9-Alkyl- and 9-Alkylidenyl-6-O-Alkyl-11,12-Carbamate- Ketolide Antimicrobials

FIELD OF THE INVENTION

The present invention relates to the field of macrolide compounds having antibacterial activity, pharmaceutical compositions containing the compounds, and methods of treating bacterial infections with the compounds.

BACKGROUND OF THE INVENTION

Erythromycins are well-known antibacterial agents widely used to treat and prevent bacterial infection caused by Gram-positive and Gram-negative bacteria. However, due to their low stability in acidic environment, they often carry side effects such as poor and erratic oral absorption. As with other antibacterial agents, bacterial strains having resistance or insufficient susceptibility to erythromycin have developed over time and are identified in patients suffering from such ailments as community- acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections. Particularly problematic pathogens include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin- and macrolide- resistant Streptococcus pneumoniae. Therefore, continuing efforts are called for to identify new erythromycin derivative compounds with improved antibacterial activity, and/or unanticipated selectivity against various target microorganisms, particularly erythromycin-resistant strains.

The following references relate to various erythromycin derivatives disclosed as having antibacterial activity:

US 6,437,106 to Stoner et al. discloses processes for preparing 6-O-substituted erythromycin derivatives.

US 5,866,549 to Or et al. and WO 98/09978 (Or et al.) disclose 6-O-substituted ketolides stated to have increased acid stability relative to erythromycin A and 6-O- methyl erythromycin A and enhanced activity toward Gram-negative bacteria and macrolide resistant Gram-positive bacteria.

US 5,750,510 to Elliott et al. discloses 3-descladinose-2,3- anhydroerythromycin derivatives stated to have antibacterial activity.

US 5,631 ,354 to Asaka et al. discloses 5-O-desosaminylerythronolide derivatives stated to have a strong antibacterial activity.

US 5,444,051, US 5,561,118, and US 5,770,579, all to Agouridas et al., disclose erythromycin compounds such as those of the formula

wherein substituents are as described in the respective references, which are all stated to be useful as antibiotics.

US 4,826,820 to E.G. Brain discloses 6-carbamate erythromycin derivatives stated to have antibacterial properties, in particular against Gram-positive bacteria but also against some Gram-negative bacteria.

WO 01/14397 (Or et al.) discloses 9a-azalides stated to have antibacterial activity.

WO 00/75156 (Phan et al.) discloses 6-O-carbamate ketolides and a method of treatment and prevention of infections in a mammal.

WO 00/71557 (Dirlam et al.) discloses 13 -methyl -erythromycin derivatives and methods of using the compounds in the treatment of infections.

WO 00/69875 (Ma et al.) discloses C-2 modified erythromycin derivatives stated to be useful in treating bacterial infections.

WO 99/21871 (Phan et al.) discloses 2-halo-6-O-substituted ketolide derivatives of the formula

wherein substituents are as described in the respective reference, which are stated to possess antibacterial activity.

WO 98/30574 and WO 97/17356 (both by Or et al.) disclose tricyclic erythromycin derivatives stated to be useful in treatment of bacterial infections.

EP 48741 1 to Agouridas et al. discloses erythromycin derivatives having such structure as

wherein substituents are as described in the reference.

EP 1 146051 (Kaneko et al.) discloses macrolide compounds of the following formula that are useful as antibacterial and antiprotozoal agents in mammals,

WO 98/09978 (Or et al) discloses synthesis of 6-0-substituted erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.

WO 02/50091 (Andreotti et al) discloses synthesis of 1 l ,12-lactone-6-O- substituted erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.

WO 02/32918 (Hlasta et al) discloses synthesis of Cl 3 modified erythromycin derivatives stated to be useful in the treatment and prevention of bacterial infections.

WO 99/21868 (Asaka, T.) discloses synthesis of 9-deoxo-9- alkoxyerythromycin A derivatives stated to be useful in the treatment and prevention of bacterial infections

SUMMARY OF THE INVENTION

The invention provides compounds of Formula (I)

(I) wherein

R _a is hydrogen or a hydroxy protecting group;

R _b is hydrogen or halogen;

R _c is selected from hydrogen, alkyl, C ₂ -C ₁₀ -alkenyl, C ₂ -C ₁₀ -alkynyl, aryl, heteroaryl, heterocyclo, aryl( C ₁ -C ₁₀ )alkyl, aryl( C ₂ -C ₁₀ )alkenyl, aryl( C ₂ -C ₁₀ )alkynyl, heterocyclo( C ₁ -C ₁₀ )alkyl, heterocyclo( C ₂ -C ₁₀ )alkenyl, heterocyclo( C ₂ -C ₁₀ )alkynyl, C ₃ - C ₆ -cycloalkyl, C ₅ -C ₈ -cycloalkenyl, alkoxyalkyl containing 1-6 carbon atoms in each alkyl or alkoxy group, and alkylthioalkyl containing 1 -6 carbon atoms in each alkyl or thioalkyl group;

one of Y and Z is R _p and the other is ORp, wherein

each R _p is independently selected from hydrogen or C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, each optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or Y and Z taken together form =CHCH(R _k )Q or =CHC(R _k )=N-OR _h , wherein 5 R _k is selected from the group consisting of:

1) hydrogen,

2) aryl,

3) substituted aryl,

4) heteroaryl,

]0 5) substituted heteroaryl,

6) C ₁ -C ₈ alkyl,

7) C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl,

8) C ₁ -C ₈ alkenyl,

15 9) C ₁ -C ₈ alkenyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, 1O) C ₁ -C ₈ alkynyl,

11) C ₁ -C ₈ alkynyl substituted with aryl, substituted aryl, heteroaryl, or . substituted heteroaryl,

20 12) C(O)-R _f , wherein R _f is selected from hydrogen, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, each optionally substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl, 13) C(O)-O-R _f , and

25 14) C(O)NR _d R _e , wherein R _d and R _e are independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, and C ₁ - C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R _d and R _e , taken together with the nitrogen atom to which they are connected, form a 3 to 7 membered ring optionally having a

30 substituent selected from the group consisting of a) hydrogen,

b) aryl, c) substituted aryl, d) heteroaryl, e) substituted heteroaryl, f) C ₁ -C ₈ alkyl, g) C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, or substituted heteroaryl, h) C(O)-R _f) i) C(O)-O-Rr, j) C(O)NR _d R _e ;

R _h is selected from the group consisting of: a) hydrogen, b) aryl, c) substituted aryl, d) heteroaryl, e) substituted heteroaryl, f) C ₁ -C ₈ alkyl, g) C(O)NR _r R _s wherein R _r and R _s are independently selected from hydrogen, or C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, each optionally substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, or S-R;, wherein Ri is selected from: i. hydrogen, ii. C(O)-R _j wherein R _j is selected from the group defined above for R _f . iii. aryl, iv. substituted aryl, v. heteroaryl, vi. substituted heteroaryl, vii. C ₁ -C ₈ alkyl optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl,

viii. C ₂ -C ₈ alkenyl optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, ix. C ₂ -C ₈ alkynyl optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, or R _r and R _s , taken together with a nitrogen atom to which they are connected, form a 4 to 7 membered ring, optionally containing another nitrogen atom in the ring, and optionally having a substituent selected from the group consisting of a. hydrogen, b. aryl, c. substituted aryl, d. heteroaryl, e. substituted heteroaryl, f. C ₁ -C ₈ alkyl, g. C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, h. C(O)-R _j , i. C(O)-O-R _j , and j. C(O)NR ₁ -R _s wherein R _r and R _s are independently selected from hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, or C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl h) C ₂ -C ₈ alkenyl, i) C ₂ -C ₈ alkenyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, j) C ₂ -C ₈ alkynyl, k) C ₂ -C ₈ alkynyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, 1) C(O)-Rj, m) C(O)-O-Rj, and

n) C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, benzyloxy, or C(O)NR _r R _s wherein R, and R _s are independently selected from hydrogen, or C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, each optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, o) C(O)NR _z NR _r- iR _s .| wherein R _z is hydrogen or alkyl, and R _r-1 and R _s-1 are independently selected from hydrogen, or C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, each optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

Q is selected from the group consisting of

1) oxo;

2) O-Ri, wherein Ri is selected from the group defined above for Rh and further including N-phthalimido; 3) NR ₁ R _u wherein R, and R _u are independently selected from: a. hydrogen, b. aryl, c. substituted aryl, d. heteroaryl, e- substituted heteroaryl, f. C ₁ -C ₈ alkyl optionally substituted with aryl, substituted aryl, heteroaryl or substituted heteroaryl, g. C ₂ -C ₈ alkenyl optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, h. C ₂ -C ₈ alkynyl optionally substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, i. C(O)-R _m , wherein R _m is selected from the group defined above for R _f , j. C(O)-O-R _n ,, wherein R _m is selected from the group defined above for R _f , k. C(O)N R _t-1 R _u-1 , wherein R,.i and R^ ₁ are independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈

alkynyl, and C ₁ -C ₈ alkyl substituted with one or more of aryl, substituted aryl, heteroaryl, substituted heteroaryl or alkoxycarbonyl, or (1) R _t and R _u join to form a five-membered heteroaromatic ring containing from 1 to 4 nitrogen atoms, wherein each carbon atom of the ring is optionally and independently substituted by R _l ,

4) S-R _q , wherein R _q is selected from the group defined above for R _i ,

5) C-(Rι) ₃ wherein each R _l is independently selected from the group previously defined, said group further including cyano,

6) hydrogen, and 7) azido;

T is selected from the group consisting of -O-, -NH-, -N(W-R _g )-, and -CH-R _g - , wherein W is absent or is selected from the group consisting of-O-, -NHCO-, - N=CH-, and -NH-, wherein R ₈ is selected from the group consisting of 1) hydrogen, and

2) C|-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of a) aryl, b) substituted aryl, c) heteroaryl, d) substituted heteroaryl, e) hydroxy, f) C ₁ -C ₆ -alkoxy, g) NRvRw, wherein R _v and R _w are independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, and C ₁ -

C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, and h) CH ₂ -M-Rv, wherein M is selected from the group consisting of i. -C(O)-NH-, ii. -NH-C(O)-, iϋ. -NH-, iv. -N=,

v. -N(CH ₃ )-, vi. -NH-C(O)-O-, vii. -NH-C(O)-NH-, viii. -O- C(O)-NH-, ix. -O- C(O)-O-, x. -O-, xi. -S(O) _n -, wherein n is 0, 1 , or 2, xii. -C(O)-O-, xiii. -O-C(O)-, and xiv. -C(O)-; or T and Y, form a six- or seven-membered heterocyclic ring having 1 nitrogen atom and 1 oxygen atom in the ring;

L is methylene or carbonyl, provided that when L is methylene, T is O;

R is selected from the group consisting of

1) methyl ,

2) methyl substituted with a moiety selected from the group consisting of a) CN, b) F, c) CO ₂ -R ₀ wherein R ₀ is selected from the group defined above for Rf, d) -S(O) _n -R ₀ , wherein n is O to 2, e) NHC(O)-R ₀ , f) NHC(O)NR _x R _y wherein R _x and R _y are independently selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, and C ₁ -C ₈ alkyl substituted with aryl, substituted aryl, heteroaryl, or substituted heteroaryl, g) aryl h) substituted aryl, i) heteroaryl, and j) substituted aryl,

3) C ₂ -C ₁₀ alkyl,

4) C ₂ -C ₁₀ alkyl substituted with one or more substituents selected from the group consisting of a) halogen, b) hydroxy, c) C ₁ -C ₃ -alkoxy, d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy, e) oxo, f) -N ₃ , g) -CHO, h) -O-SO ₂ -(substituted C ₁ -C ₆ -alkyl), i) NR _x R _y , j) -CO ₂ -Ro, k) -CO-NR _x R _y , 1) =N-O-R _x , m) -CN, n) O-S(O) _n -R ₀ , wherein n is O to 2, o) aryl, p) substituted aryl, q) heteroaryl, r) substituted heteroaryl s) C ₃ -C ₈ -cycloalkyl, t) substituted C ₃ -C ₈ -cycloalkyl, u) C ₁ -C ₁₂ -alkyl substituted with heteroaryl , v) heterocycloalkyl, w) substituted heterocycloalkyl, x) NHC(O)-R ₀ , y) =NHC(O)NR _x R _y , z) =N-NR _x R _y , aa) =NR _X , bb) =N-NHC(O)R ₀ , and

cc) =N-NHC(O)NR _x R _y , 5) C ₃ -alkenyl substituted with a moiety selected from the group consisting of a) halogen, b) -CHO, c) CO ₂ R ₀ , d) -C(O)R ₀ , e) -C(O)NR _x R _y , f) -CN, g) aryl, h) substituted aryl, i) heteroaryl, j) susbstituted heteroaryl, k) C ₃ -C ₇ -cycloalkyl, and

1) C ₁ -C ₇ -alkyl substituted with heteroaryl, 6) C ₄ -C ₁₀ alkenyl,

7) C ₄ -C ₁₀ alkenyl substituted with one or more substituents selected from the group consisting of a) halogen, b) hydroxy, c) C ₁ -C ₃ -alkoxy, d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy e) 0x0, f) -N ₃ , g) -CHO, h) -O-SO ₂ -(substituted C ₁ -C ₆ -alkyl), i) NR _x R _x , j) -CO ₂ -R ₀ , k) -CO- NR _x R _y ,

1) =N-O-R _x , m) -CN, n) O-S(O) _n -R ₀ , wherein n is 0 to 2,

o) aryl, p) substituted aryl, q) heteroaryl, r) substituted heteroaryl, s) C ₃ -C ₈ -cycloalkyl, t) substituted C ₃ -C ₈ -cycloalkyl, u) C ₁ -C ₁₂ -alkyl substituted with heteroaryl, v) heterocycloalkyl, w) substituted heterocycloalkyl, x) NHC(O)-R ₀ , y) =NHC(O)NR _x R _y , z) =N-NR _x R _y , aa) =NR _X , bb)=N-NHC(O)R _o , and cc) =N-NHC(O)NR _x R _y ,

8) C ₃ -C ₁₀ -alkynyl;

9) C ₃ -C ₁₀ alkynyl substituted with one or more substituents selected from the group consisting of a) aryl, b) substituted aryl, c) heteroaryl, d) substituted heteroaryl, and e) trialkylsilyl;

or an optical isomer, enantiomer, diastereomer, racemate or racemic mixture thereof, or a pharmaceutically acceptable salt, esters or pro-drugs thereof.

Compounds of Formula (I) are useful as antibacterial agents for the treatment of bacterial infections in a subject such as a human or an animal.

The present invention is also directed to a method of treating a subject having a condition caused by or contributed to by bacterial infection, which comprises administering to said subject a therapeutically effective amount of the compound of Formula (I).

Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing specification.

DETAILED DESCRIPTION

Relative to the above description, certain definitions apply as follows.

Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

Unless specified otherwise, the terms "alkyl", "alkenyl", and "alkynyl," whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, or any number within this range. The term "alkyl" refers to straight or branched chain hydrocarbons. "Alkenyl" refers to a straight or branched chain hydrocarbon with at least one carbon-carbon double bond. "Alkynyl" refers to a straight or branched chain hydrocarbon with at least one carbon-carbon triple bound. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. "Alkoxy" radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups.

"Cycloalkyl" groups contain 3 to 8 ring carbons and preferably 5 to 7 ring carbons.

The alkyl, alkenyl, alkynyl, cycloalkyl group and alkoxy group may be independently substituted with one or more members of the group including, but not limited to, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, oxo, aryl, heteroaryl, heterocyclo, CN, nitro, -OCOR,, -OR,, -SR,, -SOR,, -SO ₂ R ₁ , -COOR ₁ 1 -NR ₁ R ₂ , -CONR ₁ R ₂ , - OCONR ₁ R ₂ . -NHCOR ₁ , -NHCOOR ₁ , and -NHCONR ₁ R ₂ , wherein R ₁ and R ₂ are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroaralkyl, and heterocycloalkyl.

The term "acyl" as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term "Ac" as used herein, whether used alone or as part of a substituent group, means acetyl.

The term "halo" or "halogen" means fluoro, chloro, bromo or iodo. (Mono-, di- , tri-, and per-)halo-alkyl is an alkyl radical substituted by independent replacement of the hydrogen atoms thereon with halogen.

"Aryl" or "Ar," whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2- naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ -alkyl, C ₂ -C ₈ -alkenyl, C ₁ -C ₈ -alkoxyl, C ₁ -C ₈ - alkylthio, C ₁ -C ₈ -alkyl-amino, arylamino, heteroarylamino, di(C ₁ -C ₈ -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ₁ -C ₈ -alkyl- CO-O-, C ₁ -C ₈ -alkyl-CO-NH-, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. "Ph" or "PH" denotes phenyl. "Bz" denotes benzoyl.

Whether used alone or as part of a substituent group, "heteroaryl" refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms.

Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, N-oxo-pyridyl, 1,1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, indazolyl, indolizinyl, benzofuryl, cinnolinyl, quinoxalinyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5- b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, and thienothienyl. The heteroaryl group may be substituted by independent replacement of 1 to 3 of the hydrogen atoms thereon with aryl, heteroaryl, halogen, OH, CN, mercapto, nitro, amino, C ₁ -C ₈ -alkyl, C ₁ -C ₈ -alkoxyl, C ₁ -C ₈ -alkylthio, C ₁ -C ₈ -alkyl-amino, arylamino, heteroarylamino, di(C ₁ -C ₈ -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ₁ -C ₈ -alkyl-CO-O-, C ₁ -C ₈ -alkyl-CO-NH-, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-lH- quinoline.

The terms "heterocycle," "heterocyclic," and "heterocyclo" refer to an optionally substituted, fully saturated, partially saturated, or non-aromatic cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 1 1-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. In addition, the heterocyclic group may be optionally

substituted with alkyl, arylalkyl, heteroarylalkyl, alkenyl, arylalkenyl or heteroarylalkenyl. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolinyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2- oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomoφholinyl; thiomorpholinyl sulfoxide; thiomoφholinyl sulfone; 1 ,3-dioxolane; dioxanyl; thietanyl; thiiranyl; 2-oxazepinyl; azepinyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; benzothiopyranyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; benzopyranyl; dihydrobenzopyranyl; indolinyl; chromonyl; coumarinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted aryl, a second substituted heteroaryl, or a second substituted heterocycle to give, for example, a 4-pyrazol-l-yl -phenyl or 4-pyridin-2-yl- phenyl.

Designated numbers of carbon atoms (e.g., C ₁ -C ₈ or C _1-8 ) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to

provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

The term "hydroxy protecting group" refers to groups known in the art for such purpose. Commonly used hydroxy protecting groups are disclosed, for example, in T.

H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition,

John Wiley & Sons, New York (1991), which is incorporated herein by reference.

Illustrative hydroxyl protecting groups include but are not limited to tetrahydropyranyl; benzyl; methylthiomethyl; ethythiomethyl; pivaloyl; phenylsulfonyl; triphenylmethyl; trisubstituted silyl such as trimethylsilyl, triethylsilyl, tributylsilyl, tri-isopropylsilyl, t- butyldimethylsilyl, tri-t-butylsilyl, methyldiphenyl silyl, ethyldiphenylsilyl, t- butyldiphenylsilyl; acyl and aroyl such as acetyl, benzoyl, pivaloylbenzoyl, 4- methoxybenzoyl, 4-nitrobenzoyl and arylacyl.

Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of

diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

The phrase "a pharmaceutically acceptable salt" denotes one or more salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, salicyclic acid and the like. Suitable salts are furthermore those of inorganic or organic bases, such as KOH, NaOH, Ca(OH) ₂ , Al(0H) ₃ , piperidine, morpholine, ethylamine, triethylamine and the like.

Included within the scope of the invention are the hydrated forms of the compounds that contain various amounts of water, for instance, the hydrate, hemihydrate, and sesquihydrate forms. The present invention also includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The term "subject" includes, without limitation, any animal or artificially modified animal. As a particular embodiment, the subject is a human.

The term "drug-resistant" or "drug-resistance" refers to the characteristics of a microbe to survive in presence of a currently available antimicrobial agent such as an antibiotic at its routine, effective concentration.

The compounds described in the present invention possess antibacterial activity due to their novel structure, and are useful as antibacterial agents for the treatment of bacterial infections in humans and animals.

In particular, the following compounds are preferred embodiments of the present invention for such purposes:

Compound 2

Compound 3

Compound 4

Compound 6

Compound 7

Compound 8

Compound 9

Compound 10

Compound 11

Compound 13

Compound 14

Compound 16

Compound 17

Compound 19

Compound 20

This invention also provides processes for preparing the instant compounds. The compounds of Formula (I) may be prepared from readily available starting materials such as clarithromycin.

SYNTHETIC METHODS

This invention also provides processes for preparing the compounds described. The compounds of Formula (I) may be prepared from readily available starting materials such as erythromycin and erythromycin derivatives well known in the art. Outlined in Schemes 1 through 42 are representative procedures, wherein R is methyl, to prepare the compounds of the instant invention. The same synthetic routes can be utilized for examples when R is not a methyl group.

Scheme 1

Schemes 1 to 7 describe the preparation of precursors to the compounds of the invention. Scheme 1 illustrates the method of synthesis of II, III and IV. Clarithromycin (I, Watanabe, Y. et. al, EP 41355 Al) is treated with aqueous acid at a temperature ranging from -20°C to 37°C for 2 to 72 hours to afford 3-descladinosyl- clarithromycin (II). The 3-hydroxy derivative is protected in the 2 '-position by treating the compound with acetic anhydride in the presence of a tertiary amine base, such as pyridine, triethylamine, or diisopropylethylamine in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for from 2 to 72 hours to provide III. Likewise, alternative protecting groups may be employed. For example, clarithromycin may be treated with benzoic anhydride, propionic anhydride, or formic acetic anhydride under similar conditions as described

above to obtain the 2'-acylated clarithromycin derivative The 3-position of HI may be protected as a silyl ether by treatment with chlorotrimethylsilane and/or trimethylsilylimidazole at a temperature ranging from from -20°C to 37°C for from 30 minutes to 72 hours in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) to afford IV. Alternatively, groups such as triisopropylsilyl may be employed as the 3-position protecting group through an analogous procedure using triisopropylchlorosilane.

Scheme 2

Scheme 2 depicts the synthesis of compounds with an 11 ,12-cyclic carbamate functionality (wherein W is absent and Rg is as defined above). The 2'-acetyl-3- silyloxy derivative IV was converted to the 11,12 -carbamate analog using a procedure similar to that developed by Baker et al., J. Org. Chem. 1988, 53, 2340. Derivative IV was treated with CDI and a suitable base such as sodium hydride, potassium tert- butoxide, or lithium isopropylamide in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 2 to 72 hours. The reaction mixture was treated with appropriate nitrogen nucleophile such as ammonia, or a primary amine in a suitable solvent such as THF, DMF or aqueous acetonitrile at a temperature ranging from -78°C to 100°C for 2 to 72 hours to afford 11 ,12-cyclic carbamate derivative V.

It will be recognized by one skilled in the art that in the conversion of IV to V two new stereocenters are formed, and consequently V may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable

chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 3

Scheme 3 depicts the synthesis of compounds VII and VIII, wherein W is absent and Rg is as defined above, and wherein Z- is a nucleophilic agent. Alkylation of ketone V is readily achieved by treatment of V with a suitable nucleophile such as, but not limited to, lithium trimethylsilylacetylide, methyl magnesium bromide, allyl magnesium bromide or ethylene magnesium bromide in a solvent such as THF, diethyl ether or dioxane at a temperature temperature ranging from -78°C to 25°C for 0.5 to 72 hours followed by acidic workup to afford the 2',3,9-trihydroxy-9-alkyl derivatives VII. Selective protection of the 2'-position with acetic anhydride in the presence of a tertiary amine base, such as pyridine, triethylamine, or diisopropylethylamine in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 2 to 72 hours provides VIII. It will be recognized by one skilled in the art that in the conversion of V to VIII a new stereocenter is formed, and consequently VIII may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid

Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 4

Scheme 4 describes the preparation of X and XI. Deprotection of the alkynyl group of the 9-hydroxy-9-alkynyl analogs (Via) can be accomplished by treatment with methanolic potassium carbonate. Selective protection of the 2 '-position may be achieved with acetic anhydride in the presence of a tertiary amine base, such as pyridine, triethylamine, or diisopropylethylamine in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 2 to 72 hours to afford Villa. Alternatively, the deprotected alkyne could be used in a coupling reaction. under transition metal mediated conditions (such as the

Sonogashira reaction) to afford substituted IX (Rk is not equal to hydrogen). In addition, the optionally substituted alkyne IX (wherein Rk is as defined above) can reduced to the 9-hydroxy-9-alkenyl (X) or 9-hydroxyl-9-alkyl analogs (XI) by catalytic hydrogenation over a transition metal catalyst such as palladium on carbon, or Lindlar's catalyst in the presence of hydrogen in a alcoholic solvent.

Alternative Preparation of HI

Scheme 5

Schemes 5 to 7 describe alternative preparative routes to precursors of the compounds of the invention. The procedures are analogous to the procedures reported in US 5955440 and US 4742049. Clarithromycin (I) is protected in the 2'-position by treating the compound with acetic anhydride in the presence of a tertiary amine base, such as pyridine, triethylamine, or diisopropylethylamine in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 2 to 72 hours to afford XII. The 4"-position may be protected as a silyl ether by treating 2'-acety ^] clarithromycin with chlorotrimethylsilane and/or trimethylsilylimidazole at a temperature ranging from from -20°C to 37°C for from 30 minutes to 72 hours in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) to afford XIII. Alternatively, groups such as triisopropylsilyl may be employed as the 4"-position protecting group through an analogous procedure using triisopropylchlorosilane.

Scheme 6

The 2'-acetyl-4"-silyloxy derivative (XIII) (i.e., where Ra is acetyl) may be converted to the 11 ,12-carbamate analog (XIV) wherein W is absent and Rg is as defined above, using a procedure similar to one developed by Baker et al., J. Org.

Chem. 1988, 53, 2340. Derivative XIII is treated with CDI and a suitable base such as sodium hydride, potassium tert-butoxide, or lithium diisopropylamide in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 2 to 72 hours. The reaction mixture may be treated with an appropriate nitrogen nucleophile, such as ammonia or a primary amine, in a suitable solvent such as THF, DMF or aqueous acetonitrile at a temperature ranging from -78°C to 100°C for 2 to 72 hours to afford 1 1,12-carbamate derivative XIV. Alternatively, this reaction may be conducted via a two step procedure, the first step involving the addition of the amine and the second involving the addition of a suitable base, such as potassium t-butoxide, to provide the 1 1 , 12-cyclic carbamate derivative XIV. It will be recognized by one skilled in the art that in the conversion of XIII to XIV two new stereocenters are formed, and consequently XIV may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 7

Scheme 7 depicts the alternative synthesis of compounds VII wherein W is absent and Rg is as defined above, and wherein Z- is a nucleophilic agent. Alkylation of ketone XIV is achieved by treatment with a suitable nucleophile such as, but not limited to lithium trimethylsilylacetylide, methyl magnesium bromide, allyl magnesium bromide or ethylene magnesium bromide in a solvent such as THF, diethyl ether or dioxane at a temperature ranging from -78°C to 25°C for 0.5 to 72 hours followed by acidic workup to afford the 2',3,9-trihydroxy-9-alkyl derivative VII. It will be recognized by one skilled in the art that in the conversion of XIV to XV a new stereocenter is formed, and consequently XV may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 8

Scheme 8 depicts the synthesis of compounds of the instant invention represented by Formula 1, wherein Y is hydroxyl, W is absent, and Z and Rg are as defined above. Oxidation of the 3-hydroxy group of VIII to yield compound XVI can be effected with DMSO (dimethylsulfoxide) and a carbodiϊmide, such as EDCI (1- ethyl-3-(3-dimethylarninopropy])carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from -20°C to 37°C. Alternative methods of oxidation include N- chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. Removal of the 2'-acetyl group is readily accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C to yield compound XVII. If a 2'-benzoyl group is optionally employed as the protecting group, its removal can be readily accomplished by transesterification with methanol for 2-72 hours at a temperature ranging from 20°C to 65°C to yield compound XVII. Alternate methods for deprotection of the 2'-acetyl include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol.

Scheme 9

XVIa XVIII

Scheme 9 depicts the synthesis of the 9,11 bicycloerythromycin derivative XVIII wherein the group Z is an optionally substituted alkene, wherein Rk is selected from a group previously defined. Alkylated ketolide XVIa is treated with a suitable base such as sodium hydride, triethylamine, or potassium tert-butoxide in a suitable solvent such as THF, DMF or DMSO (dimethylsulfoxide) for 0.1-2 hours at a temperature ranging from -2O°C to 65°C. The reaction mixture is treated with CDI for 0.1-2 hours at a temperature ranging from 0°C to 65°C to afford XVIII.

Scheme 10

XVIII

Scheme 10 depicts the synthesis of compounds of the instant invention of Formula I, wherein Y and Z together form =CHCH(R _k )Q. Compounds XVIa or XVIII undergo an acid-catalyzed rearrangement reaction in the presence of an appropriate nucleophile to yield the corresponding substituted propylidene derivative XIX. Group Q, the nucleophilic species in the reaction depicted in Scheme 10, may be O-R|, NR ₁ R _u , S-R _q , C-(Rι) ₃ or azido, as defined above. It will be recognized by one skilled in the art that in the conversion of XVIa or XVIII to XIX a new stereocenter and potential geometrical isomers are formed, and consequently XIX may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or HPLC, or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Method A (Bronsted Acid) O = Q-R ₁ or NR _t R _u

Scheme 11 depicts the protic acid promoted rearrangement of XVIa or XVIII to the 9-alkylidene ketolide XIXa (Rk is as previously defined and Q is a suitably substituted alcohol (O-Ri). Bronsted acids including, but not limited to trifluoroacetic acid, or acetic acid promote the rearrangement of XVIa or XVIII to XIXa. The reaction conditions require XVIa or XVIII to be treated with neat Bronsted acid or as a

mixture of Bronsted acid and a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 135°C for 2 to 72 hours.

Scheme 12

In Scheme 12, when trifluoroacetic acid is Used as the Bronsted acid the resulting trifluoroacetate of XIXa (R ₁ is trifluoroacetate) may be selectively removed by treating the compound with methanol for a period of less than 1 hour at a temperature ranging from -20°C to 37°C to afford XX. In the case where acids other than trifluoroacetic acid is used, the 2'- protecting group may be cleaved preferentially to afford ketolides XXl.

Scheme 13

Scheme 13 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is OC(O)NR _r R _s and R _r , R _s , and Rk are as defined above (i.e., XXIII). The hydroxy group of XX may be derivatized by treatment with a base such as sodium hydride, potassium tert-butoxide or triethylamine, and carbonyldiimidazole (CDI) in a suitable solvent such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for 1-24 hours to yield the acylimidazolide (XXII). Alternatively, 4-nitrophenylchloroformate may be used to acylate the hydroxyl group to provide the corresponding 4- nitrophenylcarbonate derivative. The acyl imidazolide XXII is treated with an appropriately substituted amine followed by 2' deprotection as described above to afford carbamate XXIII.

Scheme 14

Scheme 14 depicts an alternate synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is OC(O)NHR _n , Rk is as defined above, and Rr is optionally substituted C ₁ -C ₈ alkyl, C ₃ -C ₈ alkenyl, or C ₃ -C ₈ alkynyl (i.e., XXIIIa). Treatment of XX with trichloroacetylisocyanate in an inert solvent, such as methylene chloride, chloroform, or THF at a temperature ranging from -20°C to 37°C for from 1- 24 hours to yields the N-trichloroacetylcarbamate (XXIV). The N- trichloroacetylcarbamate functionality can be hydrolyzed to the corresponding carbamate (XXV) by treatment with a suitable base, such as 10% sodium hydroxide, in a biphasic solvent system, such as ethyl acetate/water, methylene chloride/water, and the like for 1-24 hours at a temperature ranging from 20°C to 8O°C. Alternative bases may likewise be used to effect this conversion, such as potassium hydroxide, sodium carbonate, potassium carbonate, or a tertiary amine base, such as triethylamine, in an aqueous solvent mixture. Reductive alkylation of primary carbamate XXV with a

suitably substituted aldehyde in the presence of trifluoroacetic acid and triethylsilane affords the secondary carbamate XXIIIa.

Scheme 15

Scheme 15 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is 0C(O)NR _z NR _r- iR _s- i, Rk is as defined above, Rz is hydrogen or alkyl, R ₅ .) is hydrogen, and R _r .i is optionally substituted C ₁ -C ₈ alkyl, C ₃ - C ₈ alkenyl, or C ₃ -C ₈ alkynyl (i.e., XXVII). The acyl imidazolide (XXII) is treated with a hydrazine derivative to afford carbazate XXVI. Alternatively, the 4- nitrophenylcarbonate derivative may be employed in the reaction with the hydrazine. Substituted carbazate XXVII is prepared by reaction with an appropriately substituted aldehyde in the presence of a reducing agent, such as but not limited to, sodium cyanoborohydride, or palladium on carbon in the presence of hydrogen gas under slightly acidic conditions at a temperature ranging from -20°C to 37°C for 1-24 hours.

Scheme 16

Scheme 16 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is oxo, and Ra is a hydroxy protecting group, and Rk is as defined above (i.e., XXVIII). The hydroxy group of XX may be oxidized by treatment with DMSO (dimethylsulfoxide) and a carbodiimide, such as EDCl (1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from -2O°C to 37°C. Alternative methods of oxidation include N- chlorosuccinimide and dimethylsulfϊde complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base.

Scheme 17

An alternate method for the preparation of XXVIII, wherein Ra is a hydroxy protecting group and Rk is as defined above, involves the reaction of Xa with trifluoroacetic acid followed by methanolysis of the resulting trifluoroacetate derivative to afford XXIX. The reaction conditions require X to be treated with neat trifluoroacetic acid or a mixture of trifluoroacetic acid and a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofυran) at a temperature ranging from -20°C to 37°C for 2 to 72 hours. The selective removal of the 9- trifluoroacetate by methanolysis is conducted for a period of less than 1 hour at a temperature ranging from -2O°C to 37°C to give XXIX. Oxidation of XXIX by treatment with DMSO (dimethylsulfoxide) and a carbodiimide, such as EDCI (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from -20°C to 37°C affords carbonyl compound XXVIII. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfide complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base.

Scheme 18

XXVIII

Scheme 18 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHC(R _k )=N-0R _h , Ra is hydrogen, and Rh and Rk are as defined above (i.e., XXX). The carbonyl compound XXVIII is treated with an appropriately substituted hydroxylamine derivative, wherein Rh is as define above, in a suitable solvent such as methanol, ethanol or tetrahydrofuran for 1 to 24 hours at a temperature ranging from -20°C to 77°C to afford the oxime XXX. Under the reaction conditions the 2'-acetyl group is removed.

Scheme 19

Scheme 19 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is NR _t R _u , R _a is hydrogen, and Rk is as defined above (i.e., XXXI)- The carbonyl compound XXVII is treated with an appropriately substituted amine and the resulting imine can be reduced to the amine in acidic medium with reducing agents such sodium cyanoborohydride, sodium

triacetoxyborohydride, or. sodium borohydride. Alternatively the intermediate imine may be reduced to the amine by treatment with hydrogen gas in the presence of a transition metal catalyst such as palladium on carbon, platinum on carbon, or rhodium. If Ra is acetyl, transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C yields compound XXXI. If the reduction is conducted in an alcoholic solvent such as methanol, the 2 '-acetyl protecting group is simultaneously removed under the reaction conditions.

Method B (Lewis Acid) Q = C(R ₁ ) ₃ O-R ₁ . S-R _q . NR ₁ R _u , or azido

Scheme 20

Scheme 20 depicts the Lewis acid promoted rearrangement of XVIII to compounds of Formula I wherein Y and Z together form =CHCH(R _k ) Q, Q is C(R _l ) ₃ , O-R _l , S-R _q , NR _t R _u , hydrogen, or azido, wherein R _k , R _l , R _q , R _t , and R _u are as defined above, with the exception of the case where Q is C(R _l ) ₃ , in which case one of R _l is hydrogen, two of R _l are C(O)R _j , and R _j is as defined above (i.e., XIXa, XIXb, XIXc,

XIXd, XIXe, and XIXf)., Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement.

