CA2301642A1

CA2301642A1 - 3-descladinose 6-o-substituded erythromycin derivatives

Info

Publication number: CA2301642A1
Application number: CA002301642A
Authority: CA
Inventors: Yat Sun Or; Leping Li; Michael J. Rupp; Daniel T. Chu
Original assignee: Individual
Current assignee: Abbott Laboratories
Priority date: 1997-09-02
Filing date: 1998-09-01
Publication date: 1999-03-11
Also published as: EP1027360A2; JP2001515844A; ZA987689B; AR017260A1; WO1999011651A2; AU8925398A; WO1999011651A3; SA99191151A; CO4960636A1

Abstract

Novel multicyclic erythromycin compounds and pharmaceutically acceptable salts and esters thereof having antibacterial activity having a formula selected from the group consisting of (I), (II), (III), (IV) and (V), compositions comprising a therapeutically eff ective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, as well as a method for treating bacterial infections by administering to a mammal a pharmaceutical composition containing a therapeutically effective amount of a compound of formulas (I)-(V).

Description

3-DESCLADINOSE 6-O-SUBST1TC1'i'Fp ERYTHRQMYCIN DERIVATIVES
Technical Field This invention relates to novel semi-synthetic macrolides having antibacterial activity, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, the invention relates to 3- descladinose 6-O-substituted erythromycin derivatives and methods for preparing them, compositions containing these compounds, and a method of treating bacterial infections with such compositions.
Background of the Invention Erythromycins A through D, represented by formula (E), NMez O
HO.,,~

OH
CH3 .
,,~~ CH3 Ho.",, Erythromycin Ra Rb ~",..
o o cH3 Ra A -OH -CH3 H H
H
C

~ CH3 o........ C _OH -H

cH3 cH3 H

., D -H -H
OH
,I

I~ORb O

(E) are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms.
Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to _ obtain analogs having modified or improved profiles of antibiotic activity.
Morimoto et al. describes the preparation of 6-O-methyl erythromycin A in J.
Antibiotics 37:187 ( 1984). Morimoto et al. further discloses 6-O-alkyl erythromycin A
derivatives in J. Antibiotics, 43: 286 ( 1990) and in European Patent Application 272,110, published June 22, 1988. European Patent Application 215,355, published March 28, 1987, discloses 6-O-loweralkyl erythromycins as stimulants of gastrointestinal contractile motion.

United States Patent 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A
derivatives in which the substituents are selected from alkyl, -CONH2, -CONHC(O)alkyl and -CONHS02alkyl. PCT application WO 97/10251, published March 20, 1997, discloses methyl 3-descladinose erythromycin derivatives, and PCT application WO
97/17356, published May 15, 1997, discloses 3-deoxy-3-descladinose erythromycin derivatives. . PCT
application WO 92/09614, published June 11, 1992, discloses tricyclic 6-O-methyl erythromycin A
derivatives. Certain intermediates to the present invention are disclosed in U.S. Patent Application Serial Number 08/888,350.
European Patent Application 596802, published May 1 l, 1994, discloses bicyclic 6-O-lU methyl-3-oxo erythromycin A derivatives.
U. S. Patent 5.523,399, published June 4, 1996 discloses 6-O-methyl 3-descladinose 3-O-carbamoyl erythromycin derivatives.
Summary of the Invention.
I S The present invention provides a novel class of 3-descladinose 6-O-substituted erythromycin derivatives which possess antibacterial activity.
In one aspect of the present invention are compounds, or pharmaceutically acceptable salts and esters thereof, having a formula selected from the group consisting of R R
I
.O O'~~.
~~.
20 (I) O
R RP NMe2 Rw O I I
0,,, \ W\ ,,~,. ~~O
~~u n ~~ U' (II), o N R Rp NMe2 I
O'~~.
i~... .~O
wn r, II u' (III), o RQ NMe2 I
'~~.
(IV), O
and RP NMe2 I
O'~..
O_ (V), O
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y and Z taken together define a group X, wherein X is selected from the group consisting of (1) =O, (2) =N-OH, (3) =N-O-R1 where R1 is selected from the group consisting of (a) unsubstituted C 1-C 12-alkyl, (b) Cl-C12-alkyl substituted with aryl, (c) C1-C12-alkyl substituted with substituted aryl, (d) C1-Ct2-alkyl substituted with heteroaryl, (e) Cl-C12-alkyl substituted with substituted heteroaryl, (i~ C3-C12-cycloalkyl, and (g) -Si-(R2)(R3)(R4) wherein R2, R3 and R4 are each independently selected from Cl-C12-alkyl and aryl;
and (4) =N-O-C(R5)(R6)-O-R1 where R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of (a) hydrogen, (b) unsubstituted C1-C12-alkyl, (c) C1-C12-alkyl substituted with aryl, (d) C~-C12-alkyl substituted with substituted aryl, (e) C~-C12-alkyl substituted with heteroaryl, and (f) C~-C12-alkyl substituted with substituted heteroaryl, or R5 and R6 taken together with the atom to which they are attached form a C3-C12-cYcloallcyl ring;
or, one of Y and Z is hydrogen and the other is selected from a group consisting of (1) hydrogen, {2) hydroxy, (3) protected hydroxy, and (4) NR~Rg wherein R~ and Rg are independently selected from hydrogen and C1-C6-alkyl, or R~ and Rg are taken with the nitrogen atom to which they are connected to form a 3- to ?-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C~-C6-alkyl-)-, -N(substituted-heteroaryl-C1-Cb-alkyl-)-, and -S-or -S(O)"-, wherein n is 1 or 2, W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH-and -NH-;
RW is selected from the group consisting of ( 1 ) hydrogen, (2) Cl-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) C1-C6-alkoxy, (g) NR~Rg, wherein R~ and Rg are as defined previously, and (h) -CH2-M-R9, 10wherein M
is selected from the group consisting of:

(i) -C{O)-NH-, (ii) -NH-C(O)-, (iii) -NH-, (iv) -N=, 15(v) -N(CH3)-, (vi) -NH-C{O)-O-(vii) -NH-C(O)-NH-(viii)-O-C(O)-NH-(ix) -O-C(O)-O-20(x) -O-, (xi) -S(O)n-, wherein n is 0, 1 or 2, {Xll) {X111)-O-C(O)-, and 25(xiv) -C(O)-, and is selected from the group consisting of:

(i) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of 30(aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, 35(iii) substituted-aryl, (iv) heteroaryl, (v) substituted-heteroaryl, and (vi) heterocycloalkyl, (3) C3-C7-cycloalkyl, (4) aryl, (5) substituted-aryl, (6) heteroaryl, and {7) substituted-heteroaryl;
RP is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of ( 1 ) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) (c) -C02R10 wherein RIO is CI-C3-alkyl or aryl substituted Ci-C3-alkyl, or heteroaryi substituted Ci-C3-alkyl, (d) S(O)"RIO where n is 0, 1 or 2 and RIO is as previously defined, (e) NHC(O)R I O where R 10 is as previously defined, (f) NHC(O)NR I I R 12 wherein R I I and R 12 are independently selected from hydrogen, Ci-C3-alkyl, CI-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-Cip-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) Ci-C3-alkoxy, {d) CI-C3-alkoxy-CI-C3-alkoxy, (e) oxo, -N3, (g) -CHO, (h) O-S02-(substituted Ci-C6-alkyl), (i) -NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (u) C 1-C 12-alkyl, (iii) substituted C 1-C 12-alkyl, (lv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted Cl-C12-alkynyl, (viii) aryl, (ix) C3-Cg-cycloalkyl, (x) substituted C3-Cg-cycloalkyl, (xi) substituted aryl, (xii) heterocycloallcyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, 1S (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) CI-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-Cg-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-Cg-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-Ct2-alkyl substituted with heteroarvl_ and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1_C3_alkYl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -C02R10 wherein R10 is as previously defined, WO 99/11651 PCTlUS98/18125 (k) -C(O)NRIIR12 wherein RI1 and R12 are as previously defined, (1) =N-O-R10 wherein R10 is as previously defined, (m) -C-N, (n) O-S(O)~R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-Cg-cycloalkyl, (t) substituted C3-Cg-cycloalkyl, (u) CI-Ci2-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)~i i R 12 wherein R 11 and R 12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NRI IR12 wherein Ri i and R12 are as previously defined;

(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -C02R 10 where R 10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR i i R 12 wherein R i i and R 12 are as previously defined, (fj _C=_N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C~-cycloalkyl, and (1) CI-C12-alkyl substituted with heteroaryl, (4) C4-Ci p-alkenyl;

(5) C-Ci p-alkenyl substituted with one or more substituents selected from the group consisting of _g_ (a) halogen, (b) Ct-C3-alkoxy, (c) oxo, (d) -CHO, (e) -C02R10 where Rt0 is as previously defined, (fj -C(O)NRtiRl2 wherein Rlt and Rt2 are as previously defined, (g) _~13R14 wherein Rt3 and Rt4 are as previously defined, (h) =N-O-R10 where Rt0 is as previously defined, (i) -C=_N, (j) O-S(O)nRtO where n is 0, 1 or 2 and Rt0 is as previously defined, (k) aryl, (1) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C~-cycloalkyl, (P) Ct-C12-a>kyl substituted with heteroaryl, (q) NHC(O)Rt0 where Rt0 is as previously defined, (r) NHC(O)NR t t R 12 wherein R t t and R t 2 are as previously defined, (s) =N-NRt3R14 wherein Rt3 and Rt4 are as previously defined, (t) =N-R9 wherein R'~ is as previously defined, (u) =N-NHC(O)Rt0 where Rt0 is as previously defined, and (v) =N-NHC(O)NRt iRl2 wherein Rt t and Rt2 are as previously defined;
(6) C3-C10-~YnYh and C3-C10-~Y~'~yl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) ~yl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
U is selected from the group consisting of:
(1) hydrogen, (2) hydroxy, (3) protected hydroxy, (4) -O-T-Rt, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, s (d) -C(S)-S-, (e) -C(O)-N(RS)-, wherein RS is H or C1-C6-alkyl, (f) -S(O)S-, wherein n is 0, 1 or 2, (g) -S(O)"-O-, wherein n is 0, 1 or 2, (h) -P(O)(ORr)~-, wherein n is 0, 1 or 2, and Rr is C1-C6-alkyl, and {i) -S02-N(RS)-, wherein RS is as defined previously;
and Rt is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryi, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR~Rg wherein R~ and Rg are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR~Rg wherein R~ and Rg are as defined previously, (c) C3-C12-cycloallcyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, WO 99/11b51 PCT/US98/18125 (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloallryl, (vi) substituted-heterocycloallcyl, (vii) hydroxy, (viii) CI-C6-alkoxy, (ix) NR~Rg wherein R~ and Rg are as defined previously, (d) aryl, (e) substituted-aryl, (fj heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;

or in compounds of formula (II) and (III) U is taken together with U' to form a double bond i5 between the carbon atoms to which they are attached;
and U' is hydrogen or in compounds of formula (II) and (III) U' is taken together with U to form a double bond between the carbon atoms to which they are attached.
The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
The invention further relates to a method of treating bacterial infections in a host mammal in need of such treatment comprising administering to a marnmal in need of such treatment a therapeutically effective amount of a compound as defined above.
In a further aspect of the present invention, processes are provided for the preparation of 6-O-substituted macrolide derivatives of Formula (I), (II), (III), (IV) and (V) above.
Detailed Description of The Lnvention In a first embodiment of the invention is a compound having the formula (I) as described above. A preferred embodiment is a compound of formula (I) wherein Y
and Z taken together define a group X which is =O.
Representative compounds of the invention having formula (I) are those selected from the group consisting of:
Compound of Formula (I): R is allyl, RP is H, X is O, U is OH;
Compound of Formula (I): R is allyl, RP is benzoyl, X is O, U is OH;
Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is OH;

Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), Rp is H, X is O, U
is O-Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is O-(4-methoxy)benzoyl;
Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is O-methanesulfonyl; and Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is O-CO-NH-(2-nitrophenyl).
In a second embodiment of the invention is a compound having the formula (II) as described above. A preferred embodiment is a compound of formula (II) wherein W is absent and RW is H.
Representative compounds of the invention having formula (li) are those selected from the group consisting of:
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is OH;
Compound of Formula (II): R is -CH2-CH =CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-acetyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(4-nitrobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-benzoyl;
Compound of Formula (Ii): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-(3,5-diphenylpyridinecarboxyi);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyi), Rp is H, W is absent, RW is H, U is O-(2-nitrobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-{3,4,5-trimethoxybenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R~' is H, U is O-(2-thiophenecarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-(2-methylbutanoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(4-bromobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(4-pyridinecarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(methoxycarbonyl);

Compound of Formula {II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-(1,1-dimethylethoxycarbonyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-(2-bromobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), Rp is H, W is absent, RW is H, U is O-(4-methoxybenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(2-furancarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-butanoyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-methanesulfonyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-(2-methylpropenoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-phenyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-allyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-CH(C(O)OCH3)-CH(CH3)2;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-CH(CH3)2;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-cyclohexyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-(4-fluorophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-(2-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, Rw is H, U is O-CO-NH-(4-methyl-2-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-{4-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, RW is H, U is O-CO-NH-(4-methoxyphenyl);
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-S{O)2-CH=CH2;
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, RW is H, U is O-S(O)2-CH2-CH2-N(CH3)2;

WO 99/11b51 PCT/US98/18125 Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-S(O)2-CH2-CH2-S-phenyl;
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, Rw is H, U is O-allyl;
Compound of Formula (In: R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R"~' is H, U is O-(4-morpholinecarbonyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R~'~' is H, U is O-pyrrolidinylcarbonyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), Rp is H, W is absent, R"~' is H, U is O-(2-tetrahydropyranyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), Rp is H, W is absent, RW is H, U is O-C(=S)-SCH3;
Compound of Formula (II): R is -CH2-CH=CH2, RP is H, U and U' taken together are double bond, W is absent, R"~' is H;
~5 Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U and U' taken together are double bond, W is absent, R"~' is H;
Compound of Formula (II): R is -CH2-CH=CH2-(6-nitro-3-quinolinyl), RP is H, U
and U' taken together are double bond, W is absent, R"" is H;
Compound of Formula (II): R is -CH2-CH=CH2-{6-methoxy-2-naphthyi), RP is H, U
and U' taken together are double bond, W is absent, R"~' is H;
Compound of Formula (II): R is -CH2-CH=CH2-(3-(5-(3-isoxazolyl)-2-furanyl)), RP is H, U
and U' taken together are double bond, W is absent, R"~' is H;
Compound of Formula (II): R is -CHI-CH=CH2, Rp is H, W is NH, RW is H, U is OH;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R"~' is H,UisH,U'isH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH(O), RP is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH2NHCH2-phenyl, RP
is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH2NHCH2CH2-phenyl, RP is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH2NHCH2CH2CH2-phenyl, Rp is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH2NHCH2CH2CH2CH2-phenyl, RP is acetyl, U is OH;
Compound of Formula (B): W is absent, RW is H, R is -CH2CH2NHCH2CH2CH2-(3-quinolyl), RP is acetyl, U is OH;
Compound of Formula {II): W is absent, RW is H, R is -CH2CH2NHCH2-(3-quinolyl), RP is acetyl, U is OH;

Compound of Formula (II): W is absent, RW is H, R is -CH2CH=NO-(phenyl}, Rp is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH=NOCH2-(phenyl), RP
is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH=NOCH2-(4-N02-phenyl), RP is acetyl, U is OH;
Compound of Formula (II): W is absent, RW is H, R is -CH2CH=NOCH2-{4-quinolyl}, RP is acetyl, U is OH;
Compound of Formula (II): W is absent, R~ is H, R is -CH2CH=NOCH2-(2-quinolyl), RP is acetyl, U is OH; and Compound of Formula (II): W is absent, RW is H, R is -CH2CH=NOCH2-(3-quinolyl), RP is acetyl, U is OH.
In a third embodiment of the invention is a compound having the formula (III) as described above.
Representative compounds of the invention having formula (III) are those selected from the group consisting of:
Compound of Formula (III): R is -CH2-CH=CH2, RP is H, U is OH, U' is H;
Compound of Formula (III): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U is OH, U' is H;
Compound of Formula (III): W is absent, RW is H, R is -CH2CH(O), Rp is H, U is OH;
Compound of Formula (III): W is absent, RW is H, R is -CH2CH2NHCH2-phenyl, Rp is H, U
is OH; and Compound of Formula (III): W is absent, RW is H, R is -CH2CH=NO(phenyl), Rp iS
H, U is OH.
In a fourth embodiment of the invention is a compound having the formula (IV) as described above.
Representative compounds of the invention having formula (IV) are those selected from the group consisting of:
Compound of Formula (IV): R is -CH2-CH=CH2, RP is acetyl, U is OH;
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), Rp is acetyl, U is OH.
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U is O-C(O) phenyl;
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U is O-C(O)-(2-nitrophenyl);
Compound of Formula (IV): W is absent, RW is H, R is -CH2CH(O), Rp is H, U is OH;
Compound of Formula (IV): W is absent, RW is H, R is -CH2CH2NHCH2-phenyl, Rp is H, U
is OH; and Compound of Formula (IV): W is absent, RW is H, R is -CH2CH=NO(phenyl), Rp is H, U is OH.

