bis 10 bromo-substituted products. An amount of 200mL of diethyl ether was added to the reaction mixture to form a precipitate. The ether was decanted, and 200 mL fresh ether added, and decanted once again. The yellow precipitate was filtered and dried under vacuum for 5 minutes and was used for the next step without any purification. Crude 2' bromo-7-acetyl-sancycline was dissolved in NMP (10 mL) and Na2SO3 (200 mg) was 15 added to prevent oxidation of products. K2CO3 (lg, 7.25mmol) was added to the reaction solution, followed by addition of 2-amino-pyrimidine (1 g, 10.52 mmol). The reaction was monitored by HPLC and LC-MS. Starting material was consumed after 30 minutes. Crude material was precipitated in diethyl ether (200 mL); the precipitate was filtered through a sintered glass funnel, and washed with fresh ether. A dark yellow solid of crude 20 material (0.95 g) remained. The crude material was purified on a C-18 Luna column using a 10-30% organic gradient (CH3CN with 0.1% TFA and Water with 0.1% TFA). The purified compound was dried in vacuo and redissolved in methanol (20 mL) saturated with HCl to exchange the salt. The compound was dried overnight over P205 to yield the product as a yellow powder. MS: (m/z) 532.2317. 1 H NMR (300MHz, CD30D): 6 9.22 25 (d, 1 H), 9.03 (d, 1 H), 8.24 (s, 1 H), .7.72-7.62 (m, 2H), 7.04 (d, 1 H), 4.13 (s, 1 H), 3.18 2.94 (m, 9H), 2.18 (t, 1H-), 1.59 (d, 1H-), 1.26 (q, 1H-). Example 4: Preparation of 7-{3'-[(ethyl-methyl-amino)-methyl]-phenyl}-sancycline 0N 1 N" - H H TE N O H OH NOA02 OH MeOH/DMF H H TOH OH O OH O HHH B(OH)N 2 H O n / ad N < (0 to prvnNxdto fpout)wr ae naei cd( L n ae 1m) he 5~~~~~ recto mitr wa-treHni otnsdsovd 5mnts ne ro topee TOHisouon H0 (3 wtH sOuio in O c, 3L.2m )wssOlHddd D ro p w is ad it o of bro in (0 1 m L0.1 m o ) g v n e o h r i e c i n h reactio was moitoredby HPLnCM n opeto fterato a obsevedwithn 1 miutes HPC/L -Sidctsth7omto-f ooadbs A mixture of 7-(3'-formyl-phenyl)-sancycline (389 mg, 0.75 mmol), N-methyl-N ethylamine (644 [tL, 7.5 mmol) and triethylamine in 1,2-dichloroethane was stirred overnight. Sodium triacetoxyborohydride (477 mg, 2.25 mmol) was added and stirred for 5 hours. Excess sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added and stirred 5 for additional 2.5 hours. The solvent was evaporated and purified by prep-HPLC (10-40% acetonitrile in water). This was converted to hydrochloride salt to give a yellow solid: MS (Mz+1 = 562); 1 H NMR (300 MHz, CD 3 0D) 67.56-7.38 (5H), 6.90 (m, 1H), 4.46 (m, 1H), 4.25 (m, 1H), 4.03 (d, J = 1.0 Hz), 3.31 (m, 1H), 3.19-2.72 (13H), 2.51 (m, 1H), 2.00 (m, 1H), 1.50 (m, 1H), 1.37 (t, 3H, J = 7.3 Hz). 10 Example 5: Preparation of 7-{1[3'-(2-methoxy-ethylamino)-methyl]-furan-2'-yl methyl}-sanscycline 11 NaCO, 0 0HE O~ I " Pd(OAc), " E N 0 ~ H - OH C OH O H H 1,2DCE O NN" MeOH/DMF - OH Na(OAc) 3 BH H H OH NH2 heat/araon_ NH2 OH NH 2 OH O OHO 0 OHO OH O 2N O

NH

2 H B(OH) 2 A mixture of 7-(3'-formyl-furan-2'yl)-sancycline (1.02 g, 2 mmol) and 2 15 methoxyethylamine (348 [tL, 4 mmol) in 1,2-dichloroethane (60 mL) was stirred for 1 hour. Sodium triacetoxyborohydride (1.272 g, 6 mmol) was added and stirred for 7 hours. The solvent was evaporated and purified by prep-HPLC to give a yellow solid: MS (Mz+1 = 568); 'H NMR (300 MHz, CD 3 0D) 6 7.67 (m, 1H), 7.50 (m, 1H), 6.96 (m, 1H), 7.77 (m, 1H), 4.09-3.98 (3H), 3.59 (m, 2H), 3.33 (s, 3H), 3.16-2.93 (m, 10H), 2.69 (m, 1H), 20 2.46 (m, 1H), 2.14 (m, 1H), 1.55 (m, 1H). Example 6: Preparation of 7-(5'-dimethylaminomethyl-1H-pyrrol-2-yl)-sancycline 0 H N I N Na 2

CO

3 x NH .N/ TEA H H OH Pd(OAc) 2 H H N 1,2-DCE NH N OH MeOH/DMF - - OH Na(OAc) 3 BH H H I - NH 2 heat/argon NH2 H OH NH HH OH O HO 0 0 H H O OH N NH 2 OH 0 O 0O NH

B(OH)

2 25 A mixture of 7-(l'-Boc-5'-formyl-pyrrol-2'-yl)-sancycline (262.2 mg, 0.36 mmol), dimethylamine hydrochloride (148 mg, 1.8 mmol), and triethylamine (254 [tL, 1.8 mmol) in 1,2-dichloroethane (17 mL) was stirred for 1 hour. Sodium triacetoxyborohydride was added and stirred overnight, after which LC-MS showed the completion of the reaction. The solvent was evaporated and purified by prep-HPLC (12-40% acetonitrile in buffer). 30 The resulting residue (85 mg) was stirred in 5 mL trifluoroacetic acid for 2 hour. - 68 - Trifluoroacetic acid was evaporated and purified by prep-HPLC (10-40% acetonitrile in water). The solvent was evaporated to give a yellow solid: MS (Mz+1 = 537); 1 H NMR (300 MHz, CD 3 0D) 6 10.89 (s, 1H), 7.50 (m, 1H), 6.87 (m, 1H), 6.39 (brt, 1H), 6.14 (brd, 1H), 4.27 (s, 2H), 4.00 (s, 1H), 3.13-2.84 (9H), 2.81 (s, 6H), 2.49 (m, 1H), 2.00 (m, 1H), 5 1.55 (m, 1H). Example 7: Preparation of 7-[2-(4-methyl-piperidin-1-yl)-acetyl]-sancycline Br NN H H- ~ c Hr N OH 0N N ~ - H HOA, - - H KN H H N H

HNH

2 c B HN H NH3 OH 2 OH 0 OH 0 0 7-acetyl sancycline (lg, 2.19mmol) was combined with acetic acid (4mL), water 10 (1mL) and HBr (33wt% solution in AcOH, 2mL, 0.Olmmol) in a 40 mL glass vial. The reaction mixture was stirred under argon until the contents were dissolved (5 minutes). Bromine (0.15mL, 1.2lumol) was added dropwise to the solution (an exothermic reaction). Reaction was monitored by HPLC and LC-MS, and the starting material was consumed within 15 minutes. Mono and bis-substituted bromine products were both 15 detected. An amount of 400 mL of diethylether was added to the reaction solution and a bright yellow solid precipitate was formed. The ether was decanted, 400mL fresh ether was added, and then decanted once again. Acetonitrile (300mL) was added to the resulting yellow precipitate and the mixture was filtered through filter paper. The filtrate was dried in vacuo to yield a dark yellow solid. The crude bromo acetyl sancycline was 20 dissolved in DMF (20mL) in a 1 OOmL round bottom flask. Argon line was attached to the reaction. TEA (1mL, 7.19mmol) was added, followed by 4-methylpiperidine (1mL, 8. Immol). The reaction was monitored by HPLC and LC-MS and the starting material was consumed after 30 minutes. Methanol (50mL) was added to quench the reaction, and the solvent was dried in vacuo. The crude material was purified on a C-18 Luna column 25 using a 10-30% organic gradient (CH 3 CN with 0.1% TFA and water with 0.1% TFA). The purified compound was dried in vacuo and redissolved in HCl saturated methanol to exchange the salt. The compound was dried overnight over P 2 0 5 to yield the product as a yellow powder. MS: (m/z) 553. 1 H NMR (300MHz, CD 3 0D) 6 7.99 (m, 1H), 6.93 (m, 1H), 4.89 (m, 1H), 4.61 (m, 1H), 4.07 (s, 1H), 3.68 (m, 1H), 3.56 (m, 1H), 3.30 (m, 1H), 30 3.11 (m, 2H), 3.01 (m, 7H), 2.47 (m, 1H), 2.15 (m, 1H), 1.89 (m, 2H), 1.55 (m, 4H), 0.96 (d, J= 9Hz, 3H). - 69 - Example 8: Preparation of 7-[2-(1-methyl-1H-pyrrole-2-yl methyl amino)-acetyl] sancycline N-N H H-r N )~ H -O c Br H -* NH 2 OH NH2 H2 OHOHH O IH 7-acetyl sancycline (lg, 2.19mmol) was combined with acetic acid (4mL), water 5 (1mL) and HBr (33wt% solution in AcOH, 3mL, 0.02mmol) in a 40 mL glass vial. Na 2

SO

3 (200mg) was added to prevent oxidation of products. The reaction mixture was stirred under argon until contents were dissolved (5 minutes). Bromine (0. l5mL, 1.2lumol) was added dropwise to the reaction solution (an exothermic reaction). The reaction was monitored by HPLC and LC-MS, and the starting material was consumed 10 within 15 minutes. Mono and bis-substituted bromine products were both detected. An amount of 400 mL of diethylether was added to the reaction solution and a bright yellow solid precipitate was formed. The ether was decanted, 400mL fresh ether added, and then decanted once again. Acetonitrile (300mL) was added to the yellow precipitate, and the mixture was filtered through filter paper. The filtrate was dried in vacuo to yield a dark 15 yellow solid. The crude bromo acetyl sancycline was dissolved in NMP (12mL). Na 2

SO

3 (200mg) was added to prevent oxidation of products. K 2 C0 3 (lg, 7.25mmol) was added to the reaction solution, followed by (1-methyl-1H-pyrrole-2-yl)-methylamine (1mL, 7.25mmol). The reaction was monitored by HPLC and LC-MS and the starting material was consumed after 30 minutes. The crude material was precipitated in diethyl ether 20 (500mL), filtered through a sintered glass funnel, and washed with fresh ether. A dark yellow solid of crude material remained. The crude material was purified on a C-18 Luna column using a 10-30% organic gradient (CH 3 CN with 0.1% TFA and water with 0.1% TFA). Purified compound was dried in vacuo and redissolved in HCl saturated methanol to exchange the salt. The compound was dried overnight over P 2 0 5 to yield the product as 25 a yellow powder. MS: (m/z) 564. 1H NMR (300MHz, CD 3 0D) 6 7.93 (m, 1H), 6.91 (m, 1H), 6.74 (m, 1H), 6.27 (m, 1H), 5.99 (m, 1H), 4.71 (m, 1H), 4.44 (m, 1H), 4.27 (m, 2H), 4.07 (s, 1H), 3.71 (s, 3H), 3.58 (m, 1H), 3.28 (s, 1H), 3.15 (s, 1H), 2.95 (m, 7H), 2.38 (m, 1H), 2.11 (m, 1H), 1.55 (m, 1H). - 70 - Example 9: Preparation of 7-(3'-dimethylamino-propenyl)-sancycline I N/ N H OH (1) Propiolaldehyde OH diethyl acetal BH, THF N NH2 (2) Pd(PPh 3

)

4 , Pd(OAC) 2 - OH OH 0 OH O0 0 (3) HN(CH 3

)

2 NH 2 Na(OAc) 3 BH OH OH 0 OH 0 0 A solution of propionaldehyde diethyl acetal 1 (12.9 mL, 90 mmol) in 60 mL THF was cooled in an ice-bath and BH 3 /THF was added dropwise and stirred. A mixture of 7 5 iodosancycline trifluoroacetate (5.889 g, 9 mmol), Pd(PPh 3

)

4 , and Palladium (II) acetate in methanol (160 mL) was purged with argon. A solution of sodium carbonate (3.82 g, 36 mmol) in water (40 mL) was added and purged for additional 5 minutes. To this mixture was added DMF (40 mL) and reaction mixture I and further purged with argon. The reaction mixture was heated to 44 'C and stirred at this temperature for 3 hour. This 10 intermediate (MS, Mz+1 = 469) was purified by short DVB column followed by prep HPLC. To a stirred solution of the intermediate (250 mg, 0.43 mmol), dimethylamine hydrochloride (70 mg, 0.86 mmol), and triethylamine (120 [tL, 0.86 mmol) in 1,2 dichloroethane (25 mL) was added sodium triacetoxyborohydride (182 mg, 0.86 mmol) and the reaction mixture was stirred for 1 hour. The solvent and excess reagent was 15 evaporated. The product was purified by prep-HPLC (5-25% acetonitrile in water) to give a yellow solid: MS (Mz+1 = 562); 1 H NMR (300 MHz, CD 3 0D) 67.79 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 15.5 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.14 (dt, J = 15.5 Hz, 7.7 Hz, 1H), 4.10 (s, 1H), 3.94 (d, J = 7.4 Hz, 2H), 3.28-2.89 (15H), 2.42 (m, 1H), 2.20 (m, 1H), 1.67 (m, 1H). 20 Example 10: Preparation of 7-(4-methyl-piperidin-1-yl methyl)-sancycline I * NdP" 3 0 H H ' H ND ', Sn 3 H H OHO OH NaCNBH 3 H OH N H 2 D M F/argoe B I N H 2 OHO O -HOHO0O - heat OHOH OH UTi OH 7-iodo sancycline (6g, 9.17mmol) was combined with NaOAc (0.75g, 9.17mmol) and DMF (100mL) in an oven-dried 500mL 2-neck round bottom flask. The reaction 25 mixture was stirred at ambient temperature for 1 hour under argon. An amount of Pd(PPh 3