Scheme 21

In particular, Scheme 21 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is ORi, wherein Ri is as defined above (i.e., XXI). In the presence of a suitably substituted alcohol (RiOH), Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 37°C for 2 to 72 hours to form XIXa. Removal of the 2'-acetyl group of compound XIXa may be accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from - 20°C to 65°C to yield compound XXI. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the conversion of XVIII to XIXa a new stereocenter is formed, and consequently XIXa or

XXI may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 22

XXXIl

Scheme 22 depicts the synthesis of compounds of Formula 1 wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is SRq, wherein R _< , is as defined above (i.e., XXXII). In the presence of a suitably substituted mercaptan (R _q SH), Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 37°C for 2 to 72 hours to form XIXb. Removal of the 2'-acetyl group of compound XIXb may be accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from - 20°C to 65°C to yield compound XXXII. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali

metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the conversion of XVIII to XIXa a new stereocenter is formed, and consequently XIXa or XXI may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 23

Scheme 23 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, and Q is N ₃ (i.e., XIXc). In the presence of trimethysilylazide, Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 100°C for 2 to 72 hours to form XIXc. Removal of the 2'-acetyl group may be accomplished

by transesterification with methanol for 2-48 hours at a temperature ranging from - 20°C to 65°C to yield compound XIXc. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the conversion of XVIII to XIXc a new stereocenter is formed, and consequently XIXc may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. In the case where Rk of XIXc is hydrogen, XIXc may undergo a subsequent cycloaddition reaction with a suitably substituted acetylene derivative, to provide compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is hydrogen, and Rk is substituted heteroaryl. In particular, the substituted heteroaryl group is a triazole, wherein X and X' represent the substituents on the triazole. Removal of the 2'-acetyl group may be accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C to yield compound XXXIII. Alternate methods for deprotection of the 2'-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the cycloaddition reaction to form the triazole two regiosiomers may be formed, and consequently XXXIII may additionally exist as mixture of regiosisomers. Once again, these regioisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid

Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 24

XXXI

Scheme 24 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is NR,R _U , and R, and R ₀ are as defined above (i.e., XXXI). In the presence of a suitably substituted amine (R ₁ R _u NH), Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 100°C for 2 to 72 hours to form XIXd. Removal of the 2'-acetyl group of compound XIXd may be accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from - 20°C to 65°C to yield compound XXXI. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the conversion of XVIII to XIXd a new stereocenter is formed, and consequently XIXd or XXXI may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column

chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 25

Scheme 25 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, and Q is C-(Ri) ₃ (i.e., XIXe). In this case, one of Ri is hydrogen, two of Ri are C(O)Rj, and Rj is as defined above. Structure XIXe is also meant to represent those cases where one of Rl is hydrogen, two of Rl are C(O)ORj and Rj is as defined above, and those cases where one of Rl is hydrogen, one of Rl is C(O)Rj, and one of Rl is C(O)ORj. In the presence of a suitably substituted carbon nucleophile such as an optionally substituted 2,4-pentanedione or an alkyl acetoacetate, Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 100°C for 2 to 72 hours to form XIXe. It will be recognized by one skilled in the art that in the conversion of

XVIII to XIXe at least one new stereocenter is formed, and consequently XIXe may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. In the case where Rk of XIXe is hydrogen, XIXe may undergo a subsequent condensation reaction with a suitably substituted hydrazine derivative in a suitable solvent such as methanol, to provide compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is hydrogen, and Rk is substituted heteroaryl. In particular, the substituted heteroaryl group is a pyrazole (XXXIV), wherein X and R, represent the substituents on the pyrazole. In the process, the hydroxy protecting group Ra may be removed concurrently, particularly in the case where Ra is acetyl. It will be recognized by one skilled in the art that in this condensation reaction two regiosiomers may be formed, and consequently XXXIV may additionally exist as mixture of regiosisomers. Once again, these regioisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 26

XXXV

Scheme 26 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above and Q is hydrogen (i.e., XXXV). In the presence of a suitable reducing agent, such as, but not limited to, triethylsilane, Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 100°C for 2 to 72 hours to form XIXf. Removal of the 2'-acetyl group of compound XIXf may be accomplished by transesterifϊcation with methanol for 2-48 hours at a temperature ranging from - 20°C to 65°C to yield compound XXXV. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol.

Method B (Lewis Acid) O is hydrogen and Rk = alkenyl. alkynyl, aryl substituted aryl heteroaryl, or substituted heteroaryl

Scheme 27

XIXh

Scheme 27 depicts the Lewis acid promoted rearrangement of XXXVI to compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is hydrogen, and R _k is alkenyl, alkynyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl (i.e., XIXg, XIXh, and XIXi). Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement.

Scheme 28

In particular, Scheme 28 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is alkenyl, and Q is hydrogen (i.e., XIXg). In the presence of a suitably substituted allyl silane, such as allyl trimethylsilane, Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethyl aluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 37°C for 2 to 72 hours to form XIXg- At this point, removal of the 2 '-acetyl group of XIXg may be accomplished by conventional methods as described above, or XIXg may be further derivatized through a palladium-mediated cross-coupling reaction (e.g., Heck reaction). In particular, reaction of XIXg with an aryl or heteroaryl halide (i.e., Ar may be aryl, substituted aryl, heteroaryl, or substituted heteroaryl) in a suitable solvent such as dimethylformamide, acetonitrile, or THF (tetrahydrofuran) at a temperature ranging from -2O°C to 150°C for 2 to 72 hours in the presence of a suitable transition metal catalyst, such as palladium(II) acetate or tetrakis(triphenyrphosphine)palladium, optionally in the presence of a phosphine ligand, such as tri-o-tolylphosphine, followed

by removal of the 2'-acetyl group by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C yields compound XXXVII. Alternate methods for deprotection of the 2'-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. In the preparation of XXXVII from XIXg two regiosiomers may be formed, and consequently XXXVII may exist as mixture of regiosisomers. These regioisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of regioisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 29

Scheme 29 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and Q is hydrogen (i.e., XIXh). In the presence of a suitably substituted aromatic or heteroaromatic compound, Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be

used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 100°C for 2 to 72 hours to form XIXh. Removal of the 2'-acetyl group of compound XIXh may be accomplished by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65 °C to yield compound XXXVIII. Alternate methods for deprotection of the 2'-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol.

Scheme 30

Scheme 30 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is alkynyl, and Q is hydrogen (i.e., XIXi). In the presence of a suitably substituted terminal alkyne (wherein X represents the substituent on the alkyne), Lewis acids including, but not limited to, boron trifluoride diethyl etherate, diethylaluminum chloride, or aluminum chloride may be used to promote the rearrangement in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 150°C for 2 to 72 hours to form XIXi. Removal of the 2 '-acetyl group of XIXi may be accomplished by

transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C to provide compound XXXIX. Alternate methods for deprotection of the T- acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol.

Other Transformations

Scheme 31

Scheme 31 depicts the synthesis of compounds of Formula I, wherein T and Y form a seven-membered heterocyclic ring having 1 nitrogen atom and 1 oxygen atom in the ring and Z is as defined above (i.e., XLIII). The 3-hydroxyl group of VIIIb is selectively protected as a silyl ether derivative by treatment with chlorotrimethylsilane and/or trimethylsilylimidazole at a temperature ranging from from -20°C to 37°C for from 30 minutes to 72 hours in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, in a suitable solvent such as methylene chloride, chloroform, or THF (tetrahydrofuran) to afford XL. Alternatively, groups such as triisopropylsilyl or tert-butyldimethylsilyl may be employed as the 3- position protecting group through an analogous procedure using triisopropylchlorosilane or tert-butyldimethylsilyl chloride, respectively. Compound XL may be further derivatized through a palladium-catalyzed ring annulation reaction with the bis-tert-butyl ester of 2-butene-l ,4-diylcarbonic acid (Uozumi, Y. et al, J. Org. Chem. 1993, 55(24), 6826-32) to form compound XLI with the seven-membered heterocyclic ring. Acid-promoted hydrolysis of the silyl ether of XLl under standard conditions to form XLII, followed by oxidation of the resulting alcohol with DMSO (dimethylsulfoxide) and a carbodiimide, such as EDCI (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from -20°C to 37°C, provides XLIII. Alternative methods of oxidation include N- chlorosuccinimide and dimethylsulfϊde complex followed by treatment with a tertiary amine base, Dess-Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. At this point, removal of the 2 '-acetyl group of XLIII may be accomplished by conventional methods as described above, or XLIII may be further derivatized through palladium-catalyzed arylation reaction of the terminal olefin (e.g., Heck reaction). In particular, reaction of XLIII with an aryl or heteroaryl halide (i.e., Ar may be aryl, substituted aryl, heteroaryl, or substituted heteroaryl) in a suitable solvent such as dimethylformamide, acetonitrile, or THF (tetrahydrofuran) at a temperature ranging from -2O°C to 150°C for 2 to 72 hours in the presence of a suitable transition metal catalyst, such as palladium(II) acetate or tetrakis(triphenylphosphine)palladium, optionally in the presence of a phosphine

ligand, such as tri-o-tolylphosphine, followed by removal of the 2'-acetyl group by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C yields compound XLV. Alternate methods for deprotection of the 2'-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. It will be recognized by one skilled in the art that in the conversion of XL to XLI a new stereocenter is formed, and consequently XLI may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step. In the subsequent conversion of XLIII to XLIV two new regioisomers may be formed, and consequently XLIV and XLV may exist as mixture of isomers. These isomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 32

Scheme 32 depicts the synthesis of compounds of Formula I wherein Y and Z . together form =CHC(R _k )=N-OR _h , R _a and R _h are hydrogen, and Rk is as defined above (i.e., XLVI), and its subsequent conversion to compounds of the Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is NR _t R _u , and R _t and R _u , are hydrogen (i.e., L). The carbonyl compound XXVIII is treated with hydroxylamine, in a suitable solvent such as methanol, ethanol or tetrahydrofuran for 1 to 24 hours at a temperature ranging from -20°C to 77°C to afford the oxime XLVI. Under the reaction conditions the 2'-acetyl group is removed. Compound XLVI can be reduced to the amine in acidic medium with reducing agents such sodium cyanoborohydride, sodium triacetoxyborohydride, or sodium borohydride. Alternatively the oxime could be reduced to the amine by hydrogen gas in the presence of a transition metal catalyst such as palladium on carbon, platinum on carbon, or rhodium. It will be recognized by one skilled in the art that in the conversion of XLVI to XLVII a new stereocenter is formed, and consequently XLVII may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid

Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 33

XXXIb

XXXIa

Scheme 33 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is NR _t R _u , Rt is optionally substituted C ₁ -C ₈ alkyl, C ₃ -C ₈ alkenyl, or C ₃ -C ₈ alkynyl, and Ru is hydrogen (i.e., XXXIa), and compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is NR ₁ R _u , Ri is C(O)-R _n ,, Rm is as defined above, and R _u is hydrogen (i.e., XXXIb).

Reaction of carbonyl compound XXVIII with benzylcarbamate in the presence of a suitable reducing agent, such as triethylsilane, and a suitable acid, such as trifluoroacetic acid provides carbamate XLVIII. Carbamate XLVIII can be converted to amine XLIX by treatment with hydrogen gas in the presence of a transition metal catalyst such as palladium on carbon, platinum on carbon, or rhodium in an acidic medium. Amine XLIX can be transformed to XXXIa by treatment with an appropriate substituted aldehyde in the presence of a suitable reducing agent, such as sodium cyanoborohydride in the presence of catalytic acid followed by removal of the 2'-acetyl protecting group as described above. Alternatively, amine XLIX can be acylated with agents such as, but not limited to, acid halides, anhydrides, or carboxylic acids in the presence of coupling agents such as dicyclohexyldiimide, optionally in the presence of a suitable inorganic or organic base, such as sodium bicarbonate, potassium carbonate, or diisopropylethylamine, followed by removal of the 2'-acetyl protecting group as described above, to afford XXXIb. It will be recognized by one skilled in the art that in the conversion of XXVIII to XLVIII a new stereocenter is formed, and consequently XLVIII may exist as a mixture of diastereoisomers. These stereoisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of stereoisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Scheme 34

Scheme 34 depicts the synthesis of compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Rk is as defined above, Q is NR,R _U , R, is C(O)NR _t-1 R _u--1 , R,-i is optionally substituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, or C ₂ -C ₈ alkynyl, and R _u-1 is hydrogen (i.e., XXXIc), and compounds of Formula I wherein Y and Z together form =CHCH(R _k )Q, Q is NR _t R _u , R _t is C(O)-O-R _m , R _m , is as defined above, and Ru is hydrogen (i.e., XXXId). Amine XLIX may be treated with carbonyldiimidazole (CDI) to afford acyl imidazolide derivative L. The acyl imidazolide may then be treated with an appropriately substituted amine to give urea derivative LI or treated with an appropriately substituted alcohol to afford carbamatederivative LII. Removal of the T- acetyl group of compound LI or LII may be readily accomplished by

transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C to yield compound XXXIc or XXXId. Alternate methods for deprotectioή of the 2'-acetyl include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. Alternatively, amine XLIX can be converted to XXXc by treatment with an appropriate substituted isocyanate to give LI, followed by removal of the 2'-acyl protecting group.

Scheme 35

Scheme 35 depicts the synthesis of compounds of Formula I wherein Z is Rp as defined above, Y is ORp, wherein this Rp is substituted C ₃ -alkenyl, Ar is aryl, substituted aryj, heteroaryl, substituted heteroaryl, W is absent and Rg is as defined above, (i.e., LVI). Reaction of the tertiary hydroxyl group of XV with a suitable allylating agent, such as allyl tert-butyl carbonate, in the presence of a transition metal catalyst, such as palladium acetate, and a phosphine ligand, such as triphenylphosphine, in a suitable solvent, such as THF, provides the allyl ether derivative LIII. Typically the reaction is conducted at temperatures from 2O°C to 100°C for from 1 to 48 hours. Removal of the cladinose sugar can be accomplished by reaction of LIII with an acid, such as hydrochloric, sulfuric, chloroacetic, and trifluoroacetic, in the presence of alcohol and water for from 0.5-24 hours at a temperature ranging from -10°C to 37°C, and the 2'-hydroxyl group may be acetylated by treatment with acetic anhydride in the presence of a tertiary amine base, such as triethylamine, diisopropylethylamine, or pyridine, and optionally an acylation catalyst, such as DMAP, in a suitable solvent such as methylene chloride, chloroform or THF at a temperature ranging from -20°C to 37°C for 2 to 48 hours to give LIV. Oxidation of the 3-hydroxy group of LIV to yield compound LV can be effected with DMSO (dimethylsulfoxide) and a carbodiimide, such as EDCI (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide), in the presence of pyridinium trifluoroacetate in a suitable solvent, such as methylene chloride, for 1 to 24 hours at a temperature ranging from -20°C to 37°C. Alternative methods of oxidation include N-chlorosuccinimide and dimethylsulfϊde complex followed by treatment with a tertiary amine base, Dess- Martin periodinane, or oxalyl chloride/DMSO followed by treatment with a tertiary amine base. LV may then be subjected to a palladium-mediated cross-coupling reaction (e.g., Heck reaction). In particular, reaction of LV with an aryl or heteroaryl halide (i.e., Ar may be aryl, substituted aryl, heteroaryl, or substituted heteroaryl) in a suitable solvent such as dimethylformamide, acetonitrile, or THF (tetrahydrofuran) at a temperature ranging from -20°C to 150°C for 2 to 72 hours in the presence of a suitable transition metal catalyst, such as palladium(ll) acetate or tetrakis(tripheny]phosphine)palladium, optionally in the presence of a phosphine

ligand, such as tri-o-tolylphosphine, followed by removal of the 2'-acetyl group by transesterification with methanol for 2-48 hours at a temperature ranging from -20°C to 65°C yields compound LVI. Alternate methods for deprotection of the 2'-acetyl group include hydrolysis in the presence of an alkali metal hydroxide or an alkali metal carbonate, such as sodium hydroxide or potassium carbonate, or ammonolysis with ammonia in methanol. In the preparation of LVI from LV two regiosiomers may be formed, and consequently LVI may exist as mixture of regiosisomers. These regioisomers may be separated at this stage by a suitable chromatographic method, such as silica gel column chromatography or High Performance Liquid Chromatography (HPLC), or the mixture of regioisomers may be carried on through the synthetic sequence, and optionally separated at a later step.

Sidechain Preparation

When the amines, alcohols, carboxylic acids, phenols, thiols, β-dicarbonyl compounds, acetylenes, hydrazines, alkoxyamines, aldehydes, or aryl halides used in the preparation of compounds XVI, XVII, XVIII, XIXa, XIXb, XIXc, XIXd, XIXe, XIXf, XIXg, XIXh, XIXi, XX, XXI, XXIa, XXIb, XXIc, XXId, XXIII, XXV, XXVI, XXVII, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVlII, XXXIX, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LII, LV, and LVI are not commercially available, they can be obtained by conventional synthetic procedures, in accordance with literature precedent, from readily accessible starting materials using standard reagents and reaction conditions.

Exemplary syntheses of several of the reagents used in the preparation of XVI,

XVII, XVIII, XIXa, XIXb, XIXc, XIXd, XIXe, XIXf, XIXg, XIXh, XIXi, XX, XXI, XXIa, XXIb, XXIc, XXId, XXIII, XXV, XXVI, XXVII, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LII, LV, and LVI are presented hereinafter as reference examples.

Scheme 36

Scheme 36 illustrates a method of synthesis of certain of the aldehydes (LVII), wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, used in the preparation of compounds of the invention. Wittig-type reaction of an aromatic aldehyde (LVII) with 1 ,3-dioxolan-2-yl-methyltriphenylphosphonium bromide under phase transfer conditions in a biphasic solvent system in the presence of an inorganic base, such as potassium carbonate, affords the corresponding vinylogous aldehyde (LVIII). The reaction is typically run from 2 to 48 hours at temperatures ranging from 0°C to 37°C. The method is more fully described in Daubresse, N., Francesch, C. and Rolando, C, Tetrahedron, 1998, 54, 10761 and Henninger WO 02/46204.

Scheme 37

Scheme 37 illustrates the synthesis of certain of the alkyl amines (LXI), wherein HNR'R" is a 5-membered aromatic heterocycle containing a nitrogen atom with a bound hydrogen atom or a 9-membered fused bicyclic aromatic heterocycle containing a nitrogen atom with a bound hydrogen atom in the 5-membered ring, and n is an integer between 1 and 8, used in the preparation of compounds of the invention. The synthetic route is analogous to the route reported in Agouridas et al. in US 5,444,051 , US 5,561 ,1 18, and US 5,770,579. Alkyl phthalimidyl alkyl bromide is treated with a suitably susbtituted nitrogen-containing heterocycle (LVIV) in the

presence of a suitable base such as sodium hydride, potassium /erf-butoxide, or triethylamine at temperatures ranging from O°C to 106°C for 2 to 48 hours. Deprotection of LX may be accomplished by treatment with hydrazine, methylamine, or sodium borohydride in a suitable solvent such as ethanol, methanol or isopropanol at a temperature ranging from 2O°C to 110°C for 2 to 72 hours to afford LXI.

Scheme 38 illustrates the preferred synthesis of 4-(4-pyridiny-3-yl-imidazol-l- yl)-butylamine (LXVI). 1 -Pyridin-3-ylethanone (LXII) is treated with bromine at temperatures ranging from 20°C to 106°C for 2 to 48 hours to afford the corresponding α-bromo ketone LXIII. The α-bromo ketone LXIII is converted to the corresponding imidazole (LXIV) by first treating with foramidine at temperatures ranging from 20°C to 106°C for 2 to 48 hours to obtain the imidazole, and then reacting the imidazole with aqueous HCl, to prepare the hydrochloride salt LXIV. The imidazole may be isolated as the free base or an acid addition salt, preferrably the hydrochloride salt. Reaction of the imidazole hydrochloride (LXIV) with 2-(4-bromobutyl)isoindole-l ,3-dione in a suitable solvent, such as dimethylformamide or N-methylpyrrolidinone, in the presence of a suitable base such as sodium hydride, potassium tert-butoxide, or triethylamine affords the desired 2-[4-(4-pyridiny-3-yl-imidazol-l -yl)-butyl]-isoindole-l ,3-dione

(LXV). Typically the reaction is carried out at temperatures ranging from 20°C to 110°C for 2 to 72 hours. Deprotection of LXV may be accomplished by treatment with hydrazine, methylamine, or sodium borohydride in a suitable solvent such as ethanol, methanol or isopropanol at a temperature ranging from 20°C to 110°C for 2 to 72 hours to afford LXVI.

Scheme 39

Scheme 39 illustrates the synthesis of but-2-enyl-l,4-diamine derivatives (LXIX) in which HNR'R" is a 5-membered aromatic heterocycle containing a • nitrogen atom with a bound hydrogen atom or a 9-membered fused bicyclic aromatic heterocycle containing a nitrogen atom with a bound hydrogen atom in the 5- membered ring using a synthetic route analogous to the procedure reported in Hlasta et al. WO 02/32918. Potassium phthalimide (LXVII) is treated with 1 ,4-dibromo-but-2- ene at temperatures ranging from 0°C to 106°C for 2 to 48 hours to afford the corresponding alkenyl bromide LXVIII. The alkenyl bromide LXVIII is converted to an amine derivative by reaction with a suitably substituted nitrogen-containing heterocycle in the presence of a suitable base such as sodium hydride, potassium tert- butoxide, or triethylamine at temperatures ranging from 0°C to 106°C for 2 to 48 hours. Typically the reaction is carried out at temperatures ranging from 20°C to 110°C for 2 to 72 hours. Deprotection of the phthalimide may be accomplished by treatment with hydrazine, methylamine, or sodium borohydride in a suitable solvent such as ethanol, methanol or isopropanol at a temperature ranging from 20°C to 1 10°C for 2 to 72 hours to afford LXIX.