WO 99/11b51 PCT/US98/18125 In a fifth embodiment of the invention is a compound having the formula (V) as described above.
Representative compounds of the invention having formula (V) are those selected from the group consisting of:
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is OH;
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is O-acetyl;
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is H, U' is H;
Compound of Formula (V): W is absent, RW is H, R is -CH2CH(O), Rp is H, U is OH;
Compound of Formula (V): W is absent, RW is H, R is -CH2CH2NHCH2-phenyl, Rp is H, U
is OH; and Compound of Formula (V): W is absent, RW is H, R is -CH2CH=NO(phenyl), Rp is H, U is OH.
The compounds of the present invention include both those in which the group at the 3 position is the natural (3S) isomer and those in which the group at the 3-position is non-natural ~ 5 (3R) isomer.
One aspect of the invention is a process for preparing a compound of formula (I) wherein Y and Z taken together define a group X which is =O, having the formula (IA) Rp NMe2 O I
0,,, ~~O
HO' (IA) O
wherein RP, R and U are as defined above, the method comprising:
(a) treating hydrolytically with acid a compound having the formula O R H NMe2 .
~~'' O
. Oi.~.
O ~~~ O- H
~~~OMe wherein R is as defined previously, to give a compound having the formula O R H NMe2 ~~O
~''~ O
'.....
O
which is a compound of formula (lA) wherein RP is H and U is hydroxy;
(b) optionally treating the compound of Step (a) with a hydroxy protecting reagent to give a compound having the formula R Rp NMe2 O
~~O

HO' O
which is a compound of formula (IA) wherein Rp is a hydroxy-protecting group and U is hydroxy, optionally followed by converting the compound having the natural (35~ isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer, (c) optionally treating the compound of formula (IA) wherein Rp is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to afford the desired 3-deoxy compound having the formula O R NMe2 ~~O
HO,,,, HO
..
O
O
which is a compound of formula (IA) wherein U is hydrogen;
(d) optionally treating the compound of formula (IA) wherein Rp is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with a hydroxy-protecting reagent to give a compound of formula (IA) wherein Rp is a hydroxy-protecting group and U
is a protected hydroxyl group;
(e) optionally treating the compound of formula (IA) wherein Rp is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with base and a reagent L-T-Ri, wherein T and R~ are as previously defined, and L is a suitable reactive leaving group to give compound having the formula O R RP NMe2 I I
0,,, ,,~, ~~O
~.
'''~ O
HO~
O-T-R~
O

(f) optionally deprotecting, and isolating the desired compound of formula (IA).
In the process for preparing compounds of formula (I), in step (e) the reagent L-T-Rt is selected from the group consisting of:
(e-i) halogen-C(O)-Rt;
(e-ii) O-(C(O)-Rh2;
(e-iii) O-(C(O)-O-Rt)2;
(e-iv) halogen-CH2-Rt;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-Rt;
(e-vi) O=C=N-Rt;
(e-vii) carbonyl diimidazole followed by N(RS)H-Rt;
(e-viiii) CI-S(O)n-O-Rt;
(e-ix) CI-P(O)(OR~n-Rt;
(e-x) Cl-S02-N(RS)-R~;
Alternately, in the process for preparing compounds of formula (I), in step (e) the reagent L-T-Rt in the presence of base is replaced with 3>4-dihydro-2H-pyran in the presence of a acid catalyst.
Another aspect of the invention is a process for preparing a compound of formula (II) R RP NMe2 Rw O i I
0~,, ~~O
~ w,.. ."~ o -II u~
(II), o wherein RP, R , U, U', W and RW are as defined above, the method comprising:
(a) optionally treating hydrolytically with acid a compound having the formula O R RP NMe2 O 0~...
HO ~~~~. ~' i...
HO~ .~~~ O O
O y..' O-RP
OMe .
wherein R is as defined above and Rp is a hydroxy protecting group to give a compound having the formula $
R Rp NMe2 O
O
~. . ' HO,,, HO ~ ~~'~ O
'.,...
I 'U
O
U' O
wherein U is hydroxy and U' is hydrogen (b) optionally treating a compound from Step (a) with an excess of sodium hexamethyldisilazide or a hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound having the formula RP NMe2 ~.
N~,. N
O
O
wherein U and U' are taken together to form a double bond;

(c) optionally treating a compound from Step (b) with aqueous ammonia to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is absent and RW is H;
(d) optionally treating a compound from Step (b) with a substituted amine compound of the formula H2N-W-RW, wherein W is absent and RW is not H but is otherwise as previously defined, to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is absent and RW is not H:
(e) optionally treating a compound from Step (b) with a hydroxylamine compound of the formula H2N-W-RW, wherein W is -O- and Rw is as previously defined, to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is -O-and RW is as previously defined;
(fJ optionally treating a compound from Step (b) with an unsubstituted hydrazine to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W
is -NH- and RW is H;
(g) optionally treating a compound from Step (b) with a substituted hydrazine compound of the formula H2N-NH-RW wherein RW is not hydrogen but otherwise is as previously defined to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is -NH-RW and RW is not H;
(h) optionally treating a compound of folTnula 14 as defined above with a strong base selected from the group consisting of (i) sodium hexamethyldisilazide and (ii) an alkali metal hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound having the formula O R RP NMe2 I
0,,, ~~O
N~
-N'I /\ .~''O
O O
O ',~~,.
O~.. O
U' O
.~~OMe (i) optionally treating a compound from Step (h) with aqueous ammonia to give a compound having the formula (16A) R"' - .- RP NMe2 I
W 0~...
O

( 16A) wherein W is absent, RW is H and U is 4"-hydroxy protected cladinose;
(j) optionally treating the compound from step (i), wherein W is absent and RW
is H and U is 4"-hydroxy protected cladinose, with an alkylating agent selected from the group consisting of RW-halogen to give a compound of formula ( 16A) wherein W is absent, U is 4"-hydroxy protected cladinose, and RW is as defined above;
(k) optionally treating a compound from Step (h) with a substituted amine compound of the formula H2N-W-RW, wherein W is absent and RW is as previously defined except not H, to give to give a compound having of formula ( 16A) wherein W is absent, U is 4"-hydroxy protected cladinose, and RW is as previously defined except not H;
(1) optionally treating a compound from Step (h) with a hydroxylamine compound of the formula H2N-W-RW, wherein W is -O- and RW is as previously defined, to give to give a compound of formula (16A) wherein W is -O-, U is 4"-hydroxy protected cladinose, and RW is as previously defined;
(m) optionally treating a compound from Step (h) with an unsubstituted hydrazine to give to give a compound of formula (16A) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and RW is H;
(n) optionally treating the compound from step (m) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and RW is H with an acylating agent selected from the group consisting of RW-C(O)-halogen or (RW-C(O))2-O to give a compound of formula ( 16A) wherein W
is -NH-CO-, U is 4"-hydroxy protected cladinose, and R~' is as defined above;

(o) optionally treating the compound from step (m) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and RW is H with an aldehyde RW-CHO, wherein R~' as defined above to give a compound of formula ( 16A) wherein W is -N=CH-, U is 4"-hydroxy protected cladinose, and R~' is as defined above;
(p) optionally treating a compound from Step (h) with a substituted hydrazine compound of the formula H2N-NH-RW, wherein RW is as defined above except not hydrogen, to give to give a compound of formula ( 16A) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and R~' is as defined above except not hydrogen;
(q) optionally treating hydrolytically with acid a compound selected from the group consisting of the compounds of Step (i), Step (j), Step (k), Step (1), Step (m), Step (n), Step (o), and Step (p) to give the desired compound of formula (II) wherein U is OH, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer, (r) optionally treating a compound of formula (II) wherein RP is a hydroxy protecting group and U is hydroxy (a compound from Step (q)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (11) wherein U is hydrogen;
(s) optionally treating a compound of formula (II) wherein RP is a hydroxy protecting group and U is hydroxy (a compound from Step (q) with base and a reagent L-T-R~, wherein T and Rt are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (In wherein U is O-T-R~; and (t) optionally deprotecting, and isolating the desired compound of formula (II).
In the process for preparing compounds of formula (Ii), in step (s) the reagent L-T-RL
is selected from the group consisting of:
(e-i) halogen-C(O)-Rt;
(e-ii) O-(C(O)-R~;
(e-lu) O-(C(O)-O-Rlh;
(e-iv) halogen-CH2-R~;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-Rt;

(e-vi) O=C=N-R~;
(e-vii) carbonyl diimidazole followed by N(RS)H-R~;
(e-viiii) Cl-S(O)n-O-Rt;
(e-~) ~-p(O)(OR~n-Rt;
(e-x) Cl-S02-N(RS)-Rt;
Alternately, in the process for preparing compounds of formula (II), in step (s) the reagent L-T-RL in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
to Another aspect of the invention is a process for preparing a compound of formula (III) _ ~ RP NMe2 O
O
(III), O
wherein RP is R, U and U' are as described above, the method comprising:
(a) optionally treating hydrolydcally with acid a compound having the formula HO~..
R Rp NMe2 O . .~~ O-Ra 14 .~~OMe wherein R is as defined above and RP is a hydroxy protecting group to give a compound having the formula $

O R Rp NMep O Oi...
HO,, ~~~~' ., ~''~ O
HO' U' wherein U is hydroxy and U' is hydrogen, optionally followed by converting the compound having the natural (35~ isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(b) treating a compound selected from the group consisting of compound 14 and compound 8_ wherein U is hydroxy and U' is hydrogen with a base selected from the group consisting of sodium hexamethyldisilazide and a metal hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound selected from the group consisting of compounds ~A
and 15B, respectively RP NMe2 _ 0....
N~ N
O
O
O
~ wherein U is -O-4"-acetyl-cladinose and U' is H, or ~$, wherein U and U' are taken together to form a double bond;
(c) treating a compound selected from the group ~ and ~ of step (b) with ethylenediamine to give a bicyclic carbamate compound selected from the group consisting of compounds ~, wherein U is O-4"-acetylcladinose, and ~, wherein U and U' form a double bond, respectively, NH2 O R Rp NMe2 I
~~O
_ ..n 0 O' t ~U
O
U' O
2~, wherein U is O-4"-acetylcladinose, 21B, wherein U and U' from a double bond, (d) treating the a compound selected from the group ~ and ~ of step (c) with dilute acid to give a compound selected from the group consisting of compounds 22A and 22B, respectively, N R NMe2 HO,,, n... ,.
O~ Nm,.
O
O
22A, U is O-4"-acetylcladinose, and 22B, U and U' form a double bond;
(e) hydrolytically removing the cladinose moiety from a compound 2~2-A) from step (d) by treatment with acid, reprotecting the 2' hydroxyl group by treatment with a hydroxy protecting reagent, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer, to give a compound having the formula (23P1, N R NMe2 O RpO~~.
NL~.. .,~~ O
0.H
_2~ o which is a compound of formula (III) wherein RP is H, U is hydroxy and U' is hydrogen;
(f) optionally treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen with base and a reagent L-T-Rl, wherein L is a leaving group and T and Rt are as defined previously, to give a compound of formula (III) wherein RP is H, U is -O-T-R~
and U' is hydrogen;
to (i) optionally treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen sequentially with an excess of NaH, CS2 and CH3I to form a 3-O-xanthate intermediate which is treated with Bu3SnH in the presence of a radical initiator to give the desired compound of formula (III) wherein RP, U and U' are hydrogen; and (j) optionally deprotecting, and isolating the desired compound of formula (III).
In the process for preparing compounds of fonmula (III), in step (fj the reagent L-T-Rl 2o is selected from the group consisting of:
(e-i) halogen-C(O)-R~;
(e-ii) O-(C(O)-R~)2;
(e-iii) O-(C(O)-O-Rt)2;
(e-iv) halogen-CH2-Rt;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R~;
(e-vi) O=C=N-R~;
(e-vii) carbonyl diimidazole followed by N(RS)H-R~;
(e-viiii) Cl-S(O)S-O-R~;
(e-ix) Cl-P(O)(OR~"-R~;
(e-x) Cl-S02-N(RS)-Rt;

WO 99/11651 PC'TlUS98/18125 Alternately, in the process for preparing compounds of formula (III, in step (f) the reagent L-T-Rt is in the prescnce of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.
Another aspect of the invention is a process for preparing a compound of formula (IV) R Rp NMe2 .O O
..
(IV), o wherein Rp, R and U are as defined above;
the method comprising:
{a) optionally treating a compound having the formula 14 - ~ Rp NMe2 I
O''..
O
O
O .~' O-Rp 14 .~'onne wherein R is as defined above and Rp is a hydroxy protecting group, with carbonyldiimidazole and sodium hexamethyldisilazide for a short time at about -30 °C to give a compound having the formula ~Q

O R RP NMep .... .~O 0....
O~ 0~..
"~ O
O O
O _ 0.~, O
O .. .~~~ O~ Ru ~OMe (b) optionally treating a compound having the formula _14 as shown in Step (a) with an alkali metal hydride and a carbonylating agent selected from the group consisting of phosgene, diphosgene and triphosgene under anhydrous conditions with careful control of the amount of base present in order to prevent base catalyzed decarboxylation to give a compound having the formula ~ as shown in Step (a);
(cj treating hydrolytically with acid a compound having the formula ~ to give a compound of t0 formula (IV) wherein U is hydroxy and Rp is a hydroxy protecting group, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
15 (d) optionally treating a compound of formula (IV) wherein U is hydroxy and RP is a hydroxy protecting group (a compound from Step (c)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (IV) 20 wherein U is hydrogen and RP is a hydroxy protecting group;
(e) optionally treating a compound of formula (IV) wherein U is hydroxy and RP
is a hydroxy protecting group (a compound from Step {c)) with base and a reagent L-T-Rt, wherein T and Rt are as previously defined, and L is a suitable reactive leaving group to give the desired 25 compound of formula (IV) wherein U is O-T-R~ and RP is a hydroxy protecting group;
(f) optionally deprotecting, and isolating the desired compound of formula (IV).
In the process for preparing compounds of formula (IV), in step (e) the reagent L-T-Rt 30 is selected from the group consisting of:

WO 99/11651 . PCT/US98/18125 (e-i) halogen-C(O)-Rt;
(e-u) 4-(C(~)-R~)2~
(e-~) 4-(C(C~O-Rt)2;
(e-iv) halogen-CH2-R~;
(e-v) allcali metal hydride followed by CSZ then followed by halogen-Rt;
(e-vi) O=C=N-Rt;
(e-vii) carbonyl diimidazole followed by N(RS)H-R~;
(e-viiii) Cl-S(O)"-O-Rt;
(e-~) ~-P(C)(~R~n-R~;
(e-x) Cl-SOZ-N(RS)-R~;
Alternately, in the process for preparing compounds of formula (IV); in step (e) the reagent L-T-R~ is in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

Another aspect of the invention is a process for preparing a compound of formula (V) Rp NMep < ~ o~
(v), o wherein Rp, R and U are as defined above, the method comprising:
(a) treating a compound having the formula 14 RP NMep 0,,, O
O
O .~' O-Rp ,~4 . ~~OMe wherein R is as defined above and Rp is a hydroxy protecting group, with a reagent selected from the group consisting of (i) formaldehyde in the presence of an acid and (ii) chloroiodomethane in the presence of base, to give a compound having the formula ~
" . q Rp NMe2 I
< , o O .,. ...~ O-RP
~OMe (b) treating hydrolytically with acid a compound from Step (a) having the formula ~ to give a compound of formula (V) wherein U is hydroxy and Rp is a hydroxy protecting group, optionally followed by converting the compound having the natural (3S~
isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(c) optionally treating a compound of formula (V) wherein U is hydroxy and RP
is a hydroxy protecting group (a compound from Step (b)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (V) wherein U is hydrogen and RP is a hydroxy protecting group;
(d) optionally treating a compound of formula (IV) wherein U is hydroxy and RP
is a hydroxy protecting group (a compound from Step (b)) with base and a reagent L-T-Rt, wherein T and Rt are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (V) wherein U is O-T-R~ and RP is a hydroxy protecting group;
(e) optionally deprotecting, and isolating the desired compound of formula (V).
In the process for preparing compounds of formula (V), in step (d) the reagent L-T-Rt is selected from the group consisting of:
(e-i) halogen-C(O)-Rt;
(e-ii) O-(C(O)-R~)2;
(e-iii) O-(C(O)-O-Rtn;
(e-iv) halogen-CH2-Rt;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-Rt;
(e-vi) O=C=N-R~;
{e-vii) carbonyl diimidazole followed by N(RS)H-R~;
(e-viiii) Cl-S(O)n-O-Rt;
(e-ix) Cl-P(O)(OR')n-Rt;
(e-x) Cl-S02-N(RS)-Rt;
Alternately, in the process for preparing compounds of formula (V), in step (d) the reagent L-T-Rt in the presence of base is replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

As used throughout this specification and the appended claims, the following terms have the meanings specified.
The terms "C1-C3-alkyl", "Cl-C6-alkyl", and "C1-C12-alkyl" as used herein refer to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C~-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of C1-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl.
Examples of Cl-C12-alkyl radicals include, but are not limited to, all the foregoing examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-docecyl.
The term "CI-C6-allcoxy" as used herein refers to an C1-C6-allcyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
Examples of Ci-C6 alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy.
The term "C~-C12-alkenyl" denotes a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term "C1-C12-aikynyl" as used herein refers to a monovalent group derived from a hydrocarbon containing from two to twelve carbon atoms and having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The term "C1-C3-allcylamino" as used herein refers to one or two C~-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
Examples of C1-C3-alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon atom in an allcyl group as defined above are replaced with a single oxygen atom (i.e. a carbonyl group).
The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heteroaryl compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physic Properties and Methods of PLrifcar;on, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloallcyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. in addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "C3-C12-cycloallryl" denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1)heptyl, and bicyclo[2.2.2]octyl.
The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term "alkylamino" refers to a group having the structure -NHR' wherein R' is alkyl, as previously defined, Examples of alkylamino include methylamino, ethylamino, iso-propylamino and the like.
The term "dialkylamino" refers to a group having the structure -NRR" wherein R' and R" are independently selected from alkyl, as previously defined. Additionally, R' and R" taken together may optionally be -(CH2)k- where k is an integer of from 2 to 6.
Examples of diallcylamino include, dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino, and the like.
The term "haloallcyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term "allcoxycarbonyl" represents an ester group; i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term "thioalkoxy" refers to an alkyl group as previously defined attached to the parent molecular moiety through a sulfur atom.

WO 99/11651 ~ PCT/US98/18125 The term "carboxaldehyde" as used herein refers to a group of formula -CHO.
The term "carboxy" as used herein refers to a group of formula -C02H.
The term "carboxamide" as used herein refers to a group of formula -CONHRR"
wherein R' and R" are independently selected from hydrogen or alkyl, or R' and R" taken together may optionally be -(CH2)g- where k is an integer of from 2 to 6.
The term "heteroaryl", as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N;
zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N;
and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term "heterocycloalkyl" as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocycloallryl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and niuogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
