CA2564020C - 6-o-substituted ketolides having antibacterial activity - Google Patents

Abstract

Antimicrobial compounds having formula (V) as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.(See formula V)

Description

This application is a division of Canadian Application No. 2,263,972, filed September 2, 1997.
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, this invention concerns to 6-O-substituted erythromycin ketolide derivatives, compositions containing these compounds, and a method of treating bacterial infections.
to Background of the Invention Eryihromycins A through 1~, represented by formula (I), NMez O
HO...

OH 2' CH3, g CH
~~ ~

Ho.,,, Ervthromycin R' R"
'' ",;.~~~
o cH3 ~~ 12 H H B -H -CH3 ~ 3 ' H3c cH3 o cH3 C -OH -H
~

o o""". D -H -H

CH3 CH 4" H

~OH
O

~~OR

(I) 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 2S antibiotic activity.

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 6-O-methyl 3-descladinose erythromycin derivatives.
European Patent Application 596802, published May 1 l, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives. - ;
PCT application WO 92/09614, published June 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives. -1o Summary of the Invention The present invention provides a novel class of 6-O-substituted erythromycin derivatives possessing increased acid stability relative to erythromycin A and 6-O-methyl erythromycin A and enhanced activity toward gram negative bacteria and macrolide resistant gram positive bacteria.
~; in one embodiment, the present invention provides compounds selected from the group consisting of Y R R~ NMe2 Z.,..
p .... ..
HO,,, 6 Ra . .~~r O O
O
(II) O , O R~ NMe2 . R 0~..
,~O
L~ T~.. .6 \ ...~ O
O~ O
O
O
20 (III) O

--V
WO 98109978 PC."TIIJS~7/1~3~~
D R~ NMe2 E,,,.
A ~ R I
o °
B ",. ,,,, ,, °~ w,..
p ~~~~ ° o .,,,..

(N) ° ;
D H
~,. N R R~ NMe2 A I I

B
pv Nu..
p ~I~f p O
(N_A) p and _ Q R° NMe2 I
R ~ O~
° ;
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein either, Y and Z taken together define a group X, wherein X is selected from the group consisting of ( 1 ) =O, (2) =N-OH, CA 02564020 2006-10-31- ' ~ "'-WO 98/09978 PCTlUS9'1J15~6 (3) =N-O-RI where R1 is selected from the group consisting of (a) unsubstituted C~-C~2-alkyl, (b) Ci-C12-alkyl substituted with aryl, (c) CI-C~2-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 C~-C12-alkyl and Aryl;
and (4) =N-O-C(RS)(R6)-O-Rl where R1 is as previously defined and RS and R6 are each independently selected from the group consisting of (a) hydrogen, (b) unsubstituted Cl-C12-alkyl, tS (c) C1-C12-alkyl substituted with aryl, (d) C1-C12-alkyl substituted with substituted aryl, (e) Ci-C12-all;yl substituted with heteroaryl, and (f) Ci-CI2-alkyl substituted with substituted heteroaryl, or R5 and R6 taken together with the atom to which they are attached form a C3-Cl?-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) NR7R~ wherein R~ and R8 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 i-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(CI-C6-alkyl-)-, -N(aryl)-, -N(aryl-Ct-C6-alkyl-)-, -N(substituted-aryl-Ct-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-CI-C6-alkyl-)-, -N(substituted-heteroaryl-Cl-C6-alkyl-)-, and -S- or -S(O)n-, wherein n is 1 or 2, Ra is hydrogen or hydroxy;

- CA 02564020 2006-10-31 . . ~.,, a. ._...~___ _ _ ~-Rb is selected from the group consisting of hydroxy, -O-C(O)-NH2 and -O-C(O)-imidazolyl;
R~ is hydrogen or a hydroxy protecting group;
L is methylene or carbonyl, provided that when L is methylene, T is -O-, T is selected from the group consisting of -O-, -NH-, and -N(W-Rd)-, wherein W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH-and -NH-;
and Rd is selected from the group consisting of ( I ) hydrogen, (2) C1-Cs-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-IvI-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-, CA 02564020 2006-10-31 . ........ .
wo 9sro~rs rcrnJS~rnsso6 (xi) -S(O)n-, wherein n is 0, I or 2, (xii) -C(O)-O-, (xiii) -O-C(O)-, and (xiv) -C(O)-, and R9 is selected from the group consisting of:

(i) CI-C6-alkyl, optionally substituted with a substituene -selected from the group consisting of (aa) aryl, (bb) substituted-aryl, (cc) heteroaryl, and (dd) substituted-heteroaryl, (ii) aryl, Is (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;

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 RIO is CI-C3-alkyl or aryl substituted CI-C3-alkyl, or heteroaryl substituted CI-C3-alkyl, (d) S(O)"RIO where n is 0, I or 2 and RIO is as previously defined, (e) NHC(O)RIO where RIO is as previously defined, (f) NHC(O)NRIIR12 wherein RII and R12 are independently selected from hydrogen, CI-C3-alkyl, CI-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, CA 02564020 2006-10-31 ' wo 9s~o9ms >QCTms~n (g) ~yl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, . (2) C2-C lp-alkyl, (3) C2-C lp-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) -CriO, (h) O-S02-(substituted C1-C6-alkyl), (i) -NR13R14 wherein R13 and R14 are selected from the group consisting of (i) hydrogen, (n) C 1-C 12-alkyl, (iii) substituted Cl-C12-alkyl, (iv) C1-C12-alkenyl, (v) substituted C1-C12-alkenyl, (vi) C1-C12-alkynyl, 2S (vii) substituted C1-C12-alkynyl, (viii) aryl, (ix) C3-Cg-cycloalkyl, (x) substituted C3-Cg-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-Cg-cycloalkyl, (xix) C1-C12-alkyl substituted with substituted C3-Cg-cycloalkyl, CA 02564020 2006-10-31 ._........ , . ...., .

(xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) C1-C12-alkyl substituted with heteroaryl, and (xxiii) C~-C12-alkyl substituted with substituted heteroaryl, or R 13 and R 14 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) Cl-C3-alkoxy-C~-C3-alkoxy, (V) 0X0, (vi) Cl-C3-alkyl, (vii) halo-CI-C3-alkyl, and (vii) C1-C3-alkoxy-C~-C3-alkyl, (j) -C02R10 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)~R1~ wherein n is 0, 1 or 2 and RIO is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-Cg-cycloalkyl, (t) substituted C3-Cg-cycloalkyl, (u) C~-CI2-alkyl substituted with heteroaryl, (v) heterocycloalkyl, (w) substituted heterocycloalkyl, (x) NHC(O)R10 where R10 is as previously defined, 3; (y) NHC(O)NRi1R12 wherein Rli and R12 are as previously defined, (z) =N-NR13R14 wherein R13 and R14 are as previously defined, (aa) =N-R9 wherein R~ is as previously defined, _g-. . CA 02564020 2006-10-31 ~ .., . . ._....., .._..

8 PCT/US9'T/1~506 (bb) =N-NHC(O)R10 wherein R10 is as previously defined, and (ccj =N-NI-1C(O)NRi 1812 wherein Rl 1 and R12 are as previously defined;

(4) C3-alkenyl substituted with a moiety selected from the group consisting of ' (a) halogen, (b) -CHO, (c) -C02R10 where R10 is as previously defined, (d) -C(O)-R~ where R~ 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-C~-cycloalkyl, and (Ij C1-C1?-alkyl substituted with heteroaryl, (5) C4-Cl p-alkenyl;

(6) C4-Cl p-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (dj -CHO.