Scheme 40

Scheme 40 illustrates the synthesis of but-3-enylamine (LXXII), wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Potassium phthalimide (LXVII) is treated with 1 -bromo-but-3-ene at temperatures ranging from 0°C to 106°C for 2 to 48 hours affords the corresponding alkenyl phthlamide LXX. Reaction of LXX with an aryl bromide, iodide, or triflate to give the arylated derivative (LXXI) is conducted under typical Heck coupling conditions, i.e., in the presence of a Pd" catalyst, typically palladium acetate and a phosphine, typically tri(ortho- tolyl)phosphine, and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 1 10°C. Deprotection of LXXI may be accomplished by treatment with hydrazine, methylamine, or sodium borohydride in a suitable solvent such as ethanol, methanol or isopropanol at a temperature ranging from 20°C to 1 10°C for 2 to 72 hours to afford LXXII.

Scheme 41

Scheme 41 illustrates the synthesis of certain of the amines (LXXV) wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl and n is an integer between 1 and 8, used in the preparation of compounds of the invention. Reaction of a Boc-protected bromophenalkylamine derivative (LXXIII) with an aryl boronic acid to • give the biaryl derivative (LXXIV) is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd ⁰ catalyst, typically palladium tetrakis(triphenylphosphine), and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 110°C. Aryl iodides and aryl triflates are also suitable substrates for this conversion. Deprotection of LXXIV may be accomplished by treatment with acid, such as trifluoroacetic acid or aqueous hydrochloric acid, in a suitable solvent such as ethanol, methanol or isopropanol at a temperature ranging from 20°C to 1 10°C for 2 to 72 hours to afford LXXV.

Scheme 42

Scheme 42 illustrates the synthesis of certain of the amines (LXXVIII), wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, used in the preparation of compounds of the invention. The synthetic route is analogous to the procedure reported in Hirst et al. WO 0172751. Reaction of a bromophenylacetamide (LXXVI) with an aryl boronic acid to give the biaryl derivative (LXXVII) is conducted under typical Suzuki coupling conditions, i.e., in the presence of a Pd ⁰ catalyst, typically palladium tetrakis(triphenylphosphine), and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 110°C. Aryl iodides and aryl triflates are also suitable substrates for this conversion. Borane reduction of the amide in a suitable solvent such as methylene chloride or THF affords the biarylphenethylamine derivative LXXVIII. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 110°C.

Scheme 43

Scheme 43 illustrates the synthesis of certain of the amines (LXXV) wherein Ar is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and n is an integer between 1 and 8, used in the preparation of compounds of the invention. The synthetic route is analogous to the procedure reported in Davison et al. WO 0168592. Reaction of the Boc-protected bromophenylalkylamine derivative (LXXIII) with a pinacoldiborane ester to give the aryl boronic ester derivative (LXXIX) is conducted under typical Miyaura conditions, i.e., in the presence of palladium diphenylphosphinoferrocine dichloride, and potassium acetate in DMSO. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 1 10 ^c C. Aryl iodides are also suitable substrates for this conversion. Boc-protected phenalkylamineboronic ester derivative (LXXIX) is treated with an aryl halide or triflate to give the biaryl derivative (LXXIV) under typical Suzuki coupling conditions, i.e., in the presence of a Pd ⁰ catalyst, typically palladium tetrakis(triphenylphosphine), and a base, typically sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, or triethylamine in a suitable solvent, such as toluene, ethanol, methanol, DME, or THF. Reaction time is typically 2 to 48 hours at a temperature ranging from 20°C to 1 10°C. Aryl iodides and aryl triflates are also suitable substrates for this conversion. Deprotection of LXXIV may be accomplished by treatment with acid, such as trifiuoroacetic acid or aqueous hydrochloric acid, in a suitable solvent

such as ethanol, methanol or isopropanol at a temperature ranging from 20°C to 110°C for 2 to 72 hours to afford LXXV.

Scheme 44

Scheme 44 illustrates the synthesis of 3-bromo-5-(2-pyrimidinyl)pyridine (21) used in the preparation of compound 17. Reaction of 5-bromo-3-pyridine carboxamide (LXXX) with phosphorus oxychloride at temperatures ranging from 2O°C to 106°C for 2 to 48 hours affords the corresponding nitrile. The nitrile is converted to the corresponding amidine (LXXXI) by first treating with gaseous hydrogen chloride and ethanol to obtain the imidate, and then reacting the imidate with ammonia, typically in an alcoholic solvent, such as methanol. The amidine may be isolated as the free base or an acid addition salt, preferrably the hydrochloride salt. Reaction of the amidine hydrochloride (LXXXI) with 1,1,3,3-tetramethoxypropane in a suitable solvent, such as dimethyl formamide or N-methylpyrrolidinone, affords the desired 3-bromo-5-(2- pyrimidinyOpyridine (21). Typically the reaction is carried out at temperatures ranging from 20°C to 1 1O°C for 2 to 72 hours.

The synthetic schemes described in the previous sections can be applied to other macrolides, in particular the 6-O-allyl macrolides described in WO 98/09978 and the 6-O-carbamoyl macrolides described in WO 02/46204 (i.e., macrolides and ketolides in which R is other than methyl. Compounds of the invention wherein the

substituent at the 13-position (i.e., R _c ) is a group other than ethyl may be prepared beginning with modified erythromycin derivatives as starting materials, such as those described in WO 99/35157, WO.00/62783, WO 00/63224, and WO 00/63225. Methods for the preparation of ketolides in which W is -O-, -NHCO-, -N=CH-, and -NH- may be found, for example in US 6,395,710.

These compounds have antimicrobial activity against susceptible and drug resistant Gram-positive and Gram-negative bacteria. In particular, they are useful as broad spectrum antibacterial agents for the treatment of bacterial infections in humans and animals. These compounds are particularly activity against S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, Enterococci, Moraxella catarrhalis and H. influenzae. These compounds are particularly useful in the treatment of community- acquired pneumonia, upper and lower respiratory tract infections, skin and soft tissue infections, meningitis, hospital-acquired lung infections, and bone and joint infections.

Minimal inhibitory concentration (MIC) has been an indicator of in vitro antibacterial activity widely used in the art. The in vitro antimicrobial activity of the compounds was determined by the microdilution broth method following the test method from the National Committee for Clinical Laboratory Standards (NCCLS). This method is described in the NCCLS Document M7-A4, Vol.17, No.2, "Methods for Dilution Antimicrobial Susceptibility Test for Bacteria that Grow Aerobically— Fourth Edition", which is incorporated herein by reference.

In this method two-fold serial dilutions of drug in cation adjusted Mueller- Hinton broth are added to wells in microdilution trays. The test organisms are prepared by adjusting the turbidity of actively growing broth cultures so that the final concentration of test organism after it is added to the wells is approximately 5 x 10 ⁴ CFU/well.

Following inoculation of the microdilution trays, the trays are incubated at 35 °C for 16-20 hours and then read. The MIC is the lowest concentration of test compound that completely inhibits growth of the test organism. The amount of growth in the wells containing the test compound is compared with the amount of growth in the growth-control wells (no test compound) used in each tray. As set forth in Tables 1-10, compounds of the present invention were tested against a variety of Gram- positive and Gram-negative pathogenic bacteria resulting in a range of activities depending on the organism tested.

Table 1 to 10 below sets forth the biological activity (MIC, μg/mL) of some compounds of the present invention.

Table 1. MIC Values (μg/mL) of Some Compounds of General Structure XIXa.

XX. and XXI (A: S. aureus A TCC29213; B: E.faecalis ATCC29212; C: S ¹ . pneumoniae ATCC49619; D: H. in uenzae ATCC49247

Table 2. MIC Values (μg/mL) of Some Compounds of General Structure XXIII and XXV

(A: S. aureus Smith; B: S. pneumoniae ATCC49619; C: H. influenzae ATCC49247)

Tahle 3. MIC Values (μg/mL) of Some Compounds of General Structure XXVI and XXVII

(A: S. aureus Smith; B: S. pneumoniae ATCC49619; C: H. influenzae ATCC49247)

Table 4. MIC Values (μg/mL) of Some Compounds of General Structure XXX

(A: S. aureus ATCC29213; B: E.faecalis ATCC29212;C: S. pneumoniae ATCC49619; D: H. influenzae

ATCC49247)

Table 5. MIC Values (μg/mL) of Some Compounds of General Structure XXXI

(A: S. aureus ATCC29213; B: E.faecalis ATCC29212;.C: 5. pneumoniae ATCC49619; D: H. influenzae ATCC49247)

Table 6. MIC Values ( μg/mL) of Some Compounds of General Structure XXXII

(A: 5. aureus ATCC29213; B: E.faecalis ATCC29212;C: S. pneumoniae ATCC49619; D: H. influenzae

ATCC49247)

Table 7. MIC Values (μg/mL) of Some Compounds of General Structure XIXc.

XXXIII. and XXXVIII

(A: S. aureus ATCC29213; B: E.faecalis ATCC29212;.C: S. pneumoniae ATCC49619; D: H. influenzae ATCC49247)

Table 8. MIC Values (μg/mL) of Some Compounds of General Structure XIXe, XIXg. XXXIV. XXXV. XXXVIII. and XXXIX

(A: 5. aureus ATCC29213; B: E.faecalis ATCC29212; C: S. pneumoniae ATCC49619; D: H. influenzae ATCC49247)

Table 9. MIC Values (ug/mL) of Some Compounds of General Structure XXXIc and XXXId

(A: S. aureus Smith; B: S. pneumoniae ATCC49619; C: H. influenzae ATCC49247)

Table 10. MIC Values (μg/mL) of Some Compounds of General Structure XVII

XLIII. XLV. and LVI

(A: S. aureus ATCC29213; B: E.faecalis ATCC29212; C: S. pneumoniae ATCC49619; D: H. influenzae ATCC49247)

This invention further provides a method of treating bacterial infections, or enhancing or potentiating the activity of other antibacterial agents, in warm-blooded animals, which comprises administering to the animals a compound of the invention alone or in admixture with another antibacterial agent in the form of a medicament according to the invention.

When the compounds are employed for the above utility, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents, and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing for example, from about 0.5% to 5% of suspending agent, syrups containing, for example, from about 10% to 50% of sugar, and elixirs containing, for example, from about 20% to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.5% to 5% suspending agent in an isotonic medium. These pharmaceutical preparations may contain, for example, from about 0.5% up to about 90% of the active ingredient in combination with the carrier, more usually between 5% and 60% by weight.

Compositions for topical application may take the form of liquids, creams or gels, containing a therapeutically effective concentration of a compound of the invention admixed with a dermatologically acceptable carrier.

In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT (2,6-di-tert-butyl-4-methylphenol) and BHA (2-tert-Butyl-4-methoxyphenol).

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacological acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating

action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.1 mg/kg to about 400 mg/kg of animal body weight, which may be given in divided doses two to four times a day, or in sustained release form. For most large mammals the total daily dosage is from about 0.07 g to 7.0 g, preferably from about 100 mg to 2000 mg. Dosage forms suitable for internal use comprise from about 100 mg to 1200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The production of the above-mentioned pharmaceutical compositions and medicaments is carried out by any method known in the art, for example, by mixing the active ingredients(s) with the diluent(s) to form a pharmaceutical composition (e.g. a granulate) and then forming the composition into the medicament (e.g. tablets).

The following examples describe in detail the chemical synthesis of representative compounds of the present invention. The procedures are illustrations, and the invention should not be construed as being limited by chemical reactions and conditions they express. No attempt has been made to optimize the yields obtained in these reactions, and it would be obvious to one skilled in the art that variations in reaction times, temperatures, solvents, and/or reagents could increase the yields.

FXPFRIMENTAL SECTION

A solution of clarithromycin (I) (10.0g., 13.4 mmol) in CH ₂ CI ₂ (25 mL)was treated with triethylamine (5.0 mL., 35.0 mmol, 2.6 equivalents) and acetic anhydride (2.8 ml., 29.4 mmol, 2.2 equivalents) at 0 °C. After stirring for 5 min., the ice bath was removed, allowed to warm to 25 °C and the reaction mixture stirred for 18h. The resulting mixture was diluted with CH ₂ Cl ₂ (50 mL), washed with saturated aqueous ammonium chloride solution (2 x100 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to afford a white solid. The residue was treated with 20% aqueous HCl (25 mL) and allowed to stir for 4h. The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL), treated with concentrated NH ₄ OH until the reaction mixture was approximately pH ~9, washed with brine (2 xlOO mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to afford III as a white residue. Purification of the residue by flash chromatography (0- 5% MeOH/ CH ₂ Cl ₂ containing 0.5% concentrated NH ₄ OH) afforded III (6.3 g, 74%) as an off white solid. MS 632 (M+H).

A solution of III (6.3 g., 9.97 mmol) in CH ₂ Cl ₂ (50 mL) was treated with trimethylsilyl imidazole (1.76 mL, 1 1.9 mmol) and chlorotrimethylsilane (0.5 mL, 3.97 mmol) at 25

°C. After stirring for 15 min., the reaction mixture became turbid and the reaction mixture was allowed to stir an additional 45 min. The resulting mixture was diluted with CH ₂ Cl ₂ (10 mL), washed with saturated aqueous ammonium chloride solution (2 x 50 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to afford IV as white foam. The residue was used without further purification. MS 704 (M+H).

Compound 22 Compound 22 or V (wherein Ra is acetyl. W is absent, and Rg is hydrogen)

A mixture of IV (6.66 g., 9.48 mmol) and CDl (6.16 g, 38 mmol) in 1 :1 mixture of DMF (40 mL) and THF (40 mL) was treated with NaHMDS (14.4 mL, 14.4 mmol) at - 10 °C via a syringe and allowed to warm to 25 °C over 5h. The reaction mixture was concentrated to Vt of its original volume in vacuo and treated with concentrated NH ₄ OH solution (38 mL) at 0 °C. The resulting mixture was diluted with isopropanol until the mixture became homogenous and the resulting solution was allowed to warm to 25 °C and stirred for 8h. The reaction mixture was diluted with ethyl acetate (150 mL), washed with saturated aqueous NH ₄ Cl (2 x 100 mL), dried and was concentrated in vacuo to afford 22 (7.1 g, 103%) as a white foam. The solid was used without further purification. MS 729 (M+H).

Compound 23 Compound 23 or VII (wherein Rg is hydrogen. W is absent, and Z is ethynyl)

A solution of 22 (6.9 g., 9.48 mmol) in anhydrous THF (50 mL) was treated with a solution of lithium trimethylsilylacetylide in THF (90.0 mL, 45.0 mmol, 0.5 M, Aldrich) over 15 minutes at 0 °C under nitrogen. After the addition is complete, the reaction mixture was allowed to warm 25 °C, and stirred for 5 hours. The reaction mixture was treated with saturated aqueous NH4CI (1 mL), diluted with ethyl acetate (150 mL), washed with saturated aqueous NH4CI solution (2 x 100mL) and concentrated in vacuo to afford a light brown foam. The residue was dissolved in methanol ( 100 mL) and treated with potassium carbonate (2.60 g.), and stirred for 18 hours. The reaction mixture was concentrated in vacuo, and the residue diluted with EtOAc (50 mL) and H ₂ O (50 mL). The organic solution was dried (MgSO ₄ ), and concentrated in vacuo to afford a brown foam. Flash chromatography (94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded 23 (1.03 g., 17%) as a beige foam. MS 641 (M+H).

Compound 20

Compound 20 or X (wherein Ra. Rg and Rk are hydrogen and W is absent)

A solution of 23 (2.2Og., 3.43 mmol) in absolute ethanol (60 ml) was treated with Lindlar's catalyst (5% Pd on CaCO ₃ poisoned with lead, 0.9 Ig., 0.429 mmol, 0.13 equivalents) and hydrogenated on a Parr apparatus under 50 psi of H ₂ for 18 hours. The reaction mixture was filtered through Celite, and concentrated in vacuo to afford 20 (2.18g., 99%) as a beige solid. The solid was used without further purification.

Compound 24

Compound 24 or X (wherein Ra is acetyl, Rg and Rk are hydrogen, and W is absent)

A solution of 20 (2.18g., 3.39 mmol) in CH ₂ Cl ₂ (50 mL) was treated with triethylamine (0.57 mL, 4.07 mmol, 1.2 equivalents) and acetic anhydride (1.3 mL, 13.6 mmol, 4.0 equivalents), and stirred for 16 hours. The solution was treated with a 0.5M aqueous sodium phosphate monobasic solution (50 mL), saturated aqueous sodium bicarbonate solution (2x 50 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford 24 (2.30g., 99%) as a beige solid. The solid was used without further purification.

Compound 1

Compound 1 or XVI (wherein Rg is hydrogen. VV is absent, and Z is vinvO

A solution of 24 (3.97g., 5.80 mmol) in CH ₂ Cl ₂ (75 mL) was treated with Dess-Martin periodinane (2.46g., 5.80 mmol, 1.0 equivalent), and stirred for 24 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (25 mL), treated with 10% aqueous sodium hydroxide solution (40 mL), washed with brine (25 mL) and concentrated in vacuo to afford 1 (3.09g., 78%) as an off-white solid. The solid was used without further purification.

Compound 26

Compound 26 or XVlII (wherein Ra is acetyl and Rk is hydrogen^

A solution of 1 (O.lOlg., 0.148 mmol) in THF (5 mL) was treated with CDI (0.096g, 0.592 mmol, 4.0 equivalents) and NaH (as a 60% dispersion in mineral oil, 0.024g., 0.592 mmol, 4.0 equivalents) at 0 °C, and stirred for 15 minutes. The reaction mixture was treated carefully with H ₂ O (5 mL) and diluted with EtOAc (10 mL). The organic phase was washed successively with H ₂ O (2x 10 mL), concentrated NH ₄ OH (10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford 26 (0.10Og., 95%) as an off-white foam. The material was used without further purification.

Alternative Preparation of Compound 23 or VII (wherein Rg is hydrogen. W is absent, and Z is ethynyl)

A solution of clarithromycin (20.Og., 26.0 mmol) in CH ₂ CI ₂ (100 mL) was treated with triethylamine (4.50 mL, 54.0 mmol, 1.2 equivalents) and acetic anhydride (5.10 mL, 54.0 mmol, 2.1 equivalents) over 5 minutes at 0 °C. After stirring for 5 min., the ice bath was removed, and the reaction mixture stirred for an additional 2 hours at 25 °C. The resulting mixture was treated with 0.5M aqueous sodium phosphate monobasic solution (100 ml), washed with CH ₂ Cl ₂ (2 xlOO mL), combined, dried (MgSO-O, filtered and concentrated in vacuo to afford XII (wherein Ri is hydrogen and Ra is acetyl) as a white solid (20.5g, 100%). The solid was used without further purification.