)

4 (1.06g, 0.917mmol) was added, and the reaction mixture was purged with CO for 20 minutes. The reaction mixture was placed in a 70'C pre-heated oil bath, and stirred under CO atmosphere for 1 hour. An amount SnBu 3 H (3.2g, 1.1 mmol) was added via syringe pump over 2 hours. The reaction was monitored by HPLC and LC-MS, and the 30 starting material was consumed 2 hours post tin addition. The reaction was quenched with CH 3 CN (50mL), and the solvent was evacuated in vacuo. Water (IL with 0.1%TFA) was added, and a heterogeneous mixture was formed. After filtration through celite to remove unwanted precipitate, the aqueous layer was loaded onto a prepared DVB column. - 71 - The product was eluted with 30% organic gradient (CH 3 CN with 0.1% TFA and water with 0.10% TFA). The solvent was evaporated to yield 7-formyl sancycline product as a yellow solid. The 7-formyl sancycline (0.5g, 1.13mmol) was combined with InCl 3 (0.025g, 0.13mmol), 4-methylpiperidine (0.267mL, 2.26mmol) and DMF (10mL) in a 5 glass vial. The reaction mixture was stirred at ambient temperature for 30 minutes under argon. An amount of NaCNBH 3 (0. 1g, 1.58mmol) was added to the reaction mixture, and the progress of the reaction was monitored by HPLC and LC-MS. After stirring overnight at ambient temperature, the starting material was consumed. Methanol (10mL) was added to quench the reaction and the solvent was evacuated in vacuo. The crude material was 10 purified on a C-18 Luna column using a 10-30% organic gradient (CH 3 CN with 0.1% TFA and water with 0.1 % TFA). The purified material was concentrated, and redissolved in HCl saturated methanol (20mL) to exchange the salt. After drying overnight under high vacuum the product was obtained as a yellow powder. MS: (m/z) 525. 1H NMR (300MHz, CD 3 0D) 6 7.54 (m, 1H), 6.86 (m, 1H), 4.22 (m, 2H), 4.03 (s, 1H), 3.44 (m, 15 1H), 3.27 (m, 1H), 3.15 (m, 1H), 2.94 (m, 9H), 2.31 (m, 2H), 1.61 (m, 6H), 0.90 (d, J= 7Hz, 3H). Example 11: Preparation of 7-(4-dimethylamino-pyridin-3-yl)-sancycline N I N N H Pd(OAc) 2 HOH

HNH

2 N OH OH 0 OH 0 0 N O NH 2 "iiOH OH 0 OH 0 0

B(OH)

2 20 In a 500 mL two-neck round bottom flask, 7-iodo-sancycline TFA salt (654 mg, 1 mmol) and Pd(OAc) 2 (22 mg, 0.1 mmol) were taken in 100 mL of MeOH. The reaction mixture was then heated to 70 0 C while purging with argon. After 5 minutes, Na 2

CO

3 (420 mg, 4 mmol, a saturated solution in 10 mL of water) was added to the reaction mixture. A yellow precipitate was obtained which was further heated at 70 0 C for 10 25 minutes. To this, 4-dimethylamino-pyridin-3-yl-boronic acid (248 mg, 1.5 mmol, dissolved in 10 mL of DMF) was added and the reaction was continued for another 3 hours. The progress of the reaction was monitored by HPLC and LC/MS. The reaction was completed in 3 hours. It was then filtered through celite to remove the catalyst. The solvent was evaporated to dryness and the crude material obtained was purified using 30 preparative HPLC using a C-18 Luna column with a 10-40% organic gradient

(CH

3 CN/0.1%o TFA and Water/0.1% TFA). The fractions collected were dried in vacuo and the solid obtained was converted to its HCl salt using a saturated solution of methanol-HCl (20mL). The compound was dried overnight over P 2 0 5 to yield the product as a yellow powder. MS: (m/z) 535.2242. 'H NMR (300MHz, CD 3 0D): 6 8.10 (d, 1H), - 72 - 7.85 (s, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 6.86 (d, 1H), 3.98 (s, 1H), 3.20 (s, 6H), 3.08-2.82 (m, 8H), 2,49 (m, 1H), 2.45 (t, 1H), 1.84-1.47 (m, 1H), 1.44-1.19 (m, 1H). Example 12: Preparation of 7-(4'-hydroxy-phenyl)-sancycline 5 OH I N' H H - OH Pd(OAc), zkNaCO N OHH H NH 2 OHOH OHI OH 0 OH 0 0 NH 2 OH 0 OH 0 0

B(OH)

2 A solution of 7-iodosanscycline trifluoroacetate (654.43 mg, 1 mmol), Pd(PPh 3

)

4 (115.6 mg, 0.1 mmol), and palladium (II) acetate (22.5, 0.1 mmol) in 20 mL methanol was purged with argon for 10 minutes. A solution of sodium carbonate (424 mg, 4 mmol) in 5 10 mL water was added and the mixture was purged for additional 5 minutes. A solution of 4-hydroxyphenyl boronic acid pinacol ester in DMF (5 mL) was purged with argon and added to the mixture. The reaction mixture was heated to 65 'C and stirred at the same temperature for 3 h. The reaction mixture was cooled and filtered through celite pad. The filtrate was taken, solvent evaporated and the crude product was precipitated from ether. It 15 was further purified by prep-HPLC (20-40% acetonitrile in water) to give a yellow solid: MS (Mz+1, 507); 1 H NMR (300 MHz, CD 3 0D) 6 7.39 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.84 (m, 1H), 4.04 (s, 1H), 3.00-2.85 (9H), 2.44 (m, 1H), 2.05 (m, 1H), 1.55 (m, 1H). 20 Example 13: Preparation of minocycline-2-acetyl amide N OAc N N H H: H H: OH

NH

2 C 3 OH ~CH 3

SO

3 HOH I OH O OH O 0 or OHO OHO 0 0

AC

2 O/pyridine OH0 H000 To a suspension of minocycline (0. 1g, 0. 19mmol) in pyridine was added acetic anhydride with stirring. The suspension became a clear solution. The reaction mixture 25 was stirred at room temperature overnight. The product was obtained after HPLC purification as a yellow powder. MS: (M+1 = 500); 'H NMR (300 MHz, CD 3 0D) 6 7.87 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 9 Hz, 1H), 4.83 (d, J = 3Hz, 1H), 3.98 (m, 1H), 3.49-3.10 (15H), 2.60 (m, 1H), 2.40 (s, 3H), 19 (m, 1H). - 73 - Example 14: Preparation of 7-(3,4,5-trifluorophenyl)-9-aminomethyl minocycline F F F N. . 1. Hydroxymethyl benzyl carbamnate I H s methane sulfonic acid / TFA IN P~ O T -H H- O 2. Pd (PPh 3

)

4 , MeCH, H 2 0, - - O

NH

2 Na 2

CO

3 HN - NH OHO OHO-P1 0 F O H IFN F OHO OH 00

B(OH)

2 7-iodo sancycline in methanesulfonic acid/TFA was treated with excess hydroxymethylbenzyl carbamate (~5 equivalents). The resulting reaction mixture was 5 stirred for several hours. The solvent was evaporated and to the residue was added to methanol/water. The insoluble material was filtered and the filterate was dried to yield the crude product. The desired intermediate was obtained by preparative HPLC. To a solution of 7-iodo-9-aminomethylsanscycline trifluoroacetate in methanol was added 0.2 equiv of tetrakis(triphenylphosphine)Palladium (0) and the resulting solution was stirred 10 under argon for 5 minutes. An amount of 3 equivalents of sodium carbonate in water was added followed by substituted phenylboronic acid. The resulting solution was heated at 70'C for several hours. The catalyst was filtered through celite, and the filtrate was dried to yield the crude reaction product. The desired material was isolated via reverse-phase preparative HPLC as a yellow solid. MS: M+1 = 574; 1H NMR (300 MHz, CD 3 0D), 6 d 15 7.54 (s, 1H), 7.15 (t, 2H), 4.2 (s, 2H), 4.08(s, 1H), 2.98-2.50(m, 10H), 2.1 (bd, 1H), 1.6 (m, 1H). Example 15: Preparation of 9-[(2-dimethylamino-acetylamino)-methyl]-doxycycline H -HH O H OHZ OH OH HMVIBC OH Reductive H 11111 N mination_ I SNH TFA H2N NH2 N NH 2 20 HO~ ~Acid chloride 0 OH 0 OH 0 An amount of 5 g of doxycycline in 50 ml of TFA was treated with excess hydroxymethylbenzyl carbamate (HMBC) (~5 equivalents). Several drops of sulfuric acid were then added and the resulting reaction mixture was stirred for several hours. The 25 solvent was evaporated and to the residue was added methanol/water. The insoluble material was filtered and the filterate was dried to yield the crude product. The intermediate (9-aminomethyl doxycycline) was obtained by preparative HPLC. An amount of 800 mg of 9-aminomethyl-doxycycline was reacted with 3 equivalents of N,N-dimethylglycinyl chloride in the presence of diisopropylethylamine (3 30 equivaltents) in DMF. The reaction mixture was stirred at room temperature for several hours. The product was obtained by preparative HPLC as a yellow solid. MS: M+1 = 559; - 74 - IHNMR (300MHz, CD 3 0D) 6 d 7.54 (d, 1H), 6.96(d, 1H), 4.47(s, 2H), 4.44(s, 1H), 3.98(s, 2H), 3.56(q, 1H), 3.34(s, 1H), 2.99-2.75(m, 14H), 2.59(q, 1H), 1.55 (d, 3H). Example 16: Preparation of 7-hydroxy-9-[(2,2-dimethyl propylamino)-methyl] 5 sancycline H O.N - H N'H

:H

9 -OH H 9 HH OH OH HMBC OH Reductive NH TFA mination _ HNH HNH2 HMC HNH 2 ordNH2 OH 0 'C 0 O'YAi hloride0 OH0 H0 0 OH0 HO OHO0 OFHO AcdcO An amount of 9-[(2,2-dimethyl propylamino)-methyl]-minocycline (2.0 g, 3.5 mmol) was added to DDI water (40 mL) and pH adjusted to pH 11 using a 1.0 N solution 10 of sodium hydroxide. Subsequently, sodium metaperiodate (700mg, 3.29 mmol) was added to the above solution and allowed to stir at room temp for 40 seconds. Subsequently, a pre-dissolved aqueous solution of ascorbic acid (5.0 g, 28 mmol) in DDI water (80 mL) was added to quench the above reaction. The reaction was added to DDI water (1.0 L) and the pH was lowered to pH 2 using trifluoroacetic acid. The solution was 15 then filtered and concentrated onto a plug of divinyl benzene (DVB) resin, eluted from the resin with acetonitrile and concentrated via rotary evaporation to 800 mg crude product. The crude product was purified by HPLC using a C-18 column, triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic phase. The fractions containing the desired compound were loaded onto a DVB plug, washed with aqueous 0.05 N HCl (1.0 20 L) and eluted with acetonitrile to give the HCl salt of the product as a yellow powder. MS: M+1 = 530; 'H-NMR (300 MHz, CD 3 0D) 6 7.1-7.3 (s, 1H), 4.2-4.3 (s, 2H), 4.0-4.1 (s, 1H), 2.9-3.2 (m, 8H), 2.8-2.9 (m, 2H), 2.1-2.3 (m, 2H), 1.6-1.9 (m, 1H),_1.0-1.1 (s, 9H). Example 17: Preparation of 9-methyl minocycline 25 "N eN N N 0H CHMgBr H HNH2 Pd(0 / Pd(II) / InCI HNH 2 'OH ~THF'"O " OH 0 O H 0 0 -78 to 25'C OH 0 OH 0 0 A 1000 mL 2 or 3 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl 3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After flask was cooled to ambient temperature and flushed with argon, anhydrous THF (240 30 mL) was added. The solution was cooled to -78'C and methyl MgBr(Cl) (122 mmol) as solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form a clear heterogeneous solution. To the reaction flask was added 9-iodominocycline (21.0 g, 36 mmol) and Pd(t-Bu 3

P)

2 (0.920 g, 1.80 mmol). The solution was heated to reflux under argon until the reaction was complete. After cooling to 35 ambient temperature, the solution was quenched with MeOH (1 mL) and poured into a - 75 stirring cold solution of IM HCl (3 L). After lh, the solution was filtered through a pad of celite rinsing with water. The water solution was loaded onto a large fritted funnel containing a bed of prepared DVB resin. At first, cold water (500 mL) was eluted then a gradient of cold acetonitrile/water was eluted in (500 mL) fractions. The fractions 5 containing product were concentrated under reduced pressure and then dried under high vacuum overnight to afford desired product as a dark yellow solid. MS: M+1 = 472; 1H NMR (300 MHz, CD 3 0D) 6 7.26 (s, 1 H), 4.22 (s, 1 H), 3.41-3.35 (m, 1 H), 2.90-2.52 (m, 15 H), 2.21-2.00 (m, 4 H), 1.68-1.55 (m, 1 H). 10 Example 18: Preparation 9-(4-pyrazol)-minocycline N "N N N PdCI 2 (dppq