Specific heterocycloalkyl rings considered useful in preparing compounds of the invention include: 3-methyl-4-(3-methyiphenyl)piperazine, 3-methylpiperidine, 4-(bis-(4-fluorophenyl)methyl)piperazine, 4-(diphenylmethyl)piperazine, 4-(ethoxycarbonyl)piperazine, 4-(ethoxycarbonylmethyl)piperazine, 4-(phenylmethyl)piperazine, 4-(1-phenylethyl)piperazine, 4-(1,1-dimethylethoxycarbonyl)piperazine, 4-(2-(bis-(2-propenyl)amino~thyl)piperazine, 4-(2-(diethylamino~thyl)piperazine, 4-(2-chlorophenyl)piperazine, 4-(2-cyanophenyl)piperazine, 4-(2-ethoxyphenyl)piperazine, 4-(2-ethylphenyl)piperazine, 4-{2-fluorophenyl)piperazine, 4-(2-hydroxyethyl)piperazine, 4-(2-methoxyethyl)piperazine, 4-(2-methoxyphenyl)piperazine, 4-(2-methylphenyl)piperazine, 4-(2-methylthiophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-nitrophenyl)piperazine, 4-(2-phenylethyl)piperazine, 4-(2-pyridyl)piperazine, 4-(2-pyrimidinyl)piperazine, 4-(2,3-dimethylphenyl)piperazine, 4-(2,4-difluorophenyl)piperazine, 4-(2,4-dimethoxyphenyl)piperazine, 4-(2,4-dimethylphenyl)piperazine, 4-(2,5-dimethylphenyl)piperazine, 4-(2,6-dimethylphenyl)piperazine, 4-(3-chlorophenyl)piperazine, 4-(3-methylphenyl)piperazine, 4-(3-trifluoromethylphenyl)piperazine, 4-(3,4-dichlorophenyl)piperazine, 4-(3,4-dimethoxyphenyl)piperazine, 4-(3,4-dimethylphenyl)piperazine, 4-(3,4-methylenedioxyphenyl)piperazine, 4-(3,4,5-WO 99/11651 PCTlUS98/18125 trimethoxyphenyl)piperaane, 4-(3,5-dichlorophenyl)piperazine, 4-(3,5-dimethoxyphenyl)piperazine, 4-(4-(phenylmethoxy)phenyl)piperazine, 4-(4-{1,1-dimethylethyl)phenylmethyl)piperazine, 4-(4-chloro-3-trifluoromethylphenyl)piperazine, 4-(4-chlorophenyl)-3-methylpiperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenyl)piperazine, 4-(4-chlorophenylmethyl)piperazine, 4-(4-fluorophenyl)piperazine, 4-(4-methoxyphenyl~iperazine, 4-(4-methylphenyl)piperazine, 4-{4-nitrophenyl)piperazine, 4-(4-trifluoromethylphenyl)piperazine, 4-cyclohexylpiperazine, 4-ethylpiperazine, 4-hydroxy-4-(4-chlorophenyl)methylpiperidine, 4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine, 4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4-{(2-furanyl)carbonyl)piperazine, 4-((1,3-dioxolan-5-yl)methyl)piperazine, 6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline, 1,4-diazacycloheptane, 2,3-dihydroindolyl, 3,3-dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, and triazole.
i5 The term "heteroarylalkyl" as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group wherein the alkylene group is of one to four carbon atoms.
"Hydroxy-protecting group", as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T.H.
Greene and P.G.M. Wuts, Protective Groups in Or~~nic Synthesis 2nd edition, John Wiley &
Sons, New York ( 1991 ). Examples of hydroxy-protecting groups include, but are not limited to, methylthiomethyl, tert dimethylsilyl, tert butyldiphenylsilyl, ethers such as methoxymethyi, and esters including acetyl benzoyl, and the like.
The term "ketone protecting group", as used herein, refers to an easily removable group which is known in the art to protect a ketone group against undesirable reactions during synthetic procedures and to be selectively removable. The use of ketone-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, c~, for example, T.H.
Greene and P.G.M. Wuts, 1'xotective Groups in Organic Synth tic 2nd edition, John Wiley &
Sons, New York ( 1991 ). Examples of ketone-protecting groups include, but are not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
A the term "protected-hydroxy" refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.

The term "protogenic organic solvent" as used herein refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example.
Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Pronertiec anrt r,~e~odc ~f Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.
The term "substituted aryl" as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, Cl-C3-alkyl, C1-C6-alkoxy, C~-C6-allcoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, vitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryi, or heterocycloalkyl group. Also, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "substituted heteroaryl" as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, CI-C6-allcoxy substituted with aryl, haloallcyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, vitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term "substituted heterocycloalkyl" as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, vitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one subsdtutent may be an aryl, heteroaryl, or heterocycloalkyl group.
Numerous asymmetric centers may exist in the compounds of the present invention.
Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art For example, S. M. Barge, et al. describe pharmaceutically acceptable salts in detail in ~ Pharmaceutical Sciences. 66: 1-19 (1977), incorporated herein by reference.
The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, malefic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, I S nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or allcaline earth metal salts include sodium, Lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pham~aceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefithisk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V.
Stella, Pry as Novel Deliverv Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B.

Roche, ed., Bioreversible Carrier, in Drug D~ American pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Antibacterial Activity Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-O l-5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different microorganisms, using a Steers replicator block. The inoculated plates were incubated at 35-37 °C for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.
An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic class as the test compound was also prepared and incubated as a further control, as well as to provide test-to-test comparability.
Erythromycin A was used for this purpose.
After incubation, each plate was visually inspected. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control. The results of this assay, shown below in Table 2 demonstrate the antibacterial activity of the compounds of the invention.

T el 9~r tibacterial Activity fMIC'cl of ~PlP.rr~ Comooundc Microorganism Organism Ery.
A

code Staphylococcus aureus ATCC AA 0.2 Staphylococcus aureus A5177BB 3.1 Staphylococcus aureus A-5278CC >100 Staphylococcus aureus CMX DD 0.39 Staphylococcus aureus NCTC10649MEE 0.39 Staphylococcus aureus CMX FF 0.39 Staphylococcus aureus 1775 GG >100 Staphylococcus epidermidis HH 0.39 Enterococcus faecium ATCC II 0.05 Streptococcus bovis A-5169 JJ 0.02 Streptococcus agalactiae KK 0.05 Streptococcus pyogenes EES61LL 0.05 Streptococcus pyogenes 930 MM >100 Streptococcus pyogenes PIU NN 6.2 Micrococcus luteus ATCC 00 0.05 Micrococcus luteus ATCC P P 0.2 Escherichia coli JUHL QQ > 100 Escherichia coli SS RR 0.78 Escherichia coli DC-2 S S > 100 Candida albicans CCH 442 TT > 100 Mycobacterium smegmatis U U 3.1 Nocardia Asteroides ATCC9970W 0.1 Haemophilis Influenzae DILLWW 4 AMP R

Streptococcus Pheumoniae XX 0.06 Streptococcus Pheumoniae W 0.06 Streptococcus Pheumoniae ZZ >128 Streptococcus Pheumoniae aA 16 * missing data is indicated by "-"
0_ Table l, continued Antibacterial Activity~MIC'sl n~ Selected Comnoum;~
OrganismExampleExample Example ExampleExample ExampleExample code 3 4 5 6 7 g g 0.2 100 25 25 1.56 0.78 0.78 BB 3.1 >100 25 12.5 3.1 0.78 0.78 CC >100 >100 25 >100 >100 >100 >100 0.2 >100 25 25 1.56 1.56 1.56 0.39 100 25 25 3.1 0.78 0.78 FF 0.2 100 12.5 25 3.1 0.78 0.78 GG >100 >100 25 >100 >100 >100 >100 HH 0.2 100 12.5 12.5 1.56 1.56 1.56 E 0.1 100 25 6.2 0.78 0.39 0.39 JJ 0.02 3.1 1.56 0.78 0.39 0.02 0.05 KK 0.02 12.5 3.1 1.56 0.1 0.1 0.1 0.02 3.1 3.1 0.39 0.1 0.01 0.01 1.5 > 100 6. 2 > 100 12.5 50 100 NN 0.39 6.2 3.1 3.1 0.78 0.39 0.39 0.05 3.1 1.56 0.78 0.39 0.1 0.05 PP 0.1 6.2 3.1 3.1 0.39 0.2 0.39 SO >100 >100 >100 >100 >100 >100 RR 1.56 6.2 >100 3.1 25 0.78 0.39 S S 1 ~ > 100 > 100 > 100 > 100 > 100 > 100 .1.1. > 100 > 100 25 > 100 > 100 > 100 > 100 UU 0.1 3.1 3.1 3.1 0.39 6.2 0.78 0.05 3.1 6.2 3.1 6.2 0.2 0.39 2 128 >128 >128 >128 16 4 XX 0.03 16 4 8 1 0.125 0.25 yy 1 32 128 32 16 2 1 16 >128 8 >128 16 32 64 1 16 8 8 2 0.5 0.5 * missing data is indicated by "-"
_. ~1-Table 1. con 'nnP~
Antibacterial Activity (MIC's) of BPiP.~-rP~ Comnoundc OrganismExampleExample ExampleExample ExampleExample Example code 10 11 12 13 14 15 16 0.39 0.78 >100 0.39 3.1 0.78 0.39 BB 0.39 0.78 >100 0.39 6.2 0.78 0.2 CC >100 >100 >100 >100 >100 >100 50 0.39 0.78 >100 0.39 3.1 0.78 0.39 0.78 0.78 0.39 3.1 0.78 0.39 FF 0.78 0.78 >100 0.39 3.1 0.78 0.2 GG >1~ 100 >100 50 >100 >100 25 HH 0.78 0.78 >100 0.39 3.1 0.78 0.39 0.39 0.39 >100 0.2 0.78 0.39 0.1 JJ 0.1 0.1 50 0.05 0.2 0.05 0.02 KK 0.1 0.1 50 0.01 0.2 0.02 0.05 0.2 0.1 12.5 0.01 0.1 0.02 0.05 25 25 50 6.2 25 25 6.2 NN 0.78 0.39 >100 0.39 1.56 0.39 0.39 0.2 0.1 50 0.1 0.78 0.2 0.1 PP 0.39 0.78 >100 0.39 1.56 0.78 0.39 >100 >100 >100 >100 >100 >100 >100 RR 12.5 12.5 > 100 6.2 25 6.2 6.2 S s > 100 > 100 > 100 > 100 > 100 > 100 > 100 .t.l, > 100 > 100 > 100 > 100 > 100 > 100 50 UU 0'78 078 100 0.39 3.1 3.1 0.39 1.56 1.56 >100 1.56 6.2 6.2 0.39 16 >128 >128 4 >128 64 8 XX 0.03 0.25 4 0.125 0.5 0.25 0.125 8 32 >128 4 16 16 4 1 1 4 0.5 2 1 1 * missing data is indicated by "-"

Fable 1. continued Antibacterial Activity~MIC'tl of Selected Compounds OrganismExampleExampleExample ExampleExample ExampleExample code 17 18 19 21 22 23 24 0.78 0.39 1.56 0.78 1.56 0.78 0.78 BB 1.56 0.39 1.56 0.78 1.56 0.39 0.78 CC >l~ >1~ >l~ 50 >100 >100 50 1.56 0.39 3.1 0.78 1.56 0.78 1.56 1.56 0.39 1.56 0.78 1.56 0.78 1.56 FF 1.56 0.39 1.56 0.78 1.56 0.78 0.78 GG 25 >100 >100 50 >100 >100 25 HH 1.56 0.39 1.56 0.78 1.56 0.78 0.78 Q 0.39 0.39 0.78 0.39 0.78 0.1 0.39 J J 0.05 0. I U.1 0.2 0.39 0.05 0.2 KK U.05 0.1 U.39 0.2 0.39 0.1 0.39 0.2 0.1 0.1 0.2 0.39 U.05 0.2 6.2 > 100 > 100 6.2 12.5 100 12.5 NN 078 0.39 0.39 0.39 1.56 0.39 0.39 0.39 0.1 0.1 0.2 0.39 0.05 0.2 PP 0.78 0.39 0.39 0.78 1.56 0.39 0.39 >100 >100 >100 >100 >100 >100 >100 RR >100 6.2 1.56 6.2 12.5 3.1 3.1 SS >1~ >1~ >100 >100 >100 >100 >100 .Ll, >100 >i00 >100 >100 >100 >100 25 UU 1.56 0.78 1.56 0.78 3.1 U.39 0.39 6.2 0.39 0.39 3.1 3.1 0.78 1.56 64 16 32 >128 64 32 16 XX 0.5 0.25 0.25 0.25 0.25 0.25 0.25 16 >128 >128 16 32 64 16 2 1 1 1 2 0.5 1 * missing data is indicated by "-"

Table 1. continued Antibacterial Activity MIC' ~ of Selected Com oundc OrganismExampleExample ExampleExample ExampleExample Example code 25 26 27 28 29 30 31 0.39 0.78 0.39 0.39 0.2 0.39 0.39 BB 0.39 0.78 0.39 - - 0.2 0.39 CC >1~ >1~ 50 >100 >100 >100 50 0.39 0.78 0.39 0.39 0.2 0.39 0.39 0.39 0.78 0.78 0.39 0.2 0.39 FF 0.39 0.78 0.39 0.39 0.39 0.2 0.39 GG >100 100 25 >100 >100 >100 50 HH 0.39 0.78 0.39 0.39 0.78 0.39 0.39 a 0.2 0.39 0.39 0.2 0.2 0.2 0.2 JJ 0.02 0.05 0.05 <=0.005 0.01 0.05 0.05 K K 0.02 0.2 0.1 0.01 U.O 0.05 0.1 0.01 U.US U.US 0.01 U.02 0.02 0.01 100 25 12.5 100 50 12.5 12.5 NN 0.39 0.39 U.39 0.2 0.39 0.2 0.39 0.05 0.05 U.05 0.02 0.1 0.05 0.1 Pp 0.39 0.39 0.39 0.2 0.39 0.2 0.2 >100 >lU0 >100 50 >100 100 100 RR 0.39 1.56 3.1 0.78 6.2 1.56 6.2 SS 100 >100 >lU0 >100 >100 >100 >100 .1..1, > 100 > 100 > 100 > 1 U0 > 100 > 100 > 100 UU 1.56 0.39 0.78 0.78 0.39 1.56 0.39 0.2 0.39 0.78 0.2 0.78 0.1 0.39 XX 0.125 0.25 0.25 0.125 0.03 0.03 0.125 >128 32 16 >128 64 32 16 2 1 1 0.25 0.5 0.25 0.25 * missing data is indicated by "-"

Table 1, can 'nnP.~
~rttibacterial Activitv (MIC'cl of Selected iC'om ndc OrganismExampleExample Example ExampleExample ExampleExample code 32 33 34 35 36 37 38 0.2 0.39 0.39 0.39 0.39 6.2 3.1 BB ' 0.39 0.39 - - 6.2 3.1 CC 25 >100 >100 50 50 >100 >100 0.39 0.39 0.39 0.39 0.39 6.2 3.1 0.39 0.39 0.39 0.78 6.2 3.1 FF 0.39 0.39 0.39 0.39 0.39 6.2 3.1 GG 25 >100 >100 25 50 >100 >100 HH 0.39 0.2 0.39 0.39 0.39 6.2 3.1 n 0.39 0.39 0.39 0.39 0.39 3.1 0.78 J J 0.1 0.1 0.2 0.2 - 0.39 0.2 KK 0.1 0.01 0.2 0.2 0.1 1.56 0.39 0.1 0.02 0.1 0.2 0.1 0.39 0.2 6.2 12.5 6.2 6.2 12.5 > 100 > 100 NN 0.39 0.2 0.39 0.39 0.39 6.2 3.1 0.2 0.05 0.1 0.2 0.1 0.78 0.39 PP 0.39 0.2 0.39 0.78 0.39 3.1 1.56 >100 >100 >100 >100 >100 >100 >100 RR 12.5 3.1 6.2 100 12.5 12.5 12.5 S S > 100 > 100 > 100 > 100 > 100 > 100 > 100 .l.h >100 >100 >100 >100 >100 >100 >100 UU 3.1 0.39 0.39 3.1 1.56 6.2 6.2 1.56 0.39 0.39 3.1 1.56 3.1 i.56 8 2 4 16 128 >64 XX 0.25 0.125 0.125 0.25 0.125 1 0.5 yy 4 2 2 4 4 16 16 16 16 8 8 16 >128 >64 1 0.25 0.25 1 0.5 8 g * missing data is indicated by "-"

Table 1. con 'nne~
Antibacterial Activity (MI ' ) of Selected Compounds OrganismExampleExample Example ExampleExampleExample Example code 39 40 41 42 43 44 46 1.56 25 0.2 0.39 0.39 0.78 0.39 BB 3.1 25 3.1 0.39 0.39 1.56 0.39 CC >1~ 50 >100 >100 100 100 >100 1.56 50 0.39 0.39 0.39 0.78 0.39 1.56 12.5 0.39 0.78 0.78 0.78 0.78 FF 1.56 25 0.39 0.39 0.78 0.78 0.39 GG >1~ 25 >100 >100 100 25 >100 HH 1.56 25 0.2 0.39 0.39 1.56 0.39 B 0.78 6.2 0.1 0.2 0.2 0.78 0.39 JJ 0.05 1.56 0.05 0.02 0.05 0.1 0.1 KK 0.1 3.1 0.05 0.1 0.1 0.1 0.2 0.1 1.56 0.02 0.1 0.02 0.1 0.1 25 12.5 > 100 12.5 50 12.5 25 NN 1.56 3.1 12.5 0.2 0.39 0.39 0.39 0.39 3.1 0.05 0.1 0.1 0.1 0.1 pP 1.56 6.2 0.39 0.39 0.1 0.39 0.39 >100 >100 50 >100 100 >100 >100 RR 25 25 0.78 3.1 3.1 3.1 0.78 S S > 100 > 100 > 100 > 100 > 100 > 100 > 100 .1.1. > 100 25 > 100 > 100 100 > 100 > 100 UU 0.78 1.56 6.2 0.39 0.78 0.39 0.78 3.1 6.2 0.1 0.2 0.78 1.56 0.39 64 >128 4 8 64 8 16 XX 0.5 4 0.125 0.03 0.25 0.5 0.25 ~ 8 32 0.5 4 4 4 2 64 16 >128 >64 64 16 >32 2 4 16 0.25 1 1 1 * missing data is indicated by "-"
_. ~_ Table 1 con my Antibacterial Activity~'cl of Sel~r~ ~cml ids OrganismExampleExampleExample Example code 47 48 49 52 - 3.1 12.5 >100 BB - 3.1 12.5 >100 CC ' 25 >100 >100 3.1 3.1 25 >100 3.1 3.1 25 >100 FF 3.1 3.1 12.5 > 100 GG >1~ 25 >100 >100 HH 3.1 3.I 25 >100 E 0.78 0.39 3.1 25 JJ 0.2 0.39 1.56 6.2 K K 0.2 U.39 1.56 12.5 LL 0.2 0.78 0.78 12.5 - - >100 >100 NN 078 1.56 6.2 50 0.39 0.39 3.1 12.5 PP 1.56 3.1 12.5 >100 >100 >100 >100 >100 RR 0.78 6.2 50 50 SS >1~ >100 >100 >100 .1.1, >IUO >100 >100 >100 UU 3.1 3.1 12.5 50 U.39 1.56 3.1 25 16 >128 >128 >128 XX 0.25 0.25 2 16 64 16 >128 >128 * missing data is indicated by "-"
_47_ Pharmaceuticals:om sition The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the ' judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyiformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in 1.5 biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h} absorbents such as kaolin and bentorute clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene-glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or mills sugar as well as high molecular weight polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredients) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and -SO-polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the 1_5 present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder;
the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of 20 administration, and rate of excretion of the specific compound employed;
the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 25 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or~submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compounds) of this invention per day in single or multiple doses.
abbreviations Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: 9-BBN for 9-borabicyclo[3.3.1]nonane; AIBN for azobisisobutyronitrile;
Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]under-7-ene; DEAD for diethylazodicarboxylate; DMAP for 4-dimethylaminopyridine; DMF for dimethyl formamide; DPPA for diphenylphosphoryl azide;
EtOAc for ethyl acetate; MeOH for methanol; NaHMDS for sodium hexamethyldisilazane;

NaN(TMS~ for sodium bis(trimethylsilyl)amide; NMMO for N-methylinorpholine N-oxide;
TEA for triethylamine; THF for tetrahydrofuran; TPP for triphenylphosphine.
Preparation of the Com»unds of the Invention , The compounds of the present invention are prepared according to the representative methods described in Schemes 1-10 below. The groups U, U', V, W, X, Y, Z, R, Rw, and RP of the compounds shown in the schemes are as defined previously for compounds of formulas (I) - (V), unless otherwise noted below.
Scheme 1 illustrates the preparation of compounds ~, which are useful as starting t0 materials for the preparation of compounds of formulas (1) - (V) of the invention. The preparation of protected erythromycin A is described in the following United States patents, US
4,990,602; US 4,331,803, US 4,680,368, and US 4,670,549 which are incorporated by reference. AIso incorporated by reference is European Patent Application EP
260,938. In general, the C-9-carbonyl group of compound 1 is protected as an oxime, (V is =N-O-R1 or is =N-O-C(RS)(R6)-O-R1 where Rt is defined previously and RS and R6 are each independently selected from the group consisting of (a) hydrogen, (b) unsubstituted Ct-C~2-alkyl, (c) C1-Ct2-alkyl substituted with aryl, and (d) Ct-Ct2-alkyl substituted with substituted aryl, or R9 and Rt0 taken together with the carbon to which they are attached form a C3-Ct2-cycloalkyl ring). An especially preferred carbonyl protecting group V is O-(1-isopropoxycyclohexyl) 20 oxime.
The 2'- and 4"-hydroxy groups of _2 are protected by reaction with a suitable hydroxy protecting reagent, such as those described by T.W. Greene and P.G.M. Wuts in Protective Groups in Or ag nic Synthesis, 2nd ed., John Wiley & Son, Ins., 1991, which is incorporated by reference. Hydroxy protecting groups include, for example, acetic anhydride, benzoic 25 anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl chloride in an aprotic solvent. Examples of aprotic solvents are dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, 30 acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction, and are preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. Protection of 2'- and 4"-hydroxy groups of 2 may be accomplished sequentially or simultaneously to provide compound ~ where RP
is a hydroxy protecting group. A preferred protecting group RP is trimethylsilyl.
35 The 6-hydroxy group of compound ~ is then allcylated by reaction with an alkylating agent in the presence of base to give compound 4. Alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. Specific examples of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, a-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyi phenyl sulfone, 3-bromo-i-trimethylsilyl-1-propyne, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bmmo-2-butanone, bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, and the like.
Examples of alkyl sulfonates are: allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl -O-methanesulfonate and the like. Examples of the solvents used are aprotic solvents such as dimethylsulfoxide, diethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Examples of the base which can be used include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, t 5 potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide and the like. Schemes 7-9 below describe procedures for further elaboration of the 6-position moiety of the compounds of the invention.
The deprotection of the 2'- and 4"-hydroxyl groups is then carried out according to methods described in literature, for example, by Greene and Wuts (op. cit.).
The conditions used for the deprotection of the 2'- and 4"-hydroxyl groups usually results in the conversion of X to =N-OH. (For example, using acetic acid in acetonitrile and water results in the deprotection of the 2'- and 4"-hydroxyl groups and the conversion of X from =N-O-Rl or =N-O-C(RS)(R6)-O-Rl,where R1, RS and R6 are as defined previously, to =N-OH.) If this is not the case, the conversion is carried out in a separate step.
The deoximation reaction can be carried out according to the methods described in the literature, for example by Greene and Wuts (op. cit.) and others. Examples of the deoximating agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulflte, sodium dithionate, potassium thiosulfate, potassium metabisulfite and the like, and inorganic nitrite salts such as sodium nitrite or potassium nitrite.
Examples of the solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or a mixture of one or more of the mentioned solvents and the like. The deoximation reaction is more conveniently carried out in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound ~ used. In a preferred embodiment, the deoximation is carried out using an organic acid such as fomvc acid in ethanol and water to give the desired product ~.

Scheme 2 illustrates the conversion of intermediate ~ to compounds of formula (I) of the invention. The cladinose moiety of macrolide 6_ is removed either by mild aqueous acid hydrolysis or by enzymatic hydrolysis to give 7. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. Reaction times are typically 0.5 to 24 hours. The reaction temperature is preferably -10 to 35 °C. Compound 7 is converted to $~ which is protected at the 2'-hydroxy position, by treatment with a suitable hydroxy protecting reagent such as acetic anhydride, benzoic anhydride, benzyl chloroformate or trialkylsilyl chloride in an aprotic solvent, as defined previously, preferably dichloromethane, chloroform, DMF, tetrahydrofuran ('IT3F), N-methyl pyrrolidinone or a mixture thereof. Prefenred protecting groups are trimethylsilyl, acetyl and benzoyl. Compounds Z and 8_ are compounds of formula (I). It is possible to reverse the order of the steps for removing the cladinose and protecting the 2'-hydroxy group without affecting the yield of the process.