A solution of XII (22.2g., 28.1 mmol) in CH ₂ Cl ₂ (225 ml) was treated with pyridine (6.8 mL, 84.3 mmol, 3.0 equivalents) and trimethylsilyl chloride (7.1 mL, 56.2 mmol, 2.0 equivalents) at 0 °C , and then stirred at 25 °C for 55 minutes. The reaction mixture was treated with 0.5M aqueous sodium phosphate monobasic solution (200 ml), washed with H ₂ O (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), brine (100 ml), dried (MgSO ₄ ), and concentrated in vacuo to afford XIII (24.2 g., 100%) as a white solid. The solid was used without further purification.

Compound 27 or XIV (wherein Ra is acetyl, Rg is hydrogen, and W is absent) Step A

A mixture of XIII (2.00 g., 2.32 mmol) in DMF (19 mL) and THF (2 mL) was treated with CDI (1 -98g., 12.2 mmol, 5.3 equivalents) followed by NaH (as a 60% dispersion in mineral oil, 0.14g., 9.72 mmol, 4.2 equivalents) at 0 °C, then stirred for 50 minutes at 25 °C. The reaction mixture was treated carefully with H ₂ O (10 mL), then diluted with EtOAc (25 mL). The organic solution was washed successively with H ₂ O (2x 25 mL) and concentrated NH ₄ OH (25 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a white foam, which was suspended in acetonitrile (10 mL) and treated with liquid ammonia (25 mL) at -40 °C (dry ice in acetonitrile). The reaction mixture was stirred for 2 hours at -40 °C, was vented to the air, and allowed to warm to 25 °C over 16 hours. The reaction mixture was concentrated in vacuo to afford the desired

compound (2.0Og., 97%) as a white solid. The solid was used without any further purification.

Step B A solution of the product from step A (2.26 g., 2.55 mmol) in THF (8 mL) was treated with a 1.0M solution of potassium tert-butoxide in THF (2.6 mL, 2.60 mmol, 1.02 equivalents) at 0 °C. The solution was stirred at 0 °C for 1 hour, then treated with 0.5M sodium phosphate monobasic solution (10 mL) and diluted with EtOAc (20 mL). The aqueous phase was washed with EtOAc (25 mL), combined, dried (MgSO ₄ ), and concentrated in vacuo to afford 27 (2.15g., 95%) as a white solid. The solid was used without further purification.

Compound 23

Compound 23 or VII (wherein Rg is hydrogen. W is absent, and Z is ethynyl)

A solution of compound 27 (2.16 g., 2.44 mmol) in anhydrous THF (50 mL) was treated with a 0.5M solution of lithium trimethylsilylacetylide in THF (50.0 mL, 25.0 mmol, 10.2 equivalents) over 15 minutes at 0 °C, allowed to warm to 25 °C, and stirred for 24 hours. The reaction mixture was treated with saturated aqueous NH ₄ Cl (100 mL), and the solid material removed by filtration. The organic solution was washed again with saturated aqueous NH ₄ Cl, dried (MgSO ₄ ), and concentrated in vacuo to afford a light brown foam which was dissolved in THF (50 mL) and treated with 20% aqueous HCl (20 mL) over 10 minutes. The reaction mixture was stirred for 3 hours, then treated slowly with concentrated NH ₄ OH (50 mL), and diluted with EtOAc (35 mL). The aqueous phase was washed with EtOAc (25 mL), the organic layers

combined, dried (MgSO ₄ ), and concentrated in vacuo to afford a light brown foam. The residue was dissolved in methanol (100 mL) and treated with potassium carbonate (2.60 g.), and stirred for 18 hours. The reaction mixture was concentrated in vacuo, and the residue diluted with EtOAc (50 mL) and H ₂ O (50 mL). The organic solution was dried (MgSO ₄ ), and concentrated in vacuo to afford a brown foam. Flash chromatography (94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded 23 (1.22g., 78%) as a beige foam.

Aldehyde Preparation

Compound 28 Compound 28 (General Structure XXIX)

A solution of Compound 1 (5.16g., 7.53 mmol) in trifluoroacetic acid (30 mL) was stirred at 0 °C for 1 hour and then at room temperature for 5 hours. The reaction mixture was poured over ice (25Og.) and treated carefully with saturated aqueous sodium bicarbonate solution (800 mL) until basic. The mixture was diluted with CH ₂ Cl ₂ (250 mL) and transferred to a separatory funnel. The organic layer was collected, washed with saturated aqueous sodium bicarbonate solution (200 mL), dried (MgSO ₄ ) and concentrated in vacuo to a brown foam which was immediately dissolved in methanol (16 mL) and stirred for 8 minutes. The reaction mixture was concentrated in vacuo to a brown foam. Flash chromatography (91 :8:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded 28 (2.61 g., 51%) as a white foam. MS 685 (M+H).

Compound 29 Compound 29 (General Structure XXVIII)

A solution of compound 28 (2.58g., 3.77 mmol) in CH ₂ Cl ₂ (50 mL) was treated with Dess-Martin periodinane (3.27g., 7.71 mmol, 2.1 equivalents), and stirred for 2 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (25 mL), treated with IN aqueous sodium hydroxide solution (50 mL), stirred vigorously, and transferred to a separatory funnel. The organic layer was collected, washed with brine (40 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford 29 (2.46g., 96%) as a white foam. The foam was used without further purification. MS 681 (M+H).

Compounds of General Structure XIXa. XX, and XXI

Compound Ol (General Structure XIXa)

A solution of compound 26 (1.44g, 2.01 mmol) in acetic acid (25 mL) was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and diluted with CH ₂ Cl ₂ (20 mL) and washed with saturated aqueous sodium bicarbonate solution (3x 30 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford Ol as a yellow foam.

Flash chromatography (96:3:1 CH ₂ Cl ₂ methanol :NU,0H) afforded Ol (0.54Og, 37%) as a pale yellow foam. MS 725 (M+H).

Compound O2 (General Stucture XIXa) A solution of compound 26 (0.203g, 0.286 mmol) in trifluoroacetic acid (5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and treated carefully with saturated aqueous sodium bicarbonate solution (25 mL). The layers were separated and the organic solution washed with saturated aqueous sodium bicarbonate solution (20 mL), dried (MgSO.;) and concentrated in vacuo to afford O2 (0.210 g, 94%) as an off-white foam. The material was used without further purification. MS 779 (M+H).

Compound O3 (General Structure XX)

Compound O2 (0.333g, 0.427 mmol) was dissolved in methanol and stirred for 10 minutes. The reaction mixture was concentrated in vacuo to afford O3 (0.29 Ig, 100%) as a pale yellow foam. MS 683 (M+H).

Compound O4 (General Structure XXI)

Compound Ol (0.042g, 0.059 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to afford O4 (0.04Og, 99%) as a white foam. MS 683 (M+H).

Compound O5 (General Structure XIXa)

Compound O2 (0.209g, 0.268 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow foam. Flash chromatography (94:5: 1 CH ₂ Cl ₂ methanol ^H ₄ OH) afforded O5 (0.085g, 49%) as a white foam. MS 641 (M+H).

Compound O6 (General Structure XXIt A solution of compound 26 (70 mg, 0.098 mmol) and benzoic acid (48 mg, 0.392 mmol) in CH ₂ Cl ₂ (1 mL) at 25 °C was treated with boron trifluoride diethyl etherate (0.1 mL, 0.78 mmol) via a syringe. After Ih, the resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ :methanol:NH4θH) afforded O6 (13 mg, 16%) as a colorless foam. MS 745 (M+H).

Compound 9 (O7) (General Structure XXI) A solution of compound 26 (50 mg, 0.07 mmol) and phenylacetic acid (38 mg, 0.28 mmol) in CH2CI2 (1 mL) at 25 °C was treated with boron tnfluoride diethyl etherate (0.07 mL, 0.56 mmol) via a syringe. After Ih, the resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a residue.

The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol:NH ₄ OH) afforded 9 (8.3 mg, 16%) as a colorless foam. MS 759 (M+H).

Compounds O8 and O9

The same starting material (i.e., compound 26) as 06 was reacted with each of the respective carboxylic acids listed using the same procedure as compound O6 to prepared each of the compounds listed in the following Table A.

Table A

Compound O10 (General Structure XXI)

A solution of compound 26 (50 mg, 0.07 mmol) and N-hydroxyphthalimide (41 mg, 0.28 mmol) in CH ₂ Cl ₂ (1 mL) at 25 °C was treated with boron trifluoride diethyl etherate (0.1 mL, 0.78 mmol) via a syringe. After Ih, the resulting mixture was treated with satd. aqueous NaHCCh (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded O10 (7 mg, 13%) as a colorless foam. MS 786 (M+H).

Compound O11 (General Structure XXI)

A solution of 26 (0.106g, 0.150 mmol) in CH ₂ Cl ₂ (5 mL) was treated with phenol (0.704g, 7.48 mmol, 50.0 equivalents) followed by boron trifluoride diethyl etherate (0.34 mL, 2.14 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 30 minutes.

The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (10 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow oil which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (97:2:1 CH ₂ Cl ₂ :methanol:NH4θH) afforded Oil (0.047g, 44%) as a white foam. MS 717 (M+H).

Compounds O12 through O15 The same starting material (i.e., compound 26) as Oil was reacted with each of the respective phenols (ArOH) listed in Table B using the same procedure as compound Oil to prepare each of the compounds listed in Table B.

Compound O16 (General Structure XXI) Step A

A solution of compound 26 (0.049g, 0.069 mmol) in CH ₂ Cl ₂ (3 mL) was treated with benzyl alcohol (0.21 mL, 2.07 mmol, 30 equivalents) followed by boron trifluoride diethyl etherate (0.16 mL, 1.24 mmol, 18 equivalents) dropwise at 0 °C, and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightens. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound as a yellow oil. Flash chromatography (98:1 :1

CH ₂ Cl ₂ :methanol INH ₄ OH) afforded the desired compound (0.03Og, 56%) as a white foam. MS 773 (M+H).

Step B

The product obtained in step A (0.03Og, 0.039 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil.

Table B

Flash chromatography (98:1 :1 CH ₂ Cl2.methanol.NH ₄ OH) afforded O16 (0.025g, 88%) as a white foam. MS 731 (M+H).

Compound 11 (O201 (General Structure XXl)

A solution of 26 (0.05 Ig., 0.072 mmol) in CH ₂ Cl ₂ (3 mL) was treated with 2-naphthaleneethanol (0.186g., 1.08 mmol, 15.0 equivalents) followed by BF ₃ etherate (0.07 mL, 0.552 mmol, 8.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightens. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow foam which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded 11 (0.022g., 38%) as a white foam. MS 795 (M+H).

Compounds O17 through O19 The same starting material (i.e., compound 26) as O16 was reacted with each of the respective alcohols (RiOH) listed in Table C using the same procedure as compound O16 to prepare each of the compounds listed in Table C.

Table C

Compound O21 (General Structure XXV) Step A Compound O3 (0.039g, 0.057 mmol) was dissolved in CH ₂ Cl ₂ (2 mL), cooled to 0 °C, and treated with trichloroacetylisocyanate (0.04 mL, 0.336 mmol, 5.9 equivalents).

The reaction mixture was stirred for 16 hours then concentrated in vacuo. The residue was redissolved in EtOAc (3 mL), treated with 10% aqueous sodium hydroxide solution (4 mL), and stirred for 72 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with saturated aqueous sodium bicarbonate solution (10 mL), brine (10 mL), dried (MgSOj), and concentrated in vacuo to afford desired compound

(0.039g, 94%) as an off-white foam. MS 726 (M+H).

Step B

The product obtained in step A (0.039g, 0.054 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a pale yellow foam. Flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NrLtOH) afforded O21

(O.OHg, 38%) as a white foam. MS 684 (M+H).

Compound O22 (General Structure XXIII)

A solution of compound O3 (50.0 mg., 0.073 mmol) in dichloromethane (1 ml.) was treated with phenylisocyanate (60 mg., 0.29 mmol), and triethylamine (20 mg., 0.2 mmol), and then stirred for 1 hour. . The reaction mixture was heated to reflux (40 °C) and stirred for 24 h. The organic solution was concentrated in vacuo and methanol (3 ml.) added, and stirred for 5 h. Purification by reverse phase semi-prep chromatography (Column, Luna, 5 micron Cl 8, 100 X 50 mm), conditions (acetonitrile/H ₂ O, 50 ml/min., gradient 25% acetonitrile to 95%, 12 minutes), afforded O22 (12 mg. -20%) as a white solid after lyophilization. MS = 761 (M+H). Compounds O23 to O24

The same starting material (i.e., compound O3) as in the prepration of O22 was reacted with each of the respective isocyanates listed in Table D using the same procedure as compound O22 to prepare each of the compounds listed in Table D.

Table D

Compound O2S (General Structure XXIII)

A solution of compound O3 (50.0 mg., 0.073 mmol) in dichoromethane (1 ml.) was treated with CDI (13 mg., 0.080 mmol) at ambient temperature, and then stirred for 1 hour. The reaction mixture was treated with 4-chlorobenzylamine (60 mg., 0.29

mmol), and triethyamine (20 ing., 0.2 mmol). The reaction mixture was heated to reflux (40 °C) and stirred for 24 h. The organic solution was concentrated in vacuo and methanol (3 ml.) added, and stirred for 5 h. Purification by reverse phase semi-prep chromatography (Column, Luna, 5 micron C 18, 100 X 50 mm), conditions (ACN/H2O, 50 ml/min., gradient 25% acetonitrile to 95%, 12 minutes), afforded O25 (12 mg. -20%) as a white solid after lyophilization. MS = 809 (M+H). Compounds O26 through O56

The same starting material (i.e., compound O3) as used in the preparation of O25 was reacted with each of the respective amines listed in Table E using the same procedure as compound O25 to prepare each of the compounds listed in Table E.

Table E

Table E (continued)

Table E continued

Table E continued

Table E continued

Table E continued

Table E continued

Table E continued

Table E cont.

Compound O57 (General Structure XXVI)

4-Nitrophenylchloro formate (401 mg, 1.99 mmol) was added to compound O3 (905 mg, 1.33 mmol) and 277 μl (1.99 mmol) of triethylamine in 20 ml of DCM at 0°C. The reaction mixture was then allowed to warm to RT. Reaction progress was monitored by LC/MS. Upon complete conversion, hydrazine (250 μl, 8.0 mmol) was added via syringe to the reaction mixture at 0 C. Once again, the reaction progress was

monitored by LC/MS until the intermediate was consumed. The reaction was then diluted with 1 M HCl and washed three times with DCM. The aqueous layer was then slowly neutralized with a saturated solution of NaHCO ₃ and extracted with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and evaporated in

vacuo to give 360 mg of the 2'-acetyl-protected product as pale yellow foam. MS 741 (M+ H). The acetyl protecting group was then removed by stirring the residue in 10 ml of MeOH for 4 hrs to give the desired product, compound O57. MS 699 (M+H).

Compound O59 (General Structure XXVII) Compound 057 (50 mg (0.068 mmol) was dissolved in a solution of methanol (2 ml) containing 34 μl (0.56 mmol) of glacial acetic acid and 1 1 mg (0.082 mmol) ofp- anisaldehyde. The reaction was stirred at ambient temperature for 2 hrs and then treated with 45 mg (0.75 mmol) of 95% NaBH ₃ CN. The reaction was stirred until completion as determined by LC/MS analysis. The reaction was then quenched with 1 M NaOH and extracted with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and evaporated to dryness. The residue was then purified by reverse phase HPLC (Cl 8, 20 to 50% CH ₃ CN/water/0.5% TFA). The collected product was then lyophilized to give the trifluoroacetic acid salt of the desired product as a white solid. MS 819 (M+H).

Compound O58 (General Structure XXVII)

By same procedure as compound O59, compound OS7 (50 mg, 0.068 mmol) was combined with quinoline-3-carboxaldehyde (13 mg, 0.082 mmol). The TFA salt of compound O58 was isolated as a white solid. MS 841 (M+H).

Compound O61 (General Structure XXVII) By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(3-thienyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). The TFA salt of the product was lyophilized from acetonitrile / water to give a white solid. MS 871 (M+H).

Compound O62 (General Structure XXVII) By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(3-pyridyl)phenylcarboxaldehyde (14 mg, 0.082 mmol). MS 866 (M+H).

Compound O63 (General Structure XXVII)

By the method of compound OS9, compound 057 (50 mg, 0.068 mmol) was combined with 4-(2-thiazoyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 872 (M+H).

Compound O64 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(4-pyridyl)phenylcarboxaldehyde (14 mg, 0.082 mmol). MS 866 (M+H).

Compound O65 (General Structure XXVII)

By the method of compound O59, compound 057 (50 mg, 0.068 mmol) was combined with 4-(5-pyπmidyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 867 (M+H).

Compound O66 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(5-thiazolyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 872 (M+H).

Compound O67 (General Structure XXVIH

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(2-pyridyl)phenylcarboxaldehyde (14 mg, 0.082 mmol). MS 866 (M+H).

Compound O68 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(2-thiazolylamino)phenylcarboxaldehyde (17 mg, 0.082 mmol). MS 887 (M+H).

Compound O69 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(2-pyrazinyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 867 (M+H).

Compound O70 (General Structure XXVIH

By the method of compound O59, compound O57 50 mg, 0.068 mmol) was combined with 4-(4-pyrimidinyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 867 (M+H).

Compound O71 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 3-[4-(2-pyrimidinyl)phenyl]propenal (17 mg, 0.082 mmol). MS 893 (M+H).

Compound O72 (General Structure XXVII)

By the method of compound OS9, compound O57 (50 mg, 0.068 mmol) was combined with 4-[(4-tert-butyl)-2-thiazolyl]benzaldehyde (21 mg, 0.082 mmol). MS 928 (M+H).

Compound O73 (General Structure XXVin

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 3-[l-(2-pyrimidinyl)-1 H-4-imidazolyl]propenal (17 mg, 0.082 mmol). MS 893 (M+H).

Compound O74 (General Structure XXVII) By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 3-[4-(2-pyridinyl)phenyl]propenal (17 mg, 0.082 mmol). MS 892 (M+H).

Compound O75 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 3-[4-(2-thiazolyl)phenyl]propenal (18 mg, 0.082 mmol). MS 898 (M+H).

Compound O76 (General Structure XXVII)

By compound O59, compound O57 (50 mg, 0.068 mmol) was combined with quinoline-6-carboxaldehyde (13 mg, 0.082 mmol) (J. Med. Chem. 2000, 3878-3894). The TFA salt of compound 076 was isolated as a white solid. MS 841 (M+H).

Compound O77 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(2-pynmidiny])phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 867 (M+H).

Compound O78 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 3-(2-thiazolyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 872 (M+H).

Compound O79 (General Structure XXVin

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 2-(2-thiazolyl)phenylcarboxaldehyde (16 mg, 0.082 mmol). MS 872 (M+H).

Compound O80 (General Structure XXVII)

By the method of compound O59, compound O57 (50 mg, 0.068 mmol) was combined with 4-(3-furanyl)phenylcarboxaldehyde (14 mg, 0.082 mmol). MS 855 (M+H).

Compounds O81 through O84

The same starting material (i.e., compound O59) as O80 was reacted with each of the respective aldehydes listed in Table F using the same procedure as compound O80 to prepare each of the compounds listed in Table F.