(e) -C02R10 where R10 is as previously defined, (f) -C(Oji'1R11R12 wherein R11 and R12 are as previously defined, (g) _~13R14 wherein R13 and R14 are as previously defined, (h ) =N-O-R 10 where R 10 is as previously defined, (i> -C=N, (jj O-S(Oj~RIO where n is 0, 1 or ~ and R10 is as previously defined, (k > aryl, (1 ) substituted aryl, (m ) heteroaryl, (n j substituted heteroaryl, (o) C3-C~-cycloalkyl, (p~ Cl-Cl?-alkyl substituted with heteroaryl, CA 02564020 2006-10-31 . ...._..,..... _ _. _._ . . ___ ..

(q) NHC(O)R10 where R10 is as previously defined, (r) NHC(O)NRI1R12 wherein R11 and R12 are as previously defined, (s) =N-NR13R14 wherein R13 and R14 are as previously defined, (t) =N-R~ 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; - , (7) C3-C10-alkynyl;

and (8) C3-Cep-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl;

and A, B, D and E, with the provision that at least two of A, B, D and E are hydrogen, are independently selected from the group consisting of:
(a) hydrogen;
(b) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
(i) aryl;
(ii) substituted-aryl;
(iii) heteroaryl;
(iv) substituted-heteroaryl;
(v) heterocycloalkyl;
(vi) hydroxy;
(vii) C1-C6-alkoxy;
(viii) halogen consisting of Br, Cl, F or I; and (ix) NR~R~, wherein R~ and Rg are as previously defined;
(c) C3-C7-cycloalkyl;
(d) aryl;

t (e) substituted-aryl;
(fj heteroaryl;
(g) substituted-heteroaryl;
(h) heterocycloalkyl; and (i) a group selected from option (b) above further substituted with -M-R9, . - wherein u/ and R9 are as previously defined;
or any one pair of substituents> consisting of AB, AD, AE, BD, BE or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-1o membered ring optionally containing a hetero function selected from the group consisting of-O-, -NH-, -N(C1-C6-alkyl-)-, -N(aryl-CI-C6-alkyl-)-, -N(substituted-aryl-C~-C6-alkyl-)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C~-C6-alkyl-)-, -S- or -S(O)"-, wherein n is 1- or 2, -C(O)-NH-, -C(O)-NR12-, wherein R12 is as previously defined, -i~'H-C(O)-, -NRt~-C(O)-, wherein R-;' a as previouslyucfined, and -C(=NH)-NH-.
The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a 2o pharmaceutically acceptable earner.
The invention further relates to a method of treating bacterial infections in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined above.
In a further aspect of the present invention are provided processes for the preparation 25 of 6-O-substituted macrolide derivatives of Formula (II), (III), (IV), (iV-A) and (V) above.
Detailed Description of the Invention In one embodiment of the present invention are compounds having the formula II, Y R R~ NMe2 Z.... t O~, ,~~0 HO,,,. ~'' R ~ ..~~ O O
O
30 (II) ~

i--WO 98!09978 PCT/US97I15506 wherein X, Y, R, Ra and Rc are as described previously.
A representative compound of formula II is the compound of Formula (II), Ra is OH, Rc is benzoyl, R is ally!.
In a preferred embodiment of the compounds of formula II of the invention are compounds wherein Ra is hydroxy and R~ is hydrogen.
In a more preferred embodiment of the compounds of formula II of the invention are compounds having the formula VIII, R NMe2 ~O H 0.,,.
.,..
H 0,,, H O~ ~~~~O O
j p ~/Rj O
wherein X is O or NOH, and R is as defined previously.
Compounds representative of this embodiment include, but are not limited to:
Compound of Formula (VIII): X is O, R is ally!;
Compound of Formula (VIII): X is NOH, R is ally!.;
Compound of Formula (VIII): X is O, R is propyI;
Compound of Formula (VIII): X is O, R is -CH~CHO;
Compound of Formula (VIII): X is O, R is -CH2CH=NOH;
Compound of Formula (VIII): X is NOH, R is -CH2CH=NOH;
Compound of Formula (VIII): X is O, R is -CH2CN;
Compound of Formula (VIII): X is O, R is -CHZCH2NI-I2;
Compound of Formula (VIII): X is O, R is -CH2CH2NI-ICH2-Phenyl;
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH?CH2-Phenyl;
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH(C02CH3)CH2-Phenyl;
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH~-(4-pyridyl);
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH2-(4-quinolyl);
Compound of Formula (VIII): X is O, R is -CH2CH=CH-Phenyl;
Compound of Formula (VIII): X is O, R is -CH2CH2CH2-Phenyl;
Compound of Formula (VIII): X is O, R is -CH~,CH=CH-(4-methoxyphenyl);
Compound of Formula (VIII): X is O, R is -CH2CH=CH-(4-chlorophenyl);

WO 98/09978 PCTlU59711~
Compound of Formula (VIII): X is O, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (VIII): X is O, R is -CH2CH2CH20H.;
Compound of Formula (VIII): X is O, R is -CH2C(O)OH;
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH3;
Compound of Formula (VIII): X is O, R is -CH2CH2NHCH20H;
Compound of Formula ( VIII): X is O, R is -CH2CH2N(CH3)2;
Compound of Formula (VIII): X is O, R is -CH2CH2(1-morpholinyl);
Compound of Formula (VIII): X is O, R is -CH2C(O)NH2;
Compound of Formula (VIII): X is O, R is -CH2NHC(O)NH2;
1o Compound of Formula (VIII): X is O, R is -CH2NHC(O)CH3;
Compound of Formula (VIII): X is O, R is -CH2F;
Compound of Formula (VIII): X is O, R is -CH2CHZOCH3;
Compound of Formula (VIII): X is O, R is -CH2CH3;
Compound of Formula (VIII): X is O, R is -CH2CH=CH(CH3)2;
:5 Co~rpcund of Foruiula (VIII): X is O, R is -CH2CH2CH(CH3)CH3;
Compound of Formula (VIII): X is O, R is -CH2CH20CH2CHZOCH3;
Compound of Formula (VIII): X is O, R is -CH2SCH3;
Compound of Formula (VIII): X is O, R is -cyclopropyl;
Compound of Formula (VIII): X is O, R is -CHZOCH3;
Zc~ Compound of Formula (VIII): X is O, R is -CH2CH2F;
Compound of Formula (VIII): X is O, R is -CH2-cyclopropyl;
Compound of Formula (VIII): X is O, R is -CHzCH2CH0;
Compound of Formula (VIII): X is O, R is -C(O)CHZCH2CH3;
Compound of Formula (VIII): X is O, R is -CH2-(4-nitrophenyl);
25 Compound of Formula (VIIij: X is O, R is -CHZ-(4-chlorophenyl);
Compound of Formula (VIII): X is O, R is -CH2-(4-methoxyphenyl);
Compound of Formula (VIII): X is O, R is -CH2-(4-cyanophenyl);
Compound of Formula (VIII): X is O, R is -CHZCH=CHC(O)OCH3;
Compound of Formula (VIII): X is O, R is -CH2CH=CHC(O)OCH2CH3:
3o Compound of Formula (VIII): X is O, R is -CH2CH=CHCH3;
Compound of Formula (VIII): X is O, R is -CH2CH=CHCH2CH3;
Compound of Formula (VIII): X is O, R is -CHZCH=CHCHZCHZCH3;
Compound of Formula (VIII): X is O, R is -CH2CH=CHSOZ-phenyl;
Compound of Formula (VIII): X is O, R is -CH2C---C-Si(CH3)3;
35 Compound of Formula (VIII): X is O, R is -CH2C=CCH2CH2CH2CH2CH2CH3;
Compound of Formula (VIII): X is O, R is -CH2G--CCH3;
Compound of Formula (VIII): X is O, R is -CH2-(2-pyridyl);