Compound _8 is then treated with an excess of NaH at from 0 to -30°C
under an inert atmosphere in an aprotic solvent such as THF, followed by reaction of the intermediate anion with CS2 and CH3I at about -5 to 10°C, to form the xanthate intermediate 9, which is then treated with about l.l-1.3 equivalents of Bu3SnH under an inert atmosphere in the presence of a catalytic amount of AIBN or other suitable radical initiator, in a solvent suitable for a free radical reaction, such as benzene or toluene, for example, at reflux conditions to afford the desired 3-deoxy compound ~, which is a compound of formula (I) wherein U is hydrogen.
Treatment of compound $ with a reagent L-T-R~, wherein T and R~ are as previously defined, and L is a suitable reactive leaving group, such as a halogen, for example, in the presence of base gives compound 11.
These reactions are well known to those skilled in the art. For example, to prepare compounds ~ wherein T is -C(O)-, having the formula O-C(O)-R~, compound $ is reacted with the appropriate aryl halide having the formula halogen-C(O)-Rl or an acyl anhydride having the formula O-(C(O)-R~)2 in an aprotic solvent and in the presence of a tertiary organic amine base, such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N-3o methylpyrrolidine, or the like, or an inorganic bases such as Na2C03, K2C03, NaH, KH, LiH, or the like, at a temperature from about 0 °C to about i 50 °C.
To prepare compounds l~l wherein T is -C(O)-O-, having the formula O-C(O)-O-Rt, compound $ is reacted with the appropriate carbonate compound of the formula RIO-C(O)-O-Rt under similar conditions.
To prepare compounds 11 wherein T is -CH2-, having the formula O-CH2-Rt, compound 8_ is reacted with a strong base, such as an alkali metal hydride or hexamethyldisilazane, for example, followed by reaction with the appropriate alkyl halide having the formula halogen-CH2-Rt.

To prepare compounds a wherein T is -C(S)-S-, having the formula O-C(S}-S-Rt, compound $ is reacted with a strong base, such as an alkali metal hydride or hexamethyldisilazane, for example, followed by reaction with CSZ then the appropriate organohalide having the formula halogen-R~.
S To prepare compounds ~ wherein T is -C(O)-N(RS)-, wherein RS is H or C1-C6-alkyl, having the formula O-C(O)-N(RS)-R~, compound $ is treated with a strong base such as NaH, LiH, NaN(TMS)2, or the like, followed by a carbamoylating reagent, or $ is reacted with the appropriate isocyanate having the formula O=C=N-Rt in the presence of a tertiary amine base.
Alternately, compound $ may be reacted with a carbonyl compound such as carbonyl diimidazole or carbonyl bis(benzotriazole) followed by reaction of the intermediate thus formed with an amine having the formula N(RS)H-Rl to prepare the desired compound.
To prepare compounds ,~,1 wherein T is -S(O)S-, wherein n is 0, 1 or 2, having the formula O-S(O)S-Rt, compound $ is reacted with the appropriate acid anhydride compound of the formula O-(S(O)"-Rl)2 in an aprotic solvent and in the presence of a tertiary organic amine base, such as triethylamine, dimethylaminopyridine, N-methylmorpholine, N-methylpyrrolidine, or the like, or an inorganic bases such as Na2C03, K2C03, NaH, KH, LiH, or the like, at a temperature from about 0 °C to about 150 °C.
To prepare compounds 11 wherein T is -S(O)"-, wherein n is 0, 1 or 2, having the formula O-S(O)"-O-Rl, compound $ is reacted with the appropriate acid chloride of the formula Cl-S(O)"-O-R~ under similar conditions.
To prepare compounds ~ wherein T is -P(O)(OR~~-, wherein n is 0, 1 or 2, and RI is C1-C6-alkyl, having the formula O-P(O)(OR~)n-Rt, compound $ is reacted with the appropriate acid chloride of the formula CI-P(O)(OR~~-R~ under similar conditions.
To prepare compounds a wherein T is -S02-N(RS)-, wherein RS is as defined previously, having the formula O-S02-N(RS)-R~, compound $ is reacted with the appropriate acid chloride of the formula Cl-S02-N(RS)-Rt under similar conditions.
To prepare compounds ~ wherein T is a 2-tetrahydropyranyi heterocycloalkyl group, compound $ is reacted with 3,4-dihydro-2H-pyran in an aprotic solvent in the presence of a acid catalyst.
The 2' hydroxy protecting group of compounds ~Q and ~, may optionally be removed by standard methods to give the desired unprotected compounds of formula {I).
When RP is an ester such as acetate or benzoate, the compound may be deprotected by treatment with methanol or ethanol. When RP is a triallcylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile.
The 9-oxime derivatives of compounds ,LQ and 11 may optionally be prepared by reaction with hydroxylamine hydrochloride in the presence of base, or hydroxylamine in the presence of acid as described in U.S. Patent 5,274,085, to form the compounds of formula (1) wherein X is =N-OH or =N-O-R1 wherein R1 is H. Reaction with the substituted hydroxylamine NH20R1, or NH2-O-C(RS)(R6)-O-Rl results in the formation of compounds in which R1 is other than H. Alternately, compounds wherein Rl is other than H
may be prepared by initial formation of the unsubstituted oxime as described above followed by ' reaction with R1X' wherein X' is a suitable leaving group such as halogen.
The 9-amino derivatives of compounds 10 and 1 I may optionally be prepared by preparing the 9-oxime, reducing the 9-oxime to the 9-amino compound by treatment with a borohydride reducing agent or hydrogen gas in the presence of a noble metal catalyst, then treatment of the amine with the appropriate aldehyde or dialdehyde to prepare an intermediate imine, and reducing the imine by treatment with a borohydride reducing agent or hydrogen gas in the presence of a noble metal catalyst to prepare desired compound wherein the 9-substitutent is an amino group of the formula HNR~Rg wherein R~ and Rg are as previously defined.

Scheme 1 O i NMe2 H i NMe2 0,,,, ~ I
.OOH O 0~~..
HO,,,, ~~.,, y 6 HO~~~.
HO ~~~~ O O ~ 6 '''~ O
'',,. _ . O
O v O''~.. 0,,,, p O
O .'~ .~,~ O- H O .~~~ O- H
OMe .~~OMe V R Rp0 NMe2 v H P NMe2 ..
,.O O R O'a I~ ~.,, ~.
HO.,, 6 O HO . ~~~~ O O
-.... ..,..
_ On. O
O O
O ,,~ ~~~~ORp O ''~~ORp OMe .~~OMe OH R H NMe2 R H NMe2 O I I
N ~ I I ,,,, ,. HO,,,.
O 0~~~' 6 HO,,~. ~~~i .,,~ O HO O O
HO p ''',..
--O 0.,, ; O
_ 0~.... O
O
O ~.,~ o- H O .,,~ .~~~ O- H
'~., OMe OMe '~

Scheme 2 O R H NMe2 O R i NMe2 O O~'. O Oro.
,' i,,~~ ,' HO,,,, HO,,,.
HO .~~r O HO
OH
O y..~ O- H O
OMe P
O R R NMe2 O R RP NMep 0~... I
.. ''O O 0~...
HO,,,. '!~., ~' ."r HO,,,.
HO O ~ '~rr O
HO
v.,,.. ,.~..-- _ O' OH
C(S)-S-CH3 ~n O
1~ $
NMe2 O R RP NMe2 0~... O On.
.' ~.
HO.
O ~ O 11 Scheme 3 illustrates the methods used to prepare compounds of formula (II) of the invention. The 6-O-substituted compound l may be converted to a hydroxy-protected compound Z and treated with acid to remove the cladinose to give compound $ as described in scheme 2.
Compound $ may be treated by oxidation of the hydroxyl group to an oxo group at the 3-position followed by selective reduction at the 3-position to give the compound $ wherein the hydroxyl group is in the non-natural (3R form). Alternately, compound $ may be treated by oxidation of the hydroxyl group to an oxo group at the 3-position followed by non-selective reduction to give the compound having 3- and 9-position hydroxyl groups, followed by selective re-oxidation of the 9-OH group to the oxo group, to give the compound $ wherein the _Sg_ hydroxyl group is in the non-natural {3R form). In these cases, it may be necessary to separate the various isomers by chromatography, as is well know in the art. The isomerization procedures may be interjected into any of the schemes below to give the desired compound having the non-natural (3R) hydroxyl group at the 3-position.
Alternately, compound 6 may be converted to a hydroxy-protected compound 14 with a suitable hydroxy protecting group by the procedures referenced previously.
Compounds $ and 14 can then treated with an excess of sodium hexamethyldisilazide or a hydride base in the presence of carbonyldiimidazole in an aprotic solvent for 8 to 24 hours at about -30 °C to room temperature to give compounds ~B and 1~A, respectively. The hydride base may be, for example, sodium hydride, potassium hydride, or lithium hydride, and the aprotic solvent may be one as defined previously. The reaction may require cooling or heating from about -20°C to about 70°C, depending on the conditions used, and preferably from about 0°C to about room temperature. The reaction requires about 0.5 hours to about 10 days, and preferably about 1-5 days, to complete. Portions of this reaction sequence follow the procedure described by Baker et al., J. Org. Chem., 19$8, 53, 2340, which is incorporated herein by reference.
Alternately, treating 8 with a sulfonylating agent, such as methanesulfonyl anhydride, methanesulfonyl chloride, ethanesulfonyl chloride, or p-toluenesulfonyl chloride, in a aprotic solvent with stirring at from about 0°C to ambient temperature for about 1 to about 24 hours to provide a selectively 3-O-sulfonated compound (not shown), followed by treatment of this 2o suifonated compound with a hydride base in the presence of carbonyldiimidazole in an aprotic solvent gives the desired 2,3 unsaturated compound 15B.
Treatment of compound 15A, wherein U is the -O-4"-acetylcladinose moiety, with aqueous ammonia results in formation of the cyclic carbamate 16A, wherein U is the -O-4"-acetylcladinose moiety RW is absent and RW is H. Treatment of compound 1~B, wherein U
and U' are taken together to form a double bond, with aqueous ammonia results in formation of the cyclic carbamate 16B, wherein U and U' are taken together to form a double bond.
Likewise, reaction of compounds ISA or ISB, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, with a substituted amine compound of the formula H2N-W-RW, wherein W is absent and RW is not H
but is otherwise as previously defined, results in formation of the N-substituted cyclic carbamates 16A or l~fi~, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, and W is absent.

Scheme 3 R i NMe2 O I
O
HO,,~.
HO
v..~.. ---O _ On...
O .~~ O- H
'%
OMe Rp NMe2 O R RP NMe2 ~ I
O 0~~.
,.....
HO,,,, J HO .,r, O
---~U
O
O ~ ,~~ ~ Rp O U.
. ~OMe UU is OHOH
R; O R Rp NMe2 - ~ Rp NMe2 I I I
v ~,,,. ~ O
O~ N~~~ .~., N~ N
O O ~ O
~U ~ O
O
U' O
16A. U is O-4"-acetvlcladinncP ISA. U is O-4"-acetylclad_inncw 16B. U and U' form a do able bond 15B. U and U' form a do able bond 18.(II).UisH
1C2A. ----~ 17. lII). U is OH
19. IIII. U is O-T-Rl Also, reaction of compounds ~ or ~, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, with a hydroxylamine compound of the formula H2N-W-RW, wherein W is absent or -O- and Rw is as previously defined, results in formation of the substituted cyclic carbamate ~
or ~$, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is-O- and Rw is as previously defined.
Reaction of compound compounds _1~A_ or 15~, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, with unsubstituted hydrazine results in formation of the cyclic carbamate 1~A or 1C~B, wherein U
is the -0-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W
is -NH- and RW is H.
Reaction of compounds 5~A or 15$, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, with a substituted hydrazine compound of the formula H2N-NH-RW wherein RW is not hydrogen but otherwise is as previously defined results in formation of the cyclic carbamate compound 16A
or 1 CAB, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is -NH-RW and RW is not hydrogen but otherwise is as previously defined.
Alternate or additional procedures may be used to prepare compounds of formula (II).
For example, treatment of a compound _1~A or 15B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, wherein W is absent and RW is H with an alkylating agent having the formula RW-halogen, wherein RW is not hydrogen but otherwise is as previously defined, gives a compound 16A or 1C~B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is absent and RW is not hydrogen.
Similarly, treatment of a compound 15A or 15B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W
is -NH- and RW is H with an alkylating agent having the formula RW-halogen, wherein RW is not hydrogen but otherwise is as previously defined, gives a compound 1~A or l~B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is -NH- and RW is not hydrogen.
Treatment of compound 15A or _1 ~B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is -NH-and RW is H with an acylating agent selected from the group consisting of the acyl halide RW-C(O)-halogen or the acid anhydride (RW-C(O))2-O, wherein RW is not hydrogen but is otherwise as previously defined, gives a compound 1~A or 1~, wherein U is the -O-4"-acetylcladinose moiety or U
and U' are taken together to form a double bond, respectively, W is -NH-CO-and RW is as previously defined.

Treatment of a compound 5~A or 1~8, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, W is -NH-and RW is H
with an aldehyde RW-CHO, wherein RW is as previously defined, gives a compound C~A or 16B, wherein U is the -O-4"-acetylcladinose moiety or U and U'~ are taken together to form a double bond, respectively, W is -N=CH- and Rw is as previously defined.
Removal of the cladinose moiety from a compound 1~A by acid hydrolysis as described previously gives a compound 17, which is a compound of formula (II) wherein U
is hydroxy and U' is H.
Compound 17 may then be treated by the procedure described previously for the conversion of compound 8 to 10 to give the desired compound 18 of formula (II) wherein U
and U'are H.
Compound 17 may also be treated by the procedure described previously for the conversion of compound 8 to 11 to give the desired compound 19 of formula (II) wherein U is -O-T-RL and U' is H.
Optional deprotection of the 2'-hydroxy group from compounds C~B, 17, 1_$ and 19, by the methods described earlier provides the desired unprotected analogous compounds of formula (II).
Scheme 4 describes the preparation of compounds of formula (III). Compound 1~
or 1_~B-, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively, is treated with ethylenediamine 20 in a suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic carbamate compound 21A or 21B, wherein U is the -O-4"-acetylcladinose moiety or U and U' are taken together to form a double bond, respectively. Compound 21 A or 21 B is then cyclized by treatment with dilute acid, such as acetic acid or HCl in a suitable organic solvent such as ethanol or propanol, to give compound 2~ or 22B.
The cladinose moiety is then removed from compound 22A. wherein U is an -O-4"-acetylcladinose moiety, to give compound 23, which is a compound of formula (III) wherein U
is hydroxy and U' is H. Compound his then converted to compounds 24 and 25 by the procedures described in Scheme 3 for conversion of compound 17 to compounds 18 and l~, 3o respectively. Compounds 22B, 2~,, 24 and 25 are embodiments of the compounds of formula (III). Optional deprotection of these compounds may be performed by methods described previously.

Scheme 4 - ~ RP NMe2 N~ N 7 O

O

15A. U is O-4"-acer<rlcla~inose_ 15B. U and U' form a double bond NH2 R RP NMe2 O I I
O O~~.
,.
O~ N,~... "~~ O
O
N R NMe2 .' I I
HO,~, O
O
U' f~lir... ,,~~ O
O O 21 A. U is O~"-acetylcl ino 21 B. U and U' form a double bond t 'U
O
U' O
N R NMe2 22A. U is O-4"-acety adinnce~ ~ p HO,,,, 22B. U and U' fofm a do ~hte hr,nrl rr...
N~~..
..~~ O O
O
..~' -U
O
U' 24. IIII). U is H O
23. U is OH
25. QIII. U is O-T-Rl Scheme 5 illustrates the preparation of the cyclic carbonate compounds of formula (IV).
In particular, the 2' protected compound 14, prepared as shown in Scheme 3, is converted to the cyclic carbonate 2_ø by controlled reaction at low temperatures (about -30 °C) for a short period (about 30 minutes) with carbonyldiimidazole and sodium hexamethyldisilazide:
Alternately, compound 2~l is prepared from 14 by careful reaction with sodium hydride or lithium hydride and phosgene, diphosgene or triphosgene under anhydrous conditions with careful control of the amount of base present in order to prevent base catalyzed decarboxyiation. Compound 2_C is hydrolyzed to give compound 27, which may be isomerized to the(3R) isomer as described above, if so desired.
Compound ~ is then converted to compounds 28 or _2~ by the procedures described in Scheme 3 for conversion of compound ~ to compounds _1$, and 19, respectively.
Compounds _2$, and 29 are additional embodiments of the compounds of formula (IV).
Optional deprotection of the these compounds is by methods described previously.

Scheme 5 O R RP NMe2 O R RP NMe2 ,, ,.O O''~~ ,,~, ~O 0~~..
HO~,,. .~II O ~ O~ W...
HO ~ O~ ~~ ~ O
.~' O- R p O
14 ~~~OMe ~ ' .~~OMe 28, IIVI. U is H
29. (IVI. U 'c n_T-Rl Scheme 6 describes the preparation of compounds of formula (V). Compound 14 may be treated with formaldehyde in the presence of an acid, or with chloroiodomethane in the presence of base (according to the procedure of Hunt et al., J. Antibiotics, (1988), 41: 1644) to give the protected 11,12-methylenedioxy compound ~Q which is a compound of formula (V) wherein RP is a hydroxy protecting group. This compound may optionally then be deprotected at the 2' position by methods described previously to give a 11,12-methylenedioxy compound of formula (V) wherein RP is hydrogen. Compound ,3Q is hydrolyzed to give compound ~.
Compound ,3,~ is then converted to compounds 32 or ~ by the procedures described in Scheme 3 for conversion of compound ~ to compounds 18 and _l~, respectively.
Compounds 32 and 33 are additional embodiments of the compounds of formula (V). Optional deprotection of the these compounds is by methods described previously.
Scheme 6 O R RP NMe2 O R RP NMe2 ,.O O''~~ , O
HOr.,. .,,r O ~ O-~ n ...r HO' .~~O-RP O ~.~'~O_RP
14 ~~~OMe 3Q ~~OMe 32.fVl.UisH
33. (Vl. U is O-T-R~

Scheme 7 describes representative examples of further elaboration of the 6-position moiety of the compounds of the invention. The desired 6-O-substituted compound may be prepared directly as described above or obtained from chemical modification of an initially prepared 6-O-substituted compound. For example, compound 3,~ where R is 6-O-CH2CH=CH2 and M' represents the macrolide ring system can be further derivatized. The double bond of the allyl compound can be (a) catalytically reduced to give the 6-O-propyl compound 3,~; (b) treated with osmium tetroxide to give the 2,3-dihydroxypropyl compound ,~
which in turn may be functionalized, such as by esterif'lcation with an acylating agent such as an acyl halide or acyl anhydride, at each oxygen atom to give ,~; (c) oxidized with m-chloroperoxybenzoic acid in an aprotic solvent to give the epoxy methyl compound ~$ which can be opened with nucleophilic compounds, for example, amines or N-containing heteroaryl compounds, to give compounds with N-containing side chains ~9_; (d) oxidized under blacker conditions as described by Henry in "Palladium Catalyzed Oxidation of Hydrocarbons", Reidel Publishing Co., Dordrecht, Holland ( 1980), to give the 6-O-CH2-C(O)-CH3 compound 4~( ;
and (e) ozonized to give the aldehyde 41 which can in turn converted to oximes 42 and 4~ by reaction with H2NOR3 or H2NOH respectively, or reductively aminated, such as with a suitable amine in the presence of a borohydride reducing agent or by formation of the imine and subsequent catalytic reduction, to give the amine 44. Reaction of the oxime _43 with diisopropyl carbodiimide in an aprotic solvent in the presence of CuCI gives the nitrite 4~.
Reaction of 34 with an aryl halide under Heck conditions in the presence of (Pd(II) or Pd(O), phosphine, and amine or inorganic base (see Organic Reactions, 1982, 27, 345-390) gives 46.
Reduction of the double bond in ,4~, for example using H2 and palladium on carbon gives ~.

Scheme 7 ORs M'- O OH
~ ~ Rs M'~ N~
I
OH R' HO
O
M ~-- ~O
M'- O OH
O
~CH3 Ms.O M,-O -'" M'-O CH3 Ar NHRs M O ~ M~ O 41 M'-O
Ar M- O ~ / N- OH
--C-N
i M,- O M'-- O
N- O
~//
M'- O 4Z
-b7-Scheme 8 illustrates an alternate procedure for preparing compounds of formula (II) wherein R is substituted alkenyl. The 6-O-allyl erythromycin compound l~A, wherein R is allyl, is converted to the compound 48 by removing the ciadinose and protecting the free 3-hydroxyl group as described in earlier Schemes. Subsequent reaction of the compound 4~ with a compound having the formula R**-halogen, wherein R** is aryl, substituted aryl, heteroaryl or substituted heteroaryl, under Heck conditions in the presence of (Pd(II) or Pd(O), phosphine, and amine or inorganic base, gives the desired compound 49 wherein R is substituted alkenyl.