NH

2 H -O H HN,

NH

2 OH 0 OX~ 0 N-B(N) OHO " 0 4

H

0 O To a solution of anhydrous 9-iodominocycline freebase (2.04 g, 3.5 mmol), pyrazolyl boronic acid (4.38 mmol) and Cl 2 Pd(dppf) (0.143 g, 0.175 mmol) in NMP (10 15 mL) was added (10 mL) of 2M K 3 P0 4 in a 20 mL Biotage microwave vial. The secured vial was placed into a Biotage microwave reactor with a temperature setting of 1 00C for 10 minutes. The reaction was cooled to rt and poured into a solution of 1% TFA/H 2 0 (150 mL). The solution was loaded onto a previously prepared funnel of DVB resin (3 x 10 cm packed DVB column). After loading, water (100 mL) was eluted and finally 1% 20 TFA/CH 3 CN to elute the desired product. The yellow solution was concentrated under reduced pressure and further purified by preparatory chromatography. The product was obtained as a brown solid. MS: M+1 = 524; 1 H NMR (300 MHz, CD 3 0D) 6 8.69 (s, 1 H), 8.32 (s, 1 H), 4.18 (s, 1 H), 3.41-2.94 (m, 15 H), 2.60-2.49 (m, 1 H), 2.35-2.29 (m, 1 H), 1.73-1.61 (m, 1 H). 25 Example 19: Preparation of 9-(thiazol-2-yl)-minocycline N N Pd 2 (dba) 3 / Cui N N j ~ P(2-furvl) / DMF I- L I i NH2 N i l iinBi NH 2 HH HH 0 ~ SH H OH O H 0 To a solution of anhydrous 9-iodominocycline freebase (2.04 g, 3.5 mmol), 30 thiazol-2-yl stannane (4.38 mmol), Cul (0.067 g, 0.350 mmol), P(2-furyl) 3 (0.163 g, 0.700 mmol) and Pd 2 (dba) 3 (0.081 g, 0.088 mmol) in DMF (20 mL) in a 20 mL Biotage microwave vial. The secured vial was placed into a Biotage microwave reactor with a temperature setting of 100 C for 10 minutes. The reaction was poured into a solution of 1% TFA/H 2 0 (150 mL). The solution was filtered through a plug of Celite rinsing with 35 1% TFA water solution. The solution was loaded onto a previously prepared funnel of - 76 - DVB resin (3 x 10 cm packed DVB column). After loading, water (100 mL) was eluted and finally CH 3 CN to elute the desired product. The yellow solution was concentrated under reduced pressure and further purified by preparatory chromatography. The product was obtained as an orange-yellow solid. MS: M+1 = 541; 'H NMR (300 MHz, CD 3 0D) 6 5 8.88 (s, 1 H), 8.12 (d, J= 3 Hz, 1 H), 7.98 (d, J= 3 Hz, 1 H), 4.19 (s, 1 H), 3.50-2.92 (m, 15 H), 2.65-2.53 (m, 1 H), 2.40-2.22 (m, 1 H), 1.76-1.61 (m, 1 H). Example 20: Preparation of 9-(3-methoxy-pro-1-ynyl)-minocycline H HINN Pd(II)/ClN N = = - OH acetonitrile - - OH NH2 diisopropylethylamine NH2 I3-methoxypropyne __ - O0 O H 0O OH 10OH 0 OH 0 OH 0OH0 An amount of 9-iodo-minocycline (free-base) (5.00g, 8.57mmol), trans-dichlorobis (triphenylphosphine)palladium(II) (152mg, 0.22mmol), palladium(II)acetate (55mg, 0.24mmol), copper(I)iodide (92mg, 0.48mmol)were loaded in anhydrous acetonitrile (86mL) in a flame-dried 1OOmL round bottom flask equipped with a magnetic stirring bar. 15 The mixture was degassed by bubbling argon through for 10 minutes, and diisopropylethylamine (4.5mL, 25.83mmol) was added, followed by 3-methoxy-propyne (1.5mL, 17.76mmol). The reaction mixture was then stirred at room temperature for 18 hours while being monitored by LC/MS. After filtration through a pad of celite, the solution was poured into a 1% TFA in water solution (1 L) and purified on a DVB column 20 by eluting with a gradient of 1%TFA in water solution and a 50/50 mixture of methanol and acetonitrile. The major peak was isolated, and all solvents were evaporated. The residue was then purified by preparative HPLC (C 18 Lumina). A salt exchange with a 0.2N HCl solution on a DVB column followed by evaporation to dryness then yielded the desired product as a yellow solid. MS: M+1 = 526. 'H-NMR (300 MHz, CD 3 0D): 8.03 25 (s, 1H), 4.38 (s, 2H), 4.15 (d, 1H), 3.45 (s, 3H), 3.33-3.36 (m, 1H), 3.24 (s, 6H), 3.06-3.24 (m, 1H), 2.94-3.04 (m, 7H), 2.54 (m, 1H), 2.31 (m, 1H), 1.68 (m, 1H). Example 21:Preparation of 9-cyano minocycline N N Pd(II) / Cul N N OH acetonitilie O d s Prop lethyla m ine - HH 2

NH

2 ZnCN

NH

2 30 OH 0 OH 0 N OH 0 OH O 0 An amount of 9-iodo-minocycline (2.00g, 3.43mmol), tetrakis(triphenylphosphine) palladium (0) (97mg, 0.34mmol), zinc cyanide (500mg, 4.17mmol) were loaded in anhydrous DMF (20mL) in a dry 20mL microwave reaction vessel equipped with a magnetic stirring bar. Argon was bubbled through for 10 minutes, and the vessel was - 77 sealed. The reaction mixture was then subjected to the microwave irradiation for 10 minutes at 100 C with the "heating while cooling" feature and is monitored by LC/MS. The reaction mixture was poured into a O.1M solution of sodium acetate. The mixture was then filtered through a pad of celite, and washed several times with the 0.1M sodium 5 acetate solution. The resulting aqueous solution was purified on a DVB column (gradient of water and acetonitrile). After evaporation of the organic solvent, the resulting residue is then purified by preparative HPLC (C18 Lumina). A salt exchange with a 0.2N HCl solution on a DVB column followed by evaporation to dryness then yielded the desired product as a yellow solid. MS: M+1 = 483. 'H-NMR (300 MHz, CD 3 0D): 8.13 (s, 1H), 10 4.13 (s, 1H), 3.40 (m, 1H), 2.90-3.16 (m, 14H), 2.52 (m, 1H), 2.28 (m, 1H), 1.65 (m, 1H). Example 22: Preparation of 9-[5-(2-methoxy-ethylamino)-methyl furan-2-yl] minocycline N N N N - ' N H 0OH OH I V, B(OH)2 I I HNH2 H (OHHNH) NaCNBH, O N NH2 N Paldium(O1) 0 0 "-'NH2 0 OH OHO0 OHO~T 0 0 - HN H 15 An amount of 9-2-formyl-furany-2-yl minocycline (0.5g, 0.91mmol) was combined with 2-methoxyethylamine (0.15 7mL, 1.81 mmol) and 1,2-DCE (20mL) in a glass vial. The reaction mixture was stirred at ambient temperature for 10 minutes under argon. NaCNBH 3 (0.086g, 1.36mmol) was added to the reaction mixture, and was stirred for 1 hour. Reaction was monitored by HPLC and LC-MS, and the starting material was 20 consumed after 1 hour. Methanol (50mL) was added to quench the reaction, and the solvent was evacuated in vacuo. The crude material was purified on a C-18 Luna column using a 5-30% organic gradient (CH 3 CN with 0.10% TFA and water with 0.10% TFA). Solvent was evacuated and, the product was redissolved in HCl saturated methanol (20mL) to exchange the salt. After drying overnight under high vacuum the product was 25 obtained as a yellow powder. MS: (m/z) 610. 'H NMR (300MHz, CD 3 0D) 6 8.49 (s, 1H), 7.16 (d, J= 3Hz, 1H), 6.75 (d, J= 3Hz, 1H), 4.37 (s, 2H), 4.12 (s, 1H), 3.67 (m, 2H), 3.37 (s, 4H), 3.31 (m, 7H), 2.98 (m, 7H), 2.51 (m, 1H), 2.32 (m, 1H), 1.67 (m, 1H). Example 23: Preparation of 9-[(4-methylphenyl)-thiocarboxylacyl]-minocycline 30 N"N N N N OHNH SSnBu, OH OH O OH O O CO/DMF O OH O OH O O To solution of 4-methylbenzenethiol sodium salt (20.0 g, 137 mmol) in anhydrous DMF (500 mL) under argon was added Bu 3 SnCl (36.9 mL, 137 mmol) drop wise. After 12 hours, the solution was poured into a 1:1 solution of hexane/water (1000 mL), and then - 78 the layers were separated. The water layer was back extracted with hexane (250 mL). The combined organic layers were dried over anhydrous MgSO 4 , filtered rinsing with hexane, and then concentrated under reduced pressure to afford 4-methylbenzenethil tributyltin (56.5 g) as colorless oil in 99% yield. To a solution of anhydrous 9 5 iodominocycline freebase (20.4 g, 35.0 mmol), 4-methylphenylthiotributyltin (15.9 g, 38.5 mmol) and Pd(PPh 3

)

4 (2.02 g, 1.75 mmol) in anhydrous DMF (175 mL) was bubbled CO for 15 minutes, then heated to 70'C with a large balloon of CO affixed to the flask to maintain a positive pressure of CO. After 12 hours, the reaction was cooled to room temperature and poured into a cold 1:1 solution of 1% TFA/H 2 0 (500 mL) and MTBE 10 (500 mL). After separating layers, the organic layer was back extracted with 1%

TFA/H

2 0 (500mL). The combined water layers were loaded onto a previously prepared funnel of DVB resin (7 x 15 cm packed DVB column). After loading, a cold solution of IM NaOAc was eluted until the eluent became basic (approx. 300 mL), then water (400 mL) and finally 1:1 CH 3 CN/THF to elute the desired product. The yellow solution was 15 concentrated under reduced pressure and further dried under high vacuum overnight to afford 18.5 g as an orange-yellow solid in 87% yield. MS: M+1 = 608; 'H NMR (300 MHz, CD 3 0D) 6 8.00 (s, 1 H), 7.38-7.26 (m, 1 H), 4.07 (s, 1 H), 3.42-2.76 (m, 15 H), 2.37 (s, 3 H), 2.32-2.67 (m, 1 H), 2.25-2.06 (m, 1 H), 1.72-1.60 (m, 1 H). 20 Example 24: Preparation of 9-propionyl minocycline N N N N OH OH I ~~Pd catalystI - NH S HNH2 Cu at HNH2 IfQT OH NH CH 3

CH

2 In OH 0 OH 0 OH 0 0 0 OH 0 OH O O A 1000 mL 2 neck round-bottomed flask with reflux condenser was charged with anhydrous InCl 3 (12.1 g, 40.5 mmol) and dried under vacuum with a heat gun. After flask 25 was cooled to ambient temperature and flushed with argon, anhydrous THF (240 mL) was added. The solution was cooled to -78'C and CH 3

CH

2 MgBr(Cl) (122 mL, 122 mmol) as a solution in THF was added. After 15 minutes, the solution was allowed to slowly warm to room temperature to form (CH 3

CH

2

)

3 1n as a clear heterogeneous solution. To a solution of 9-[(4-methylphenyl)-thiocarboxyl acyl]-minocycline (1.70 g, 2.80 mmol), Cu(I) 30 thiophenecarboxylate (0.801 g, 4.20 mmol), Pd 2 (dba) 3 (0.064 g, 0.070 mmol) and P(2 furyl) 3 (0.130 g, 0.560 mmol) in anhydrous THF (5 mL) under argon was added a 0.1M solution of previously prepared (CH 3

CH

2

)

3 1n (56.0 mL, 5.60 mmol), then the solution was heated to reflux until reaction was complete. After cooling to room temperature, the solution was poured into cold 0. 1M HCl (mL) and stirred for 1 hour. The solution was 35 added to celite and then filtered through a large plug of Celite rinsing with cold water. The cold solution was loaded onto a prepared column of DVB resin (3 x 10 cm packed - 79 - DVB column). When the loading was complete, water (300 mL) was eluted, and then

CH

3 CN was eluted until the eluent became colorless. The yellow solution was concentrated under reduced pressure, the further purified by preparatory chromatography. The product was obtained as a yellow solid. MS: M+1 = 514; 1H NMR (300 MHz, 5 CD 3 0D) 6 8.28 (s, 1 H), 4.13 (s, 1 H), 3.42-2.91 (m, 17 H), 2.63-2.47 (m, 1 H), 2.32-2.15 (m, 1 H), 1.70-1.54 (m, 1 H), 1.14 (t, J= 7 Hz, 3 H). Example 25: Preparation of 9-{1-[(E)-methoxyimino]-ethyl}-minocycline H H- OH H NH 2

OCH

3 NOH NH -TIH

NH

2 E OH 0 ' N OH 0 OH 0 0 10 0 OH O OHO 0 O 9-acetyl-minocycline (3.00g, 5.24mmol) was dissolved in methanol (50mL) at room temperature in a dry 1 OOmL round bottom flask equipped with a magnetic stirring bar. Methoxylamine hydrochloride (2.23g, 26.17mmol) was then loaded in one portion, and the mixture was stirred at room temperature for 3 hours while being monitored by LC/MS. 15 The solvent was evaporated to dryness, and a 1% TFA in water solution was added in order to purify the product on a DVB column. The product was eluted with a gradient of 1%TFA in water solution and a 50/50 mixture of methanol and acetonitrile. All solvents were evaporated and the residue was purified by preparative HPLC (C18 Lumina). After evaporating the volatiles, the aqueous solution was then loaded on a DVB column and 20 washed with water to yield the product (a free base) as a yellow solid. MS: M+1 = 529. 1 H-NMR (300 MHz, CD 3 0D): 7.35 (s, 1H), 3.94 (s, 3H), 3.76 (t, 1H), 3.39 (dd, 1H), 2.89 (m, 1H), 2.73 (s, br, 6H), 2.66 (m, 1H), 2.61 (s, 6H), 2.22 (m,1H), 2.21 (s, 3H), 2.12 (m, 1H), 1.65 (m, 1H). 25 Example 26: Preparation of 9-methoxyethylester minocycline N N N N H