wo 9sio9rrs rcrnrsrrnssso6 Compound of Formula (VIII): X is O, R is -CHZ-(3-pyridyl);
Compound of Formula (VIII): X is O, R is -CH2-(4-pyridyl);
Compound of Formula (VIII): X is O, R is -CH2-(4-quinolyl);
Compound of Formula (VIII): X is O, R is -CH2N02;
Compound of Formula (VIII): X is O, R is -CH2C(O)OCH3;
Compound of Formula (VIII): X is O, R is -CHZC(O)-phenyl; -Compound of Formula (VIII): X is O, R is -CH2C(O)CH2CH3;
Compound of Formula (VIII): X is O, R is -CH2Cl; - - .
Compound of Formula (VIII): X is O, R is -CH2S(O)2-phenyl;
1o Compound of Formula (VIII): X is O, R is -CH2CH=CHBr;
Compound of Formula (VIII): X is O, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (VIII): X is O, R is -CH2CHZCH2-(4-quinolyl);
Compound of Formula (VIII): X is O, R is -CHZCH=CH-(5-quinolyl);
Compound of Formula (VIII): X is O, R is -CH2CH2CH2-(5-quinolyl);
t Compound of roe mula ('Jill): X is O, R is -CI-i2CH=Ci-i-(4-benzbxazoiyi) Compound of Formula (VIII): X is O, R is -CH2CH=CH-(7-benzimidazolyl);
Compound of Formula (VIII): X is O, R is CH2-(3-iodophenyl);
Compound of Formula (VIII): X is O, R is CH2-(2-naphthyl);
Compound of Formula (VIII): X is O, R is CH2-CH=CH-(4-fluorophenyl); and 20 Compound of Formula (VIII): X is O, R is CH2-CH(OH)-CN.
Preferred compounds of formula VIII are selected from the group consisting of:
Compound of Formula (VIII): X is O, R is allyl;
Compound of Formula (VIII): X is O, R is -CH2CH=CH-phenyl; and 25 Compound of Formula (VIII): X is O, R is -CH2CH=CH-(3-quinolyl).
In one embodiment of the invention is a process for the preparation of 6-O-substituted macrolide compounds having the Formula:
Y R R~ NMe2 Z ~~,. I
O
1-10,,,_ ,.,I o R~ o 30 (II) o ;

wherein either, Y, Z, Ra, R~, and R are previously defined, the method comprising:
(a) treating a compound having the formula R p NMe2 I
O
,.
HO,,,, Ra .,~~ O O
- 0,,~. O
H
O ~ .''n- Rv H3C-O ~
> >
wherein RP is a hydroxy protecting group and V is =N-O-R1 or =N-O-C(RS)(R6)-O-wherein R1, R9 and R10 are as previously defined, with a base in an aprotic solvent followed by treatment with an alkylating agent to give a compound having the formula R R p NMez ( ,,~ ,'~O
HO,,,_ Ra 'I~~ O o .'>'.
_ 0~,. O
H
O .,.0-RP

wherein Ra and RP are as previously defined, V is =N-O-R~ or =N-O-C(RS)(R6)-O-RI
wherein R1, R5 and R6 are as previously defined, and R is the "allcyl group"
derived from the corresponding allcylating agent;
(b) deprotecting the 2'- and 4"-hydroxyl groups to give a compound of the formula _.. _. CA 02564020 2006-10-31 ,T-i t WO 98/09978 PCT/US97I1~06 OH
t H NMe2 N~ R I
O
..,. ,,.
HO,,~
Ra .~~~ ~ o I . 0~... O _ _ .
O
H
O .~~0- H .

wherein Ra is as previously defined and R is the "alkyl group" derived from the corresponding alkylating agent;
(c) deoximarion in the presence of acid in a suitable solvent to give the desired intermediate having the formula O R H NMe2 I
O
,,.
HO,, ~a .II ~ O O
r, H
O ..'O-H

(d) removing the cladinose moiety by hydrolysis with acid, and protecting the 2' hydroxyl group by treatment with a hydroxy-protecting reagent to give a 3-hydroxy erythromycin compound having the formula CA 02564020 2006-10-31 . -- -' WO 98/09978 ~'CT/U~9/155Q6 R RP NMe2 .., ,.O
HOr,,, Ra,~ p p ; and (e) oxidizing the 3-hydroxy group, optionally deprotecting the 2'-hydroxyl group, and isolating the desired compound.
In a preferred embodiment of the process immediately above, in step (a) the base is selected from the group consisting of potassium hydroxide, cesium hydroxide, tetraallcylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potasaiurrt tPrt-butc~ide and potassium isobutoxide, the alkylating agent is selected from the group consisting of allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, oc-bromo-p-tolunitrile, cinnamyl bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-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-bromo-2-butanone, bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, and n-butyl-O-methanesulfonate, and the reaction is performed at a temperature from about -15 °C to about 50 °C for a period from 0.5 hours to 10 days: in step (b) deprotection is accomplished by use of acetic acid in water and acetonitrile; and in step (c) the deoximating reagent is an inorganic sulfur oxide compound is selected from the group consisting of sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, and potassium ?5 metabisulfite, or an inorganic nitrite salt in the presence of acid selected from the group consisting of sodium nitrite and potassium nitrite, and the solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, trimethyIsilanol or a mixture of one or more thereof; in step (d) the hydroxy protecting reagent is selected from the group consisting of a trialkysilyl halide, an acyl anhydride or an acyl halide; in step (e), the ._ WO 98/09978 PCT/(TS97/15506 oxidizing is selected from N-chlorosuccinimide-dimethyl sulfide and carbodiimide-dimethylsulfoxide, and the optional deprotection is carried out by stirring in methanol.
In another embodiment of the present invention are compounds having formula III, O R Rc NMe2 ' -.~ _o T~,, L\ 6 . ....0 ~
O .
(III) O
wherein R, R~, L and T are as. described previously.
Preferred compounds of formula III are those selected from the group consisting of:
Compound of Formula (III); Rc is acetyl, L is CO, T is NH, R is -CH2CH=CH2;
Compound of Formula (III): R~ is acetyl, L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (III): R~ is benzoyl, L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (III): R~ is propanoyl, L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl); and Compound of Formula (III): R~ is ethylsuccinoyl, L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl).
In a more preferred embodiment of the compounds of formula III of the invention are compounds having the formula IX. .
NMe2 O
,O H 0,,, L i T.... ~
O
O
(IX) O
-1$-WO 98/09978 ~CT/US97/R
wherein L, T, and R are defined above.
Compounds representative of this embodiment include, but are not limited to:

Compound of Formula L is CO, T is O, R is -CH2CH=CH2;
(IX):

Compound of Formula L is CO; T is O, R is -CH?CH=CH-phenyl;
(lx):

Compound of Formula L is CO, T is O, R is -CH2CHZCH2-Phenyl;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-chlorophenyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(3-quinolyl);
(ix):

Compound of Formula L is CO, T is O, R is -CH2CH2CH3.;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2NH2.;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=NOH.;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2CH20H;
(IX):

Compound of Formula L is CO, T is O, R is -CH2F;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2-phenyl;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2-(4-pyridyi)w (IX):

Compound of Formula L is CO, T is O, R is -CH2CH2-(4-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH(OH)CN;
(IX):

Compound of Formula L is CO, T is O, R is -CH(C(O)OCH3)CH2-phenyl;
(IX):

Compound of Formula L is CO, T is O, R is -CH2CN;
(lx):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-methoxyphenyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-fluorophenyl);
(lx):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(8-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2NHCH2-phenyl;
(IX):

Compound of Formula L is CO, T is O, R is -CH2-phenyl;
(IX):

Compound of Formula L is CO, T is O, R is -CH2-(4-pyridyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2-(4-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-pyridyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2CH2-(4-pyridyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH2CH2-(4-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(5-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH~CH~CH2-(5-quinolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-benzoxazolyl);
(IX):

Compound of Formula L is CO, T is O, R is -CH2CH=CH-(4-benzimidazolyl);
(1X):

Compound of Formula L is CO, T is NH, R is -CH~CH=CH2;
(IX):

Compound of Formula L is CO, T is NH, R is -CH2CH=CH-Phenyl;
(IX):

Compound of Formula L is CO, T is ~r'I-I, R is -CH~CH=CH-(3-quinolyl);
(IX):

Compound of Formula (IX):L is CO, T is -CHZCH2CH3.;
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH2NH2.;
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH=NOH.;
NH, R is Compound of Formula (IX):L is CO, T is -CHZCH2CH20H;
NH, R is Compound of Formula (IX):L is CO, T is -CH2F;
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH2-phenyl; - .
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH2-(4-pyridyl);
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH(OH)CN; ' , NH, R is Compound of Formula (IX):L is CO, T is -CH2CH2-(4-quinolyl);
NH, R is Compound of Formula L is CO, T is -CH(C(O)OCH3)CH2-phenyl;
(IX): NH, R is Compound of Formula (IXj:L is CO, T is -CH2CN;
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH=CH-(4-chlorophenyl);
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH=CH-(4-fluorophenyl);
NH, R is Compound of Formula (IX):L is CO, T is -CH2CHZCH2-(4-methoxyphenyl);
NH, R is i~ Compound-of Formula L is CO, T isivi-i, (iXj: R is -CH2CH=CH-(~=methoxyphenylj;

Compound of Formula (IX):L is CO, T is -CH2CH=CH-(3-chloro-6-quinolyl);
NH, R is Compound of Formula (IX):L is CO, T is -CH2CHZNHCH2CH2-(2-NH, R is chlorophenyl);

Compound of Formula (IX):L is CO, T is -CHZ-phenyl;
NH, R is Compound of Formula L is CO, T is -CH2-(4-pyridyl);
(IX): NH, R is Compound of Formula (IX):L is CO, T is -CH2-(4-quinolyl);
NH, R is Compound of Formula (IX):L is CO, T is -CH2CH=CH-(4-pyridyl);
N'H. R is Compound of Formula (IX):L is CO, T is -CH2CH2CH~-(4-pyridyl);
NH, R is Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=CH-(3-fluoro-6-quinolyl);

Compound of Formula L is CO, T is -CH2CH2CH2-(4-quinolyl);
(IX): NH, R is Compound of Formula (IX):L is CO, T is -CH2CH=CH-(3-cyano-6-quinolyl);
NH, R is , Compound of Formula (IX):L is CO, T is -CH2CH2CH2-(5-quinolyl);
NH, R is Compound of Formula (IX):L is CO, T is CH2CH=CH-(4-benzoxazolyl);
lv'H, R is -Compound of Formula (IX):L is CO, T is CH2CH=CH-(4-benzimidazolyl);
h'H, R is -Compound of Formula L is CO, T is -CH2CH=CH-(3-methoxy-6-(IX): NH, R is quinolyl);
Compound of Formula (IXj: L is CO, T is NH, R is -CH2-(2-naphthyl);
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH2:
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH-(3-quinolyl);
3, Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CHZCH=CH2;
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH~CH=CH-(3-quinolyl);

---WO 98/09978 PCT/IJS97/155~
Compound of Formula (IX): L is CO, T is N(CH2CH=CH2), R is -CH2CH=CH2:
Compound of Formula (IX): L is CO, T is T is N(CH2CH=C-(3-quinolyl)), R is -CH2CH=CH-(3-quinolyl):
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-naphthyl);
Compound of Formula (IX): L is CO, i is NH, R is -CH2CH=CH-(4-isoquinolinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH~CH=CH-(3,4-methylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-indolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-chloro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3,4-ethylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CHZCH=CH-(3-nitrophenyl);
t 5 Compo»nd of Formula (IX): L is CO, T iwJH, R is -CH2CH=Ctrl-(6-qainolyl);
Compound of Formula (1X): L is CO, T is NH, R is -CH2CH=CH-(6-nitroquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-quinolyl);
. Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-methyl-6-quinolyl);
Compound of Formula (III): L is CO, T is NH, R~ is acetyl; R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-isoquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(7-vitro-6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-amino-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(1,8-naphthyridin-3-y1);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-(acetylamino)-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-carbazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-benzimidazolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(-3-hydroxy-2-(N-(2-methoxyphenyl)amido)-7-naphthyl);
Compound of Formula (1X): L is CO, T is NH, R is -CH2CH=CH-(6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-hydroxy-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxy-3-quinolyl);

WO 98/09978 PGTlCTS97/15506 Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-vitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-vitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-quinolyI);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-carboxyl-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-fluoro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxycarbonyl-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-aminocarbonyl-3-.
quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-cyano-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-bromo-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)H;
Conupuund of Forrrmia (IX): L is CO; °T is NH; R is =CH2Ci-12N-1-ICI-H2t henyl, Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2Phenyl:
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2CH2Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2CH2CH2Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2CH2CH2-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH. R is -CH2CH2NHCH2(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH2NHCH2(6-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NO(phenyl);
Compound of Formula L is CO, T is NN, R is -CH2CH=NOCH2(phenyl);
(IX):

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2(4-N02-phenyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2(4-quinolyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2(2-quinolyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2(3-quinolyl);

Compound of Formula L is CO, T is NH, R is -CH2CH=NOCH2-(6-quinolyl);
(IX):

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2-(1-naphthyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH=NOCH2-(2-naphthyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH2NHOCH2-(phenyl);

Compound of Formula (IX):L is CO, T is NH, R is -CH2CH?NHOCH2-(4-N02-phenyl);

Compound of Formula L is CO, T is NH, R is -CH2C(O)-phenyl;
(IX):

Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)-(4-F-phenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=NNHC(O)phenyl;