Alternately, compound ~, wherein R is allyl, is converted to the 6-O-(substituted to alkenyl) compound of formula ~( by reaction with an aryl halide, a substituted aryl halide, an heteroaryl halide or substituted heteroaryl halide under Heck conditions with (Pd(II) or Pd(O), phosphine, and amine or inorganic base, as just described. Compound 5Q may then be converted to the desired compound 4~ wherein R is substituted4 alkenyl, by removing the cladinose and optionally deprotecting as described in earlier Schemes.
is These procedures may be employed whenever any other modification of the 6-O-substitutent is also performed, such as with the modifications described in Schemes 7 or 9.
Representative examples of still further elaboration of the 6-position are shown in Scheme 9. The desired 6-O-substituted compound may be prepared by chemical modification of an initially prepared 6-O-propargyl compound. For example, compound ~, which 20 illustrates a compound of the invention where R is propargyl and M' represents the macrolide ring system, can be further derivatized. The triple bond of compound 51 can be treated with an aryl halide, a substituted aryl halide, a heteroaryl halide or substituted heteroaryl halide in the presence of Pd(triphenylphosphine)2C12 and CuI in the presence of an organic amine, such as triethylamine, to give the compound 52. Compound 52 can be further selectively reduced to 25 the corresponding cis-olefin compound ~ by catalytic hydrogenation in ethanol at atmospheric pressure in the presence of 5% PdBaS04 and quinoline {Rao et al., J. Org.
Chem., (1986), ~: 4158-4159). Compound 51 may also be treated with a boronic acid derivative HB(ORT~), wherein RZZ is H or Cl-Clp-alkyl, in an aprotic solvent at 0 °C to ambient temperature to give compounds 54, which are then treated with Pd(triphenylphosphine)4 and an aryl halide, a 30 substituted aryl halide, an heteroaryl halide or substituted heteroaryl halide under Suzuki reaction conditions to give compounds ~. Compound ~ 1 may also be treated with N-halosuccirumide in acetic acid to give compounds S~C. Also, compound S I may be treated with a substituted alkenyl halide, such as Ar-CH=CH-halogen, wherein Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, in the presence of Pd(triphenylphosphine)2C12 and CuI in 35 the presence of an organic amine, such as triethylamine, to give the appropriately substituted compounds ,52.

Scheme 8 R ~ O RP NMe2 R \ O Rp NMe2 ~- ~''O O',~ W ~i 'O
O \ N~ ...
O~ N~~~.
O O O O '~~~ O O
''....
1 ' O-Z, -,--~ _ O O~ O' Rp O "
O
1iA
Z' is 4"-acety lariinncr~
R""
R'"
Rw ~ RP w NMe2 R ' Rp NMe2 W 0~~~. W O
v O~ O
O ~ ~ O
O O
Z' is 4"-acyyl-cfadinose Scheme 9 Aryl Aryl M'- O ~ M'- O
M'-O
M'- O
Halogen M'- O
Aryl Aryl M'-O
M'- O

The foregoing may be better understood by reference to the following examples which are presented for illustration and not to limit the scope of the inventive concept.
Exam es The procedures described above for preparing the compounds of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
le 1 Comvound of Formula (Il~ R is ~yl Rp ,s H X is O L1 is OH
la: Com 4 o c m i - 1-' ro x c oh x 1 RP is trimethylsi,~,vl.
To a 0 °C solution of 2',4"-bis-D-trimethylsilylerythromycin A 9-[O-(1-isopropoxycyclohexyl)oxime (1.032 g, 1.00 mmol), prepared according to the method of U.S.

WO 99/11651 PCTlUS98/18125 Pat. No. 4,990,602 in 5 mL of DMSO and 5 mL of THF was added freshly distilled allyl bromide (0.73 mL, 2.00 mmol). After approximately 5 minutes, a solution of potassium tert-butoxide ( 1M 2.0 mL, 2.0 mL) in 5 mL of DMSO and 5 mL of THF was added dropwise over 4 hours. The reaction mixture was taken up in ethyl acetate and washed with water and brine.
The organic phase was concentrated in vacuo to give the desired compound (1.062 g) as a white foam.
Stew I b: Compound 5 from Scheme 1 ~ V is NOH R is allyl To a solution of the compound from step l a ( 1.7 g) in 17 mL of acetonitrile and 8.5 mL
of water was added 9 mL of acetic acid at ambient temperature. After several hours, the reaction mixture was diluted with 200 mL of toluene and concentrated in vacuo.
The residue obtained was found to contain unreacted starting material, so additional acetonitrile (15 mL), water (70 mL) and HOAc (2 mL) was added. After 2 hours, an additional 1 mL
aliquot of HOAc was added. After approximately three more hours, the reaction mixture was placed in i S the freezer overnight. The reaction mixture was allowed to warm to ambient temperature, diluted with 200 mL of toluene and concentrated in vacuo. The residue was chased twice with toluene and dried to constant weight (1.524 g).
Step lc: Comuound 6 from Scheme 1' R is allvl The compound resulting from step 1 b ( 1.225 g) in 16 mL of 1:1 ethanol-water was treated with NaHS03 (700 mg) and formic acid ( 141 ~L) at 86 °C for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with 5-6 mL of water, basified with 1 N NaOH to pH 9-10 and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo.
The crude material was purified by column chromatography, eluting with I% MeOH in methylene chloride containing 1% ammonium hydroxide, to give 686 mg (57%) of the title compound.
13C ~R (CDC13) b 219.3 (C-9), 174.8 (C-1), 135.5 (C-17), 116.3 (C-18), 101.9 (C-1'), 95.9 (C-1"), 79.7 (C-5), 78.8 (C-6), 78.5 (C-3), 74.1 {C-12), 72.4 (C-3"), 70.6 (C-I1), 68.1 (C-5'), 65.5 (C-16), 65.1 (C2'), 49.0 (C-3" O-CH3), 45.0 (C-2), 44.1 (C-8), 39.7 {NMe2), 37.9 (C-4), 37.1 (C-10), 34.6 (C-2"), 28.4 (C-4'); 21.0, 20.6 (C-3" CH3, C-6' CH3), 20.8 (C-14), 18.3 (C-6"), 18.1 (C-8 CH3), 15.7, 15.6 (C-2 CH3, C-6 CH3), I 1.9 (C-10 CH3), 10.1 (C-15), 8.9 (C-4 CH3). MS (FAB)+ m/e 774 [M+H]+, 812 (M+K)+.
Step ld: Compound of Formula (IO R is allyl RP is H X i O U i OH
To a suspension of the compound from step lc (7.73 g, 10.0 mmol) in ethanol (25 mL}
and water (75 mL) was added aqueous 1 M HCl ( 18 mL) over 10 minutes. The reaction mixture was stored for 9 hours at ambient temperature, then was left standing in the refrigerator overnight. Aqueous 2 M NaOH (9 mL, 18 mmol) was added, which resulted in the formation of a white precipitate. The mixture was diluted with water and filtered. The solid was washed with water and dried under vacuum to give the des-cladinosyl compound ,~ from Scheme 2) (3.11 g).
Ex 2 Compound of Formula (Iy R is allvl RP is benz2vl X is O ~IJ is O~H
To a solution of the product of Example 1 (2.49 g, 4.05 mmol) in dichloromethane (20 mL) was added benzoic anhydride (98%, 1.46 g, 6.48 mmol) and triethylamine (0.90 mL, 6.48 mmol), and the white suspension was stirred for 26 hours at ambient temperature.
1o Aqueous 5% sodium carbonate was added, and the mixture was stirred for 20 minutes then extracted with dichloromethane. The organic phase was washed with aqueous 5%
sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexanes) gave the title compound (2.46 g) as a white solid. MS (ESl) m/z 720 [M+H]+.
Example _3 Compound of Formula fIl: R is -CHI-CH=CH2-f3-q iu nolinvll RP is H X is O U is OH
Step 3a. Compound 8. Scheme 1 ~ R is -CH2-CH=CHI-l3-quinolinyll RP is benzovl To a sample of the compound from Example 2 (21.57g, 30 mmoi) in acetonitrile (200 mL) were added 3-bromoquinoline (6. I 1 mL, 45 mmol), palladium acetate ( 1.03 mg, 4.5 mmol), tri-(o-tolyl)phosphine (2.74 mg, 9.0 mmol) and triethylamine (8.36 mL, 60 mmol).
The mixture was degassed by bubbling N2 through it for 30 minutes, sealed in a tube under nitrogen, then heated at 60 °C for 1 hour and at 100 °C for 14 hours. The mixture was cooled ~5 to room temperature and diluted with ethyl acetate. The organic phase was separated, washed with saturated NaHC03 and brine, and dried over MgS04. The solvent was removed to give crude product which was purified by chromatography on silica gel, eluting with 40-60%
acetone/hexane to give the title compound (15.0 g, 60%). MS (ESI) m/z 847 +H
+, HRMS:
calcd for C4gH6~N201 ~, 847.4739; found, 847.4434.
Step 3b Compound of Formula fI)~ R is CH2 CH-CHI (3 qui olinyl) RP is H X is O
U
is OH
A solution of the compound from step 3b (200 mg, 0.118 mmol) in methanol (5 mL) was stirred at reflux for 6 hours. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) to give the title compound (170 mg) as a white foam. 13C NMR (CDCl3):
219.9, 175.0, 150.0, 147.4, 132.8, 129.9, 129.3, 129.1, 129.0, 128.8, 128.2, 128.0, 126.6, 106.5, 88.3, 79.0, 78.9, 76.6, 74.3, 70.6, 70.2, 69.3, 65.7, 64.0, 45.7, 44.5, 40.3, 38.2, WO 99/11651 PG"T/US98/18125 37.7, 36.0, 28.2, 21.6, 21.3, 19.7, 18.2, 16.4, 15.2, 12.5, 10.6, 8.31. MS m/z [M+H]+.
c 1 4 n f Form ~ R i - H - H - inol' RP ' i i O- 1 Stev 4a Compound of Formula lIl R is CHI CH-CH2 (3 uiq nolinyll RP is b~enzovl X is O. U is O-acetyl A sample of the compound from Example 3, Step 3a (100 mg, 0.118 mmol) was treated with acetic anhydride (29 p,L, 0.295 mmol), triethylamine (40 pL,, 0.295 mmol) and N,N-dimethylaminopyridine (2 mg, 0.0164 mmol) in dichloromethane (1mL) at room temperature for 3 days.
Step 4b. Compound of Formula (IO R i -CHI-CH-CH2 ( auinolin~l) RP is H X is O
U
is O-acetyl Methanol (6 mL) was then added to the reaction mixture from Step 4a, and the mixture was heated at reflux for 5 hours to remove the 2'-benzoyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the residue was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide ( 10:1:0.05 to 20:1:0.05) to give the title compound (79.6 mg, 86%) as a white foam. MS (ESI) m/z 785 [M+H]+, HRMS: calcd for C43H65N2011~ 785.4588; found, 785.4593.
Ex a Compound of Formula lIO R is -CH2-CH=CH2-f3-auinolin~rll RP is H X is O
2_5 U i s O-(4-methoxy)benzoyl_ Sa. m o of I ~ -C = C - - i o 'n 1 RP ' nz 1 X i O U is O-l4-methoxy)benzQ,~
A sample of the compound from Example 3, Step 3a (120 mg, 0.142 mmol) was treated with p-methoxybenzoyl anhydride (80 mg, 0.279 mmol) and N,N-dimethylaminopyridine (20 mg, 0.164 mmol) in anhydrous toluene (1mL) at 100°C for 4 days.
n F I' H- H= i in 1 Pi H Ui O-f4-methoxy),1 Methanol (6 mL) was added to the reaction mixture from Step 5a, and the mixture was heated at reflux for 5 hours to remove the 2'-benzoyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide (10:1:0.05 to 20:1:0.05) to give the title compound (105 mg, 85%) as a white foam. MS (ESI) m/z 877 [M+H]+, HRMS: calcd for C4gH6gN2011, 877.4$51; found, 877.4845.

Compound of Formula (IO R i -CH2 CH-CH2S_3~uinolin~rl) RP is H X is O
U is O-methanesulfonvl A sample of the compound from Example 3, Step 3a (4.94 g, 5.84 mmol) was treated methanesulfonyl anhydride (3.75 g, 21.9 mmol) and triethylamine (7.0 mL, 50.2 mmol) in anhydrous dichloromethane (50 mL) at 0°C to room temperature for 20 hours. The mixture was further diluted with dichloromethane, washed with aqueous NaHC03, dried, and concentrated.
Purification by flashing chromatography on silica gel with 3:2 hexane/acetone to give 2.14 g of product and 2.00 g of unreacted starting material.
A 50 mg sample of the above mixture was heated in methanol (3 mL) at reflux for 3 hours to remove the 2'-benzoyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide ( 10:1:0.05 to 20:1:0.05) to give the title compound (105 mg, 85%) as a white foam. MS (ESI) m/z 821 [M+H]+, HRMS: calcd for C42H65N2O~2S, 821.4258; found, 821.4258.
m 1 7 ComDOUnd of Formula (1O R is -CHI-CH=CHI-l3-c~uinolinyl) RP it H X"~"O U is O
CO
~2-nitrophenvl) Step 7a ComDOUnd of Formula (I)' R is -CH2 CH-CHI (3 quinolinyi) RP is benzoyl X is O. U is O-CO-NH-(2-nitro~henvl) A sample of the compound from Example 3, Step 3a ( 130 mg, 0.154 mmol) was treated with o-nitrophenyl isocyanate (38.0 mg, 0Ø232 mmol) and N,N-dimethylaminopyridine (24 mg, 0.197mmol) in anhydrous toluene (2 mL) at 100 °C for 4 hours.
7 . o of F r la I ~ R ' H= H= _ in lip 1 RP is H X i U
is O-CO-NH-(2-nitronhen~rl) Methanol (8 mL) was then added to the reaction mixture from Step 7a, and the mixture was heated at reflux for 5 hours to remove the 2'-benzoyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide ( 10:1:0.05 to 20:1:0.05) to give the title compound ( 129 mg, 93%) as a yellow foam. MS
(ESI) m/z 907 [M+H]+, HRMS: calcd for C4gH6~N3013, 907.4699; found, 907.4690.

nle 8 m f 1 II ~ i - H - =C olio 1 P i w ' H. U is OH
Step 8a. Compound 14 of Scheme 3 R is allyl RP is acetyl To a solution of the compound from Example 1 (80 g, 103 mmol and DMAP (4.0 g, 32.7 mmol) in dichloromethane (200 mL) was added acetic anhydride (40 mL, 400 mmol).
The solution was stirred for 5 hours at ambient temperature, and the mixture was diluted with dichloromethane (800 mL). The organic phase was washed with 5% Na2C03, saturated NaHCO3 and brine, and dried over MgS04. The solvent was removed under vacuum, and the residue was dried. The residue was crystallized from acetonitrile to give the title compound (60.0 g). MS (APCI) m/z 858 [M+H]+.
Step 8b Compound 15A of Scheme 3 R is allyl Rp is acetyl U is 4"
acetylcladin~se To a solution of the compound from Step 8a (42.85 g, 50 mmol) in THF (250 mL) t5 cooled to -40 °C in a dry ice-acetonitrile bath was added sodium bis(trimethylsilyl)amide (65.0 mL, I M in THF, 65.0 mmol) over 30 minutes. After 45 minutes, a solution of 32.43 g (200 mmol) of carbonyldiimidazole in 150 mL of THF and l0U mL of DMF was added. The mixture was stirred for 2.5 hours at -40 °C and I 8 hours at room temperature.
The reaction was quenched by adding a solution of 0.5 M NaH2P04 (500 mL). The product was isolated by extraction of the reaction mixture with ethyl acetate. The extract was dried with MgS04 and concentrated to give the crude product, which was purified by flash chromatography using 40-60% acetone/hexanes, yielding 46 g (100%) of the title compound. MS (APCI) m/z [ M+H]+.
Steu 8c. Compound 16A of Scheme 3 R is allyl R~ is acet~ U is 4"-acetylcladinose W is absent. RW is H
To a solution of the compound from Step 8b (40.0 g, 42.9 mmol) in acetonitrile (1000 mL) and THF (100 mL) was added concentrated ammonium hydroxide (28-30%, 120 mL).
The mixture was stirred at room temperature for 7 days, then the solvents were removed under vacuum and the residue was taken up in ethyl acetate. The organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide ( 10:1:0.05) to give the title compound (23.07 g). MS: [M+H]+ at m/z 883. HRMS: calculated m/z for [M+H]+
C45H74N2015:883.5162; Found: 883.5165.

Step 8d. Compound 16A of Sci,Pr"P ~ It ;~ _CH2_(rH-CH2 (~-a innli y1) Rpis acet<rl LT is 4"-4"-acetvlcladinose. W is absent R~' is H
To a solution of the compound from Step 8c (20.5 g, 23.2 mmol) in acetonitrile (200 mL) were added 3-bromoquinoline (6.47 mL, 31.1 mmol), palladium acetate ( 1.07 g, 4.76 mmol), tri-(o-tolyl)phosphine (2.43 g, 7.97 mmol) and triethylamine (9.13 mL, 65.5 mmol).
The mixture was degassed by bubbling N2 through it for 30 minutes, sealed in a tube under nitrogen, and heated at 60 °C for 1 hour and 14 hours at 100 °C.
The mixture was cooled and diluted with ethyl acetate, and the organic layer was separated and washed with saturated NaHC03 and brine, then dried over MgS04. The solvents were removed and the crude l0 product was purified by chromatography on silica gel eluting with 40-60%
acetone/hexane to give the title compound (21.0 g).
Step 8e. Compound of Formula /n~~ R ;s -CH2- H- H2~auinolin'rl) Rp is acet, 1 C1 is OH. W is absent. RW is H
Hydrolytically treating the compound of Step 8d with acid according to the procedure of Example 1, Step ld, gave the title compound. MS (APCI) m/z 810 [M+H]+.
Step 8f. Compound of Form na rllo R ;~ _CH~_~2~~uino i~2y1) RP is H U i OH
W is absent. RW is H
2U The product of Step 8e ( 100 mg, 0.124 mmol) was heated in refluxing methanol (2 mL) for 3 hours to remove the 2'-acetyl protecting group. At the completion of the reaction, the solvents were removed by evaporation, and the reside was purified by flash chromatography on silica gel eluted with dichloromethane/methanol/ammonium hydroxide (10:1:0.05 to 20:1:0.05) to give the title compound (90 mg, 94.8%). 1H (CDCl3) d 9.06 (1H, d, J = 2.4 Hz), 8.23 ( I H, d, J = 2.4 Hz), 8.06 ( 1 H, d, 8.4 Hz), 7.82 ( 1 H, dd, J =
8.7, 1.5 Hz), 7.65 ( 1 H, d, J = 8.1, 1.5 Hz), 7.51 ( 1 H, td, J = 8.1, 1.5 Hz), 6.70 ( 1 H, d, J
= 15.9 Hz), 6.39 ( 1 H, dt, J = 15.9, 6.6 Hz), 5.46 ( 1 H, s), 5.18 ( 1 H, dd, J = 10.2, 2.4 Hz), 4.46 ( 1 H, d, J =
7.2 Hz), 3.96 (m, 2H), 3.82 ( 1 H, s), 3.73 ( 1 H, s), 3.63 ( 1 H, d, J = 8.7 Hz), 3.51 ( 1 H, m), 3.24 ( 1 H, dd, J = 9.0, 6.9 Hz), 2.96 ( 1 H, q, J = 6.6 Hz), 2.73 ( 1 H, dq, J = 8.7, 6.6 Hz), 2.61 ( 1 H, m), 2.48 ( 1 H, m), 2.25 (6H, s), 2.03 ( 1 H, dd, J = 14.4, 7.2 Hz), 1.88 ( 1 H, m), I .66 ( 1 H, m), 1.57 ( 1 H, dd, J = 14.4, I .0 Hz), 1.51 ( 1 H, m), 1.47 (3H, s), 1.31 (3H, d, J =
6.6 Hz), 1.23 (3H, d, J = 6.0 Hz), 1.19 (3H, d, J = 8.1 Hz), 1.11 (3H, d, J =
6.9 Hz), 1.10 (3H, d, J = 6.6 Hz), 0.85 (3H, t, J = 7.5 Hz). MS (APCI) m/z 768 [M+H]+.

WO 99/11b51 PC"T/US98/18125 Ex lne9 H= Rp . W . Rw .
H. U is O-acetyl A mixture of a solution of the compound of Example 8, Step 8e (50 mg, 0.062 mmol) and DMAP (catalytic amount) in pyridine ( 1.0 mL) and acetic anhydride (0.5 mL) was stirred for 5 hours at ambient temperature. At the completion of the reaction, solvents were removed by evaporation under vacuum. The reside was redissolved in methanol (2 mL) and heated at reflux for 3 hours to selectively remove the 2'-acetyl protecting group.
Solvent was evaporated, and the crude product was purified by flash chromatography on silica gel to give the title compound (35 mg). MS (APCI) m/z 810 { M+H]+, HRMS: calcd for Cq~H~N3011, 810.4541; found, 810.4559.
Compound of Formula IIII R i~ H2 CH-CH2,~,n,v1) Rp is H W is ah nr aw;
H. U is O-(4-nitroben -ovl) A solution of the compound of Example 8, Step 8e, 4-nitrobenzoic anhydride (O.lOg, 0.316 mmol), DMAP (0.017 g, 0.135 mmol), and tributylamine (0.05 g, 0/059 mL, 0.247 mmol) in toluene (5 mL) was heated at 100 °C for 4 hours. The solution was diluted with ethyl acetate (40 mL), and the organic layer was washed with sodium carbonate, water and brine, dried (Na2S04), filtered and concentrated under vacuum. The crude product was purified by flash chromatography (7:3 acetone:hexane) to give 0.075 g (64%) of yellow foam. The product was dissolved in methanol (5 mL) and heated at reflux for 3 hours. The solvent was removed under vacuum, and the crude product was purified by flash chromatography with (94:5:1 dichloromethane:methanol:ammonium hydroxide) to give 0.075 g (64%) of the title compound. MS (ESI) m/z 917 [M+H]+.
Ex~ples 11-25 Following the procedures of Example 10, except substituting the acylating reagent shown in the table below for the 4-nitrobenzoic anhydride of Example 10, the compounds of 3o Examples 11-25 with U as shown in the table below were prepared.
p' w~
Vii. U is as shown x. No. ac Latin ent U is _ ~

benzoic y a nzoyl _ MS (E 722 [M+H+H]+

ac. J,J- v-t3,~- MS (ESn m/z 1025 [M+H]+
Xiphcen~ylhp diphenylpyridinecarbox ~ mecarbo is z-mtrot~enzoic O- -rut<obenzoyl MS (ESI) m/z 917 [M+H]+
anh Bride _77_ 14 3,4,5- O- 3,4,5- - MS (ESI) m/z 962 [M+H]+
trin~ethoxybenzoictrimethoxybenzoyl) anh Bride 15 2-thiophene carboxoylO-~2- MS (ESI ) m/z 878 [M+H]+

chlonde thiophenecarboxoyl)mss; calcd for ~9H64N3S01 i : 878.4262;

found, 878.4270 16 2-methylpropanoylO-(2-methylpropanoyl)MS (ESI ) m/z 852 [M+H]+

chloride HRMS: calcd for C47H69N3011: 852.5010;

found, 852.5018 17 4-bromobenzoic -( omobenzoyl) MS {ESI ) m/z 950 [M+H]+

anhydride HRMS: calcd for C49rN3011: 950.3802;

found, 950.3828 18 4-pyridinecarboxoyl-{ pyridinecarboxoyl)MS (ESI ) m/z 873 [M+H]+

chlonde HRMS: calcd for C48I;64N4011: 873.4650;

found, 873.4651 19 dimethyl drlcarbonate(me oxycarbonyl) MS (ESI ) m/z 826 [M+H]+

20 di-t-butyl-Bicarbonate-(1,1- MS P I m/z dimethylethoxycarbonyl[M+H]+

) 21 2-bromobenzolc -bromobenzoyl) MS (ESI ) m/'z 952 [M+H]+

anh Bride 22 4-methoxybenzoic-{ methoxy nzoyl) MS (ESI ) m/z 902 (M+H]+

anh Bride 23 2-furancarboxoyl-furancarboxoyl) MS (ESI ) m/z 862 [M+H]+

chloride utanolc anhy butanoyl MS (ESI ) m/z 838 de [M+H]+

25 methanesul~onyl -methanesu onyl MS (ESI ) m/z 846 [M+H]+

chloride HRMS: calcd for C43H64N3012S: 846.4211;

found, 846.4 26 2-methyl-propenoic-( - _ MS (ESI ) m/z 836 [M+H]+

anhydride methylpropenecarboxyo 1) _78-WO 99/11b51 PCTNS98/18125 mound of Formula IIIO R is -CH2-CH~H~-(3~t~inoLnyD RP is H X is O W is absent. RW is H U is O-CO-NH-nhen~
A solution of the compound of Example 8, Step 8e, (100 mg, 0.124 mmol), phenylisocyanate ( 19.4 mg, 1.61 mmol), and N,N-dimethylaminopyridine ( 15.1 mg, 0.124 mmol) in anhydrous toluene (2 mL was heated at 90°C for until the complete consumption of starting material as indicated by TLC analysis. The mixture was cooled to room temperature, and methanol (4 mL) was then added. The mixture was heated at reflux for 4 hours to remove t0 the 2'-acetyl group. Solvents were removed by evaporation, and the residue was purified by flash chromatography on silica gel eluting first with dichloromethane and then with dichloromethane/methanol/ammonium hydroxide ( 10:1:0.05) to give the title compound ( 105 mg, 100%). MS (APCI ) m/z 887 [M+H]+. HRMS: calcd for C49H6~N4011, 887.4806;