NH

2 CO NH 2 IH Pd catalyst Y6 OH 0 OH 0 O 0 OH 0 OH 0 0 To a bomb was added 9-iodominocycline free base (4.00g, 6.86mmol), 2-methoxy 30 ethanol (50 mL), tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.29 mmol), triethylamine (1.5 mL, 2.7 g, 20 mmol). The bomb was closed and charged with carbon monoxide (500 psi), heated to 70 'C and allowed to stir for 3 hours. The reaction was added to water (1.0 L) and the pH was lowered to 2 using trifluoroacetic acid. The solution was then filtered through celite to remove the catalyst, concentrated onto a plug - 80 of divinyl benzene (DVB) resin, eluted from the resin with acetonitrile and concentrated via rotary evaporation to give the crude product (4.5 g). The crude product was purified by HPLC using a C-18 column, triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic phase. The fractions containing the desired compound were 5 loaded onto a DVB plug, washed with aqueous 0.05 NaOAc (1.0 L) and eluted with acetonitrile to give the free base of 9-methoxyethylester minocycline as a dark red solid. MS: M+1 = 560; 1 H-NMR (300 MHz, CD 3 0D) 6 8.7-7.9 (m, 1H), 4.3-4.5 (m, 3H), 3.7 3.8 (m, 2H), 3.4-3.6 (m, 3H), 2.9-3.0 (m, 3H), 2.5-2.8 (m, 12H), 2.2-2.4 (m, 1H), 2.0-2.2 (m, 1H), 1.6-1.9 (m, 1H). 10 Example 27: Preparation of 9-carboxylic acid minocycline N N N" N H H HN2 Pd catalyst HH

INH

2 HO . NH 2 OH 0 OH O0 0 0 OH 0 OH O0 0 To a 1.0 L round bottom flask was added 9-iodo minocycline free base (30.0 g, 15 51.6 mmol), [1,1'-Bis(diphenylphosphino)-ferrocene] dichloropalladium(II) complex with dichloro methane 1:1 (5.0 g, 6.13 mmol), DMF (500 mL) and carbon monoxide (1 atm) was heated to 60'C for 1 hour. Subsequently, a 1:1 solution of aqueous saturated sodium bicarbonate and DMF (300 mL) was slowly added to the reaction. The reaction was allowed to stir overnight then reduced to half the volume using rotory evaporation (5 mm 20 Hg, 60'C). The reaction was added to water (4.0 L) and the pH was lowered to 3 using trifluoroacetic acid. The solution was then filtered through celite to remove the catalyst, concentrated onto a plug of divinyl benzene (DVB) resin, eluted from the resin using a 5 25o% gradient of acetonitrile in water buffered with an overall concentration of 0.1% TFA. The fractions containing compound were concentrated via rotary evaporation to 11.0 g 25 crude product. Some of the crude product (1.0 g) was purified using HPLC using a C-18 column, triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic phase. The fractions containing the desired compound were loaded onto a DVB plug, washed with aqueous 0.05 N HCl (1.0 L) and eluted with acetonitrile to give the HCl salt of the 9-carboxy minocycline as a dark yellow solid. MS: M+1 = 502; 'H-NMR (300MHz, 30 CD 3 0D) 6 8.5 (s 1H), 4.2 (s, 1H), 3.4-3.6 (m, 6H), 2.9-3.2 (m, 8H), 2.5-2.7 (m, 1H), 2.3 2.5 (m, 1H), 1.6-1.9 (m, 1H). - 81 - Example 28: Preparation of 9-(alpha-keto acid)-minocycline N N N" N H H OH CO - !- OH NH2 HO

HNH

2 2 H 2 0 HO 1Z H OH OH 0 OH O0 0 0 OH 0 OH O0 0 To a bomb was added 9-iodo minocycline free base (4.00 g, 6.86 mmol), DMF (50 5 mL), Pd(0) (1.59 g, 1.37 mmol), triethylamine (2.0 mL, 2.8 g, 2.7 mmol) and piperidine (7.88 g, 6.78 mL, 6.8 mmol). The bomb was closed and charged with carbon monoxide (400 psi), heated to 70'C and allowed to stir for 3 h until the 9-piperidine amide dicarbonyl minocycline intermediate was seen (M+1 = 597). The intermediate was then hydrolyzed to the product by adding the reaction to water (1.0 L). The pH was lowered to 10 2 using trifluoroacetic acid and the solution was then filtered through celite to remove the catalyst, concentrated onto a plug of divinyl benzene (DVB) resin, eluted from the resin with acetonitrile and concentrated via rotary evaporation to 4 g crude product. The crude product was purified by HPLC using a C-18 column, triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic. The fractions containing the desired 15 compound were loaded onto DVB plug, washed with aqueous 0.05 HCl (1.0 L) and eluted with acetonitrile to give the free base of 9-alpha-keto acid minocycline as a yellow solid. MS: M+1 = 530; 1 H-NMR (300MHz, CD 3 0D) 6 8.1-8.3 (m 1H), 4.1 (s, 1H), 3.4-3.6 (m, 9H), 2.9-3.2 (m, 11H), 2.5-2.8 (m, 1H), 2.3-2.5 (m, 1H), 1.6-1.9 (m, 1H). 20 Example 29: Preparation of 9-carboxylic acid amide minocycline N N N N H H O OHN 1 N-Hydroxy succinimide -N - NH 2 CO /Pd(O) /NMP IN 0 N ~ NH 2 OH 2. aq. NH 4 0H 4 OH OH O OH O 0 NH 2 OH O OH O 0 To 2 L flask was added (2.50 g, 4.30 mmol) 9-iodo minocycline free base, NMP (16.5 mL), N-hydroxysuccinimide (2.50 g, 221 mmol). To remove residual water from 25 the above reactants toluene was added (500 mL), the flask was placed on the rotary evaporator (35 mm Hg, 45C) until all the toluene was evaporated. The flask was backfilled with argon and the contents were then transferred via cannula to a dry 50 mL flask. To the 50 mL flask was added tetrakis-(triphenylphosphine)palladium(0) (0.50 g, 0.40 m mol) and DIEA (3.0 mL, 174 m mol). The flask was placed under vacuum (20 30 mm Hg) and purged with carbon monoxide three times. The flask was then heated to 60 'C under 1.0 ATM of carbon monoxide and let stir for 3 h until all 9-iodo minocycline was consumed and a peak for the corresponding N-hydroxysuccinimide-ester intermediate (M+1 = 599) was formed as determined via LC/MS. Subsequently, 37% aqueous ammonia hydroxide (3.0 mL) was added and the reaction was allowed to stir for 5 min. - 82 - The reaction was added to water (1.0 L) and the pH was lowered to 2 using trifluoroacetic acid. The solution was then filtered through celite to remove the catalyst, concentrated onto a plug of divinyl benzene (DVB) resin, eluted from the resin with acetonitrile and concentrated via rotary evaporation to 800 mg crude product. The crude product was 5 purified by HPLC using a C-18 column, triethanolamine (0.002 M) pH 7.4 aqueous buffer and acetonitrile as the organic phase. The fractions containing the desired compound were loaded onto DVB plug, washed with aqueous 0.05 N HCl (1.0 L) and eluted with acetonitrile to give the HCl salt of 9-carboxamide minocycline as a beige colored solid. MS: M+1 = 501; IH-NMR (300MHz, CD 3 0D) 6 8.4 (s 1H), 4.5 (s, 1H), 2.9-3.5 (m, 15H), 10 2.5-2.7 (m, 1H), 2.2-2.4 (m, 1H), 1.6-1.9 (m, 1H). Example 30: In vitro Minimum Inhibitory Concentration (MIC) Assay The following assay is used to determine the efficacy of the tetracycline compounds against common bacteria. 2 mg of each compound is dissolved in 100 1tl of 15 DMSO. The solution is then added to cation-adjusted Mueller Hinton broth (CAMHB), which results in a final compound concentration of 200 tg per ml. The tetracycline compound solutions are diluted to 50 [L volumes, with a test compound concentration of .098 jLg/ml. Optical density (OD) determinations are made from fresh log-phase broth cultures of the test strains. Dilutions are made to achieve a final cell density of 1x10 6 20 CFU/ml. At OD=1, cell densities for different genera should be approximately: E. coli 1x10 9 CFU/ml S. aureus 5x10 8 CFU/ml Enterococcus sp. 2.5x10 9 CFU/ml 25 S. pseumoniae 3x10 8 CFU/mL 50 1tl of the cell suspensions are added to each well of microtiter plates. The final cell density should be approximately 5x10 5 CFU/ml. These plates are incubated at 35'C in an ambient air incubator for approximately 18 hour. The plates are read with a 30 microplate reader and are visually inspected when necessary. The MIC is defined as the lowest concentration of the tetracycline compound that inhibits growth. The compounds shown in Table 2 below were determined to have no measurable antibacterial activity. Table 3 gives the MIC ( g/mL) of selected substituted tetracycline compounds 35 against S. aureus, S. pseumoniae, and E. coli. Compounds which showed superior inhibition of S. aureus, S. pseumoniae and E. coli are indicated by "***," and compounds which showed very good or good inhibition of S. aureus, S. pseumoniae and E. coli are - 83 indicated by "**" or "*" respectively. The designation "ND" indicates that no value was obtained. Table 2 HHHC NCH, HC OHC N CH, HC N CH, H H N NH2 HC O OH O OH Of O NH ,O H OHO O-H HHC CH OHO OH O O HI CIH C, HC N H ,C ' , H O - NH 2 HC NH2H O HNH2 OH OH 0 OH 0 OH 0 0 CH H H N C'NN HCH C H 0 H C 0 0 HC 'CH OH 0 OH 0 0 HH CH HNCHCH, HCCH, HH3 CH H CH CHH OH 3 O"N NH H N H'N HHH H O H H OH - - OH r O H HCC'N'CH HCC.H C NH 2 SOH NH 2 O OH HOH NH2 N O 0 OH O-HOO OH O OHO H OH OH 0 OH 0 01 CHN HC CH HC CH C HC H3 'H o H N CH , N HH H H H H HC NH2N H N H H2 O O O O OHO 0 0 OH 0 0 H2N JN HHC H3C CH H C CH3 CH CHCH H E 3: H t o A aHn - - OH N C H ~ ~ N OH NH 2 CH -- O

CH

3 0 OH m O SwHO 0 HN 0 HWsNtCHe Hmneal wh 16 H 2 H H~ - OHOH OH 0 ' - 8NH OH 0 OH 0 HGC CH, HG CH3FrO .F C C N' 3C N - -N" F, OF FN H Hr OF H -S O r r OH NH2 HO - .. - NH 2 F \~ ~ O 0 O OF OH FOFH O 0 0 OHO0 OHO0 0 C OHC N CH3 OHC CH3 CH, H~C C CH OH NH OH NN 7 OH OH ~ OH NH 2 NH2 OH OH 0 NH 0 0 HGCI OH 0 OH 0 0O 5 Example 3 1: Assessment of Antimalarial Activity In Vivo The assessment is performed with P. vinckei, a murine parasite that consistently causes a rapidly fatal malaria, and is an excellent model for drug efficacy. However, other murine parasites which are available (e.g. P. berghei) can also be studied using similar methodology. 10 20 gm Swiss Webster mice are inoculated intraperitoneally with 106 p. vinckei-infected erythrocytes obtained from another infected mouse. Twelve hours after infection, treatment is initiated by the intraperitoneal injection of test compounds. Treatment is continued twice-a-day (BID) for four days. The progress of malaria infections in experimental and control (injected with diluent only) mice is followed by 15 daily examinations of blood smears obtained from tail veins. The pharmacological - 84 endpoint is parasitemia >50%. Uninfected animals are followed for 6 weeks, and the animals that remain uninfected through this period are considered long-term cures. The test compounds are injected into the stomach of the test mice by gavage. A number of variations of standard in vivo protocol may be utilized for specific purposes. 5 For example, dosing intervals may be altered based on the known pharmacokinetics or observed initial efficacy data for a compound. Protocols may also be altered to more closely mimic true treatment (with delay of therapy after inoculation of parasites) or chemoprophylaxis (with treatment before the inoculation of parasites) conditions. For all in vivo experiments, the mice are monitored daily, for at least the first two 10 weeks of an experiment, with blood smears. Counts per 1000 erythrocytes provide parasitemias, and the parasitemias are then plotted over time, and results for control and experimental animals are compared. Example 32: Mammalian Cytotoxicity Assay 15 COS-1 and CHO-KI cell suspensions were prepared, seeded into 96-well tissue culture treated black-walled microtiter plates (density determined by cell line), and incubated overnight at 370C, in 5% CO 2 and approximately 95% humidity. The following day, serial dilutions of drug were prepared under sterile conditions and transferred to cell plates. Cell/Drug plates were incubated under the above conditions for 24 hours. 20 Following the incubation period, media/drug was aspirated and 50 [d of Resazurin (0.042 mg/ml in PBS w/Ca and Mg) was added. The plates were then incubated under the above conditions for 2 hours and then in the dark at room temperature for an additional 30 minutes. Fluorescence measurements were taken (excitation 535 nm, emission 590 nm). The IC 50 (concentration of drug causing 50% growth inhibition) was then calculated. The 25 cytotoxicity of both unsubstituted minocycline and doxycycline were found to be greater than 25. Table 3 shows the results of this assay. Compounds which showed superior cytotoxicity are indicated by "***," and compounds which showed very good or good cytotoxicity are indicated by "**" or "*" respectively. The designation "ND" indicates that no value was obtained. 30 - 85 - EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of the present 5 invention and are covered by the following claims. The contents of all references, patents, and patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the present invention and embodiments thereof. 10 DEFINITION Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. - 86 -

Claims

1. A tetracycline compound of Formula (I): - OH N(Me), 0H R'j NH, 5 OH 0 OH H 0 O wherein R 9 is substituted or unsubstituted aminocarbonylalkyl, aminoalkylcarbonylaminoalkyl, carboxylate, arylalkylaminoalkyl, alkylcarbonylaminoalkyl, dialkylaminoalkyl, N-piperazinyl alkyl substituted phenyl, 10 alkoxy substituted phenyl, substituted furanyl, alkylaminocarbonyl and pharmaceutically acceptable salts, esters, and prodrugs thereof.