Compound of Formula (IX): L is CO, T is NH, R is -CH?CH2CH2-(3-quinolyl);

Compound of Formula (IX): L is CO, T is NH, R is -CH2-(2-(3-quinolyl)cyclopropyl);

Compound of Formula (IX): L is CO, T is NH, R is -CH2-C=C-H;

Compound of Formula (IX): L is CO, T is NH, R is -CHI-C-C-(3-quinolyl);

Compound of Formula (IX): L is CO, T is NH, R is -CHI-C=C-(6-vitro-3-quinolyl);

. . - - Compound of Formula L is CO, T is lV~i, R is -CHI-C---C-phenyl;
(IX):

Compound of Formula (IX): L is CO, T is NH, R is -CHI-C=C-naphthyl;

_ - Compound of Formula (1X): L is CO, T is NH, R is -CHI-C=C-(2-naphthyl) ;

Compound of Formula (IX): L is CO, T is ~1H, R is -CHI-C---C-(6-methoxy-2-naphthyl);

Compound of Formula (IX): L is CO, T is N'H, R is -CHI-C=C-(b-chloro-2-naphthyl);

Compound of Formula (IX): L is CO, T is ~IH, R is -CHI-C=C-(6-quinolyl);

Compound of Formula (IX): L is CO, T is iV-H, R is -CHI-C=C-(2-methyl-6-quinolyl);

Compound of Formula (IX): L is CO, T is NH, R is -CHI-C-C-{5-(N-(2-pyridyl)amino)carbonyl)furanyl);

1 ~ Compound of Formula (IX): L is C O; T is ~TH, R- is -CHI-C--C-( 1=phenylethenyl);

Compound of Formula (IX): L is CO, T is I~'H, R is -CHI-C---C-Br;

Compound of Formula (TX): L is CO, T is \rH, R is -CHI-(2,2-dimethyl-I,3-dioxolan-4-Yl);

Compound of Formula (IX): L is CO, T is ~1~H, R is -CH~CH(OH)-phenyl;

2o Compound of Formula (IX): L is CO, T is I~H, R is -CH~CH(OH)CH20H;

Compound of Formula (IX): L is CO, T is ~THNH2, R is -CH~CH=CHI;

Compound of Formula (IX): L is CO. T is \'HNH~, R is -CHZCH=CH-(3-quinolyl);

Compound of Formula (1:X): L is CO. T is i~HNH2, R is -CH2CH~CH~-(3-quinolyl);

Compound of Formula (IX): L is CO. T is'~H2, R is -CH~CH=CH-naphthyl;

25 Compound of Formula (TX): L is CO, T is ~-HZ, R is -CH~CH=CH-(3-(2-furanyl)-6-quinolyl);

Compound of Formula (IX): L is CO. T is ~H2, R is -CH~CH=CH-(8-chloro-3-quinolyl);

Compound of Formula (IX): L is CO. T is '~-H2, R is -CH~CH=CH-(4-chloro-2-trifluoromethyl-6-quinolyl):

:i~ Compound of Formula (1X): L is CO. T is i\-H~, R is -CH~CH=CH-(9-fIuorenone-2-yl);

Compound of Formula (IX): L is CO. T is ~H~, R is -CH~CH=CH-(6-benzoyl-2-naphthyl);
Compound of Formula (IX): L is CO. T is '~~-I2, R is -CH~CH=CH-(7-methoxy-2-naphthyl);
35 Compound of Formula (IX): L is CO. T is NH2, R is -CHaCH=CH-(3-phenyl-6-quinolyl);

Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-(2-pyridyl)-6-quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(3-(2-thiophenyl)-quinolyl);

Compound of Formula L is CO> T is NH2, R is -CH2CH=CH-(4-methylnaphthyl);
(IX):

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(6-(3-D- ' - .

galactopyranosyl-2-naphthyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(7-quinolyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(4-fluoronaphthyl);

Compound of Formula (IX):L is CO> T is NH2, R is -CH2CH=CH-(3-biphenyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(5-nitronaphthyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(4-pyrrolylphenyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(6-methoxy-2-naphthyl);

t5 Conpound of Formula L is CO; T is ivri2, R is -CH2i:i-1=CI-I=(3;~-dichlorophenyl) {IX):

Compound of Formula (IX):L is CO, T is NH2, R is -CH2-(3-iodophenyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2-(3-(2-furanyl)phenyl);

Compound of Formula (IX):L is CO, T is NH2, R is -CH2CH=CH-(6-hydroxy-2-naphthyl);

20 Compound of Formula L is CO, T is NH2, R is -CH2CH=CH-(6-(2-bromoethoxy)-(IX):

2-naphthyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(6-(2-(tetrazolyl)ethoxy-2-naphthyl), Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-naphthyl;
2a Compound of Formula (IX): L is CO, T is NH, R is -CH2-C_--C-(2-phenylethenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(3-isoxazolyl)-thiophenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl); and 30 Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(2-pyridyl)aminocarbonyl-2-furanyl).
Preferred compounds of formula IX are those selected from the group consisting of:
Compound of Formula (IX): L is CO, T is O, R is -CH2CH=CH2;
3S Compound of Formula (IX): L is CO, T is O, R is -CH2CH=CH-Phenyl;
Compound of Formula (IX): L is CO, T is O, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH2;

WO 98!09978 PCT/US97/15506 Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-Phenyl;
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH2;
Compound of Formula (IX): L is CO, T is N(CH3), R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CHZ:
Compound of Formula (IX): L is CO, T is N(CH2CH2N(CH3)2), R is -CH2CH=CH-(3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3-pyridyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-naphthyl);
l0 Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-isoquinolinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(3,4-methylenedioxyphenyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (IX): L is CO, T is NI<-I, R is -CH2CH=CH-(6-quinolyl);
Compound of Formula (~): L is CO, T is NH, R is -C H2CH=CH-(6-nitroquinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-amino-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(1,8-naphthyridin-3-yl);
Compound of Formula (IX): L is CO, T is NH, R is -CHZCH=CH-(6-(acetylamino)-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-quinoxalinyl);
Compound of Formula (IX): L is CO, T is NH, R is -CHZCH=CH-(6-hydroxy-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxy-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(5-vitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(8-vitro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(2-quinolyl);
Compound of Formula (1X): L is CO, T is NH, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(4-carboxyl-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-fluoro-3-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-methoxycarbonyl-quinolyl);
Compound of Formula (IX): L is CO, T is NH, R is -CH2CH=CH-(6-aminocarbonyl-3-quinolyl);

t'~
WO 98/09978 PCT/US97/1550~
Compound of Formula (IX): L is CO, T is NH, R is =CH2CH=CH-(6-cyano-3-quinolyl);

Compound of Formula L is CO, T is NH, R is -CH2CH=CH-(3-bromo-6-quinolyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2CHZCH2-(3-quinolyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-(2-(3-quinolyl)cyclopropyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C=C-H;
(IX):

Compound of Formula L is CO, T is NH, R is -CHZ-C=C-(3-quinolyl);
(IXj:

Compound of Formula L is CO, T is NH, R is -CH2-C---C-(6-vitro-3-quinolyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C=C-phenyl; -(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C=C-naphthyl;
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C--_C-(2-naphthyl) (IX): ;