Table F

Compound O57A (General Structure XXVI)

By an analogous procedure to compound O57, the N-methyl carbazate was prepared by addition of methylhydrazine, in place of hydrazine, to the reaction mixture at -40 °C.

The intermediate was isolated as in compound O57 as pale yellow foam, MS 755 (M+H).

Compound O60 (General Structure XXVII) Without further purification, compound O57A (50 mg, 0.066mmol) was reacted with 4-(3-pyridyl)phenylcarboxaldehyde (15mg, 0.082 mmol) according to the procedure outlined in example O59. Compound O60 was isolated as the TFA salt, white solid upon lyophilization. MS 881 (M+H).

Compounds 085 through O88

The same starting material (i.e., compound O57A) as 060 was reacted with each of the respective aldehydes listed in Table G uding the same procedure as compound 060 to prepare each of the compounds listed in Table G.

Table G

Compounds of General Structure XXX

Compound NO1 (General Structure XXX)

A solution of compound 29 (95 mg, 0.131 mmol) and O-benzylhydroxylamine hydrochloride (43 mg, 0.346 mmol) in MeOH (1 mL) was warmed to 65 °C and stirred under nitrogen. After 2h, resulting mixture was allowed to cool to 25 °C, and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded NOl (21 mg, 22 %) as a colorless foam. MS 744 (M+H).

Compound 12 (NO4) (General Structure XXX)

A solution of compound 29 (50 mg, 0.07 mmol) and O-phenylbutylhydroxylamine (20 mg, 0.12 mmol) in MeOH (1 mL) was warmed to 65 °C and stirred under nitrogen.

After 2h, resulting mixture was allowed to cool to 25 °C, and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded NO4 (14 mg) as a colorless foam. MS 787 (M+H).

Compounds NO2, NO3, and NO5 through NO9

The same starting material (i.e., compound 29) as NO2 was reacted with each of the respective alkoxyamines listed in Table H using the same procedure as compound NO4 to prepared each of the compounds listed in Table H.

Table H

Table H continued

Compounds of General Structure XXXI

Compound Nl (General Structure XXXl) A solution of compound 29 ( 100 mg, 0.147 mmol) and methylamine hydrochloride (30 mg, 0.44 mmol) in MeOH (1 mL) at 25 °C was treated with glacial acetic acid (4 drops) and allowed to stir for 12h. The resulting mixture was treated with sodium cyanoborohydride (30 mg, 0.47 mmol), and bromocresol green (indicator, -1 mg) to afford a green solution. Glacial acetic acid was added until the solution turned dark yellow and the reaction mixture was allowed to stir for 2h. The resulting mixture was treated with satd. aqueous NaHCC> ₃ (1 mL), diluted with CH2CI ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (K ₂ CO3), and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol !NH ₄ OH) afforded Nl (64 mg, 65 %) as a colorless foam. MS 654 (M+H).

Compound 4 (N26) (General Structure XXXI)

A solution of compound 29 (75 mg, 0.11 mmol) and 4-quinolin-3-yl-but-3-enylamine (44 mg, 0.22 mmol) in MeOH (1 mL) at 25 °C was treated with glacial acetic acid (4 drops) and allowed to stir for 12h. The resulting mixture was treated with sodium cyanoborohydride (35 mg, 0.55 mmol), and bromocresol green (indicator, ~1 mg) to afford a green solution. Glacial acetic acid was added until the solution turned dark yellow and the reaction mixture was allowed to stir for 2h. The resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (K ₂ CO ₃ ), and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ :methanol:NH-iOH) afforded compound 4 (N26) (45 mg, 50 %) as a colorless foam. MS 822 (M+H).

Compound 5 (N35) (General Structure XXXI) A solution of compound 29 (100 mg, 0.15 mmol) and 4-quinolin-7-yl-but-3-enylamine (57 mg, 0.29 mmol) in MeOH (1 mL) at 25 °C was treated with glacial acetic acid (4 drops) and allowed to stir for 12h. The resulting mixture was treated with sodium cyanoborohydride (35 mg, 0.55 mmol), and bromocresol green (indicator, ~1 mg) to afford a green solution. Glacial acetic acid was added until the solution turned dark yellow and the reaction mixture was allowed to stir for 2h. The resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (K ₂ CO ₃ ), and concentrated in vacuo to

afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded compound 5 (N35) (26 mg, as a colorless foam. MS 822 (M+H).

Compound 7 (N9) (General Structure XXXI)

^' A solution of compound 29 ( 100 mg, 0.15 mmol) and 2-(5-phenyl-tetrazol- 1 -yl)- ethylamine (64 mg, 0.29 mmol) in MeOH (1 mL) at 25 °C was treated with glacial acetic acid (4 drops) and allowed to stir for 12h. The resulting mixture was treated with sodium cyanoborohydride (35 mg, 0.55 mmol), and bromocresol green (indicator, ~1 mg) to afford a green solution. Glacial acetic acid was added until the solution turned dark yellow and the reaction mixture was allowed to stir for 2h. The resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ CI2 (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (K ₂ CO ₃ ), and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5

CH ₂ CI ₂ -.methanol ^H ₄ OH) afforded compound 7 (N9) (21 mg) as a colorless foam. MS 813 (M+H).

Compounds N2 through N8, NlO through N25, N27 through N34 and N36 through N47

The same starting material (i.e., compound 29) as Nl and N26 was reacted with each of the respective amines listed in Table 1 using the same procedure as example Nl and N26 to prepare each of the compounds listed in Table I.

Table I

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Table I continued

Compound N48 (General Structure XXXI)

A solution of compound 4 (N26) (18 mg, 0.022 mmol), acetic anhydride (0.2 mL, 0.22 mmol), and triethylamine (0.4 mL, 0.28 mmol) in CH ₂ Cl ₂ (1 mL) at 25 °C was allowed to stir for 12h. The resulting mixture was treated with satd. aqueous NaHCθ ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NH ₄ Cl (2 x 10 mL), dried (K ₂ CO ₃ ), and concentrated in vacuo to afford a residue. The residue was resuspended in MeOH (2 mL) and allowed to stir for 12 h at 25 °C. The resulting mixture was concentrated in vacuo to afford a light yellow residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol ^H ₄ OH) afforded N48 (8 mg, 42 %) as a colorless foam. MS 864 (M+H).

Compounds N49 through N52 The same procedure was employed as described for the preparation of N48 except that the respective amines listed in Table J were used in place of compound 4 (N26) to prepare each of the compounds listed in Table J.

Table J

Compounds of General Structure XXXII

Compound Sl (General Structure XXXII)

Step A

A solution of compound 26 (0.229g, 0.323 mmol) in thiolacetic acid (5 mL) was treated with boron trifluoride diethyl etherate (0.33 mL, 2.60 mmol, 8.0 equivalents) dropwise at room temperature and stirred for 30 minutes. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (100 mL) and stirred vigorously. CH2CI ₂ (25 mL) was added, the organic layer separated, washed with saturated aqueous sodium bicarbonate solution (2x 25 mL), dried (MgSO ₄ ), and concentrated in vacuo to an orange foam. Flash chromatography (98:1 :1

CH ₂ Cl ₂ :methanoI:NH ₄ OH) afforded the desired compound (0.180g, 75%) as an orange foam. MS 741 (M+H).

Step B

The product obtained in step A (0.180g, 0.243 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to afford

Sl (0.170g, 100%) as a white foam. MS 699 (M+H).

Compound S2 (General Structure XXXH)

A solution of compound 26 (0.05Og, 0.071 mmol) in CH ₂ Cl ₂ (3 mL) was treated with benzyl mercaptan (0.12 g, 0.966 mmol, 15.0 equivalents) followed by dimethylaluminum chloride (0.5M solution in hexanes; 1.1 mL, 0.550 mxnol, 8.0 equivalents) dropwise at O°C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a yellow oil, which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (98:1 :1 CH ₂ Cl ₂ methanol -.NH ₄ OH) afforded S2 (0.015g, 28%) as a white foam. MS 747 (M+H).

Compound S3 (General Structure XXXII)

A solution of compound 26 (0.052g, 0.073 mmol) in CH ₂ Cl ₂ (3 mL) was treated with 2-quinolinethiol (0.174g, 1.08 mmol, 15.0 equivalents) followed by dimethylaluminum chloride (1.0M in hexanes; 0.60 mL, 0.600 mmol, 8.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a yellow oil which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol :NH ₄ OH) afforded S3 (0.017g, 29%) as a white foam. MS 784 (M+H).

Compound S4 (General Structure XXXII)

A solution of compound 26 (50 mg, 0.07 mmol) and thiophenol (0.03 mL, 0.28 mmol) in CH ₂ CI ₂ (1 mL) at 25 °C was treated with boron trifluoride diethyl etherate (0.1 mL, 0.78 mmol) via a syringe. After 1 h, the resulting mixture was treated with satd. aqueous NaHCO ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCO ₃ (2 x 10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded S4 (1.2 mg, 13%) as a colorless foam. MS 734 (M+H).

Compounds S5 through Sl 2

The same starting material (i.e., compound 26) as S4 was reacted with each of the respective thiols listed in Table K using the same procedure as compound S4 to prepare each of the compounds listed in Table K.

Table K

Table K continued

Compounds of General Structure XIXc and XXXIII

Compound 3Nl (General Structure XIXc) A solution of compound 26 (0.102g, 0.144 mmol) in CH ₂ Cl ₂ (3 mL) was treated with trimethylsilyl azide (0.94 mL, 7.08 mmol, 50.0 equivalents) followed by boron trifluoride diethyl etherate (0.32 mL, 2.53 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH2CI2 (5 mL) was added, the organic layer separated, dried (MgSO^), and concentrated in vacuo to afford 3Nl (0.102g, 100%) as a soft yellow foam. The material was used without further purification. MS 708 (M+H).

Compound 3N2 (General Structure XXXIII)

Compound 3Nl (0.104g, 0.147 mmol) was combined with methyl propiolate (0.13 mL, 14.6 mmol, 10.0 equivalents), dissolved in toluene (1 mL) and heated at reflux temperature for 4 hours. The reaction mixture was concentrated in vacuo to a yellow oil which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (98:1 :1

CH ₂ Cl ₂ :methanol:NH4OH) afforded a 1 :1 mixture of regioisomers 3N2 (0.032 g, 29%) as a white foam. MS 748 (M+H).

Compound 18 (3N3) (General Structure XXXIII) Step A

Compound 3Nl (0.102g, 0.144 mmol) was combined with 2-ethynylpyridine (0.060 g, 0.582 mmol, 4.0 equivalents), dissolved in toluene (1 mL) and heated at reflux temperature for 48 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Flash chromatography (96:3:1 CH ₂ Cl ₂ :methanol:NH4θH) afforded the desired compound (0.059 g, 50%) as an off-white white foam. MS 811 (M+H). Step B

The product obtained in step A (0.059g, 0.073 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography (98:1 :1 CH ₂ Cl2:methanol:NH4θH) afforded 3N3 (0.041 g, 73%) as a white foam. MS 769 (M+H).

3N4

Compound 3N4 (General Structure XXXIII)

Step A

Compound 3Nl (0.139g, 0.196 mmol) was combined with l-ethynyl-4-fluorobenzene (0.094g, 0.782 mmol, 4.0 equivalents), dissolved in toluene (1 mL) and heated at reflux temperature for 4 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography (97:2: 1 CH ₂ CI ₂ methanol :NH ₄ OH) afforded the desired compound (0.077g, 47%) as an off-white white foam. MS 828 (M+H).

Step B

The product from step A (0.077g, 0.093 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography (98:1 : 1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded 3N4 (0.050g, 70%) as a white foam. MS 786 (M+H).

Compound 19 (3N5) (General Structure XXXVIII)

A solution of compound 26 (50 mg, 0.07 mmol) and 1-phenyltetrazole (41 mg, 0.28 mmol) in CH ₂ Cl ₂ (1 mL) at 25 °C was treated with boron trifluoride diethyl etherate (0.1 mL, 0.78 mmol) via a syringe. After Ih, the resulting mixture was treated with satd. aqueous NaHCθ ₃ (1 mL), diluted with CH ₂ Cl ₂ (2 mL), washed with satd. aqueous NaHCU ₃ (2 x 10 mL), dried (MgSO.,), and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ C] ₂ :methanol:NH ₄ OH) afforded 3N5 (15 mg, 28%) as a colorless foam. MS 770 (M+H).

Compounds of General Structure XIXe. XIXg. XXXIV. XXXV. XXXVIII. and

XXXIX

C1

Compound Cl (General Structure XXXV)

Step A

A solution of compound 26 (0.05 Ig, 0.072 mmol) in CH2CI2 (3 mL) was treated with triethylsilane (0.16 mL, 1.29 mmol, 18.0 equivalents) followed by boron trifluoride diethyl etherate (0.40 mL, 2.52 mmol, 35.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound (0.037g, 77%) as a yellow foam. The material was used without further purification. MS 667 (M+H). Step B

The product obtained in Step A (0.037g, 0.055 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to give Cl (0.018g, 97%) as an off-white foam. MS 625 (M+H).

Compound 14 (C2) (General Structure XXXVIII)

Step A

Compound 23 (0.503g, 0.785 mmol) was dissolved in acetonitrile (10 mL) and treated with copper (I) iodide (0.015g, 0.079 mmol, 0.10 equivalents), triethylamine (0.44 mL, 3.16 mmol, 4.0 equivalents) and iodobenzene (0.26 mL, 2.32 mmol, 3.0 equivalents). The solution was degassed with nitrogen for 5 minutes, dichloro(bis)triphenylphosphine palladium(O) (0.028g, 0.040 mmol, 0.05 equivalents) was added. The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo and dissolved in CH ₂ Cl ₂ (25 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL), 0.5M aqueous sodium phosphate monobasic solution (25 mL), brine (25 mL), dried (MgSO ₄ ), and concentrated in vacuo

to a tan foam. Purification by flash chromatography (94:5:1 CH ₂ Cl ₂ methanol NH ₄ OH) afforded the desired compound (0.48g, 86%) as a yellow foam. MS 717 (M+H).

Step B

A solution of product from step A (0.48Og, 0.669 mmol) in absolute ethanol (10 mL) was treated with 10% palladium on activated charcoal (0.07 Ig, 0.067 mmol, 0.10 equivalents) and hydrogenated on a Parr apparatus under 50 psi of H ₂ for 18 hours. The reaction mixture was filtered through Celite, and concentrated in vacuo to afford the desired compound (0.37Og, 77%) as light yellow foam. The foam was used without further purification. MS 719 (M+H).

Step C

A solution of product from step B (0.37g, 0.515 mmol) in CH ₂ Cl ₂ (5 mL) was treated with triethylamine (0.09 mL, 0.646 mmol, 1.2 equivalents) and acetic anhydride (0.20 mL, 2.14 mmol, 4.0 equivalents), and stirred for 16 hours. The solution was diluted with CH ₂ CI ₂ (10 mL), treated with a 0.5M aqueous sodium phosphate monobasic solution (15 mL), saturated aqueous sodium bicarbonate solution (2x 10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound (0.359g, 92%) as a white foam. The foam was used without further purification. MS 761 (M+H).

Step D

A solution of the product of step C (0.359g, 0.472 mmol) in CH ₂ Cl ₂ (5 mL) was treated with Dess-Martin periodinane (0.24g, 0.566 mmol, 1.2 equivalents), and stirred for 3 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), treated with 10% aqueous sodium hydroxide solution (15 mL), washed with brine (10 mL) and concentrated in vacuo to afford the desired compound (0.350g, 98%) as a light yellow foam. The foam was used without further purification. MS 759 (M+H).

Step E

A solution of the product from step D (0.350g, 0.461 mmol) in THF (5 mL) was treated with CDI (0.300g, 1.85 mmol, 4.0 equivalents) and NaH (as a 60% dispersion in mineral oil, 0.074g, 1.85 mmol, 4.0 equivalents) at 0 °C, and stirred for 15 minutes. The reaction mixture was treated carefully with H ₂ O (5 mL) and diluted with EtOAc (10 mL). The organic phase was washed successively with H ₂ O (2x 10 mL) and saturated aqueous NH ₄ Gl (10 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compund (0.350g, 97%) as an off-white foam. The foam was used without further purification. MS 785 (M+H).

Step F

A solution of the product from step E (0.35Og, 0.446 mmol) in CH ₂ Cl ₂ (7 mL) was treated with triethylsilane (2.50 mL, 15.65 mmol, 35.0 equivalents) followed by boron trifluoride .diethyl etherate (1.02 mL, 8.05 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (25 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (15 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound (0.310g, 94%) as a yellow foam. The material was used without further purification. MS 743 (M+H).

Compound 14 (C2)

Step G

The product obtained in step E (0.310g, 0.417 mmol) was dissolved in methanol (10 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow foam. Flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded C2 (0.161g, 55%) as a white foam. MS 701 (M+H).

C3

Compound C3 (General Structure XXXIX)

Step A

A solution of compound 26 (0.05Og, 0.071 mmol) in CH ₂ Cl ₂ (3 mL) was treated with trimethylsilylacetylene (0.30 mL, 2.12 mmol, 30.0 equivalents) followed by boron trifluoride diethyl etherate (0.16 mL, 1.01 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened.

Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO^, and concentrated in vacuo to a light yellow oil. Purification by flash chromatography

(98:1 :1 CH ₂ Cl ₂ :methanol:NH4θH) afforded the desired compound (0.012g, 25%) as a white foam- MS 691 (M+H).

Step B

The product obtained in step A (0.012g, 0.017 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to afford C3 (0.01 Og, 89%) as a white foam. MS 649 (M+H).

C4

Compound C4 (General Structure XXXIX)

Step A

A solution of compound 26 (0.05 Ig, 0.072 mmol) in CH ₂ Cl ₂ (3 niL) was treated with phenylacetylene (0.24 mL, 2.53 mmol, 30.0 equivalents) followed by boron trifluoride diethyl etherate (0.16 mL, 1.01 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened.

Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow oil. Purification by flash chromatography

(98.5:0.5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded desired compound (O.OlOg, 19%) as a white foam. MS 767 (M+H).

Step B

The product obtained in step A (0.010g, 0.013 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a light yellow film. Purification by flash chromatography (98.5:0.5:1

CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded C4 (0.006g, 60%) as a white foam. MS 725

(M+H).

C5 Compound C5 (General Structure XXXVIH)

Step A

A solution of compound 26 (0.05Og, 0.071 mmol) in CH ₂ Cl ₂ (3 mL) was treated with N-methylindole (0.14 mL, 1.09 mmol, 15.0 equivalents) followed by dimethyl aluminum chloride (1.0M solution in hexanes; 0.56 mL, 0.560 mmol, 8.0 equivalents) dropwise at O°C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ CI ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow oil. Purification by flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded desired compound (0.032g, 57%) as a white foam. MS 796 (M+H).

Step B

The product obtained in step A (0.032g, 0.040 mmoiywas dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a light yellow oil. Purification by flash chromatography (98: 1 :1 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded C5 (0.015g, 49%) as a white foam. MS 754 (M+H).