2. The compound of claim 1, wherein said substituted aminocarbonylalkyl is t-butyl substituted aminocarbony alkyl. 15

3. The compound of claim 1, wherein said dialkylaminoalkyl is dimethylaminoalkyl.

4. The compound of claim 1, wherein said arylalkylaminoalkyl is phenylalkylaminoalkyl. 20

5. The compound of claim 1, wherein said alkoxy substituted phenyl is further substituted by pyrrolidinyl alkyl.

6. The compound of claim 1, wherein said substituted furanyl is carbonyl substituted. 25

7. The compound of claim, 1 wherein said substituted furanyl is dialkylaminoalkyl substituted.

8. The compound of claim 7, wherein said dialkylaminoalkyl is dimethylamino. 30

9. The compound of claim 1, wherein said substituted furanyl is pyrrolidinylalkyl substituted.

10. The compound of claim 1, wherein said compound is: - 87 - H C_)H - H HHHO HHNH2 O HNH2 HNH O O OH O OH O O HNC)HHH H H11C1CH 0 OHO0 OHO0 0 6H OH Hr OH OH 0 OH 0 0 NHN-C F CC H H _H N HHH OH - H NOH N - OH, 1;16 OHl H -OjH O OH OH 0 HO OO 0 OF 0 OF 0 0 R7 N(Me) H CH, OHC COHHN CH OH NH HH OH OOH OH NH~ ~ , Oh h~ - ~NH 2 OHO 0 Oh 0 0 HC -OH 0 OH 0 0 OH 0? 0 h - OH-'N . OH'N" HH OH HH O NH 2 NH 2 -50 OHO 01O? 0 NOOH O 0

11. A tetracycline compound of Formula (k): R7 N(Me), OH NH, H 0 OH 0H 0 I 5 wherein R 7 is dimethylamino, substituted phenyl, substituted pyridinyl, alkoxycarbonylalkylamino carbonyl, pyridinylalkylaminoalkyl, pyridinylalkylaminocarbonyl, substituted or unsubstituted arylaminoalkylcarbonyl, substituted or unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl, 10 alkylaminoalkylcarbonyl, heteroarylaminoalkylcarbonyl, alkoxylcarbonyl substituted alkylaminoalkylcarbonyl or arylaminoalkylcarbonyl; R 9 is ethyl, aminomethyl, dialkylaminocarbonylalkyl, hydrogen, alkoxy substituted alkynyl, carboxylate substituted alkynyl, alkoxycarbonyl substituted alkynyl, dialkylamino substituted phenyl, cyano, acyl, substituted carboxylate aminomethyl, 15 alkylaminocarbonyl, and pharmaceutically acceptable salts, esters and prodrugs thereof.

12. The compound of claim 11, wherein R 7 is dimethylamino.

13. The compound of claim 12, wherein R9 is ethyl, dialkylaminocarbonylalkyl, 20 alkyoxysubstituted alkynyl, carboxylate substituted alkynyl, alkoxycarbonyl substituted - 88 - alkynyl, dialkylamino substituted phenyl, cyano, acyl, substituted carboxylate aminomethyl or alkylaminocarbonyl

14. The compound of claim 13, wherein said dialkylaminocarbonylalkyl is 5 dimethylaminocarbonylalkyl.

15. The compound of claim 13, wherein said alkyoxysubstituted alkynyl is methoxysubstituted alkynyl. 10 16. The compound of claim 13, wherein said alkoxycarbonyl substituted alkynyl is methoxycarbonyl substituted alkynyl.

17. The compound of claim 13, wherein said dialkylamino substituted phenyl is dimethylamino substituted phenyl. 15

18. The compound of claim 13, wherein said alkylaminocarbonyl is n propylaminocarbonyl or t-butylaminocarbonyl.

19. The compound of claim 11, wherein R9 is hydrogen. 20

20. The compound of claim 19, wherein substituted pyridinyl, alkoxycarbonylalkylaminocarbonyl, pyridinylalkylaminoalkyl, substituted or unsubstituted arylaminoalkylcarbonyl, substituted or unsubstituted tetrahydropyridinyl, cycloalkylaminoalkylcarbonyl, alkylaminoalkyl carbonyl, heteroarylaminoalkylcarbonyl or 25 alkoxylcarbonyl substituted alkylaminoalkylcarbonyl.

21. The compound of claim 20, wherein said substituted pyridinyl is methyl substituted pyridinyl. 30 22. The compound of claim 20, wherein said alkoxycarbonylalkylamino carbonyl is methyoxycarbonylalkylamino carbonyl.

23. The compound of claim 20, wherein said arylaminoalkylcarbonyl is phenylaminoalkylcarbonyl. 35

24. The compound of claim 20, wherein said substituted tetrahydropyridinyl is alkyl substituted. - 89 -

25. The compound of claim 24, wherein said alkyl substituted tetrahydropyridinyl is isopropyl substituted tetrahydropyridinyl.

26. The compound of claim 20, wherein said substituted tetrahydropyridinyl is 5 dialkylaminoalkylcarbonyl substituted tetrahydropyridinyl.

27. The compound of claim 20, wherein said dialkylaminoalkylcarbonyl substituted tetrahydropyridinyl is dimethylaminoalkylcarbonyl substituted tetrahydropyridinyl. 10 28. The compound of claim 20, wherein cycloalkylaminoalkylcarbonyl is cyclohexylaminoalkylcarbonyl or morpholinoaminoalkylcarbonyl.

29. The compound of claim 20, wherein said heteroarylaminoalkylcarbonyl is pyrimidinylaminoalkylcarbonyl. 15

30. The compound of claim 11, wherein R 9 is aminomethyl.

31. The compound of claim 30, wherein R 7 is substituted phenyl. 20 32. The compound of claim 31, wherein said substituted phenyl is dichloro substituted phenyl.

33. The compound of claim 11, wherein the compound is: CI CN NN NO H H NH 2 HIN NH2 o OHO O H OHO O 0 OH O OHO 0 N N N N NH2 HNH H HNH H H OH 0 OH- O OH 0 - OHH0O OMe OH N N N N N- N H HN H H H. H O OH OH 0 OHNH NH 2 A NH 2 -0- OHO 0 OH 0 0HN O~~Oe OH 0OHb O~~e 90 0- H MeO 0 HN : H NNON HN S H HN OH HHH NH 2 H2 NH 2 OHO O IO OH O NH OH N OHH O NH 2 0 OH O NH O OOH H O 0 HN N O N N N H O N OHNH H 2 H H OH OH0H OH NH 2 NH 2 OHO OH 0 OHO O ? 0 OHO O O HNIO N 0 N"N -- 0N NN NH2 H H H H H H O OH O OH OH NH 2 NH 2 NH 2 H0 OPH OH 0 4 H 0 OH 0 OPH 0 5H N N HNt N 0 0 'N N"H H NOHH H H OH O OH OH NNH 2 NH 2 NH 2 OH O H O OH 1 ID 0 OH 0 0 OHO OH0 0 H0 N-- \ N ~--'- 91 - N 0 0 OH HH H HNH OH H ---- NH 2 yNH 2 NH 2 0 OHO0 OPH OHO 014 H 0OH OH 0 H H OHI N y NH 2 0r OH 0OHO 0

34. A tetracycline compound of Formula (111): OR' 0 ) 0 OH 0 0(I wherein 5 R~is R'O-N=CR"-,R'-O C(=O-, R~aR~N(OH mtoycroy susiue aRyn9 imethylamino-C(O-,R9a~bC=O_,mthcarbonylccorymehlainsutttd - 91 - pyridinyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, pyrimidinyl, alkoxycarbonyl substituted alkynyl, oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl, alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted or unsubstituted arylthiocarbonyl, cyano, deuterated alkylaminoalkyl, pyrrolidonylcarbonyl, 5 carboxylatecarbonyl, alkylcarbonyl substituted phenyl, cyano substituted pyridinyl, aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted furanyl, alkylcarbonylamino substituted pyridinyl, dialkylamino substituted phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or piperazinylcarbonyl; 10 R 10 is hydrogen or alkenyl; R' is unsubstituted alkyl, amino substituted alkyl, methoxy substituted alkyl, halogen substituted alkyl; R" is alkyl; R9a is hydrogen or alkyl; 15 R 9 b is alkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, cycloalkyl or aminoalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that when R 9 is halogen, then R 10 is alkenyl. 20 35. The compound of claim 34, wherein R 10 is alkenyl.

36. The compound of claim 35, wherein R 9 is halogen.

37. The compound of claim 36, wherein said halogen is iodine. 25

38. The compound of claim 34, wherein R 1 0 is hydrogen.

39. The compound of claim 38, wherein R 9 is R'-O-N=CR"-. 30 40. The compound of claim 39, wherein R" is alkyl.

41. The compound of claim 40, wherein said alkyl is methyl.

42. The compound of claim 39, wherein R' is unsubstituted alkyl. 35

43. The compound of claim 42, wherein said unsubstituted alkyl is methyl.

44. The compound of claim 38, wherein R 9 is R'-OC(=O)-. - 92 -

45. The compound of claim 44, wherein R' is unsubstituted alkyl, amino substituted alkyl, halogen substituted alkyl or methoxy substituted alkyl. 5 46. The compound of claim 45, wherein said unsubstituted alkyl is ethyl or isopropyl.

47. The compound of claim 45, wherein said amino substituted alkyl is dialkylamino substituted alkyl. 10 48. The compound of claim 47, wherein said dialkylamino substituted alkyl is dimethylamino substituted alkyl.

49. The compound of claim 45, wherein said halogen substituted alkyl is trifluoromethyl substituted alkyl. 15

50. The compound of claim 38, wherein R 9 is R 9 aR 9 NC(=O)-.

51. The compound of claim 50, wherein R 9a and R9b are each alkyl. 20 52. The compound of claim 50, wherein R9a and R are each methyl or ethyl.

53. The compound of claim 50, wherein R9a is alkyl.

54. The compound of claim 51, wherein said alkyl is methyl. 25

55. The compound of claim 52, wherein R is alkoxyalkyl.

56. The compound of claim 55, wherein said alkoxyalkyl is methoxyalkyl. 30 57. The compound of claim 50, wherein R9a is ethyl and R is n-propyl.

58. The compound of claim 50, wherein R 9 a is hydrogen.

59. The compound of claim 58, wherein R 9 b is hydrogen, hydroxy, alkoxy, 35 hydroxyalkyl, alkyl, cycloalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, aryl or aminoalkyl.

60. The compound of claim 59, wherein said alkoxy is methoxy, ethoxy or t-butyloxy. - 93 -

61. The compound of claim 59, wherein said alkyl is methyl-t-butyl, n-propyl, ethyl, t butyl or n-butyl. 5 62. The compound of claim 59, wherein said cycloalkyl is cyclopropyl.

63. The compound of claim 59, wherein said alkylcarbonylaminoalkyl is methylcarbonylaminoalkyl. 10 64. The compound of claim 59, wherein said alkoxycarbonylalkyl is methoxycarbonylalkyl.

65. The compound of claim 59, wherein said aryl is phenyl. 15 66. The compound of claim 34, wherein R 9 is methoxycarbonyl substituted alkynyl, pyrazinyl, methoxymethyl, cyclopropyl, methyl, methoxymethyl substituted alkynyl, amino substituted pyridinyl, alkylcarbonyl, arylcarbonyl, pyrimidinyl, oxazolyl, pyrazolyl, carboxylate, pyridinyl, thiazolyl, substituted or unsubstituted thiophenyl, piperidinylcarbonyl, dialkylaminomethyl, cyano, substituted or unsubstituted 20 arylthiocarbonyl, deuterated alkylaminoalkyl, substituted furanyl, isoxolazolyl, cyano substituted pyridinyl, alkylcarbonylamino substituted pyridinyl, dialkylamino substituted phenyl, pyrrolidonylcarbonyl, azepanylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted phenyl, aminocarbonyl substituted phenyl, carboxylate substituted phenyl or piperazinylcarbonyl. 25

67. The compound of claim 66, wherein said alkylcarbonyl is ethylcarbonyl or isopropylcarbonyl.

68. The compound of claim 66, wherein said arylcarbonyl is phenylcarbonyl. 30

69. The compound of claim 66, wherein said dialkylaminomethyl is di-n butylaminomethyl.

70. The compound of claim 66, wherein said substituted arylthiocarbonyl is p 35 methylphenylthiocarbonyl. - 94 -

71. The compound of claim 66, wherein said substituted furanyl is methoxyalkylaminomethyl substituted furanyl, alkylaminomethyl substituted furanyl or halogenated alkylaminomethyl substituted furanyl. 5 72. The compound of claim 66, wherein said halogenated alkylaminomethyl furanyl is fluoroalkylaminomethyl substituted furanyl.

73. The compound of claim 66, wherein said dialkylamino substituted phenyl is para dimethylamino substituted phenyl. 10

74. The compound of claim 66, wherein said alkylcarbonylamino substituted pyridinyl is acylamino substituted pyridinyl.

75. The compound of claim 66, wherein said alkylcarbonyl substituted phenyl is meta 15 acyl substituted phenyl.

76. The compound of claim 66, wherein said aminocarbonyl substituted phenyl is para-aminocarbonyl substituted phenyl or meta-aminocarbonyl substituted phenyl. 20 77. The compound of claim 66, wherein said substituted thiophenyl is carboxylate substituted thiophenyl.