Compound of Formula L is CO, T is NH, R is -CH2-C---C-(6-methoxy-2-naphthyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C--__C-(6-chloro-2-naphthyl);
(IX):

Compound of Formula L is CO, T is NH, R is -CH2-C=C-(6-quinolyl);
(IX):

Compound of Formula L is CO, T is N(NH2), R is -CHZCH=CHZ;
(IX):

IS Compound of Formula L is CO, T is N(NH2), R is -CH2CH=CH=(3-quinolyl);
(IX):

Compound of Formula L is CO, T is N(NHZ), R is -CHZCH2CH2-(3-quinolyl);
(IX):

Compound of Formula L is CO, T is NH2, R is -CH2CH=CH-naphthyl;
(IX):

Compound of Formula L is CO, T is NH2, R is -CHZCH=CH-(3-(2-pyridyl)-6-(IX):

quinolyl);
Compound of Formula (IX): L is CO, T is NH2, R is -CH2CH=CH-(7-quinolyl); and Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(3-isoxazolyl)-thiophenyl).
In another embodiment of the invention is a process for the preparation of 6-O-substituted macrolide compounds having the Formula:
- r~ f~p NMep I
R
o ~ o' ' O
wherein R and RP
R is selected from the group consisting of ( l ) methyl substituted with a moiety selected from the group consisting of VVO 98/09978 ~CT/iJS97/Y
(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)nRlO 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, to (g) aryl, (h) substituted aryl, (i) heteroaryl, and (j) substituted heteroaryl, .

1; (2) C2-C l0-alkyl, (3) C2-C 10-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, 20 (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e} oxo, -N3, (g) -CHO, 2; (h) O-S02-(substituted C1-C6-alkyl), (l) _~13R14 wherein R13 and R14 are selected from the group consisting of (l) hydrogen, (ii) Ci-C12-alkyl, 30 (iii) substituted C1-C12-alkyl, (ivj C1-C12-alkenyl, (v) substituted C~-C12-alkenyl, (vi) C1-C12-alkynyl, (vii) substituted C1-C12-alkynyl, 35 (viii) aryl, (ix) C3-Cg-cycloalkyl, (x) substituted C3-Cg-cycloalkyl, f WO 98/09978 PCT/US97/15~~6 (xi) substituted aryl, (xii) heterocycloalkyl, (xiii) substituted heterocycloalkyl, (xiv) Ci-Ci2-alkyl substituted with aryl, (xv) Ci-Ci2-alkyl substituted with substituted aryl, (xvi) Ci-Ci2-alkyl substituted with heterocycloalkyl, (xvii) Ci-Ci2-alkyl substituted with substituted heterocycloalkyl, (xviii) Ci-Ci2-alkyl substituted with C3-Cg-cycloalkyl, (xix) Ci-Ci2-alkyl substituted with substituted C3-Cg-cycloalkyl, (xx) heteroaryl, (xxi) substituted heteroaryl, (xxii) Ci-Ci2-alkyl substituted with heteroaryl, and (xxiii) Ci-Ci2-alkyl substituted with substituted heteroaryl, i5 or _ R i3 and R i4 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) C i-C3-alkoxy, (iv) Ci-C3-alkoxy-Ci-C3-alkoxy, (v) oxo, (vi) Ci-C3-alkyl, (vii) halo-Ci-C3-alkyl, and (vii) Ci-C3-alkoxy-Ci-C3-alkyl, (j) -C02Ri0 wherein Ri0 is as previously defined, (k) -C(O)NR i i R 12 wherein Ri i and R i2 are as previously defined, (1) =N-O-Ri0 wherein Ri0 is as previously defined, (m) -C---N, (n) O-S(O)~RIO wherein n is 0, 1 or 2 and Ri0 is as previously defined, (o) aryl, (p) substituted aryl, (q) heteroaryl, (r) substituted heteroaryl, (s) C3-Cg-cycloalkyl, (t) substituted C3-Cg-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;
(4) C3-alkenyl substituted with a moiety selected from the group consisting of IS (a) halogen, (b) -CHO, (c) -C02R10 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) FYI, (h) substituted aryl, (i) heteroaryl, (j) substituted heteroaryl, (k) C3-C7-cycloalkyl, and (1) C1-C12-alkyl substituted with heteroaryl, (5) C4-Clp-alkenyl;

(6) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) CI-C3-alkoxy, (c) oxo, (d) -CHO, (ej -C02R10 where R10 is as previously defined, (f) -C(O)NR11R12 wherein R11 and R12 are as previously defined, (gj -~,-R13R14 wherein R13 and R~4 are as previously defined, (h) =N-O-RIO where RIO is as previously defined, (i) -C=N, (j) O-S(O)~RIO where n is 0, 1 or 2 and RIO is as previously defined, (k) aryl, (1) substituted aryl, (m) heteroaryl, - .

(n) substituted heteroaryl, (o) C3-C~-cycloalkyl, (p) CI-C12-alkyl substituted with heteroaryl, l0 (q) NHC(O)RIO where RIO is as previously defined, (r) NHC(O)NRIIR12 wherein RI I 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)RIO where RIO is as previously defined, and (v) =N-NHC(O)NRI IR12 wherein RI I and R12 are as previously defined;

(7) C3-C10-alkynyl;

and (8) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of (a) trialkylsilyl, (b) aryl, (c) substituted aryl, (d) heteroaryl, and (e) substituted heteroaryl;

Re is H
or W-Rd, wherein W is absent or is selected from the group consisting of -O-, -NH-CO-, N=CH- and -NH-, and Rd is selected from the group consisting - of ( 3 ) hydrogen, (2) C1-Cb-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, CVO 98/09978 PCT1US97/g~
(f) C1-Cb-alkoxy, (g) 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 7-membered ring which, when the ring is a S- to 7-membered ring, may optionally . _ contain a hetero function selected from the group consisting of -D-, -NH-, -N(C~-C6-alkyl-)-, -N(aryl)-, -N(aryl-C1-C6-alkyl-)-, - -N(substituted-aryl-Ci-C6-alkyl-)-, -N(heteroaryl)-, -N(heteroaryl-C1-C6-alkyl-)-, -N(substituted-heteroaryl-C1-C6-alkyl-)-, and -S- or -S(O)S-, wherein n is 1 or 2, and (h) -CH2-M-R9 wherein M is selected from the group consisting of:

(i) -C(O)-IVH-, \ IS . (ii) -NH-C(O)-, (iu) -NH-(iv j -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)"-, wherein n is 0, 1 or 2, (xii) -C(O)-O-, (xiii) -O-C(O)-, and (xivj -C(Oj-, and R9 is selected from the group consisting of:

(ij 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, WO 98/09978 PCTIL1S9'1/15306 (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) treating a compound having the formula O R Rp NMe2 i O
HO,,,_ '' '"~ O
HO~ O
O
Z' O ;
wherein R is as previously defined,Rg is a hydroxy protecting group and Z' is 4"-hydroxy-protected cladinose, with sodium hexamethyldisilazide and carbonyldiimidazole to give a compound having the formula O R RP NMe2 I
0...
~O
N~ N O / CH3 '~~~ O O
'..,:
O
O, Z' O -(b) treating the compound from step (a) with a reagent selected from the group consisting of ammonia, Re-NH2, hydrazine, substituted hydrazine, hydroxylamine, and substituted hydroxylamine to give a compound having the formula O R Rp NMez f 0,,, R~ H3C.... ,.O
~N~i,..
O~ _ ...~ O O
O
~O, ,.
O