found, 887.4803 t5 Exam les 28-36 Following the procedures of Example 27, except substituting the isocyanate reagent shown in the table below for the phenyl isocyanate of Example 27, the compounds of Examples 28-36 with U as shown in the table below were prepared.
Compounds of Formula (II): R is -CH2- .H=CH2-(3-a, iu nolin~) RP is H W is absent RW is H. U is as shown Ex. isocyanate reagentis al. ata o.

allyl lsocyanate~ -NH-allyl MS (APCI ) m/z 851 [M+H]+

HRMS: calcd for C46H67N4011. 851.4806;

found, 851.4813 29 L-valine me yl - - H- MS (APCI ) m/z 925 ester [M+H]+

isocyanate CH(C(O)OCH3)- HAS: calcd, 925.5174;

CH(CH3)2 found, 925.5165 2-propy lsocyanate- O-NH- _ MS (APCI ) m/z 853 [M+H]+

CH(CH3)2 HRMS: calcd for C4gH~3N4013, 853.4963;

found, 853.4934 31 cyclohexyl isocyanate- O-NH- MS (APCI ) m/z 893 [M+H]+

cyclohexyl calcd for C49H~3N4011~

893.5276; found, 893.5279 32 4-fluorophenyl - - - - MS (ESI ) m/z 905 [M+H]+

isocyanate fluorophenyl) ~S; calcd for 0494011 ~ X5.4712;

found, 905.4710 -mtrophenyl ~$'~1 I-(~ MS (APCIJ m/z 932 [M+H]+
isocyanate nitrophenyl) CMS; calcd for CdgH~FN4011, 932.4657;
measured, 932.4648 s4 4-methyl-Z- O-CO-NH-(4- MS (APCI ) m/z 946 nitrophenyl isocyanatemethyl-2- [M+H]+

CMS; calcd for nitrophenyl) CSpH6~N50i3, 946.4814;

found, 946.4822 35 4-nitrophenyl - ~-( - MS (APCI ) m/z 932 [M+H]+

isocyanate nitrophenyl) HRMS: calcd for C49H66N5013~ 932.4657;

found, 932.4661 36 4-methoxyphenyl O- -NH-( MS (APCI ) m/z 917 [M+H]+

isocyanate methoxyphenyl} I~MS; c~cd for CSOH69N4012~ 917.4912;

found, 917.4899 ~~Z
Compounds of Formula (IIO R is -CH -~rH-~H~-(3 g iu nolinyl) RP is H W is absent Rw is H. U is O-S(O)S CH=CHI
To a stirred solution of the compound of Example 7, Step7e, (0.53 g, 0.655 mmol) in pyridine (17 mL), cooled to 0°C was added dropwise 2-chloro-I-ethanesuifonyl chloride (0.32 g, 0.21 mL, 1.97 mmol). The mixture was warmed to ambient temperature and stirred overnight. The mixture was diluted with ethyl acetate (40 mL), and the organic layer was washed with saturated sodium bicarbonate, water and brine, dried (Na2S04), filtered, and concentrated under vacuum. The crude material was purified by column chromatography eluting with 94:5: I dichloromethane:methanol:ammonia hydroxide. The product was dissolved in methanol (5 mL) and refluxed for 3 hours. The solvent was removed under vacuum, and the material was purified by column chromatography eluting with 94:5:1 dichloromethane:methanol:ammonia hydroxide, to give the title compound (0.071 g, 13%). MS
is (ESI) m/z 858 [M+H]+
Exggm lid C m oun o rm I 'R' i I P' H Wi wis H. U is O-Sl0)~ CHI-CHI-N(CH~I
To a solution of the compound from Example 37 (0.2g, 0.023 mmol) in acetonitrile (2 mL) was added dimethylamine (0.004 mL, 2M in THF). The solution was stirred for 12 hours, the solvent removed under vacuum, and the material was purified by column chromatography eluting with 70:30:2 acetone:hexaneariethylamine, to give the title compound (0.007g, 34%) of white foam. MS (ESI) m/z 903 [M+H]+.

Exam lp a 39 Compounds of Formula (Ii): R is -CHI _CH-CH~~uino inyl) RP is H W is absent.
R~ is H, U is O-S(O)2;~~~2-S-vhenvl Following the procedure of Example 38, except replacing the dimethylamine with thiophenol the title compound was prepared (O.OlSg, 38%). MS (ESI) m/z 968 [M+H]+.
1ae40 Compounds of Formula 111): R is -CH2-CH-CH2-l~ mL~~linyl) RP is H W is absent R~' is To a stirred solution of the compound of Example 8, Step 8e (0.08 g, 0.099 mmol) and allyl bromide, (0.023g, 0.017 mL, 0.198 mmol) in THF (2 mL) cooled to 0°C was added NaH (0.02 g, 60% in mineral oil, 0.495 mmol). The mixture was stirred overnight, then diluted with ethyl acetate (20 mL), washed with water and brine, dried {Na2S04), filtered, and concentrated under vacuum. The crude material was purified by column chromatography eluting with 94:5:1 dichloromethane:methanol:ammonia hydroxide. The product was dissolved in methanol (5 mL), and refluxed for 3 hours. The solvent was removed under vacuum, and the material was purified by column chromatography eluting with 94:5:1 dichloromethane:methanol:ammonia hydroxide, to give the tide compound (0.014 g, 18°k) as a white foam. MS (ESI) m/z 808 [M+H]+.
Example 41 (~omnound of Formula (In: R is~CH-~-CH-Cjj~ (3-a,L~'nniinyll_ RP is H W it abc nt R W i H. U is O-(4-morpholinecarbonyl)_ To a sample of the compound from Example 8, Step 8e (95 mg, 0.117 mmol) in dry THF (2 mL) cooled to -40 °C and flushed with nitrogen was added sodium bis(trimethylsilyl)amide (0.235 mL. 0.235 mmol) dropwise, and the mixture was stirred at -40 °C for 10 minutes. To this mixture was added 4-morpholinecarbonyl chloride (38.5 mg, 0.258 mmol. The mixture was stirred while the temperature was raised from -40°C to -10°C over 2 hours. TLC analysis indicated there was some starting material remained. The reaction mixture was cooled to -40°C, the both reagents were added in the same manner described above, and the reaction was let to proceed for an additional 2 hr with temperature slowly rising to room temperature. The reaction was diluted with ethyl acetate, washed with 5%
sodium bicarbonate and brine, dried over Na2S04, and concentrated to give crude product This material was treated with methanol (6 mL) at refluxing for 4 hours to remove the 2'-acetyl group to give the title compound. MS (ESI) m/z 881 [M+H]+. Calcd for Cø~H6gN4012, 881.4912;
found, 881.4926.

ale 42 Compound of Formula QI): R is -CHI-CH=CHI-f3-y nL~n~nh'n,~x~, RP is H W it ahcenrRW i H. U is O-R3rrrolidin_ylcarbonvl Following the procedure of Example 41, except replacing the 4-morpholinecarbonyl chloride with pyrolidinylcarbonyl chloride the title compound was prepared in 32 96 yield. MS
(ESI) m/z 865 [M+H]+.
Exam , le 4~
Compound of Formula IIII: R is -CH~-CH~CH2-l~~y~yl) RP is H W is hsenr RW i H. U is O-(2-tetrah~Ry~y~
A sample of the compound from Example 8, Step 8e (50 mg, 0.062 mmol) in dichloromethane (2 mL) was treated with 3,4-dihydro-2H-pyran (0.10 mL, 1.10 mmol) and a catalytic amount of p-toluenesulfonic acid at room temperature for 2 hours.
The reaction mixture was washed with aqueous NaHC03, dried, concentrated. The 2'-acetyl group was removed by the usual treatment with hot methanol to give the tide compound after chromatographic purification with 94:5:1 dichloromethane:methanol:ammonia hydroxide, (38 mg, 73.0%). MS (ESI) m/z 852 [M+H]+. HRMS: calcd for C47H~ON3011, 852.5010;
found, 852.5005.
Exam 1~
Compound of Formula fill: is -CHI-CH=CH~~uinolinvl) RP is H W is absent Rw is H. U is O-C(=S)-SCH~
To a solution of the compound from Example 8, Step 8e in THF at -20 °C
under an inert atmosphere was added excess NaH slowly over a 5 minute period, then after several minutes CS2 was added. Several minutes later methyl iodide was added, and the reaction mixture was allowed to gradually warm to 10°C. After 1 hour the reaction mixture was quenched with ethyl acetate. The organic layer is washed with saturated aqueous NaHC03 and brine, dried (MgS04), and concentrated to afford the crude product.
Chromatographic purification (silica, acetone/hexane ranging from 1:1 to 4:1 ) affords the C-3 xanthate compound. The 2'-acetyl group was removed by treatment overnight with hot methanol to give the title compound. MS (ESI) m!z 858. HRMS: calcd for C4q,H64.N201pS2, 858-4033;
Found, 858.4056.

Compound of Formula (In: R is -CHI-CH=CH? RP is H U and U' taken together are double bond. W is absent. R~' is H
Sten 45a. Compound of Formula lII): R is -CHI _H~H~ RP is benzcyrl U and U' taken together are double bond. W is absent. R~ i H
To a solution of the compound from Example 2 ( 10.0 g, 13.9 mmol) and CDI ( 11.5 g, 69.5 mmol) in THF ( 160 mL) and DMF (80 mL) cooled at -40 °C in a dry ice-acetonitrile bath was added sodium bis(trimethylsilyl)amide (60.0 mL, 1 M in THF, 60.0 mmol) over 30 minutes. The mixture was stirred for 2.5 hours at -40 °C and for 18 hours at room temperature. The reaction was quenched by adding a solution of 0.5 M NaH2P04 (200 mL).
The product was isolated by extraction of the reaction mixture with ethyl acetate. The extract was dried with MgS04 and concentrated to give the crude product. Without purification this material was dissolved in acetonitrile (160 mL), THF (16 mL) and concentrated ammonium hydroxide (28-30%, 32 mL). The mixture was stirred at room temperature for 3 weeks.
Solvents were removed in vacuo, and the residue was taken up in ethyl acetate.
The organic layers were washed with brine, dried over MgS04 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/MeOH/ammonium hydroxide (10:1:0.05) to give the title compound.
,fin 45b Compound of Formula IIII R is -CHI-CH-CH2 RP is H U and U' taken together are double bond. W is absent. RW is H
A sample of compound from Step 45a was treated with methanol at refluxing for hours to give the title compound. MS (ESI) m/z 623 [M+H]+.
E,~ a 46 Comnound of Formula (II): R is -CHZ-CH=CH2-(3-auinolin3rl) RP is H U and U' taken together are double bond W is absent RW is H
To a solution of the compound from Example 45, Step 45b (305 mg, 0.49 mmol) in acetonitrile (4 mL) were added 3-bromoquinoline (0.133 mL, 0.98 mmol), palladium acetate (22 mg, 0.098 mmol), tri-(o-tolyl)phosphine (45 mg, 0.147 mmol) and triethylamine (0.171 mL, 1.22 mmol). The mixture was degassed by bubbling N2 through for 30 minutes, sealed in a tube under nitrogen, and heated at 60 °C for 1 hour and 14 hours at 80 °C. The mixture was cooled and diluted with ethyl acetate, which was separated and washed with saturated NaHC03 and brine, then dried over MgS04. The solvents were removed and the crude product was purified by chromatography on silica gel eluting with 40-60%
acetone/hexane to give product (160 mg, 45%). MS m/z 750 {M+H]+. HRMS: calcd for C42H6pN309, 750.4330; found, 750.4317.

Examples 47-49 Following the procedures of Example 46, except substituting the aryl halide reagent shown in the table below for the 3-bromoquinoline reagent of Example 46, the compounds of Examples 47-49 with R as shown in the table below were prepared.
Ex. reagent K = Analytical data -_ No.

47 3-bromo-6- w w " MS m/z 795 [M+H]+. HRMS:

nitroquinoline( N ~ calcd for C2H59N4011~

795.4180; found, 795.4197.

~ z-bromo-6- ~ ~ ~ ~ MS m/z 779 [M+H]+. HRMS:

methoxynaphthal~ ~ o,~. calcd for C~H63N2010.

e~ 779.4483; found, 779.4487.

49 3-(5-bromo-2- ~ s , ~ MS (ESI) m/z 772 [M+H]+.

furanyl)isoxazole Example 50 Compound of Formula IIVO R is -CHI-CH-CH2 RP is acetyl U is OH
Sten SOa Compound of Formula (IV) R is -CHI-CH-CH2 RP is acetyl U is 4"
To a solution of the compound from Step 8a ( 10.0 g, l l .b mmol) in THF ( 150 mL) cooled to -40 °C in a dry ice-acetonitrile bath was added sodium bis(trimethylsilyl)amide (12.8 mL, 1 M in THF, 12.8 mmol) over 30 minutes. After 15 minutes, a solution of carbonyldiimidazole (6.8 g, 41.9 mmol) in 90 mL of THF was added. The mixture was stirred for 2.5 hours at -40 °C, and warmed to room temperature for 30 minutes.
The reaction was quenched by adding a solution of 0.5 M NaH2P04 (50 mL). The product was isolated by extraction of the reaction mixture with ethyl acetate. The extract was dried with MgS04 and concentrated to give the crude product, which was purified by flash chromatography using 40-60% acetone/hexanes, yielding 6.41 g (62%) of the title compound. MS (ESI) m/z 8 84[M+H]+.
Step SOb Compound of Formula (IV) R is CH2 CH-CHI RP is acetyl U is OH
To a solution of the compound from Step SOa (6.35 g, 7.18 mmol) in ethanol ( 14 mL) and water (14 mL) was added hydrobromic acid (4 mL, 48%, 8.8 M) slowly, which caused the solution to become clear. At the completion of the reaction as judged by TLC, 2 N NaOH
( 17.8 mL) was added to quench the reaction. Ethanol was removed in vacuo, and the residue was taken up in ethyl acetate (250 mL). The ethyl acetate solution was washed with NaOH
{0.5 M), water, brine, dried over Na2S04, and concentrated. The crude product was purified by silica gel chromatography with 95:5:1 CH2C12:MeOH:NH40H to give the title compound as a white foam (3.72 g, 75.8% yield). MS (ESI) m/z 684 [M+H]+.
Example 51 Compound of Formula IIVI: R is -CH2-CH=CHI-i3-quinoliny~~ RP is acetyl U is OH
To a solution of the compound from Example 50 ( 1.6 g, 2.34 mmol) in acetonitrile (20 mL) were added 3-bromoquinoline (0.511 g, 2.46 mmol), palladium acetate (53 mg, 0.022 mmol), tri-(o-tolyl)phosphine (71 mg, 0.022 mmol) and triethylamine (0.61 g, 4.68 mmol).
The mixture was degassed by bubbling N2 through it for 30 minutes, sealed in a tube under nitrogen, and heated at 60 °C for 1 hour and 14 hours at 100 °C.
The mixture was cooled and diluted with ethyl acetate, and the organic layer was separated and washed with saturated NaHC03 and brine, then dried over MgS04. The solvents were removed and the crude product was purified by chromatography on silica gel eluting with 40-60%
acetone/hexane to give the title compound. MS (ESI) m/z 811 [M+HJ+.
IS
Example 52 Compound of Formula IIII): R is -CH2-CH=CHI RP is H U is OH U' is H
Step 52a. Compound 21A of Scheme 3. R is allvl RP is acetyl 2o To a solution of compound from Example 8, Step 8b (3.65 g, 3.91 mmol) in acetonitrile (40 mL) and THF (4 mL) was added ethylenediamine (2.67 mL, 39.1 mmol). The solution was stirred under nitrogen overnight at room temperature, then heated at 80 °C for 3 hours. Solvents were removed by evaporation, and the residue was taken up in ethyl acetate.
The solution was washed with NaHC03, brine, dried and concentrated.
Step 52b. Compound 22A of Scheme 3. R is allyl RP is H
The compound from Step 52a was redissolved in a mixture of ethanol/acetic acid (40 mL/0.4 mL), and the mixture was heated at reflux for S hours. Ethanol was evaporated off, residue was taken up in dichloromethane, which was then washed with aqueous sodium bicarbonate, brine, dried and concentrated.
Step 52c. Comvound 22A of Scheme 3 R is allyl RP is acetv_1 A solution of the crude product from Step 52b in dichloromethane (50 mL) was treated with acetic anhydride (2.40 mL) and triethylamine (3.50 mL) at room temperature for 24 hours.
Solvent and unreacted reagents were evaporated off, and the crude product was purified by chromatography with 10:1:0.05 CH2C12:MeOH:NH40H to give the title compound (2.70 g, 90.2% yield for three steps). MS (ESI) m/z 908 [M+HJ+.

WO 99/11651 PC'T/US98/18125 step 52d. Compound 22A of Scheme 3. R is all~rl.
To a suspension of the compound from Step 52c (2.10 g, 2.32 mmol) in ethanol (20 mL) was added aqueous 2 N HCl (20 mL) over 10 minutes. The reaction mixture was stirred at ambient temperature for 16 hours, at which time TLC analysis indicated completion of the reaction. A 50 mL portion of ethyl acetate was added to the reaction mixture followed by 20 mL 2 N aqueous NaOH. The mixture was further diluted with ethyl acetate and saturated NaCI. Layers were separated, the organic phase was washed with saturated NaCI
solution, dried and concentrated under vacuum to give the des-cladinosyl title compound, (1.29 g, 78.8%). MS (ESI) m/z 708 [M+H]+; HRMS: calcd for C37H62N3010: 708.4435; Found, t0 708.4420.
Stgp 52e Corr~oynd of Formula (III)' R is -CHI-CH-CHI RP is H U is OH U' is H
A sample of compound from Step 52d was refluxed in methanol for 4 hours to removing the 2'-acetyl group and give the title compound. MS (ESI) m/z 666 [M+H)+.
Example 53 Compound of Formula (lII): R is -CHI-CH=CH2-(3-quinolinyl) RP is H U is OH U' is H
Step 53a. Compound of Formula (IIl): R is -CND-CH=CH,2-(3-quinolinyl) RP is acetyl U is OH. U' is H
Following the procedure of Example 46, except substituting the compound of Example 52, Step 52d for the starting material in example 46, the title compound was prepared. MS
(ESI) m/z 935 [M+H]+.
Step 53b. Com~~ound of Formula (III): R is -CH2-CH=CH2-(_3-auinolinyl). RP is H, U is OH. U' is H
A sample of compound from Step 53a was refluxed in methanol for 4 hours to remove the 2'-acetyl group and give the title compound. MS (ESI) m/z 793 [M+H]+.
Exam In a 54 Compound of Formula (tV): R is -CHI-CH=CH2~3;~uinolinyl~ RP is H U is O-C(O)-phenvl Following the C3-O-acylation and C2'-deacetylation procedures described in Example 10, except substituting benzoic anhydride for the acetyl anhydride thereof, the title compound was prepared in two-steps. MS (ESI) m/z 897 [M+H]+.

E~~m In a 55 Compound of Formula lIV): R is -CH2-CH~CH2-l,~auinolinyl) RP is H U is O-C(O)-l2-nitrophenvl) Following the C3-O-acylation and C2'-deacetylation procedures described in Example I0, except substituting 2-nitrobenzoic anhydride for the acetyl anhydride thereof, the title compound was prepared in two-steps. MS (ESI) m/z 942 [M+H]+.
Example 56 ~omR2und of Forrr~ula IIIO R is -CH2-CIA=CIA RP is H W is NH Rw is H U is OH
~g 56~ a. Compound 16A of Scheme 3. R is alltrl RP is acetyl U is 4"-acet~rlcladinose W is NH. RW is H
To a solution of the compound from Step 8b (3.65 g, 3.91 mmol) in acetonitrile (30 mL) and THF (3 mL) was added anhydrous hydrazine (0.37 mL, 11.7 mmol). The solution was stirred under nitrogen at room temperature for 24 hours. Solvents were removed by evaporation, and the residue was purified by silica gel chromatography with acetone/hexanes from 60:40 to 80:20 to give the title compound (0.48 g). MS (ESI) m/z 898 [M+H]+.
Step 56b. Compound of Formula (II): R is all. RP is acetyl U is OH W is NH RW
is H
The compound (of formula (II): R is -CH2-CH=CH2, IMP is acetyl, W is NH, RW is H, U is 4"-acetylcladinose) from Step 56a was treated with 2 N HCl in ethanol following the procedure of Example 1, Step ld, to give the descladinose compound.
Step 56c. Compound of Formula lII): R is -CHI-CH=CHI RP is H W is NH RW is H U
is OH
A sample of the compound from Step 56b was refluxing in methanol for 5 hours removing the 2'-acetyl group to give the title compound. MS (ESI) m/z 656 (M+H]+.
x m 7 Compound of Formula (Vj: R is -CH2-CH=CH2. RP is H. U is OH
A sample of the compound from Example 8, Step 8a (compound 14 of Scheme 3) is treated at -30 °C for about 30 minutes with carbonyldiimidazole and sodium hexamethyldisilazide. That intermediate product is treated with ethanolic HCI, to give the intermediate descladinose compound wherein RP is acetyl. This compound is refluxed with methanol overnight The crude product is purified by chromatography on silica gel to give the title compound.
_87_ Exam lp a 58 Co~r hound of Formula (V~n R is -CH?-CH-CHI Rp is H U is O-acetyl A sample of the intermediate descladinose compound wherein RP is acetyl from Example 57 is treated with acetic anhydride to give the intermediate compound wherein RP is acetyl and U is O-acetyl. This compound is refluxed with methanol overnight.
The crude product is purified by chromatography on silica gel to give the title compound.
Exam~59 Compound of Formula (V)' R is -CH2-CH=CHI RP is H U is H U' is H
A sample of the intermediate descladinose compound wherein RP is acetyl from Example 57 is treated with tri(n-butyl)tin hydride under nitrogen atmosphere and a catalytic amount of AIBN in toluene at reflux to give the 2'acetylated intermediate. The 2'-acetyl group is removed by treatment overnight with hot methanol to give the title compound.
Example 60 Comvound of Formula (II): R is -CH2-CH=CHI-(,3~uinolinvl) RP is H W is absent RW is H.UisH,U'isH
A sample of the intermediate xanthate compound wherein RP is acetyl from Example 44 is treated with tri(n-butyl)tin hydride under nitrogen atmosphere and a catalytic amount of AIBN in toluene at reflux to give the 2'acetylated intermediate. The 2'-acetyl group is removed by treatment overnight with hot methanol to give the title compound.
Examgle fi 1 Compound of Formula lII): W is absent RW is H R is -CH~CH(O) RQ is H U is OH
The compound from Example 8, Step 8b, is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
3o Example 62 Compound of Formula (II): W is absent RW i H R i -CH~CH2NHCH2-phenyl RP is H U
is H
The compound from Example 61 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4~). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
-88_ WO 99/11b51 PCTNS98/18125 ~c ale 63 Compound of Formula IIIh W is absent Rw is H R is -CH~CH~NHCH; CH~~~ ly RP is H.UisOH
The compound from Example 61 is treated with phenethylamine in dry dichloromethane in the presence of molecular sieves (4~). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 64 Compound of Formula,jIIO W is absent RW is H R is -CH2CH~NHCH~CH,~CH~-phenyl RP is H. U is OH
The compound from Example 61 is treated with 3-phenyl-1-propylamine in dry dichloromethane in the presence of molecular sieves (4A). The resulting imine is treated with a I S catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 65 Compound of Formula (II): W is absent. RW is H R is -CH~CH?NHCH~CH~CH~CH~-hen~rl. RP is H. U is OH
The compound from Example 61 is treated with 4-phenyl-1-butylamine in dry dichloromethane in the presence of molecular sieves t4t~). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 66 Compound of Formula (II): W is absent RW is H R is -CH~CH~NHCH~CH~CH~-(3-~uinolyll, RP is H, U is OH