78. The compound of claim 66, wherein said carboxylate substituted phenyl is meta carboxylate substituted phenyl. 25

79. The tetracycline compound of claim 34, wherein said compound is: NH NN HNH2 ONH 2 N H H ONH 2 OHO OHHO OH H O O 0 OHOO OH N N H H OH N N O HNH O NH2 O NH, -'Hp H Hr N OH O OH O O O OH OHOOOOHOO O N" N N H H N H Hr OOH OH OH-I O O NH 2 OH NH 2 N O NH2 OH 0 H0O .0 OH 0 OHFL 0 . N OH 0 OH 0 N N N" N N H HOH H H- OH I NH, H NH2 FPOI OH O OH 2 O OHO OH 0 H 2 N OH O OH O 0 0 OH O OH O0 -95- H" H' H H H H N - OH H - OH OH -NH, F~- 0 ~H 2 NH 2 OH 0F OHIO 6Ho OH 0 H o01 0 OH -- O OHO 0 OH H N" N" N" N" H HN H H H H 0 H H - OH .- ~ .NH, ,- .NH, N . NH, OH OH 0N OHF NN"N" N' N" N H OH H Hr H H O - - H- OH H NH, 0 O 0 PH 0 o 0H H OH0 OH HN:7 0 O H OMe ' NOHO OH 0 H H N N OH N H Hr H H - - OH II H. 0. NH, O N OHO0 OHH 0 'I 0 0DH 0 0 N_ N N" H H H NOH = OH OH O -H II I I H NH 2 N - NH 2 - - - NH MeO 0[ OHO 0 F 0 OH 0 Oi-P 0 0 OH 0 4r? N N NN NN " N" H H- 0 H H- H Hr - - OH - OH "I - 7 OH NNH 2 .: NH 2 N - NH 2 .0~~ C- HOaO OHO0 OFi0-N OH 0 V- S OHO0 OHO 00 N" 11N"11 " 1 1N"- N" H H-N H N ~ H H r OHOH OH OHI 'S NH 2 NH 2 NH 2 OH OH 0 H 0 0OH 0 OHP 0 0 N .1 H H N - " 1 1 . = OH N H H~ N H NH 2 u OH OH NH OH0 orP 0 NW NH 2 /N 2 o KN OHO0 OF? 0 S 1 OHO F NN H N I I I H H-rr H H N HO HH H0 H H = = O N'0qH 0~ "OH 01 H0 0 NH 0 H N N " NH H H N H NOH OHOHH NIb OHO 0 1 H 0 N H 2 H OHO 0 0 N N NN N " HH HH H H 2 N OH A ~ N N O H 0 O HP 0 0 0D O H ON H N O H F H NNN'N N H HT H HN -N H H OH OH = r OH H Hj NH 2 HO' N ~.NH 2 MeO' N - ~ NH 2 HN-N OH 0OH 0 OHO ? p OHO 01 d o - 96 - N H H N N OH N " H H - H H 2 NH2 N HNH2 HNH 2 OH O OH O o OHHO O O o OHHO o o N N NN" N N N H HN N" H H N H HN - - OH OH H OH NH 2 HON' NH 2 MeON N NH 2 O OH O O O 0 OH O O 0 0 OH O O O N N N A N N NN N H 0 - OH - OH OH O ~NNI~~NH 2 HNH HONH H NN. 2N N HH N H N N" Hy*, rNH2 HONH2 Ne HNH2 O OHO0 oF? 0 0 OHO 0i? 0 OH oF0 N H HN N H HN NNA H HN H OH H OH N OH HO k:N NH2 N NH 2 H 2 N-- 'N NH 2 O OHO OF? 0 0 OH O o O NN A 4N AN NA NA H ~N H H ~ H HHH OH - OH OH H NH2 '---NNH 2 > ' N KA ~NH 2 NH O OH O o o OHO . & 80 At Hn t a N A Forml (VN) H OH HHN= O RN" RH N(Me)H H OH NH 2 H T -- NH 2 0 OH 0F o& >r N AJ NH 2 = S OHO 0oF? NH 2 OH NA NA NAN H H 0 N ~~OH O O ( H A3H =O H 2 N R s NH 2 HO aNH 2 N-iedn NH 2 -OHO 0oF? 0 OH oF? 0 0 OHO 0F 0 o N" isNN A N hydr N H N H HNN H H OH H NNN OH NANA 'A NNH 2 N ~ NNH 2 O N ANH 2 OOHO 0 F? 0 7"O4H00F? 0 0 OHO oF 0o N" H HN OH -,,,NNH 2 0OHO0 o F? o

80. A tetracycline compound tetracycline compound of Formula (IV): OH 0 OH O 0 0(IV) wherein 5 R 7 , is methoxy, dialkylaminomethyl, substituted N-piperdinyl methyl, fluorine, or hydrogen; R 7bis hydrogen; - 97 - R"' is alkoxyalkylaminoalkyl, halogenated N-piperdinyl methyl, hydroxyl, dialkylaminoalkylamino, dialkylaminomethyl, substituted N-piperidinyl methyl, substituted N-pyrrolyl methyl, or hydrogen; R7d is arylalkylaminoalkyl, arylalkyl substituted alkylaminoalkyl, 5 substituted N-piperidinylmethyl, N-piperidinyl substituted aminomethyl, cyclopropylamino methyl, piperdinyl substituted alkyl, dialkylaminomethyl, heteroaryl substituted dialkylaminomethyl, alkylaminomethyl, cycloalkylaminomethyl, alkylaminoethyl, cyano substituted dialkylaminomethyl, N-pyrrolidinyl substituted methyl, N-pyrrolyl substituted methyl, methoxy substituted dialkylaminomethyl, 10 alkoxyalkylaminomethyl, substituted carboxylate alkylaminomethyl, hydrogen or linked with R7' by a -O-CH 2 -0- linker; R 7 is hydrogen, and pharmaceutically acceptable salts, esters and prodrugs 7a 7b 7c 7d 7' thereof, provided that each of R a, R , R , R , and R are not hydrogen. 15 81. The compound of claim 80, wherein R 7 , is hydrogen.

82. The compound of claim 81, wherein R and R are each hydrogen.

83. The compound of claim 82, wherein R is methoxy and R is substituted N 20 piperidinylmethyl.

84. The compound of claim 82, wherein R 7 a is halogen and R 7 d is substituted N piperidinylmethyl. 25 85. The compound of claim 84, wherein said halogen is fluorine.

86. The compound of claim 80, wherein R is methoxy and R7d is arylalkyl substituted alkylaminoalkyl. 30 87. The compound of claim 86 wherein said arylalkyl substituted alkylaminoalkyl is phenylmethyl substituted alkylaminoalkyl.

88. The compound of claim 81, wherein R 7, R and R are each hydrogen. 35 89. The compound of claim 88, wherein R7d is dialkylaminomethyl, substituted N piperidinylmethyl, cycloalkylaminomethyl, alkylaminomethyl, - 98 -

90. The compound of claim 89, wherein said dialkylaminomethyl is methylisopropylaminomethyl, methylcyclohexylaminomethyl, methylethylaminomethyl, methylpropylaminomethyl, methylisobutylaminomethyl, propylisopropylaminomethyl, ethylisopropylaminomethyl, propylcyclopropylmethylaminomethyl, cyano-substituted 5 ethylmethylaminomethyl, methoxy-substitutedethylaminomethyl, t-butoxy substituted ethylmethylaminomethyl or pyridine substituted methymethylaminomethyl.

91. The compound of claim 89, wherein said substituted N-piperidinylmethyl is dimethyl substituted N-piperidinylmethyl, trifluoromethyl substituted N-piperidinylmethyl 10 or halogen substituted N-piperidinylmethyl,

92. The compound of claim 91, wherein said halogen substituted N-piperidinylmethyl is fluorine substituted N-piperidinylmethyl. 15 93. The compound of claim 89, wherein said cycloalkylaminomethyl is cyclopropylaminomethyl, dimethylpyrrolidinylaminomethyl or dimethylpyrrolylaminomethyl.

94. The compound of claim 89, wherein said alkylaminomethyl is t 20 butylmethylaminomethyl.

95. The compound of claim 81, wherein R 7, R and R7d are each hydrogen.

96. The compound of claim 95, wherein R 7 ' is alkoxyalkylaminoalkyl, hydroxy, 25 dialkylaminoalkylamino, dialkylaminomethyl, substituted N-piperidinylmethyl, substituted N-pyrrolyl or substituted carboxylate alkylaminomethyl,

97. The compound of claim 96, wherein said alkoxyalkylaminoalkyl is methoxyalkylaminoalkyl. 30

98. The compound of claim 96, wherein said dialkylaminomethyl is diisopropylaminomethyl. 7b 7c 7d

99. The compound of claim 81, wherein R , R and R are each hydrogen. 35

100. The compound of claim 99, wherein R 7 a is dialkylaminomethyl. - 99 -

101. The compound of claim 100, wherein said dialkylaminomethyl is dimethylaminomethyl.

102. The compound of claim 81, wherein R 7 b is hydrogen. 5

103. The compound of claim 102, wherein R 7 a is substituted N-piperidinylmethyl and R7d is linked with R7' by a -O-CH 2 -0- linker.

104. The compound of claim 80, wherein the compound is: N NH N |6 O N" N"OH O0 H OH H2 OH H NH OH NH2 OH OH 0 OH 0 0 OH O HO OH 0 OH 0 0 H P 0 SN N HNN NN H H N OOH H H ,NH OH OH NH 2 NH2 OH O OH O O OH O OH 0 0 OH O OH O 0 N " N N N ,N'OH OH H Hr I OH N2 NH NH 2 H NH 2 OH O OH O 0 OH O OH O 0 OHH0 OH 0 OH 0 0 N INj N N" OH OH H H OH - NH 2 NH 2 ~ . NH, OHO OHO 0 OHO OHO O OH0 OHO 0 HNN NI N H H N OH OH H H OH NH NH 2 - NH2 HOH 0 OH OHO OHO O OHO OHO O0 - 100 - F F HN N N N N N H H H H= SO OHOH H NH 2 NH 2 H OHO OHO 0 OHO OHO O OH 0 OH 0 0 N N N N H HF N HHr OH H H OH - OHOH NH, NH 2 NH 2 OH 6H OH OH O OH O 0 OHO OH O 0 OH O OH O 0 ar' Nr N Q NH H NF H H O HHH H OO O OH OH N. N~- NNH 2 NH 2 NH 2 HH 0 OH 01 NH N FP 0O OH 0O H O OHH H H Ho OH - - OH HH H - - NH H NH- - CH HN OH 2 0 OHE O 0 NH 2 m O 0o 0 N H o H H H- H H H -- HHH - H - - QHI -i -: O NH2 NH 2 NH- 2 OHHO O H O 0 H - H H OH OH CH - H H NH 2 OH0 0 CH1 0H 0o 0

105. A tetracycline compound of Formula (V): - 101 - R7, R7h, R7 T N(Me) OH - NH, OH O OH OH O O (V wherein T is NH or 0; R 7is dialkylaminoalkyl, N-piperidinylamino alkyl, substituted or 5 unsubstituted N-piperdinylalkyl, N-pyrrolidinylamino alkyl, substituted or unsubstituted N-pyrrolidinylalkyl, substituted or unsubstituted N-pyrrolylalkyl, alkenenyl substituted dialkylaminoalkyl, N-decahydroisoquinolinylalkyl, alkoxyalkylaminoalkyl, or hydrogen; R7 is hydrogen; R7h is heteroaryl substituted alkylaminoalkyl, dialkylaminoalkyl, 10 substituted N-piperidinylalkyl or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that each of R R , and R 7 h are not hydrogen.

106. The compound of claim 105, wherein T is NH. 15 107. The compound of claim 106, wherein R 7 f and R7 are each hydrogen.

108. The compound of claim 107, wherein R7h is dialkylaminoalkyl or substituted N piperidinylalkyl. 20 109. The compound of claim 108, wherein said dialkylaminoalkyl is dimethylaminomethyl.

110. The compound of claim 108, where said substituted N-piperidinylalkyl is methyl substituted N-piperidinylmethyl. 25

111. The compound of claim 105, wherein T is O.

112. The compound of claim 111, wherein R 7 f and R7 are each hydrogen. 30 113. The compound of claim 111, wherein R7h is heteroaryl substituted alkylaminoalkyl, - 102 -

114. The compound of claim 113, wherein said heteroaryl substituted alkylaminoalkyl is pyridinyl substituted methylaminomethyl or methyl substituted isoxazolylmethylaminomethyl. 5 115. The compound of claim 111, wherein R7 and R 7 h are each hydrogen.

116. The compound of claim 115, wherein R 7 f is dialkylaminoalkyl, substituted N piperidinylalkyl, substituted N-pyrrolylalkyl, substituted N-pyrrolidinylalkyl, N decahydroisoquinolinylalkyl or alkoxyalkylaminoalkyl. 10

117. The compound of claim 116, wherein said dialkylaminoalkyl is methylisopropylaminomethyl or allylmethylaminomethyl.

118. The compound of claim 116 wherein said substituted N-piperidinylalkyl is methyl 15 substituted N-piperidinylmethyl or halogen substituted N-piperidinylmethyl.

119. The compound of claim 118, wherein said halogen substituted N piperidinylmethyl is fluorine substituted N-piperidinylmethyl. 20 120. The compound of claim 116, wherein said substituted N-pyrrolylalkyl is methyl substituted N-pyrrolylmethyl.