I$
~5 wherein Re is H_or W-Rd, wherein W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH- and -NH-, and Rd is as defined previously, (c) optionally treating the compound from step (b) wherein Re is H with an alkylating agent having the formula Rd-halogen, wherein Rd is as defined previously, to give a compound of the formula shown in step (b) wherein R~ is W-Rd, W is absent and Rd is as defined previously;
(d) optionally treating the compound from step (b) wherein Re is W-Rd and W is -NH-and Rd is H, with an alkylating agent selected from the group consisting of Rd-halogen, wherein Rd is as defined previously, to give a compound of the formula shown in step (b) wherein Re is W-Rd, W is -NH- and Rd is as defined above;
(e) optionally treating the compound from step (b) wherein Re is W-Rd and W is -NH-and Rd is H, with an acylating agent selected from the group consisting of R~-C(CO)-halogen or (Rd-C(CO)-O)2 to give a compound wherein Re is W-Rd, W is -NH-CO-and Rd is as defined above;
(f) optionally treating the compound from step (b) wherein Re is W-Rd and W is -NH-and Rd is H, with an aldehyde having the formula Rd-CHO, wherein Rd as defined above to give a compound wherein Re is W-Rd, W is -N=CH- and Rd is as defined above;

,-WO 98/09978 PCT/L1S97/1~50~
(g) removing the cladinose moiety by hydrolysis with acid to give a compound having the formula Ra NMe2 O R I
0,,, R \ H3C''~~ . ~~O
N~~...
O~ - ,~I~ O O
H
'' .~0, O
(h) oxidizing the 3-hydroxyl group; and (i) optionally deprotecting, and isolating the desired compound.
In a preferred embodiment of the process immediately above, R is an allyl or propargyl group substituted ~,vith a moiety selected from the group consisting of 1-phenylethenyl, 2-chlorophenyl, 2-fluorenyl, 2-methyl-6-quinolyl, 2-naphthyl, 2-phenylethenyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl, 3-quinolyl, 3-(2-thiophenyl)-6-quinolyl, 3-biphenyl, 3-bromo-6-quinolyl, 3-carbazolyl, 3-chloro-6-quinolyl, 3-cyano-6-quinolyl, 3-fluoro-6-quinolyl, 3-hydroxy-2-(N-(2-methoxyphenyl)amido)-7-naphthyl, 3-iodophenyl, 3-methoxy-6-quinolyl, 3-nitrophenyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-benzoxazolyl, 4-carboxyl-3-quinolyl, 4-chloro-trifluoromethyl-6-quinolyl, 4-chlorophenyl, 4-fluoronaphthyl, 4-fluorophenyl, isoquinolinyl, 4-methoxyphenyl, 4-methylnaphthyl, 4-pyridyl, 4-pyrrolylphenyl, quinolyl, 5-(2-pyridyl)aminocarbonyl-2-furanyl. ~-(3-isoxazolyl)-2-thiophenyl, benzimidazolyl, 5-indolyl, 5-isoquinolyl, ~-vitro-3-quinolyl, 5-nitronaphthyl, 5-(N-(2-pyridyl)amino)carbonyl)furanyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-(2-(tetrazolyl)ethoxy-2-naphthyl, 6-(2-bromoethoxy)-2-naphthyl, 6-amino-3-quinolyl, 6-anunocarbonyl-3-quinolyl, 6-~i-D-galactopyranosyl-2-naphthyl, 6-benzoyl-2-naphthyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxv-2-naphthyl, 6-hydroxy-3-quinolyl, 6-methoxy-2-naphthyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl, 6-nitroquinolyl, 6-quinolyl, 6-quinoxalinyl, 7-methoxy-2-naphthyl, 7-vitro-6-quinoxalinyl, 7-quinolyl, 8-chloro-3-quinolyl, 8-vitro-3-quinolyl. 8-quinolyl, 9-oxofluoren-2-yl, 1,3-dimethyl-2,4-dioxo-5-pyrimidinyl, 1,8-naphthyridin-3-yl, 3,4-methylenedioxyphenyl, 3,5-dichlorophenyl, naphthyl, and phenyl, and in step (b) the reagent is selected from the group WO 98/09978 PCT/US99/1.'~r506 consisting of ammonia and Re-NH2; optional steps (c), (d) and (e) are omitted;
and in step (g) the oxidizing reagent is selected from N-chlorosuccinimide-dimethyl sulfide and carbodiimide-dimethylsulfoxide; and in step (h) the optional deprotection is carried out by stirring in methanol.
- In a more preferred embodiment of the process immediately above, R is an allyl or propargyl group substituted with a moiety selected from the group consisting of 2-methyl-6-quinolyl, 2-quinolyl, 3-(2-furanyl)-6-quinolyl, 3-(2-pyridyl)-6-quinolyl, 3-quinolyl, 3-(2-thiophenyl)-6-quinolyl, 3-bromo-6-quinolyl, 3-chloro-6-quinolyl, 3-cyano-6-quinolyl, 3-IU fluoro-6-quinolyl, 3-methoxy-6-quinolyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-carboxyl-3-quinolyl, 4-chloro-2-trifluoromethyl-6-quinolyl, 4-isoquinolinyl, 4-quinolyl, 5-isoquinolyl, 5-nitro-3-quinolyl, 5-quinolyl, 6-(acetylamino)-3-quinolyl, 6-amino-3-quinolyl, b-aminocarbonyl-3-quinolyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy-3-quinolyl, 6-methoxy-3-quii<olyl, 6-methoxycarbonyl-3-quinolyl, 6-nitroquinolyl, 6-quinolyl, 7-I_5 quinolyi, 8-chloro-3-quinolyi, 8-nitro-.s-quinolyi and ~-quinolyl.
In another embodiment of the invention is a process for preparing a compound having the formula N~OR~o Rp NMe2 I
..
R~
O ~ O

wherein Re is H or W-R~, wherein W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH- and -NH-, and Rd is as defined previously, and RIU is H
or CI-C3-alkyl, aryl substituted Ct-C3-alkyl, or heteroaryl substituted C1-C3-alkyl, the method comprising (a) treating a compound having the formula wo 9sio~s PcrrUS~nss~
RP NMe2 O l 0,,, R \ H3C~... ..O
N,.,.. .,,~ O
O~. O
O
' O
O
with ozone to give a compound having the formula O
. ~ ~ RP NMe2 R~
O~ ~ o O
(b) treating the compound of step (a) with a hydroxylamine compound having the formula NH2-O-R10, wherein RIO is as previously defined; and (c) optionally deprotecting, and isolating the desired compound.
In a preferred embodiment of the process immediately above, Re is H.
In another embodiment of the invention is a process for preparing a compound having the formula WO 9810~9?>3 PCT/US97/15506 R~3 ~V
Rp NMe2 I
O''..
R
O~ ~ O
O
wherein Re is H or W-Rd, wherein W is absent or is selected from the group consisting of -O-, -NH-CO-, -N=CH- and -N>H-, and Rd is as defined above, ' is the method comprising (a) reductively aminating a compound having the formula Rp NMe2 I
R
O
O
1~> with an amine compound having the formula NH2-R13, wherein R13 is as previously defined; and (b) optionally deprotecting, and isolating the desired compound.