C6

Compound C6 (General Structure XIXe) Step A A solution of compound 26 (0.235g, 0.331 mmol) in CH ₂ Cl ₂ (5 mL) was treated with 2,4-pentanedione (0.51 mL, 4.97 mmol, 15.0 equivalents) followed by boron trifluoride diethyl etherate (0.34 mL, 2.14 mmol, 8.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow oil. Purification by flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol !NH ₄ OH) afforded desired compound (0.188g, 74%) as a white foam. MS 765 (M+H). Step B The product obtained in step A (0.188g, 0.246 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to afford C6 (0.177g, 100%) as a white foam. MS 723 (M+H).

Compound C7 (General Structure XIXe)

A solution of 26 (0.05Og, 0.071 mmol) in CH ₂ Cl ₂ (3 mL) was treated with methylacetoacetate (0.11 mL, 1.02 mmol, 15.0 equivalents) followed by boron trifluoride diethyl etherate (0.07 mL, 0.552 mmol, 8.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to a light yellow oil which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol .NH ₄ OH) afforded C7 (0.027g, 53%) as a white foam. MS 739 (M+H).

Compound 15 (C8)

Compound 15 (C8) (General Structure XIXe) Step A

A solution of compound 26 (0.05 Ig, 0.072 mmol) in CH ₂ Cl ₂ (3 mL) was treated with benzoylacetone (0.175g, 1.08 mmol, 15.0 equivalents) followed by boron trifluoride diethyl etherate (0.07 mL, 0.552 mmol, 8.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened.

Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to yield an off-white foam. Purification by flash chromatography (98: 1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded the desired compound

(0.027g, 45%) as a white foam. MS 827 (M+H).

Step B

The product obtained in step A (0.027g, 0.032 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil. Purification by flash chromatography (98:1 :1 CH ₂ Cl ₂ methanol -.NH ₄ OH) afforded C8 (0.018g, 70%) as a white foam. MS 785 (M+H).

Compound C9 (General Structure XXXIV)

The product obtained in C6 (0.05 Ig, 0.067 mmol) was treated with hydrazine (0.02 mL, 0.61 mmol, 10.0 equivalents), dissolved in ethanol (2 mL) and heated at reflux temperature for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford C9 (0.035g, 73%) as an off-white foam. MS 719 (M+H).

Compound C10 (General Structure XXXIV)

The product obtained in C6 (0.050g, 0.065 mmol) was treated with phenylhydrazine (0.06 mL, 0.61 mmol, 10.0 equivalents), dissolved in ethanol (2 mL) and heated at reflux temperature for 2 hours. The reaction mixture was cooled to room temperature

and concentrated in vacuo to a yellow oil. Flash chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded ClO (0.026g, 50%) as a white foam. MS 795 (M+H).

Compounds CIl through C13

Compound C6 was reacted with each of the hydrazines listed in Table L using the same procedure to prepare ClO to yield each of the compounds listed in Table L.

Table L

Compound C14 (General Structure XIXe)

A solution of compound 26 (1.04 g, 1.46 mmol) in CH ₂ CI ₂ (5 mL) at 0 °C was treated with boron trifluoride diethyl etherate (1.11 mL, 8.76 mmol) via a syringe. After 5 min, allyltrimethylsilane (7 mL, 43.8 mmol) was added dropwise to the reaction mixture over 30 min and the reaction mixture was allowed to warm to 25 °C. After 10 min, additional boron trifluoride diethyl etherate (1.11 mL, 8.76 mmol) and trimethylsilane (7 mL, 43.8 mmol) was added via a syringe. The resulting mixture was allowed to stir for 20 min, quenched with satd. aqueous NaHCO ₃ (10 mL), diluted with CH ₂ Cl ₂ (50 mL), washed with satd. aqueous NaHCO ₃ (2 x 20 mL), dried (MgSO ₄ ), and concentrated 1« vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded C14 (0.280 g, 27%) as a colorless oil. MS 707 (M+H).

Compound C15 (General Structure XXXVII) A solution of compound C14 (50 mg, 0.07 mmol), 3-bromoquinoline (0.05 mL, 0.35 mmol), palladium acetate (1.5 mg, 0.007 mmol), tri-ør/Arø(tolyl)phosphine (4.2 mg, 0.014 mmol), and triethylamine (0.06 mL, 0.4 mmol) in degassed acetonitrile (1 mL)

was warmed to reflux temperature. After 12h, the resulting mixture was diluted with ethyl acetate (10 mL), washed with satd aqueous NH ₄ Cl (2 x 5 mL), dried (MgSO*) and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ methanol:NH ₄ OH) afforded C15 (5 mg, 10%) as a colorless foam. MS 793 (M+H).

Compounds C16 through C19

Compound C14 was reacted with each of the aryl halides listed in Table M using the same procedure as for compound CIS to prepare each of the compounds listed in Table M.

Table M

Compounds of General Structure XVII. XLIIL XLV. and LVI

Compound Xl (General Structure XVII) Step A A solution of compound 27 (500 mg., 0.56 mmol) in anhydrous THF (5 mL) was treated with a solution of methyllithium in diethyl ether (1.6mL, 2.24 mmol, 1.4 M Aldrich) over 5 minutes at 0 °C, allowed to warm to 25 °C, and stirred for Ih. The reaction mixture was treated with saturated aqueous NH4CI (1 mL), diluted with ethyl acetate (25 mL), washed with saturated aqueous NH ₄ Cl (2 x 2OmL), dried (MgSO ₄ ), and concentrated in vacuo to afford a white foam. The residue was diluted with THF (5 mL), treated with aqueous 2 N HCl (1 mL) and allowed to stir for 3h. The solution was diluted CH ₂ Cl ₂ (10 mL), washed with 1 N NaOH (2 x 5 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford a white foam. Purification by flash chromatography (92:8:0.5 CH ₂ Cl ₂ methanol NH ₄ OH ) afforded desired compound (181 mg., 78%) as a white foam. MS 631 (M +H).

X1

Step B

A solution of the product from step A (181 mg, 0.286 mmol) in CH ₂ Cl ₂ (3 mL) was treated with Ac ₂ O (0.81 mL, 0.86 mmol) and triethylamine (0.043 mL, 0.86 mmol) at 25°C. After 12h, the reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), treated with a 0.5M aqueous sodium phosphate monobasic solution (50 mL), saturated aqueous sodium bicarbonate solution (2x 50 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford the desired product as a white foam. The residue was diluted with CH ₂ Cl ₂ (5 mL) was treated with Dess-Martin periodinane (242 mg, 0.572 mmol), and stirred for 2 h. The reaction mixture was diluted with CH ₂ Cl ₂ (5 mL), treated with 10% aqueous sodium hydroxide solution (4 mL), washed with brine (25 mL) and concentrated in vacuo to afford an off-white foam. The residue was diluted with MeOH (2 mL), and was stirred for 12h. The reaction mixture was concentrated in vacuo and purification by flash chromatography (94:5:1 CH ₂ Cl ₂ methanol :NH ₄ OH) afforded Xl (71 mg) as white foam. MS 629 (M + H).

Compound X4 (General Structure XVII)

Step A

A solution of compound 27 (1.9Og., 2.14 mmol) was dissolved in THF (100 mL), cooled to 0 °C and treated with a 1.0M solution of allyl magnesium bromide in THF (11.0 mL, 1 1.0 mmol, 5.10 equivalents) over 5 minutes, allowed to warm to 25 °C, and stirred for 16 hours. The reaction mixture was treated with saturated aqueous NH ₄ Cl (50 mL), transferred to a separatory funnel, and the layers separated. The organic solution was washed again with saturated aqueous NH ₄ Cl, dried (MgSO ₄ ), and concentrated in vacuo to afford a mixture of products containing the 2'-acetate and the

2'-OH. The residue was resuspended in CH ₂ Cl ₂ (85 mL), treated with triethylamine (0.38 mL) and acetic anhydride (0.86 mL), and stirred for 16 hours. The reaction mixture was treated with 0.5M aqueous sodium phosphate monobasic solution (40 mL), diluted with CH ₂ Cl ₂ (50 mL), transferred to a separator/ funnel, and the layers separated. The organic phase was washed with saturated aqueous sodium bicarbonate solution (60 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the desired product (2.0Og., 100%) as a pale yellow foam. The foam was used without further purification. MS 929 (M+H).

Step B

A solution of the product from step A (2.00g., 2.15 mmol) in THF (100 mL) was treated with 20% aqueous HCl (10 mL) over 5 minutes. The reaction mixture was stirred for 5 hours, then treated slowly with concentrated NH ₄ OH (30 mL, or until pH > 10), diluted with EtOAc (25 mL) and stirred vigorously. The organic phase was collected, dried (MgSO ₄ ), and concentrated in vacuo to afford the des-cladinosyl macrolide (1.02g., 68%) as a light brown foam. The foam was used without further purification. MS 700 (M+H).

Step C .

A solution of the product from step B (1.02 g., 1.46 mmol) in CH ₂ Cl ₂ (12 mL) was treated with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.94 g., 10.12 mmol, 6.93 equivalents) and dimethyl sulfoxide (1.95 mL, 27.48 mmol, 18.82

equivalents) and cooled to 0 °C. A solution of pyridinium trifluoroacetate (1.94 g., 10.05 mmol, 6.89 equivalents) in CH ₂ Cl ₂ (10 mL) was added dropwise, the ice bath removed, and the reaction mixture stirred for 4 hours. The reaction mixture was treated with H ₂ O (50 mL), stirred vigorously and transferred to a separatory funnel. The organic layer was collected, washed with water (2 x 50 mL), saturated aqueous sodium bicarbonate solution (75 mL), brine (50 mL), dried (MgSO ₄ ), and concentrated in vacuo. Flash chromatography (SiO ₂ , 94:5:1 CH ₂ Cl ₂ :methanol NH ₄ OH) afforded the corresponding ketolide (0.55Og., 54%) as an off-white foam. MS 697 (M+H).

Step D

The product obtained in step C (107 mg, 0.153 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to afford X4 (100 mg, 100%) as a white foam. MS 655 (M+H).

Compound X5 (General Structure XVII)

Compound X4 (123 mg, 0.198 mmol) was dissolved in methanol (5 mL), 10% Pd/C (25 mg) was added, and the mixture was placed under a hydrogen atomosphere (50 psi) for 4 h. The reaction mixture was filtered through celite and concentrated in vacuo to afford a residue. Purification by flash chromatography (SiO ₂ , 94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded X5 (9.2 mg, 7%) as a white foam. MS 657 (M+H).

X6

Compound X6 (General Structure XVIl)

Step A

A solution of the product from step C of X4 (0.150g., 0.215 mmol) in DMF (5 mL) was treated with tri-ø-tolylphosphine (0.007g., 0.022 mmol, 0.10 equivalents), triethylamine (0.12 mL, 0.860 mmol, 4.0 equivalents) and iodobenzene (0.07 mL, 0.645 mmol, 3.0 equivalents). The solution was degassed, and palladium acetate (0.003 g., 0.011 mmol, 0.05 equivalents) was added. The reaction mixture was heated at 100 °C for 16 hours, cooled to room temperature and concentrated in vacuo. The residue was resuspended in CH ₂ CI ₂ (20 mL), washed with saturated aqueous sodium bicarbonate solution (25 mL), washed with 0.5M aqueous sodium phosphate monobasic solution (20 mL), dried (MgSO ₄ ), filtered, and concentrated in vacuo. Purification by flash chromatography (SiO ₂ , 94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded a residue (0.103g., 62%) as an off-white foam. MS 773 (M+H). Step B

The product of step A (0.103g., 0.133 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo. Flash chromatography (94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded X6 (0.046g., 47%) as a white foam. MS 741 (M+H).

Compound 2 (X7) (General Structure XVII) Step A

A solution of (3aS,4R,7R,8S,9S,10R,11R,13R,15R,15aR)-10-[[2-O-acetyl-3,4,6 - trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-8-[( 2,6-dideoxy-3-C- methyl-3-0-methyl-α-L-ribohexopyranosyl)oxy]-4-ethyldecahyd ro-1 1 -methoxy-

3a,7,9, 11 , 13 , 15-hexamethyl- 1 -(4-phenylbutyl)- 2H-oxacyclotetradecino[4,3-d]oxazole- 2,6,14(1 H,7H)-trione (prepared as decribed in WO 2003042228, 1.28 g., 1.26 mmol) in anhydrous THF (25 mL) was treated with a solution of methyllithium in diethyl ether (3.6mL, 5.04 mmol, 1.4 M Aldrich) over 5 minutes at 0 °C, allowed to warm to 25 °C, and stirred for Ih. The reaction mixture was treated with saturated aqueous NH ₄ CI (1 mL), diluted with ethyl acetate (25 mL), washed with saturated aqueous NH ₄ CI (2 x 2OmL), dried (MgSO ₄ ), and concentrated in vacuo to afford a white foam. The residue was diluted with THF (5 mL), treated with aqueous 2 N HCl (1 mL) and allowed to stir for 3h. The solution was diluted with CH ₂ Cl ₂ (10 mL), washed with 1 N NaOH (2 x 5 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford a white foam. Purification by flash chromatography (92:8:0.5 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded a residue (56 mg., 6.0 %) as a white foam. MS 763 (M +H). Step B A solution of the product from step A (56 mg, 0.07 mmol) in CH ₂ Cl ₂ (3 mL) was treated with Ac ₂ O (0.02 mL, 0.22 mmol) and triethylamine (0.01 mL, 0.073 mmol) at 25 °C. After 12h, the reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), treated with a 0.5M aqueous sodium phosphate monobasic solution (50 mL), saturated aqueous sodium bicarbonate solution (2x 50 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford the desired product as a white foam. The residue was diluted with CH ₂ Cl ₂ (5 mL), treated with Dess-Martin periodinane (242 mg, 0.572 mmol), and stirred for 2 h. The reaction mixture was diluted with CH ₂ Cl ₂ (5 mL), treated with 10% aqueous sodium hydroxide solution (4 mL), washed with brine (25 mL) and concentrated in vacuo to afford an off-white foam. The residue was diluted with MeOH (2 mL), and was stirred for 12h. The reaction mixture was concentrated in vacuo to afford a white

foam. Purification by flash chromatography (94:5:1 CH ₂ Cl ₂ methanol .NH ₄ OH) afforded X7 (11 9 mg) as a white foam. MS 762 (M + H).

X8

Compound X8 (General Structure LVI) Step A

The white foam obtained after methyllithium addition to compound 27 (see step A of synthesis procedure for Xl) (0.642g., 0.69 mmol), allyl-tert-butyl carbonate (0.16Og., 1.01 mmol, 1.5 equivalents) and triphenylphosphine (0.008g., 0.03 mmol, 0.05 equivalents) in degassed THF (5 mL) was treated with palladium acetate (0.008g., 0.03 mmol, 0.05 equivalents) and heated at reflux temperature for 16 hours. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo to afford a colorless foam. A solution of the residue in THF (5 mL) was treated with 20% aqueous HCl (5 mL). The reaction mixture was stirred for 1 hour, then treated slowly with NH ₄ OH (5 mL, or until pH > 10), and diluted with EtOAc (15 mL). The organic phase was collected, dried (MgSO ₄ ), and concentrated in vacuo to afford a yellow foam, which was used without further purification. This residue was dissolved in CH ₂ Cl ₂ (3 mL) was treated with triethylamine (0.04 mL, 0.299 mmol, 1.2 equivalents) and acetic anhydride (0.07 mL, 75.0 mmol, 3.0 equivalents), and stirred for 12 hours. The solution was diluted with CH ₂ Cl ₂ (10 mL), treated with a 0.5M aqueous sodium phosphate monobasic solution (10 ml.), saturated aqueous sodium bicarbonate solution (2x 10 ml.), dπed (MgSO ₄ ), and concentrated in vacuo. Purification by flash

chromatography (98:1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded the desired compound (0.140g., 79%) as a colorless foam. MS 713 (M+H).

Step B

A solution of the product from step A 0.14Og., 0.196 mmol) in CH ₂ Cl ₂ (5 mL) was treated with Dess-Martin periodinane (0.092g., 0.205 mmol, 1.1 equivalents), and stirred for 16 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), treated with 10% aqueous sodium hydroxide solution (15 mL), washed with brine (25 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford the desired compound (0.125g., 90%) as a white foam. The foam was used without further purification. MS 711 (M+H). Step C

A solution of the product of step B (0.063g., 0.089 mmol), tri-o-tolylphosphine (0.003g., 0.009 mmol, 0.10 equivalents), triethylamine (0.05 mL, 0.035 mmol, 4.0 equivalents) and 3-bromoquinoline (0.04 mL, 0.027 mmol, 3.0 equivalents) in degassed DMF (3 mL) was treated with palladium acetate (0.001 g., 0.005 mmol, 0.05 equivalents) and heated at 100 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was resuspended in CH ₂ Cl ₂ (10 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), washed with 0.5M aqueous sodium phosphate monobasic solution (10 mL), dried (MgSO ₄ ), filtered, and concentrated in vacuo. Flash chromatography (98: 1 :1 CH ₂ Cl ₂ :methanol:NH ₄ OH) gave an off-white foam which was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (98: 1 : 1 CH ₂ Cl2:methanol:NH ₄ OH) afforded X8 (0.044g., 62%) as a white foam. MS 798 (M+H).

Compound X9 (General Structure XLIII)

Step A

The white foam obtained after methyllithium addition to compound 27 (see step A of synthesis procedure for Xl) (250 mg, 0.322 mmol), the bis-tert-butyl ester of 2-butene- 1,4-diylcarbonic acid (185 mg, 0.644 mmol), and dppb (2.6 mg, 0.006 mmol) in THF (2 mL) was treated with Pd ₂ (dba) ₃ (2.9 mg, 0.003 mmol) at 25°C under nitrogen. The resulting mixture was warmed to reflux temperature and allowed to stir for 1 h. The reaction mixture was allowed to cool to 25°C, treated with 10 % aqueous HCl (1 mL) and allowed to stir for 2 h. The reaction mixture was neutralized by the addition of aqueous NH ₄ OH (1.5 mL) until the pH ~ 8, diluted with CH ₂ Cl ₂ (50 mL), washed with brine (2 x 25 mL), dried (MgSO ₄ ), and concentrated in vacuo to afford a reisdue. Purification by flash chromatography (94:5:1 CH ₂ Cl ₂ methanol NH ₄ OH) afforded the desired compound (458 mg) as white foam. MS 683 (M + H). Step B A solution of the product of step A (302 mg, 0.44 mmol) in acetone (3 mL) was treated with Ac ₂ O (0.06 mL, 0.66 mmol) and potassium carbonate (77 mg, 0.56 mmol) at 25 °C. After 24 h, the reaction mixture was diluted with CH ₂ Cl ₂ (10 mL), treated with a 0.5 M aqueous sodium phosphate monobasic solution (20 mL), saturated aqueous sodium bicarbonate solution (2x 50 mL), dried (MgSO ₄ ), and concentrated in vacuo to affordthe 2-acetyl derivative as a white foam. The residue was diluted with CH ₂ Cl ₂ (5 mL) was treated with Dess-Martin periodinane (353 mg, 0.833 mmol), and stirred for 2 h. The reaction mixture was diluted with CH ₂ Cl ₂ (5 mL), treated with 10% aqueous sodium hydroxide solution (4 mL), washed with brine (25 mL) and concentrated in vacuo to afford an off-white foam. The residue was diluted with MeOH (2 mL), and was stirred for 12h. The reaction mixture was concentrated in vacuo to afford a white foam. Purification by flash chromatography (94:5:1 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded X9 (77.1 mg) as white foam. MS 681 (M + H).