121. The compound of claim 116, wherein said substituted pyrrolidinylalkyl is methyl substituted N- pyrrolidinylmethyl. 25

122. The compound of claim 116, wherein said alkyoxyalkylaminoalkyl is methoxyalkylaminomethyl.

123. The compound of claim 105, wherein said compound is: N N N N NH H OH H H H H HO NH 2 / NH 2 NH 2 OHO OHO OH O 0 OH 0 F N 0 \ N 0 ON~ - 0 H H N N OH H H OHH H O KNH, NH, NH, 5H H 0 OHO 0 H OHO0 OHO0 0 OHO0 OHO 00 - 103 - F F F 0 0 N" N N"~ H O N H H N- H -H OH - - OH OH NH2 NH2 NH, OH O OHO 0 OHO OHO 0 N1I3 O N N 0 H H H H N_ HH - CH OH - NH, NH 2 mCo NH0 0 -OH 0 01-10 0 OH 0 OH 0 0 N 0r H H H 0 H H H O NH 2 CHO0 0

124. A tetracycline compound of Formula (VI): R'3 N N(Me)7 OH NH, 05H OH OH (VI) 5 wherein R' is fluorine or hydrogen; R 7 j is trifluoromethyl, alkyloxycarbonyl, methyl, cyano, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that both of R 7 i and R 7 j are not hydrogen. 10

125. The compound of claim 124, wherein R7' is hydrogen.

126. The compound of claim 125, wherein R 7 j is methyl, cyano, trifluoromethyl, or alkyloxycarbonyl. 15

127. The compound of claim 125, wherein said alkyloxycarbonyl is methoxycarbonyl.

128. The compound of claim 124, wherein R 7 ' is fluorine and R 7 j is hydrogen. 20 129. The compound of claim 124, wherein the compound is: - 104 - F CN N N N FF N N OH H H = OH H2 H NH, NH, OH OO O OHO O OH 0 F ( 0 F N NN H HN" H Hr H H HOH NH 2 NH 2 OH OPH

130. A tetracycline compound of Formula (VII): R 7 k OH 0 OH 0 0 (VII) wherein 5 p is a single or double bond; R 7 k is alkyl, cycloalkyl, dialkylaminoalkylcarbonyl, alkoxyalkylcarbonyl, halogen substituted alkyl, halogen substituted cycloalkyl, or hydrogen, and pharmaceutically acceptable salts, esters and prodrugs thereof. 10 131. The compound of claim 130, wherein p is a single bond.

132. The compound of claim 131, wherein R 7 k is alkyl or hydrogen.

133. The compound of claim 132, wherein said alkyl is isopropyl. 15

134. The compound of claim 130, wherein p is a double bond.

135. The compound of claim 134, wherein R 7 k is hydrogen, alkyl, cycloalkyl, halogen substituted alkyl, halogen substituted cycloalkyl, alkoxyalkylcarbonyl or 20 dialkylaminoalkylcarbonyl.

136. The compound of claim 135, wherein said alkyl is isopropyl. - 105 -

137. The compound of claim 135, wherein said cycloalkyl is cyclohexyl or cyclopropylmethyl.

138. The compound of claim 135, wherein said halogen substituted alkyl is 5 trifluoromethyl substituted propyl.

139. The compound of claim 135, wherein said halogen substituted cycloalkyl is trifluoromethyl substituted cyclohexyl. 10 140. The compound of claim 135, wherein said alkoxyalkylcarbonyl is methoxymethylcarbonyl.

141. The compound of claim 135, wherein said dialkylaminoalkylcarbonyl is dimethylaminomethylcarbonyl. 15

142. The compound of claim 130, wherein said compound is: H N N N H H 7 H H OH N H N" N r OH OH NH 2 OOOOH O NH 2 - NH 2 OHO0 OHO0 0 6O OH O OH 0 OHO OHO F F0N N N N NN H H - H H N 2OH OH O OH O O OH O OH OHOO O H H H H OHOH - OH N H 0 NH 2 I - NH2 - NH 2 OH 0 OH 00 O OH O OH O O OH 0 OH 0 0 F_ F F H 7 N N H HH N" WeOH H Hr HH OH O H r Ou rH- N H 2 N2 0 N. NHOH NH OHO0 OH- 0 0H OHO 0 OH O HO 0 0 - 06e N H H OH I NH 2 - 106 -

143. A tetracycline compound of Formula (VIII): R7 N(Me), OH - NH, 06H OH 0 OH 0 0 (VIII) 5 wherein R' is fluoro substituted N-pyrrolidinylalkyl, N-piperidinylalkylcarbonyl, dialkylaminoalkylaminocarbonyl, aminoalkyl, N-pyrroyl alkyl, dialkylamino substituted pyridinyl, substituted or unsubtituted phenyl substituted N-piperizinyl alkyl, alkylaminoalkyl, alkoxy substituted pyrimidinyl, 1-H-pyrimidin-2-onyl, cyano substituted 10 pyridinyl, substituted or unsubstituted N-pyrrolidinyl alkyl, halogen substituted pyridinyl, substituted or unsubstituted arylalkylamino alkyl, alkoxyalkylaminoalkyl, N imidizolylalkylcarbonyl, N-dihydroimidizolylalkylcarbonyl, alkylaminoalkyl, imidizopyrimidinyl, substituted or unsubstituted imidizopyridinyl, or substituted or unsubstituted pyrizinyl substituted alkylaminoalkyl, alkoxyalkylcarbonyl; and 15 pharmaceutically acceptable salts, esters and prodrugs thereof.

144. The compound of claim 143, wherein said fluoro substituted N-pyrrolidinylalkyl is difluoro substituted N-pyrrolidinylmethyl. 20 145. The compound of claim 143, wherein said aminoalkyl is aminomethyl.

146. The compound of claim 143, wherein said N-pyrroyl alkyl is N-pyrroyl methyl

147. The compound of claim 143, wherein said dialkylamino substituted pyridinyl, is 25 dimethylamino substituted pyridinyl.

148. The compound of claim 143, wherein said substituted phenyl substituted N piperizinyl alkyl is para-fluorophenyl substituted phenyl N-piperizinyl methyl. 30 149. The compound of claim 143, wherein said alkoxy substituted pyrimidinyl is methoxy substituted pyrimidinyl.

150. The compound of claim 143, wherein said substituted N-pyrrolidinyl alkyl is dimethyl substituted N-pyrrolidinyl methyl. 35 - 107 -

151. The compound of claim 143, wherein said halogen substituted pyridiyl is fluorine substituted pyridinyl.

152. The compound of claim 143, wherein said arylalkylamino alkyl is 5 phenylmethylaminomethyl.

153. The compound of claim 143, wherein said alkoxyalkylaminoalkyl is methoxyalkylaminomethyl. 10 154. The compound of claim 143, wherein said alkylaminoalkyl is methylaminomethyl.

155. The compound of claim 143, wherein said substituted arylalkylamino alkyl is hydroxy substituted phenylmethylamino methyl. 15 156. The compound of claim 143, wherein said substituted pyrizinyl substituted amino alkyl is methyl pyrizinyl substituted methylaminomethyl.

157. The compound of claim 143, wherein said substituted imidizopyridinyl is halogen substituted imidizopyridinyl. 20

158. The compound of claim 157, wherein said halogen substituted imidizopyridinyl is fluorine substituted imidizopyridinyl.

159. The compound of claim 143, wherein said alkoxyalkylcarbonyl is 25 methoxymethylcarbonyl.

160. The compound of claim 143, wherein said compound is: F N F NNH 2 OH - OH NH2 HH NH H2 OH H H OH O ONHH O OH - N 2 OH .- NH 2 5OHO U HO 00 OH 0 OH 0 0 OH 0 OH 0 0 N' N FN N N N H N H N H H H H OH 0 O H NH 2 HNH2 OH OHO OHO O OHO O H0 OH 0 0 - 108 - OMe 0 OLN N N HN N N N "N N H HN H H:H - OH : OH H C: H HNH2 H H NH 2 NH2 OHO ? 0 OH 0 OF? 0 OH 0 OH NN NN NNN FN N H H OH OH H H I OH NH 2 NH 2 SNH 2 OHO O 0 OHO O - O O H O O O O OMe HN HN N2HN HNH2HNH N N HOH H H: OH O H O NH2 NH 2 NH 2 NHe NH OHO si- 0& 0 OH 0 OH 0 OHO 0 -? 0 ON N OHHN N NOH HN H H: H H-HH - - OH OHOH NH 2 NH 2 NH 2 OH 0 0O-? 0 H 0 OF? OO OH 0 O . O~e NH OO ReH NH OHH O OH OH O OH O5H wNHi NH 2 OCH NH6 H I OH00 O C HO OHO0 0 OHO0 OHO 00

161. A tetracycline compound of Formula (IX): R 7 N(Me) 2 OH R 9 cHN -.- NH 2 OH 0 OH 0 0 (IX) 5 wherein R 7 is dialkylaminomethyl, alkoxy substituted phenyl, hydroxy, halogen substituted phenyl, halogenated alkyl substituted phenyl, naphthyl; R 9 - is hydrogen, fluoridated alkyl or unsubstituted alkyl and pharmaceutically acceptable salts, esters and prodrugs thereof. 10

162. The compound of claim 161, wherein R 9 ' is hydrogen.

163. The compound of claim 162, wherein R 7 is dialkylaminomethyl, alkoxy substituted phenyl or halogen substituted phenyl or halogenated alkyl substituted phenyl. - 109 -

164. The compound of claim 163, wherein said dialkylaminomethyl is dimethylaminomethyl. 5 165. The compound of claim 163, wherein said alkoxysubstituted phenyl is para trifluoromethoxy substituted phenyl.

166. The compound of claim 163, wherein said halogen substituted phenyl is chlorine substituted phenyl or trifluoro substituted phenyl. 10

167. The compound of claim 166, wherein said chlorine substituted phenyl is further substituted with trifluoromethyl.

168. The compound of claim 163, wherein said halogenated alkyl substituted phenyl is 15 di-trifluoromethyl substituted phenyl.

169. The compound of claim 162, wherein R 9 ' is fluorinated alkyl.

170. The compound of claim 169, wherein R 7 is halogen substituted phenyl. 20

171. The compound of claim 169, wherein said halogen substituted phenyl is difluoro substituted phenyl.

172. The compound of claim 162, wherein R 9 ' is unsubstituted alkyl. 25

173. The compound of claim 172, wherein R 7 is hydroxy.

174. The compound of claim 161, wherein said compound is: F F- CI F 0 FF H H =OH H H H 2 N NH 2 OH OH OHOH HN N - NH, OHO OH 0 H 2 N NH2 S OH OHO OH O 0 OH 0 OH 0 F F F FtNF - F F Fl F N H H- N H H rOOH H H - - OH - - OH HN H 2 N NH 2 H2N NH H 2 . H O 2 ~ N2 OH 0 OH H O OOH OH 0 0 -110 - F OH N H H OH FHR N H, N H N H 2 H' NH 2 Fy ~ ' ~..0 H OH 0 0O F OHO OHO O

175. A tetracycline compound of Formula (XI): OH 0 O H 0(XI) 5 wherein R 7 , is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl and pharmaceutically acceptable salts, esters and enantiomers thereof.

176. The compound of claim 175, wherein said dialkylaminoalkyl is 10 dimethylaminomethyl.

177. The compound of claim 175, wherein said substituted N-piperidinylalkyl is methyl substituted N-piperidinylmethyl. 15 178. The compound of claim 175, wherein said compound is: ..-N NON 0 NN N H H N H H: - OH H OH 1 - NH 2 NH 2 NH 2 OHO 01-? 0 OH 0 O 0 OH 0 OF 0 - 111 -

179. A tetracycline compound of Formula (XII): RIS W N H H -N-0 OH NH2 OH O OHO O(XII) wherein 5 W is N or CH; and R s is substituted or unsubstituted alkyl, aryl, alkoxycarbonyl, alkylcarbonyl, cycloalkyl, or aminocarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof. 10 180. The compound of claim 179, wherein W is CH.

181. The compound of claim 180, wherein R s is unsubstituted alkyl.

182. The compound of claim 181, wherein said unsubstituted alkyl is methyl. 15

183. The compound of claim 179, wherein W is N.

184. The compound of claim 183, wherein R 7 , is alkoxycarbonyl, alkylcarbonyl, cycloalkyl, aryl, alkyl or aminocarbonyl. 20

185. The compound of claim 184, wherein said alkoxylcarbonyl is ethoxycarbonyl.

186. The compound of claim 184, wherein said alkylcarbonyl is acyl. 25 187. The compound of claim 184, wherein said cycloalkyl is cyclohexyl.

188. The compound of claim 184, wherein said aryl is phenyl.

189. The compound of claim 184, wherein said alkyl is isopropyl. 30

190. The compound of claim 179, wherein said compound is: -112- N N H HN N - - OH H H OH H H NH 2 IOH NH2 NH2 NH 2 OH0 OH 0 H 0 O O O OHO 0O 0 N N) N (NH N N N H OH H OH - OH NH 2 _ NH 2 NH 2 OH 0 O 0 OH 0 01 0 OH O 0H O O NH2 NN N H H - OH NH 2 OHO O? 0

191. The tetracycline compound of Formula XIII: NR 7t'R7t" O )n N H H OH - I NH2 OH O OH O O (XIII) 5 wherein nis0, 1 or2; R 7 t' is hydrogen, alkyl, alkenyl or cycloalkyl; R 7 t" is unsubstituted alkyl, dialkylaminoalkyl, halogenated alkyl, alkoxyalkyl, substituted or unsubstituted arylalkyl, cycloalkyl, alkenylalkyl, heterocyclic, 10 cyano substituted alkyl, alkoxy substituted alkyl, heteroarylalkyl, aminocarbonylalkyl, aryl, hydrogen, alkylcarbonyl, aminoalkyl or alkoxycarbonyl; and pharmaceutically acceptable salts, esters and enantiomers thereof.

192. The compound of claim 191, wherein n is 0. 15

193. The compound of claim 192, wherein R t' is hydrogen.

194. The compound of claim 193, wherein R7t" is dialkylaminoalkyl. -113 -

195. The compound of claim 191, wherein n is 1.

196. The compound of claim 195, wherein R t " is alkoxyalkyl or alkyl. 5 197. The compound of claim 196, wherein said alkoxyalkyl is methyoxyethyl.

198. The compound of claim 197, wherein said alkyl is isopropyl.

199. The compound of claim any one of claim 195-198, wherein Ri is alkyl. 10

200. The compound of claim 199, wherein said alkyl is methyl.

201. The compound of claim 195, wherein R7' is alkenyl. 15 202. The compound of claim 199, wherein R t " is alkoxycarbonyl or alkylcarbonyl.