The compound from Example 61 is treated with 3-(3-quinolyl)-1-propylamine in dry dichloromethane in the presence of molecular sieves (4~). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.

Ex~ple 67 Compound of Formula (IIO W is absent. RW is H R i -CH~CH~NHCH~(3-quinolyl) RP
is H.UisOH
The compound from Example 61 is treated with 3-(aminomethyl)quinoline in dry dichloromethane in the presence of molecular sieves (4th). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
t0 ~m lie 68 Compound of Formula IIIO W is absent RW is H R is -CH~CH=NO(~enyl) RP is H U
is OH
The compound from Example 61 is treated with O-phenylhydroxylamine~HCl in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic is HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 69 Compound of Formula (I1): W is absent RW is H R is -CH~C,~ OCH~(phenyl) RP is H
20 U i H
The title compound was prepared from the compound of Example 61 (and O-benzylhydroxylamine~HCl in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title 25 compound.
Example 70 Compound of Formula (II): W is absent. RW is H R i -CH~CH=NQCH~(4-IVY-phenvl) RP
isH.UisOH
30 The title compound was prepared from the compound of Example 61 and D-(4-nitrobenzyl)hydroxylamine~HCl in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.

Example 71 ~r~o3md of Formula lIW W is absent RW is H R is -CH2CH=NOCH~(4-guinoly 1 Rp i H. U is OH
The compound from Example 61 and O-(4-quinolyl)methylhydroxylamine in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Ex 72 to Com o~und Qf Formula (IIO W is absent RW is H R is -CH~CH=NOCH~(2~uino13r1~
RP is H.UisOH
The title compound was prepared from the compound of Example 62 and O-(2-quinolyl)methylhydroxylamine in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol t5 overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Exam lie 73 Compound of Formula (IIO W is absent Rw is H R is -CH2CH=NOCH,2(3-auinolyl) RP
is 21) H. U is OH
The title compound was prepared from the compound of Example 62 and O-(3-quinolyl)methylhydroxylamine in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title 25 compound.
Exam l~e 74 Comyound of Formula (III): W is absent RW is H R i~,~H2CH(O) RP is H U is OH
The compound from Example 52 is treated with ozone under N2 followed by treatment 30 with dimethylsulfide and triphenylphosphine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Eacar~ple 75 35 Com n of : W i ~' ' i - H H - h 1 RP ' H
UisOH
The compound from Example 74 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4th). The resulting imine is treated with a catalytic amount of WO 99/11651 PCTlUS98/18125 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanohc Hc:l, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 76 Compound of Formula lIII1 W is absent RW is H R is -CH~CH=NO(nhen,vl) RP is H
U is The compound from Example 74 is treated with O-phenylhydroxylamine~HCl in dry dichloromethane in the presence of triethjrlamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Exam 1R a 77 Compound of Formula (IVI: W is absent RW is H R is -CH~CH(O) RP is H U is OH
The compound from Example 50 is treated with ozone under N2 followed by treatment with dimethylsulfide and triphenylphosphine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 78 Compound of Formula (IV)' W is absent RW is H R is -CH~CH~NHCH~-~nhenyl RP is H
UisOH
The compound from Example 77 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4~). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 79 Compound of Formula (lVl: W is absent RW is H R is -CH~CH=NO hen,~l) RP is H U
is The compound from Example 77 is treated with O-phenylhydroxylamine~HCl in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 80 Compound of Formula (V): W is absent RW is H R is -CH~CH(O) RP is H U is OH

WO 99/11651 . PGT/US98/18125 The compound from Example 57 is treated with ozone tinder N2 followed by treatment with dimethylsulftde and triphenylphosphine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is petrified by chromatography on silica gel to give the title compound.
Exam 1R a 81 ComRound of Formula (V): W is absent. RW is H R is -CH~CH~NHCH~-phenyl RP is H
U
is OH
The compound from Example 80 is treated with benzylamine in dry dichloromethane in the presence of molecular sieves (4th). The resulting imine is treated with a catalytic amount of 10% Pd on carbon under 1 atm of H2. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.
Example 82 Compound of Formula (V): W is absent. RW is H R is -CH2CH=NO~phenyl) RP is H U
is OH
The compound from Example X0 is treated with O-phenylhydroxylamine~HCl in dry dichloromethane in the presence of triethylamine. The intermediate is treated with ethanolic HCI, and that product is refluxed with methanol overnight. The crude product is purified by chromatography on silica gel to give the title compound.

Claims

WHAT IS CLAIMED IS:

1. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y and Z taken together define a group X, wherein X is selected from the group consisting of (1) =O, (2) =N-OH, (3) =N-O-R1 where R1 is selected from the group consisting of (a) unsubstituted C1-C12-alkyl, (b) C1-C12-alkyl substituted with aryl, (c) C1-C12-alkyl substituted with substituted aryl, (d) C1-C12-alkyl substituted with heteroaryl, (e) C1-C12-alkyl substituted with substituted heteroaryl, (f) C3-C12-cycloalkyl, and (g) -Si-(R2)(R3)(R4) wherein R2, R3 and R4 are each independently selected from C1-C12-alkyl and aryl;
and (4) =N-O-C(R5)(R6)-O-R1 where R1 is as previously defined and R5 and R6 are each independently selected from the group consisting of (a) hydrogen, (b) unsubstituted C1-C12-alkyl, (c) C1-C12-alkyl substituted with aryl, (d) C1-C12-alkyl substituted with substituted aryl, (e) C1-C12-alkyl substituted with heteroaryl, and (f) C1-C12-alkyl substituted with substituted heteroaryl, or R5 and R6 taken together with the atom to which they are attached form a C3-C12-cycloalkyl ring;
or, one of Y and Z is hydrogen and the other is selected from a group consisting of (1) hydrogen, (2) hydroxy, (3) protected hydroxy, and (4) NR7R8 wherein R7 and R8 are independently selected from hydrogen and C1-C6-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of -O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-, -N(substituted-aryl-C1-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, and -S-or -S(O)n-, wherein n is 1 or 2, W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH-and -NH-;
R W is selected from the group consisting of (1) hydrogen, (2) C1-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) C1-C6-alkoxy, (g) NR7R8, wherein R7 and R8 are as defined previously, and (h) -CH2-M-R9, wherein M is selected from the group consisting of:
(i) -C(O)-NH-, (ii) -NH-C(O)-, (iii) -NH-, (iv) -N=, (v) -N(CH3)-, (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)-, and R9 is selected from the group consisting of:
(i) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, (iii) substituted-aryl, (iv) heteroaryl, (v) substituted-heteroaryl, and (vi) heterocycloalkyl, (3) C3-C7-cycloalkyl, (4) aryl, (5) substituted-aryl, (6) heteroaryl, and (7) substituted-heteroaryl;
RP is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (f) -N3, (g) -CHO, (h) O-SO2-(substituted C1-C6-alkyl), (i) NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (l) =N-O-R10 wherein R10 is as previously defined, (m) -C~N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;

(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (f) -C=N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl, (4) C4-C10-alkenyl;
(5) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -NR13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(6) C3-C10-alkynyl;
and (7) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
U is selected from the group consisting of:
(1) hydrogen, (2) hydroxy, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R s)-, wherein R s is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n-O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R s)-, wherein R s is as defined previously;
and R t is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;
or in compounds of formula (II) and (III) U is taken together with U' to form a double bond between the carbon atoms to which they are attached;
and U' is hydrogen or in compounds of formula (II) and (III) U' is taken together with U to form a double bond between the carbon atoms to which they are attached.

2. A pharmaceutical composition for treating bacterial infections comprising a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt or ester thereof in combination with a pharmaceutically acceptable carrier.

3. A method for treating bacterial infections comprising administering to a mammal in need of such treatment a pharmaceutical composition containing a therapeutically-effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt or ester thereof.

4. A compound according to Claim 1 having the formula (I)

5. A compound according to Claim 4 wherein Y and Z taken together define a group X which is =O.

6. A compound according to Claim 4 which is selected from the group consisting of:
Compound of Formula (I): R is allyl, RP is H, X is O, U is OH;
Compound of Formula (I): R is allyl, RP is benzoyl, X is O, U is OH;
Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is OH;
Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, U
is O-acetyl;

Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, X is O, U
is O-(4-methoxy)benzoyl;
Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, X is O, U
is O-methanesulfonyl; and Compound of Formula (I): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, X is O, U
is O-CO-NH-(2-nitrophenyl).

7. A process for preparing a compound of formula (n wherein Y and Z taken together define a group X which is =O, having the formula (IA) wherein RP is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0.1 or 2 and R10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, (f) NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (f) -N3, (g) -CHO, (h) O-SO2-(substituted C1-C6-alkyl), (i) -NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroalkyl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (l) =N-O-R10 wherein R10 is as previously defined, (m) -C=N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR13R14 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (f) -C=N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl, (4) C4-C 10-alkenyl;
(5) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -NR13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(6) C3-C10-alkynyl:
and C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;

and U is selected from the group consisting of:
(1) hydrogen, (2) hydroxy, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-(b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R s)-, wherein R s is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n-O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R s)-, wherein R s is as defined previously;
and R t is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;
the method comprising:
(a) treating hydrolytically with acid a compound having the formula wherein R is as defined previously, to give a compound having the formula which is a compound of formula (IA) wherein R p is H and U is hydroxy;
(b) optionally treating the compound of Step (a) with a hydroxy protecting reagent to give a compound having the formula which is a compound of formula (IA) wherein R p is a hydroxy-protecting group and U is hydroxy, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(c) optionally treating the compound of formula (IA) wherein R p is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to afford the desired 3-deoxy compound having the formula which is a compound of formula (IA) wherein U is hydrogen;

(d) optionally treating the compound of formula (IA) wherein R p is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with a hydroxy-protecting reagent to give a compound of formula (IA) wherein R p is a hydroxy-protecting group and U is a protected hydroxyl group;
(e) optionally treating the compound of formula (IA) wherein R p is a hydroxy-protecting group and U is hydroxy (the compound from Step (b)) with base and a reagent L-T-R t, wherein T
and R t are as previously defined, and L is a suitable reactive leaving group to give compound having the formula (f) optionally deprotecting, and isolating the desired compound of formula (IA).

8. A process according to Claim 7 wherein in step (e) the reagent L-T-R t is selected from the group consisting of:
(e-i) halogen-C(O)-R t;
(e-ii) O-(C(O)-R t)2;
(e-iii) O-(C(O)-O-R t)2;

112~

(e-iv) halogen-CH2-R t;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R t;
(e-vi) O=C=N-R t;
(e-vii) carbonyl diimidazole followed by N(R s)H-R t;
(e-viiii) Cl-S(O)n-O-R t;
(e-ix) Cl-P(O)(OR r)n-R t;
(e-x) Cl-SO2-N(R s)-R t;

9. A process according to Claim 7 wherein in step (e) the base and the reagent L-T-R t are replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

10. A compound according to Claim 1 having the formula (II)

11. A compound according to Claim 8 wherein W is absent and R W is H.

12. A compound according to Claim 8 which is selected from the group consisting of:
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is OH;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-acetyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(4-nitrobenzoyl),;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-benzoyl;

Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(3,5-diphenylpyridinecarboxyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-nitrobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-{3-quinolinyl), RP is H, W is absent, R W is H, U is O-(3,4,5-trimethoxybenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-thiophenecarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-methylbutanoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(4-bromobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(4-pyridinecarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(methoxycarbonyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(1,1-dimethylethoxycarbonyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-bromobenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(4-methoxybenzoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-furancarboxoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-butanoyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-methanesulfonyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-methylpropenoyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-phenyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-allyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-CH(C(O)OCH3)-CH(CH3)2;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-CH(CH3)2;

Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-cyclohexyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-(4-fluorophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-(2-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-(4-methyl-2-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-(4-nitrophenyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, X is O, W
is absent, R W is H, U is O-CO-NH-(4-methoxyphenyl);
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-S(O)2-CH=CH2;
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-S(O)2-CH2-CH2-N(CH3)2;
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-S(O)2-CH2-CH2-S-phenyl;
Compounds of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-allyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(4-morpholinecarbonyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-pyrrolidinylcarbonyl;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-(2-tetrahydropyranyl);
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, W is absent, R W is H, U is O-C(=S)-SCH3;
Compound of Formula (II): R is -CH2-CH=CH2, RP is H, U and U' taken together are double bond, W is absent, R W is H;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U and U' taken together are double bond, W is absent, R W is H;
Compound of Formula (II): R is -CH2-CH=CH2-(6-nitro-3-quinolinyl), RP is H, U
and U' taken together are double bond, W is absent, R W is H;
Compound of Formula (II): R is -CH2-CH=CH2-(6-methoxy-2-naphthyl), RP is H, U
and U' taken together are double bond, W is absent, R W is H;
Compound of Formula (II): R is -CH2-CH=CH2-(3-(5-(3-isoxazolyl)-2-furanyl)), RP is H, U
and U' taken together are double bond, W is absent, R W is H;

Compound of Formula (II): R is -CH2-CH=CH2, R p is H, W is NH, R w is H, U is OH;
Compound of Formula (II): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, W is absent, R w is H, U is H, U is H;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH(O), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2-phenyl, R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2CH2-phenyl, R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2CH2CH2-phenyl, R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2CH2CH2CH2-phenyl, R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2CH2CH2-(3-quinolyl), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH2NHCH2-(3-quinolyl), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NO-(phenyl), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NOCH2-(phenyl), R
p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NOCH2-(4-NO2-phenyl), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NOCH2-(4-quinolyl), R p is acetyl, U is OH;
Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NOCH2-(2-quinolyl), R p is acetyl, U is OH; and Compound of Formula (II): W is absent, R w is H, R is -CH2CH=NOCH2-(3-quinolyl), R p is acetyl, U is OH.

13. A process for preparing a compound having the formula (II) wherein R p is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0, 1 or 2 and R 10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, (f) NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (f)~-N3, (g) -CHO, (h) O-SO2-(substituted C1-C6-alkyl), (i) -N13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (l) =N-O-R10 wherein R10 is as previously defined, (m) -C~N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (f) -C~N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with-heteroaryl, (4) C4-C10-alkenyl;
(5) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -NR13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(6) C3-C10-alkynyl;
and (7) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
and U is selected from the group consisting of:
(1) hydrogen, (2) hydroxy, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R s)-, wherein R s is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n-O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R s)-, wherein R s is as defined previously;
and R t is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;
or U is taken together with U' to form a double bond between the carbon atoms to which they are attached;
U' is hydrogen or is taken together with U to form a double bond between the carbon atoms to which they are attached;
W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH-and -NH-;
and R w is selected from the group consisting of (1) hydrogen, (2) C1-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) C1-C6-alkoxy, (g) NR7R8, wherein R7 and R8 are as defined previously, and (h) -CH2-M-R9, wherein M is selected from the group consisting of:
(i) -C(O)-NH-, (ii) -NH-C(O)-, (iii) -NH-, (iv) -N=, (v) -N(CH3)-, (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)-, and R9 is selected from the group consisting of:
(i) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, (iii) substituted-aryl, (iv) heteroaryl, (v) substituted-heteroaryl, and (vi) heterocycloalkyl, (3) C3-C7-cycloalkyl, (4) aryl, (5) substituted-aryl, (6) heteroaryl, and (7) substituted-heteroaryl;

the method comprising:
(a) optionally treating hydrolytically with acid a compound having the formula wherein R is as defined above and Rp is a hydroxy protecting group to give a compound having the formula 8 wherein U is hydroxy and U' is hydrogen (b) optionally treating a compound from Step (a) with an excess of sodium hexamethyldisilazide or a hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound having the formula wherein U and U' are taken together to form a double bond;
(c) optionally treating a compound from Step (b) with aqueous ammonia to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is absent and R W is H;
(d) optionally treating a compound from Step (b) with a substituted amine compound of the formula H2N-W-R W, wherein W is absent and R W is not H but is otherwise as previously defined, to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is absent and R W is not H;
(e) optionally treating a compound from Step (b) with a hydroxylamine compound of the formula H2N-W-R W, wherein W is -O- and R W is as previously defined, to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is -O- and R W is as previously defined;