X10

Compound 3 (XlO) (General Structure XLV)

A solution of the off-white foam from Dess-Martin periodinane oxidation in step B of the synthesis procedure for X9 (50 mg, 0.07 mmol), iodobenzene (0.23 mL, 0.21 mmol), palladium acetate (1.5 mg, 0.007 mmol), tri-orthotolylphosphine (4.2 mg, 0.014 mmol), and triethylamine (0.06 mL, 0.4 mmol) in degassed acetonitrile (1 mL) was warmed to reflux temperature. After 12h, the resulting mixture was diluted with ethyl acetate (10 mL), washed with satd aqueous NH ₄ Cl (2 x 5 mL), dried (MgSO ₄ ) and concentrated in vacuo to afford a residue. The resulting residue was dissolved in methanol (1 mL), allowed to stir for 12h, and concentrated in vacuo to afford a residue. Purification by flash chromatography (95:5:0.5 CH ₂ Cl ₂ :methanol:NH ₄ OH) afforded XlO (3 mg) as a colorless foam. MS 757 (M+H).

Preparation of NO (General Structure XLVIl)

Step A

Aldehyde 29 was treated with aqueous hydroxylamine at 60°C for 1 h. The solvent was removed in vacuo and the resulting foam was used without further purification. Step B

The oxime from step A and 10% palladium on carbon was placed under a hydrogen atmosphere in a Parr hydrogenator at 25°C for 1 h. The catalyst was removed by filtration and the reaction mixture was concentrated in vacuo.

Compounds of General Structure XXXIc

Compound 13 (NCNl) (General Structure XXXIc)

A solution of NO (40.0 mg, 0.06 mmol) in anhydrous THF (1.0 ml.) was treated with CDl (12.0 mg, 0.07 mmol) at ambient temperature, and then stirred for 1 hour. The reaction mixture was treated with 4-(pyridin-3-yl)benzylamine (60.0 mg, 0.4 mmol), and TEA (20 mg, 0.2 mmol). The reaction mixture was heated to (55°C) and stirred for 24 hours. The organic solution was concentrated in vacuo, methanol (20 ml.) added to the residue, and the solution stirred over night. Reverse phase semi-prep chromatography (Column, Luna, 5 micron Cl 8, 100 X 50 mm), conditions (ACN/H2O, 50 ml/min., gradient 10% ACN to 75%, 25 minutes), afforded compound 13 (10 mg -20%) as a white solid after lyophilization. MS 850 (M+H).

Compounds NCN2 through NCN8

The same starting material (i.e., compound NO) as used in NCNl was reacted with each of the respective amines listed in Table N using the same procedure as compound NCNl to prepare each of the compounds listed in Table N.

Table N

Table N continued

Compounds of General Structure XXXId

Compound NCO1 (General Structure XXXId)

Step A A solution of compound 26 (0.099g, 0.140 mmol) in CH ₂ Cl ₂ (3 mL) was treated with benzyl carbamate (0.530g, 3.51 mmol, 25.0 equivalents) followed by boron trifluoride diethyl etherate (0.32 mL, 2.01 mmol, 18.0 equivalents) dropwise at 0 °C and stirred for 16 hours. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound as a yellow oil. Purification by flash chromatography (97:2:1 CH ₂ Cl ₂ :methanol NH ₄ OH) afforded the desired product (0.046g, 40%) as a white foam. MS 816 (M+H).

Step B The product obtained in step A (0.046g, 0.056 mmol) was dissolved in methanol (5 mL) and stirred for 16 hours. The reaction mixture was concentrated in vacuo to give NCOl (0.039g, 90%) as white foam. MS 774 (M+H). Alternative Preparation of Compound NCOl (General Structure XXXId)

A solution of 29 (100 mg, 0.147 mmol), benzyl carbamate (89 mg, 0.587 mmol), and triethylsilane (0.1 mL, 0.587 mmol) in acetonitrile (1 mL) was treated with trifluoroacetic acid (0.1 mL, 0.587 mmol) and stirred for 16 hours at room temparture. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution (10 mL) and stirred vigorously until the color lightened. Additional CH ₂ Cl ₂ (5 mL) was added, the organic layer separated, dried (MgSO ₄ ), and concentrated in vacuo to afford the desired compound as a yellow oil. The residue was dissolved in methanol and stirred for 16 h. Purification by flash chromatography (97:2:1 CH ₂ Cl ₂ :methanol:NH4θH) afforded the desired product (98 mg, 82%) as a white foam. MS 816 (M+H).

Compound NCO2 (General Structure XXXId)

A solution of NO (50.0 mg, 0.08 mmol) in anhydrous THF (1.0 ml.) was treated with CDI (15.0 mg, 0.09 mmol) at ambient temperature, and then stirred for 1 hour. The reaction mixture was then cooled to 0°C and treated with 4-(thiazol-2-yl)benzyl alcohol (70.0 mg, 0.4 mmol), and potassium tert-butoxide (0.2 mmol). The reaction mixture was warmed to ambient temperature and stirred for 24 hours. The organic solution was concentrated in vacuo. Purification by reverse phase semi-prep chromatography (Column, Luna, 5 micron Cl 8, 100 X 50 mm), conditions (acetonitrile/H20, 50 ml/min., gradient 10% acetonitrile to 75%, 25 minutes), afforded NCO2 (10 mg -15%) as a white solid after lyophilization. MS = 858 (M + H).

Compounds NCO3 through NCO6

The same starting material (i.e., compound NO) as NCO2 was reacted with each of the respective alcohols listed in Table O using the same procedure as compound NCO2 to prepare each of the compounds listed in Table O.

Table O

Sidechain Preparation

Compounds of General Structure LXI

Compound Zl (General Structure LXI)

Step A

A mixture of N-(2-bromoethyl)phthalimide (1.Og., 3.93 mmol) and 4-phenylimidazole (0.57g., 3.95 mmol) in DMF (20 mL) was treated with NaH (60% dispersion in mineral oil, 0.16g., 3.94 mmol) and stirred at 25 °C for 16 hours. The mixture was poured over a slurry of water and ice ( 100 mL). The resulting white precipitate was collected by filtration. The solid was recrystallized from methanol-water to afford desired compound (0.97g., 78%) as a white solid. MS = 318 (M + H).

Step B

A mixture of product from step A (970 mg, 3.06 mmol) in EtOH (30 mL) was treated with hydrazine (300 mg, 9.38 mmol) and warmed to reflux temperature for 4 hours. After cooling to room temperature, the solid precipitate was removed by filtration and the filtrate was concentrated in vacuo to afford a white residue. This residue was rinsed with CH ₂ Cl ₂ (4 x 15 mL), and the rinses concentrated in vacuo to afford Zl (0.37g., 65%) as an oil. The oil was used without further purification. MS = 188 (M + H).

Compounds Z2 through Z6

N-(2-Bromoethyl)phthalimide as Zl was reacted with each of the nucleophiles listed in Table P using the same procedure as compound Zl to prepare each of the respective compounds listed in Table P. In addition, the number of the inventive compounds derived from each of these reagents is listed in Table P.

Table P

Compounds Z7 through ZIl were prepared by the same procedure as for Zl except that N-(4-bromobutyl)phthalimide was used instead of N-(2-bromoethyl)phthalimide. The compounds are illustrated in Table Q. In addition, the number of the inventive compounds derived from each of these reagents is listed in Table Q.

Table Q

Compound LXVI

Step A

A l-L 4-neck round bottom flask was equipped with a thermocouple controller, an overhead mechanical agitator, a pressure-equalization dropping funnel, a condenser and nitrogen inlet/outlet adapter. This vessel was charged with 3-acetylpyridine LVII (99%, 18.0 g, 0.149 mol, Aldrich) and a solution of hydrogen bromide (HBr, 200 mL, 30% in acetic acid) at 10 °C. The thick slurry was cooled to 0 °C, bromine (Br ₂ , 25.84 g 0.162 mol) was added drop-wise over a 30-min period. After the addition, the mixture was warmed to 40 °C for 1.5 h and then 58 °C for 1 h. The reaction was cooled to 0 °C, and diluted with Et ₂ O (400 mL). The solids was filtered off and washed with Et ₂ O (80 mL x 3). The resulting crude compound was boiled in a solution of MeOH/Et ₂ θ (300 mL/400 mL), and the solid was filtered and dried under house vacuum (200 mmHg) at 20 °C for 16 h, there was obtained 39.4 g (94% yield) of 3- (bromoacetyl) pyridine hydrogen bromide LXIII salt. This material was used in the next step without further purification.

Step B

A 1-L 3-neck RBF was equipped with a thermocouple controller, a magnetic stirbar, a condenser, and nitrogen inlet/outlet adapter. This vessel was charged with bromide salt LXIII (37.0 g, 0.132 mol) and formamide (47.4 g, 1.053 mol) at 20 °C. The mixture was heated to 160 °C and stirred for 2 h. The reaction was cooled to 80 °C, it was poured into a solution of 37% HCl (15.0 mL) in acetone (1000 mL) at 0°C and agitated vigorously for 10 min. The acetone phase was decanted, and the resulting brown semi¬ solid was boiled in EtOH (600 mL) at 82°C while the solution was adjusted to pH = 9 with the addition Of NaHCO ₃ . The solvent was removed in vacuo to give 52.2 g of crude material, that was purified by chromatography to afford 8.58 g (46% yield) of 4-

(5)-(3-pyridyl)imidazole LXIV as a free base. This free base was dissolved in EtOH (60 mL) and stirred at 0°C under nitrogen, followed by the addition of 37%HC1 (11.6 mL) dropwise over 10 min. The salt was filtered off, washed with Et ₂ O (20 mL), and then dried in an oven at 6O°C under vacuum (10 mmHg) for 2 h, there was obtained 8.68 g of 4-(5)-(3-pyridyl)imidazole dihydrogen chloride LXIV as a yellowish solid. Step C

A l-L 3-neck RBF was equipped with a thermocouple controller, a magnetic stirbar, and nitrogen inlet/outlet adapter. This vessel was charged with sodium hydride (NaH, 60%, 5.34 g, 0.134 mol) and anhydrous DMF (100 mL), and the suspension was stirred under nitrogen and cooled to 0 °C. 4-(5)-(3-Pyridyl)imidazole dihydrogen chloride LXIV (8.82 g, 0.04 mol) was added as one portion, followed by the addition of a solution of N-(4-bromobutyl)phthalimide (96%, 1 1.89 g, 0.04 mol, Lancaster) in anhydrous DMF (100 mL) over 10 min. The reaction was warmed to 20 °C and agitated for 18 h. The reaction was cooled to 0 °C, and quenched by dropwise addition of HOAc (10.6 mL, 0.178 mol). The mixture was poured into sat. NaHCO ₃ solution (1.5 L) with vigorously agitation at 10 °C for 10 min and the solid was filtered off, there was collected 38.8 g of crude compound LXV (contains some NaHCO ₃ ). This material was used in the next step without further purification. Step D A l-L 3-neck RBF was equipped with a thermocouple controller, a magnetic stirbar, a dropping funnel, a condenser, and nitrogen inlet/outlet adapter. This vessel was charged with the above crude phthalimide LXV (38.8 g, 0.1 12 mol), EtOH (220 mL) and hydrazine monohydrate (98%, 5.89 g, 0.1 18 mol). The mixture was heated to reflux temperature (at 82 °C) for 3 h. The reaction was cooled to 20 °C and the solid was filtered off, and the cake was washed with EtOH (400 mL). The combined filtrate was condensed in vacuo to give 1 1.8 g of the crude product. This crude was re- dissolved in CH ₂ Cl ₂ (600 mL) and the insoluble material was filtered off, and the filtrate was condensed in vacuo again to afford 5.74 g (66% yield over two steps) of the desired amine LXVI as a yellow oil. This material was used in the next step without further purification.

Compound Zl 2 was prepared by the same procedure as for Zl except that N-(6- bromohexyl)phthalimide was used instead of N-(2-bromoethyl)phthalimide (Table R).

Table R

Compounds Z13 and Z14 were prepared by the same procedure as for Zl except that N-(4-bromobut-2-enyl)phthalimide (Hlasta, D. et. al WO0232918) was used instead of N-(2-bromoethyl)phthalimide. The compounds are illustrated in Table S.

Table S

Compounds of General Structure LXXII

ZHAM Compound ZHAr1(General Structure LXXII)

Step A

A solution of N-(3-buten-l-yl)phthalimide (500 mg, 2.48 mmol) and iodobenzene (571 mg, 2.8 mmol) in degassed acetonitrile (50 mL) was treated with tή-ortho- tolylphosphine (73 mg, 0.24 mmol), triethylamine (0.7 mL, 5 mmol) and palladium acetate (28 mg, 0.12 mmol). The resulting mixture was warmed to reflux temperature. After 14 h, the reaction mxiture was allowed to cool to room temperature, diluted with ethyl acetate (25 mL), washed with satd. aqueous KHPO4 (25 mL), and the organic layer separated and dried (MgSO ₄ ). The reaction mixture was filtered and concentrated in vacuo and purification by flash chromatography (0-25% hexanes / ethyl acetate) afforded the desired compound (359 mg, 52 %) as a white solid. MS = 278 (M + H). Step B

A mixture of the product from step A (359 mg, 1.29 mmol) in EtOH (30 mL) was treated with hydrazine (206 mg, 6.4 mmol) and warmed to reflux temperature for 4 hours. After cooling to room temperature, the solid precipitate was removed by filtration and the filtrate was concentrated in vacuo to afford a white residue. This residue was rinsed with CH ₂ Cl ₂ (4x 15 mL), and the rinses' concentrated in vacuo to afford ZHArI (150 mg, 78%) as a brown oil. The oil was used without further purification. MS = 148 (M + H).

Compounds ZHAr2 through ZHAr11

The N-(3-buten-l -yl)phthalimide used in the preparation of ZHAr1 was reacted with each of the aryl halides listed in Table T using the same procedure as for compound ZHArI to prepare each of the respective compounds listed in Table T. In addition, the

number of the inventive compounds derived from each of these reagents is listed in Table T.

Table T

Table T continued

Compounds of General Structure LXXIII, LXXV, and LXXIX

Compound ZAr1 (General Structure LXXIII. n is 1) A solution of 4-bromobenzylamine (40.Og, 217.0 mmol) in THF (150 ml.) was treated with di-tert-butyl dicarbonate (46.Og, 217 mmol) at ambient temperature, and then stirred for Ih. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (80:20 Hexanes: ethyl acetate) afforded ZArI (63.0 g, 95%) as a white solid. MS = 287 (M+H).

Compound ZAr2 (General Structure LXXIX)

A solution of compound ZArI (30.0g, 98.0 mmol) in DMSO (100 ml.) was treated with bis(pinacolato)diboron (30.Og, 1 18 mmol), KOAc (30.Og, 306 mmol), and PdCl ₂ (dppf) (0.2 mmol) and was warmed to 85°C for 12h. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2 x 150 mL) and brine (100 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (80:20 hexanes: ethyl acetate) afforded ZAr2 (31.0 g, 97%) as a white solid. MS = 334 (M+H).

Compound ZAr3 (General Structure LXXV)

Step A A solution of compound ZAr2 (1.50g, 5.0 mmol) in toluene (15 ml.) and EtOH (10ml) was treated with 4-bromopyridine (0.5g, 2.5 mmol), 2M aqueous K2CO ₃ (10 ml), and Pd(PPh ₃ ) ₄ ( 0.2 mmol) and the reaction mixture was warmed to 85°C overnight. The organic solution was diluted with ethyl acetate (250 mL) and washed (2x) with water (150 mL) and brine (100 mL). The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (80:20 hexanes: ethyl acetate) afforded the desired compound (0.8 g, 56%) as a white solid. MS = 285 (M+H).

Step B

The product of step A (350mg) is diluted in 30ml DCM, and 10ml TFA, stirred for lhour. The solvent and acid is removed under reduced pressure. The crude amine TFA salt is diluted with 30 ml methanol and neutralized with 50% NaOH (1mI).

Methanol/water is removed under reduced pressure to give the crude amine product ZAr3 (350mg). The product was used without further purification. MS 184 (M+H).

Compounds ZAr4 through ZAr13 Compound ZAr2 used in the preparation of ZAr3 was reacted with each of the aryl halides listed in Table U using the same procedure as for compound ZAr3 to prepare each of the respective compounds listed in Table U. In addition, the number of the inventive compounds derived from each of these reagents is listed in Table U.

Table U

Table U continued

Compound ZAr14 (General Structure LXXIII, n is 2)

A solution of 4-bromophenethylamine (9.0g, 45.0 mmol) in THF (100 ml.) was treated with di-tert-butyl dicarbonate (10.8g, 50 mmol) at ambient temperature, and then stirred for 1 hour. The reaction mixture was concentrated in vacuo. Purification by flash chromatography (80:20 hexanes: ethyl acetate) afforded ZArl4 (13.5 g, 100%) as a white solid. MS = 301 (M + H).

Compound ZAr15 (General Structure LXXIX)

A solution of ZAr 14 (5.0g, 17.0 mmol) in DMSO (50 ml.) was treated with bis(pinacolato)diboron (5.0g, 20 mmol), KOAc (5.0g, 51 mmol), and PdCl ₂ (dppf) (0.2 mmol) and the reaction mixture was warmed to 85°C overnight. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2 xl 50 mL) and brine (100 mL). The organic layer was dried (NaSO _{4 )} and concentrated in vacuo. Purification by flash chromatography (80:20 Hexanes: ethyl acetate) afforded ZArIS (5.0 g, 86%) as a white solid. MS=348 (M+H).

Compound ZAr16 (General Structure LXXV)

Step A

A solution of ZArl5 (1.50g, 5.0 mmol) in toluene (15 ml.) and EtOH (10ml) was treated with 2-bromothiazole (0.5g, 2.5 mmol), 2M K ₂ CO ₃ (10 ml), and Pd(PPh ₃ ) ₄ (0.2 mmol) at 85°C overnight. The organic solution was diluted with ethyl acetate (250 mL) and washed with water (2 x 150 mL) and brine (100 mL). The resulting mixture was

dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by flash chromatography (80:20 hexanes: ethyl acetate) afforded the desired compound (1.2g, 90%) as a white solid. MS = 305 (M+H). Step B A solution of the product of step A (350mg), diluted in 30ml DCM and 10ml TFA, was stirred for Ih. The solvent and acid was removed under reduced pressure. The crude amine TFA salt is diluted with 30 ml methanol and neutralized with 50% NaOH (ImI). Methanol/water is removed under reduced pressure to give the crude amine product ZAr16 (350mg). The product was used without further purification. MS 205 (M+H).

Compounds ZAr17 through ZAr22

Compound ZAr15 used in the preparation of ZAr16 was reacted with each of the aryl halides listed in Table V using the same procedure as for compound ZAr16 to prepare each of the respective compounds listed in Table V. In addition, the number of the inventive compounds derived from each of these reagents is listed in Table V.

Table V

The invention has been described in detail with particular reference to the above embodiments thereof. The above embodiments and examples are given to illustrate the scope and spirit of the present invention. These embodiments and examples will make apparent, to those skilled in the art, other embodiments and examples. These other embodiments and examples are within the contemplation of the present invention. It will be understood that variations and modifications can be effected within the spirit and scope of the invention; therefore, the instant invention should be limited only by the appended claims.