203. The compound of claim 201, wherein said alkoxycarbonyl is methoxycarbonyl.

204. The compound of claim 201, wherein said alkylcarbonyl is acyl. 20

205. The compound of claim 195, wherein R t " is alkoxycarbonyl or alkylcarbonyl.

206. The compound of claim 205, wherein said alkoxycarbonyl is methoxycarbonyl. 25 207. The compound of claim 205, wherein said alkylcarbonyl is acyl.

208. The compound of any one of claims 205-207, wherein R7' is cycloalkyl.

209. The compound of claim 208, wherein said cycloalkyl is cyclopropyl. 30

210. The compound of claim 195, wherein R7 is hydrogen.

211. The compound of claim 210, wherein R t " is halogenated alkyl, unsubstituted alkyl, cycloalkyl, arylalkyl, alkenylalkyl, cyano substituted alkyl, heteroarylalkyl, 35 aminocarbonylalkyl, alkoxy substituted alkyl, aryl, alkenylalkyl or aminoalkyl.

212. The compound of claim 211, wherein said halogenated alkyl is fluoroethyl, difluoroethyl or trifluoroethyl. -114 -

213. The compound of claim 211, wherein said unsubstituted alkyl is methyl, ethyl, t butylmethyl, t-butyl or diethylmethyl. 5 214. The compound of claim 211, wherein said cycloalkyl is cyclohexyl, cyclopropyl, morpholino, cyclobutyl, bicyclo[2.2.1 ]heptenyl or cyclopentyl.

215. The compound of claim 211, wherein said arylalkyl is phenylmethyl. 10 216. The compound of claim 211, wherein said unsubstituted heteroarylalkyl is pyridnylmethyl, furanylmethyl or N-methylpyrrolylmethyl.

217. The compound of claim 211, wherein said aminocarbonylalkyl is aminocarbonylmethyl. 15

218. The compound of claim 211, wherein said alkoxy substituted alkyl is methoxy substituted alkyl.

219. The compound of claim 211, wherein said aryl is pyridinyl or phenyl. 20

220. The compound of claim 211, wherein said aminoalkyl is aminomethyl.

221. The compound of claim 211, wherein said substituted arylalkyl is difluorophenyl. 25 222. The compound of claim 221, wherein n is 2.

223. The compound of claim 222, wherein R 7 t is hydrogen.

224. The compound of claim 223, wherein R 7 " is alkyl. 30

225. The compound of claim 224, wherein said alkyl is methyl.

226. The compound of claim 223, wherein R 7 " is alkylcarbonyl. 35 227. The compound of claim 226, wherein said alkylcarbonyl is acyl.

228. The compound of claim 191, wherein the compound is: -115- FN F NN " H H O H Hr OH HN 0N - NH 2 - HNH 2 OHO0 OHO OHO0 0 HO 0 OH 0 0 00 HN 0N H H : : OH H H- OH OH NH 2 NH 2 NH OH 0 O 0 OH 0 0 HP 0 OH 0 o F? o O HN H N 0 H N H OH H H- OHH OH N H 2 . H 2 N H 2 OH 0 oiP 0O 0 0 OH F 0 'F F H NA HN HNH HN N H0NH H" H H- H OH - : OH IOH NH 2 ~- NH 2 - NH 2 OH 0 ol-? o OH 0 OF? 0 OH 0 OFH NH Z 4 'N -k NN HN' 0 O 0 0 N H H: H H H H OH =OH H H OH NH 2 NH 2 NH 2 OH0 oH-? 0 OH0 OPH 0OHO0 oFP 0o CN N -- H 2 N 0H NH H N H H- N H- - O H OH H H OH OHI NH 2 NH NH 2 OHO OFH 0 OH 0 0H 0HH 0[ MeO( N HNHNJQ)HN O 0 ~ 0 N N O H N HH H- H HH H-H NH 2 -NH 2 NH 2 OH 0 OHOOH 0 O ? 0 OH 0 OF? 0 > INH 0? NH N HN H H: 0 N 0 NH 2 NHII NH 2 NH OH 0 O?0OH 0 Oi- OH0OF0 -116- NH NH 2 NHN HN H H H H N OH OH H H- OH NH 2 ONH 2 "I U N H 2 O H 0 0 H OHO O ONH2 OH OOHO OH 0 O OMe O NH N - 'N O O " N N OH H OH OH NH 2 NH 2 NH2 OH O O O OH O O 0 OH 0 OH N O HNC 0 No NO H H N H Hr - OHN H OH - H OH NH 2 NH 2 NH 2 OH 0 H 0~ OH 0 O O OH 0 OH 0 0 OH 0 O 0 NH NH F F 0 0 LINH H H OH H N H H -~ ~ £ NH I IOH OHNH2 NH 2 HNH 2 OHO 0 OFPHX OHO OH O 0 OHO OH O

229. The tetracycline compound of Formula XIV: R 7u H HOF OH NH2 OH O OH O 0 (XIV) wherein 5 R 7 u is substituted or unsubstituted N-piperidinylalkyl, dialkylaminoalkyl, alkoxyaminoalkyl, alkylaminoalkyl or dipiperidinium methyl; and pharmaceutically acceptable salts, esters and enantiomers thereof.

230. The compound of claim 229, wherein R 7 u is substituted N-piperidinylalkyl 10

231. The compound of claim 230, wherein said substituted N-piperidinylalkyl is methyl substituted N-piperidinylalkyl or halogen substituted N-piperidinylalkyl.

232. The compound of claim 231, wherein said halogen substituted N-piperidinylalkyl 15 is fluorine substituted N-piperidinylalkyl. - 117-

233. The compound of claim 229, wherein said dialkylaminoalkyl is dimethylaminomethyl.

234. The compound of claim 229, wherein said alkylaminomethyl is 5 methylaminomethyl.

235. The compound of claim 229, wherein said alkoxyaminoalkyl is methoxyaminoalkyl. 10 236. The compound of claim 229, wherein said compound is: N N N N H H N OH OH - OH NH 2 NH 2 NH 2 OH 0 Or- O OH 0 O? 0 OH 0 O 0 F 'OCH 3 F N N N N K~KK)HN H H H H - N HOH OH H H: OH N - - OH- O- O NH 2 NH 2 H OH 0 OH 0 OH 0 OF? 0 NH OHO OF? 0 HN N H OH I NH 2 OHO OF? 0

237. A tetracycline compound of formula (XV): R 7v 0 N H H OH I0 | NH2 OH O OH O 0 (XV) 15 wherein R 7 v is heteroaryl; and pharmaceutically acceptable salts, esters and enantiomers thereof.

238. The compound of claim 237, wherein said heteroryl is imidizolyl, methyl 20 imidizolyl, imidizolidinyl or methyl imidizolidinyl. -118 -

239. The compound of claim 237, wherein said compound is: fUN -N 5,1 N N ...-- N O N N'0 N OH H H OH H H OH NH 2 NH 2 NH2 OHO O? 0 OH 0 O OH 0 O o -- N N N OO N OH OH K-NH 2 1 NH2NH 2 OHO O- O OHO

240. A tetracycline compound of formula (XVI): R7 R R5' R 4 R8 X OR' NR 2 R2' R9 OR12 5 OR10 N -NR" O O (XVI) wherein: R2, R2", R a, and R are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 R 10 , R" and R 12 are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; R 3 is hydroxyl, hydrogen, or a pro-drug moiety; R4 is NR 4aR4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen; R 5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, 15 aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; R and R6' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 20 R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 - 3 (NR 7) 0 _ 1 C(=W')WR7a -119- R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 -3(NRc)o- 1 C (=E')ER8a. R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 5 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 - 3 (NR9c)o- 1 C(=Z')ZR9a. 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R I, R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, 10 heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR8dRe, S, NR 8 or 0; E' is 0, NR', or S; 157d 7e 7b 15 WisCR R , S, NR or 0; W' is 0, NR 7 f, or S; X is CHC(R Y'Y), C=CR Y, CRR', S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 20 alkylamino, or an arylalkyl; Z is CR9dR**, S, NR9b or 0; Z' is 0, S, or NR , and pharmaceutically acceptable salts, esters and enantiomers thereof. 25 241. The tetracycline compound of claim 240, wherein R 2 ', R 3 , R 10 , R", and R 12 are each hydrogen or a prodrug moiety; R 4 is N(Me) 2 ; X is CR R6' ; and R 2", R , R , R6, and R6' are each hydrogen.

242. The tetracycline compound of claim 240, wherein R 5 and R 5 are hydrogen and X 6 6' 6' 30 is CR6R , R 4 is N(Me) 2 ; wherein R6 is methyl and R 6 is hydroxy.

243. The tetracycline compound of claim 240, wherein R 5 is hydroxyl; X is CR 6 R 6 '; R 6 is methyl; R4 is N(Me) 2 ; and R and R6' are hydrogen. 35 244. The tetracycline compound of claim 240, wherein R 4 is N(Me) 2 ; X is CR 6 R 6 '; R , R , R6 and R 6 ' are hydrogen atoms and R is dimethylamino. - 120 -

245. The tetracycline compound of any one of claims 240-244, wherein R 8 and R9 are hydrogen.

246. The tetracycline compound of any one of claims 240-245, wherein R 7 is 5 dimethylamino or hydrogen.

247. The tetracycline compound of claim 240, wherein said compound is: H 3 C'N CH 3 H 3 C N'CH 3 H H 2 R - OH K - NH 2 H N R2a OR10 O OR" O O O (XVII) wherein: R 2 is alkyl or aryl; 15 R 4 a and R 4 b are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 10 11 12 R , R and R are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; 20 R 3 is hydroxyl, hydrogen, or a pro-drug moiety; R4 is NR 4aR4 , alkyl, alkenyl, alkynyl, hydroxyl, halogen, or hydrogen; R 5 and R 5 are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; 25 R 6 and R 6 ' are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; R 7 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, 30 acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 - 3 (NR 7)o 0 iC(=W')WR7a - 121 - R 8 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 - 3 (NRc)o- 1 C(=E')ER8a R 9 is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, 5 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or -(CH 2 ) 0 - 3 (NR9c)o- 1 C(=Z')ZR9a 7a 7b 7c 7d 7e 7f 8a 8b 8C 8d 8e 8f 9a 9 C R a, R 6, R ', R d, R e, R I, R a, R E, R ', R d, R ", R I, R a, RGb , R ', R9d, 9e 9 R , and R9f are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, 10 heteroaromatic or a prodrug moiety; R is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; E is CR8dRe, S, NR 8 or 0; E' is 0, NR', or S; 157d 7e 7b 15 WisCR R , S, NR or 0; W' is 0, NR 7 f, or S; X is CHC(R Y'Y), C=CR Y, CRR', S, NR6, or 0; Y' and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, 20 alkylamino, or an arylalkyl; Z is CR9dR**, S, NR9b or 0; Z' is 0, S, or NR , and pharmaceutically acceptable salts, esters and enantiomers thereof. 25 249. The tetracycline compound of claim 248, wherein R 3 , R 1 0 , R", and R 12 are each hydrogen or a prodrug moiety; R 4 is N(Me) 2 ; X is CRR 6'; and R 2", R , R , R , and R' are each hydrogen.

250. The tetracycline compound of claim 248, wherein R 5 and R 5 are hydrogen and X 6 6' 6' 30 is CR6R , R 4 is N(Me) 2 ; wherein R6 is methyl and R 6 is hydroxy.

251. The tetracycline compound of claim 248, wherein R5 is hydroxyl; X is CR 6 R 6 '; R 6 is methyl; R4 is N(Me) 2 ; and R and R6' are hydrogen. 35 252. The tetracycline compound of claim 248, wherein R4 is N(Me) 2 ; X is CR 6 R 6 '; R , R , R6 and R 6 ' are hydrogen atoms and R is dimethylamino.

253. The tetracycline compound of any one of claims 248-252, wherein R 8 is hydrogen. - 122 -

254. The tetracycline compound of any one of claims 248-253, wherein R 9 is alkylaminoalkyl, hydrogen, or alkyl. 5 255. The tetracycline compound of any one of claims 248-254, wherein R 7 is dimethylamino, halogen or hydrogen.

256. The tetracycline compound of any one of claims 248-255, wherein R 2 a is alkyl. 10 257. The tetracycline compound of claim 256, wherein R 2 a is methyl.

258. The tetracycline compound of claim 248, wherein said compound is: H 3 C' N CH 3 H 3 C'N'ICH 3 H 3 C'N, CH 3 H 3 C'NCH 3 ' H Hr H Hr - ~ - - O C 3 rrOH OH HCCH H N CH N CH H N CH OH3 H3 r H 3 C H 3 OHO_ OH 0 0 YHOHOHOFP1OFH OH 0 HO 0CH 3 OH 0 OH 0 0 H 3 3 15 259. A method for treating a tetracycline responsive state in a subject, comprising administering to said subject an effective amount of a tetracycline compound of any one of claims 1-258, such that said subject is treated.

260. The method of claim 259, wherein said tetracycline responsive state is malaria. 20

261. The method of claim 259, wherein said tetracycline responsive state is a bacterial infection, a viral infection, or a parasitic infection.

262. The method of claim 261, wherein said bacterial infection is associated with E. 25 coli.

263. The method of claim 261, wherein said bacterial infection is associated with S. aureus. 30 264. The method of claim 261, wherein said bacterial infection is associated with E. faecalis.

265. The method of claim 259, wherein said bacterial infection is resistant to other tetracycline antibiotics. 35 - 123 -

266. The method of claim 259, wherein said tetracycline associated state is multiple sclerosis.

267. The method of claim 259, wherein said subject is a human. 5

268. The method of anyone of claims 259-267, wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.

269. A pharmaceutical composition comprising a therapeutically effective amount of a 10 tetracycline compound of any one of claims 1-268 and a pharmaceutically acceptable carrier. PARATEK PHARMACEUTICALS, INC. 15 WATERMARK PATENT AND TRADE MARKS ATTORNEYS P38635AU01 - 124 -