(f) optionally treating a compound from Step (b) with an unsubstituted hydrazine to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W
is -NH- and R W is H;
(g) optionally treating a compound from Step (b) with a substituted hydrazine compound of the formula H2N-NH-R W wherein R W is not hydrogen but otherwise is as previously defined to give the desired compound of formula (II) where U and U' are taken together to form a double bond, W is -NH-R W and R W is not H;
(h) optionally treating a compound of formula 14 as defined above with a strong base selected from the group consisting of (i) sodium hexamethyldisilazide and (ii) an alkali metal hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound having the formula (i) optionally treating a compound from Step (h) with aqueous ammonia to give a compound having the formula (16A) wherein W is absent, R W is H and U is 4"-hydroxy protected cladinose;
(j) optionally treating the compound from step (i), wherein W is absent and R
W is H and U is 4"-hydroxy protected cladinose, with an alkylating agent selected from the group consisting of R W-halogen to give a compound of formula (16A) wherein W is absent, U is 4"-hydroxy protected cladinose, and R W is as defined above;
(k) optionally treating a compound from Step (h) with a substituted amine compound of the formula H2N-W-R W, wherein W is absent and R W is as previously defined except not H, to give to give a compound having of formula (16A) wherein W is absent, U is 4"-hydroxy protected cladinose, and R W is as previously defined except not H;

(1) optionally treating a compound from Step (h) with a hydroxylamine compound of the formula H2N-W-R W, wherein W is -O- and R W is as previously defined, to give to give a compound of formula (16A) wherein W is -O-, U is 4"-hydroxy protected cladinose, and R W is as previously defined;
(m) optionally treating a compound from Step (h) with an unsubstituted hydrazine to give to give a compound of formula (16A) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and R W is H;
(n) optionally treating the compound from step (m) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and R W is H with an acylating agent selected from the group consisting of R W-C(O)-halogen or (R W-C(O))2-O to give a compound of formula (16A) wherein W is -NH-CO-, U is 4"-hydroxy protected cladinose, and R W is as defined above;
(o) optionally treating the compound from step (m) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and R W is H with an aldehyde R W-CHO, wherein R W as defined above to give a compound of formula (16A) wherein W is -N=CH-, U is 4"-hydroxy protected cladinose, and R W is as defined above;
(p) optionally treating a compound from Step (h) with a substituted hydrazine compound of the formula H2N-NH-R W, wherein R W is as defined above except not hydrogen, to give to give a compound of formula (16A) wherein W is -NH-, U is 4"-hydroxy protected cladinose, and R W
is as defined above except not hydrogen;
(q) optionally treating hydrolytically with acid a compound selected from the group consisting of the compounds of Step (i), Step (j), Step (k), Step (l), Step (m), Step (n), Step (o), and Step (p) to give the desired compound of formula (II) wherein U is OH, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(r) optionally treating a compound of formula (II) wherein RP is a hydroxy protecting group and U is hydroxy (a compound from Step (q)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (II) wherein U is hydrogen;

(s) optionally treating a compound of formula (II) wherein R p is a hydroxy protecting group and U is hydroxy (a compound from Step (r) with a reagent L-T-R t, wherein T
and R t are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (II) wherein U is O-T-R t;
(t) optionally deprotecting, and isolating the desired compound of formula (II).

14. A process according to Claim 13 wherein in step (s) the reagent L-T-R t is selected from the group consisting of:
(e-i) halogen-C(O)-R t;
(e-ii) O-(C(O)-R t)2;
(e-iii) O-(C(O)-O-R t)2;
(e-iv) halogen-CH2-R t;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R t;
(e-vi) O=C=N-R t;
(e-vii) carbonyl diimidazole followed by N(RS)H-R t;
(e-viiii) Cl-S(O)n-O-R t;
(e-ix) Cl-P(O)(OR r)n-R t;
(e-x) Cl-SO2-N(R S)-R t.

15. A process according to Claim 13 wherein in step (s) the base and the reagent L-T-R t are replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

16. A compound according to Claim 1 having the formula (III)

17. A compound according to Claim 12 which is selected from the group consisting of:
Compound of Formula (III): R is -CH2-CH=CH2, RP is H, U is OH, U' is H;
Compound of Formula (III): R is -CH2-CH=CH2-(3-quinolinyl), RP is H, U is OH, U' is H;
Compound of Formula (III): W is absent, R W is H, R is -CH2CH(O), Rp is H, U
is OH;
Compound of Formula (III): W is absent, R W is H, R is -CH2CH2NHCH2-phenyl, Rp is H, U
is OH; and Compound of Formula (III): W is absent, R W is H, R is -CH2CH=NO(phenyl), Rp is H, U is OH.

18. A process for preparing a compound having the formula (III) wherein RP is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -C02R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, (f) NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (17 -N3, (g) -CHO, (h) O-SO2-(substituted C1-C6-alkyl), (i) -NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C2-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl.
and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attaches form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (1) =N-O-R10 wherein R10 is as previously defined, (m) -C~N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, {r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R11 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11 R12 wherein R11 and R12 are as previously defined, (f) -C~N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl, (4) C4-C10-alkenyl;
(5) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -NR13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;

(6) C3-C10-alkynyl;
and (7) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
U is selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R S)-, wherein R S is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n -O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R S)-, wherein R S is as defined previously;
and R t is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;
or U is taken together with U' to form a double bond between the carbon atoms to which they are attached;
and U' is hydrogen or is taken together with U to form a double bond between the carbon atoms to which they are attached;
the method comprising:
(a) optionally treating hydrolytically with acid a compound having the formula wherein R is as defined above and RP is a hydroxy protecting group to give a compound having the formula 8 wherein U is hydroxy and U' is hydrogen, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(b) treating a compound selected from the group consisting of compound 14 and compound 8 wherein U is hydroxy and U' is hydrogen with a base selected from the group consisting of sodium hexamethyldisilazide and a metal hydride base in the presence of carbonyldiimidazole in an aprotic solvent to give a compound selected from the group consisting of compounds 15A
and 15B, respectively 15A, wherein U is -O-4"-acetyl-cladinose and U' is H, or 15B. wherein U and U' are taken together to form a double bond;
(c) treating a compound selected from the group 15A and 15B, of step (b) with ethylenediamine to give a bicyclic carbamate compound selected from the group consisting of compounds 21A, wherein U is O-4"-acetylcladinose, and 21B, wherein U and U' form a double bond, respectively, 21A, wherein U is O-4"-acetylcladinose, 21B, wherein U and U' from a double bond, (d) treating the a compound selected from the group 21A and 21B of step (c) with dilute acid to give a compound selected from the group consisting of compounds 22A and 22B.
respectively, 22A. U is O-4"-acetylcladinose, and 22B, U and U' form a double bond;
(e) hydrolytically removing the cladinose moiety from a compound (22A) from step (d) by treatment with acid, reprotecting the 2' hydroxyl group by treatment with a hydroxy protecting reagent, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer, to give a compound having the formula (23P), which is a compound of formula (III) wherein RP is H, U is hydroxy and U' is hydrogen;
(f) optionally treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen with base and a reagent L-T-R t, wherein L is a leaving group and T and R t are as defined previously, to give a compound of formula (III) wherein RP is H, U is -O-T-R t and U' is hydrogen;
(i) optionally treating the 3-hydroxy group of the product compound from step (e) having the formula (III) wherein R is as defined previously and RP is H, U is hydroxy and U' is hydrogen sequentially with an excess of NaH, CS2 and CH3I to form a 3-O-xanthate intermediate which is treated with Bu3SnH in the presence of a radical initiator to give the desired compound of formula (III) wherein RP, U and U' are hydrogen;
(j) optionally deprotecting, and isolating the desired compound of formula (III).

19. A process according to Claim 18 wherein in step (f) the reagent L-T-R t is selected from the group consisting of:
(e-i) halogen-C(O)-R t;
(e-ii) O-(C(O)-R t)2;
(e-iii) O-(C(O)-O-R t)2;
(e-iv) halogen-CH2-R t;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R t;
(e-vi) O=C=N-R t;
(e-vii) carbonyl diimidazole followed by N(R s)H-R t;
(e-viiii) Cl-S(O)n-O-R t;
(e-ix) Cl-P(O)(OR r)n-R t;
(e-x) Cl-SO2-N(R s)-R t.

20. A process according to Claim 18 wherein in step (f) the base and the reagent L-T-R t are replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

21. A compound according to Claim 1 having the formula (IV)

22. A compound according to Claim 15 which is selected from the group consisting of:
Compound of Formula (IV): R is -CH2-CH=CH2, R p is acetyl, U is OH;
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), R p is acetyl, U is OH.
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, U is O-C(O)-phenyl;
Compound of Formula (IV): R is -CH2-CH=CH2-(3-quinolinyl), R p is H, U is O-C(O)-(2-nitrophenyl);
Compound of Formula (IV): W is absent, R W is H, R is -CH2CH(O), R p is H, U
is OH;
Compound of Formula (IV): W is absent, R W is H, R is -CH2CH2NHCH2-phenyl, R p is H, U
is OH; and Compound of Formula (IV): W is absent, R W is H, R is -CH2CH=NO(phenyl), R p is H, U is OH.

23. A process for preparing a compound having the formula (IV) wherein R p is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, (f) NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (f) -N3, (g) -CHO, (h) O-SO2 -(substituted C1-C6-alkyl), (i) -N13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (1) =N-O-R10 wherein R10 is as previously defined, (m) -C~N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;

(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (f) -C~N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl, (4) C4-C12-alkenyl;
(5) C4-C12-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -NR13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(6) C3-C10-alkynyl;
and (7) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
U is selected from the group consisting of:
(1) hydrogen, (2) hydroxyl, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R s)-, wherein R s is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n-O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R s)-, wherein R s is as defined previously;
and R t is selected from the group consisting of:
(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;
the method comprising:
(a) optionally treating a compound having the formula 14 wherein R is as defined above and R p is a hydroxy protecting group, with carbonyldiimidazole and sodium hexamethyldisilazide for a short time at about -30 °C to give a compound having the formula 29 (b) optionally treating a compound having the formula 14 as shown in Step (a) with an alkali metal hydride and a carbonylating agent selected from the group consisting of phosgene, diphosgene and triphosgene under anhydrous conditions with careful control of the amount of base present in order to prevent base catalyzed decarboxylation to give a compound having the formula 29 as shown in Step (a);
(c) treating hydrolytically with acid a compound having the formula 29 to give a compound of formula (IV) wherein U is hydroxy and R p is a hydroxy protecting group, optionally followed by converting the compound having the natural (3S) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(d) optionally treating a compound of formula (IV) wherein U is hydroxy and R
p is a hydroxy protecting group (a compound from Step (c)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (IV) wherein U is hydrogen and RP is a hydroxy protecting group;
(e) optionally treating a compound of formula (IV) wherein U is hydroxy and RP
is a hydroxy protecting group (a compound from Step (c)) with base and a reagent L-T-R t, wherein T and R t are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (IV) wherein U is O-T-R t and RP is a hydroxy protecting group;
(f) optionally deprotecting, and isolating the desired compound of formula (IV).

24. A process according to Claim 24 wherein in step (e) the reagent L-T-R t is selected from the group consisting of:
(e-i) halogen-C(O)-R t;
(e-ii) O-(C(O)-R t)2;
(e-iii) O-(C(O)-O-R t)2;
(e-iv) halogen-CH2-R t;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R t;
(e-vi) O=C=N-R t;
(e-vii) carbonyl diimidazole followed by N(R s)H-R t;
(e-viiii) Cl-S(O)n-O-R t;
(e-ix) Cl-P(O)(OR r)n-R t;
(e-x) Cl-SO2-N(R s)-R t.

25. A process according to Claim 24 wherein in step (e) the base and the reagent L-T-R t are replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.

26. A compound according to Claim 1 having the formula (V)

27. A compound according to Claim 18 which is selected from the group consisting of:
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is OH;
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is O-acetyl;
Compound of Formula (V): R is -CH2-CH=CH2, RP is H, U is H, U' is H;
Compound of Formula (V): W is absent, R w is H, R is -CH2CH(O), RP is H, U is OH;
Compound of Formula (V): W is absent, R w is H, R is -CH2CH2NHCH2-phenyl, RP
is H, U
is OH; and Compound of Formula (V): W is absent, R w is H, R is -CH2CH=NO(phenyl), RP is H, U is OH.

28. A process for preparing a compound having the formula (V) wherein RP is hydrogen or a hydroxy protecting group;
R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) CN, (b) F, (c) -CO2R10 wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, (d) S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (e) NHC(O)R10 where R10 is as previously defined, (f) NHC(O)NR11R12 wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, (2) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) oxo, (f) -N3, (g) -CHO, (h) O-SO2-(substituted C1-C6-alkyl), (i) -NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (ii) C1-C12-alkyl, (iii) substituted C1-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-C8-cycloalkyl, (x) substituted C3-C8-cycloalkyl, (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) C1-C12-alkyl substituted with aryl, (xv) C1-C12-alkyl substituted with substituted aryl, (xvi) C1-C12-alkyl substituted with heterocycloalkyl, (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C1-C12-alkyl substituted with substituted heteroaryl, or R13 and R14 are taken together with the atom to which they are attached form a 3-10 membered heterocycloalkyl ring which may be substituted with one or more substituents independently selected from the group consisting of (i) halogen, (ii) hydroxy, (iii) C1-C3-alkoxy, (iv) C1-C3-alkoxy-C1-C3-alkoxy, (v) oxo, (vi) C1-C3-alkyl, (vii) halo-C1-C3-alkyl, and (vii) C1-C3-alkoxy-C1-C3-alkyl, (j) -CO2R10 wherein R10 is as previously defined, (k) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (l) =N-O-R10 wherein R10 is as previously defined, (m) -C~N, (n) O-S(O)n R10 wherein n is 0, 1 or 2 and R10 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-C8-cycloalkyl, (t) substituted C3-C8-cycloalkyl, (u) C1-C12-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, (y) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R9 is as previously defined, (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (cc) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(3) C3-alkenyl substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10 where R10 is as previously defined, (d) -C(O)-R9 where R9 is as previously defined, (e) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (f) -C~N, (g) aryl, (h) substituted aryl, (i) heteroaryl, (j)~ substituted heteroaryl, (k) C3-C7-cycloalkyl, and (l) C1-C12-alkyl substituted with heteroaryl, (4) C4-C10-alkenyl;
(5) C4-C10p-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (g) -R13R14 wherein R13 and R14 are as previously defined, (h) =N-O-R10 where R10 is as previously defined, (i) -C~N, (j) O-S(O)n R10 where n is 0, 1 or 2 and R10 is as previously defined, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C3-C7-cycloalkyl, (p) C1-C12-alkyl substituted with heteroaryl, (q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NR11R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R9 wherein R9 is as previously defined, (u) =N-NHC(O)R10 where R10 is as previously defined, and (v) =N-NHC(O)NR11R12 wherein R11 and R12 are as previously defined;
(6) C3-C10-alkynyl;
and (7) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, (e) halogen, and (f) substituted heteroaryl;
U is selected from the group consisting of:
(1) hydrogen, (2) hydroxy, (3) protected hydroxy, (4) -O-T-R t, wherein T is absent or selected from the group consisting of:
(a) -C(O)-, (b) -C(O)-O-(c) -CH2-, (d) -C(S)-S-, (e) -C(O)-N(R s)-, wherein R s is H or C1-C6-alkyl, (f) -S(O)n-, wherein n is 0, 1 or 2, (g) -S(O)n-O-, wherein n is 0, 1 or 2, (h) -P(O)(OR r)n-, wherein n is 0, 1 or 2, and R r is C1-C6-alkyl, and (i) -SO2-N(R s)-, wherein R s is as defined previously;
and R t is selected from the group consisting of:

(a) C1-C6-alkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (b) C3-C6-alkenyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (c) C3-C12-cycloalkyl, optionally substituted with a substituent selected from the group consisting of (i) aryl, (ii) substituted-aryl, (iii) heteroaryl, and (iv) substituted-heteroaryl, (v) heterocycloalkyl, (vi) substituted-heterocycloalkyl, (vii) hydroxy, (viii) C1-C6-alkoxy, (ix) NR7R8 wherein R7 and R8 are as defined previously, (d) aryl, (e) substituted-aryl, (f) heteroaryl, (g) substituted-heteroaryl, and (h) heterocycloalkyl;

the method comprising:

(a) treating a compound having the formula 14 wherein R is as defined above and Rp is a hydroxy protecting group, with a reagent selected from the group consisting of (i) formaldehyde in the presence of an acid and (ii) chloroiodomethane in the presence of base, to give a compound having the formula 33 (b) treating hydrolytically with acid a compound from Step (a) having the formula 33 to give a compound of formula (V) wherein U is hydroxy and Rp is a hydroxy protecting group, optionally followed by converting the compound having the natural (3R) isomeric configuration into the compound having the non-natural (3R) isomeric configuration by oxidation of the 3-hydroxyl group and selective reduction of the 3-oxo group to give the non-natural (3R) isomer;
(c) optionally treating a compound of formula (V) wherein U is hydroxy and Rp is a hydroxy protecting group (a compound from Step (b)) with an excess of NaH in an aprotic solvent followed by reaction of the intermediate anion with CS2 and CH3I to form a xanthate intermediate which is then treated with Bu3SnH under an inert atmosphere in the presence of a catalytic amount of a suitable radical initiator to give the desired compound of formula (v) wherein U is hydrogen and RP is a hydroxy protecting group;
(d) optionally treating a compound of formula (IV) wherein U is hydroxy and RP
is a hydroxy protecting group (a compound from Step (b)) with base and a reagent L-T-R t, wherein T and R t are as previously defined, and L is a suitable reactive leaving group to give the desired compound of formula (V) wherein U is O-T-R t and RP is a hydroxy protecting group;
(e) optionally deprotecting, and isolating the desired compound of formula (V).

29. A process according to Claim 29 wherein in step (e) the reagent L-T-R t is selected from the group consisting of:
(e-i) halogen-C(O)-R t;
(e-ii) O-(C(O)-R t)2;
(e-iii) O-(C(O)-O-R t)2;
(e-iv) halogen-CH2-R t;
(e-v) alkali metal hydride followed by CS2 then followed by halogen-R t;
(e-vi) O=C=N-R t;
(e-vii) carbonyl diimidazole followed by N(R s)H-R t;
(e-viiii) Cl-S(O)n-O-R t;
(e-ix) Cl-P(O)(OR r)n-R t;
(e-x) Cl-SO2-N(R s)-R t.

30. A process according to Claim 29 wherein in step (e) the base and the reagent L-T-R t are replaced with 3,4-dihydro-2H-pyran in the presence of a acid catalyst.