WO 981x9978 PCT/US97/15506 In another embodiment of the present invention are compounds having formula N
D
,,,, \ R R~ NMez ~, ,,. ,,~~ ,~O
O~ Nr~..
n_ ~~~~ O _p O
(IV) O
wherein R, R~, A, B, D and E are as defined previously.
In a more preferred embodiment of the compounds of formula N of the invention are compounds having the formula VII, p.
E''~ NMe2 N ~ R
A
i 0,,, B .,.. N
O~O O O
.~ C
(~) O
wherein A, B. D, E, and R are defined previously.
Compounds representative of the embodiment of formula VII include. but are not limited to:
Compound of Formula (VII): A, B, D, and E are H, R is allyl;
i5 Compound of Formula (VII): A, B, D, and E are H, R is -CH2CHZCH3;
Compound of Formula (VII): A, B, D, and E are H, R is -CHZCH21V'H2;
Compound of Formula (VIIj: A, B, D, and E are H, R is -CH2CH=NOH;
Compound of Formula (VII): A, B, D, and E are H, R is -CH?CH2CH20H;
Compound of Formula (VII): A. B, D, and E are H, R is -CH2F;
Compound of Formula (VII): A, B, D, and E are H, R is -CHZCN;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH(OH)CN;
Compound of Formula (VII): A. B, D, and E are H, R is -CH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2-(4-pyridyl);

Compound of Formula (VII): A, B, D, and E are H, R is -CHZ-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-chlorophenyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-fluorophenyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH~CH=CH-(4-. . methoxvphenyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2CH2-(4-pyridyl);
1o Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CHZCH2-(4-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CHZCH=CH-(5-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CHZCH2CH2-(5-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-benzoxazolyl);
15 Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(4-benzimidazolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(8-quinolyl);
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH2NHCH2-phenyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CHzNHCH2-(4-pyridyl);
Compound of Formula (VII): A, B, D, and E~are H, R is -CHZCH~NHCH2-(4-quinolyl);
20 Compound of Formula (VII): A, B, D, and E are H, R is -CHZCH2NHCH(CHZ-phenyl)C(O)OCH3;
Compound of Formula (VII): A, B, D, and E are H, R is -CHZCHzNHCH2CH2-(2-chlorophenyl);
Compound of Formula (VII): A, B and E are H, D is benzyl, R is allyl;
25 Compound of Formula (VII): A is benzyl, B, D and E are H, R is allyl;
Compound of Formula (VII): A and E are phenyl, B and D and are H, R is allyl;
Compound of Formula (VII): A is methyl, B, D and E are H, R is aliyl;
Compound of Formula (VII): A and D are methyl, B and E are H, R is allyl;
Compound of Formula (VII): A and E taken together is -CH2CH~CH2-, B and D are H, R
3o is allyl;
Compound of Formula (VI1): A, B, D, and E are H, R is -CH2CH=CH-{3-quinolyl);
and Compound of Formula (VII): A, B, D, and E are H, R is 3-(3-quinolyl)propyl.
Preferred compounds of formula VII are those in the group consisting of:
35 Compound of Formula (VII): A, B, D, and E are H, R is allyl;
Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH=CH-(3-quinolyl);
and Compound of Formula (VII): A, B, D, and E are H, R is -CH2CH~CH~-(3-quinolyl) a WO 98/099'18 PGT1LTS97115506 In another embodiment of the invention is the process for preparing a compound having the formula TV
R° NMe2 E,,,.
I . _ ..
0 0,,.
,. .,,, ,,, O~ N~".
o ,~~~ O O
I 'O
O
s (IV) o ;
wherein R~, R, A, B, D and E are as defined previously, the method comprising:
(a) treating a compound having the formula o R R~ NMe2 i O
..,. ,.
HO,,,.
HO .~~~ O
v'' I 'O
O
(II) o ;
wherein R is as defined previously, and Rc is a hydroxy protecting group, by treatment with i5 methanesulfonic anhydride in pyridine, then treating the methansulfonyl derivative with an amine base to give a compound having the formula WO 98109978 PCTlUS97/13506 R' NMep O R I
HO / \ CH3 I~~ O O
f ~O
O
O
(b) treating the compound from step (a) with an alkali metal hydride base and carbonyldiimidazole to give a compound having the formula O R R° NMe2 0~...
,~'O ..
N~ N ~ ~ CH3 '''~ O~~
O ' ~O _ O
(c) treating the compound of step (b) with a diamine having the formula NHz E~~..
A
8~~~~ NHZ
wherein A. B, D and E are as defined previously, to give a compound having the formula WO 98!09978 PCT/US9'7/15506 D NH2 R° NMe2 Ei~,. O R 1 A ,.O 0.,.
H3Cn,.
N..,.. '''~ O
O O
O
O
O
(d) cyclizing the compound of step (c) with dilute mineral or organic acid, optionally deprotecting, and isolating the desired compound.
An alternate to the process described immediately above is that process wherein steps (c) and (d) are replaced by the steps (c)-(f) consisting of .
(c) treating the compound of step (b) with an amine having the formula .
D Y
E ~...
A
B~~~~ NH2 wherein A, B, D and E are as defined therein, and Y is hydroxy, to give a compound having the formula D Y O R° NMe2 R
E~~.. O
A
8~,,. H3C~... ~~
O~ Nn,.. .,,~ O O
-'~O
O
O, O
(d) treating the compound of step (c) with triphenylphosphine and diphenylphosphoryl azide and diethylazodicarboxylate in tetrahydrofuran to give the analogous compound of 2u wherein Y is N3, and removing the deprotecting group to give the analogous compound wherein Y is N3 and R~ is H;

')V0 98/09978 PGTlUS97/15506 (e) treating the compound of step (d) with a reducing agent selected from the group consisting of triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, and dialkylaluminum hydride, to give the compound having the formula D NHS _ ~ I NMep E r...
p O~ ~ O
and (f) -cyclizing the compound of step (e) with dilute mineral Or Organ,'_c acid ~;d isolating the desired compound.
In another embodiment of the present invention are compounds having formula IV-A
R R~ NMe2 A 1 0...
". i,,~ ~ O
O N~~~.
~n_ O O
O
(N-A) ~ ;
wherein R, R~, A, B, D and E are as defined previously.
In a preferred embodiment are compounds having formula IV-A wherein R~ is H, and R, A, B, D and E are as defined previously.

In another embodiment of the present invention are compounds having formula V' o R R~ NMe2 'O

' '~n O r O - ., v.,'' I 'O -O
(V) O ;
wherein R, R~ and Rd are as defined previously.
In a preferred embodiment of the compounds of formula V of the invention are compounds having the formula VI

NMe2 O ~ H 0~,, ,,, HO / 'CH3 ~~~~O 0 CH3 ~~,,.. O CHs O

wherein R is as defined previously.
Compounds representative of compounds of formula VI include, but are not limited to:
Compound of formula (VI): R is -CH2CHZCH3, Compound of formula (VI): R is -CH2CH=CH, Compound of formula (VI): R is -CHZCH=CH-Phenyl, Compound of formula (VI): R is -CH2CH2CH2-Phenyl, Compound of formula (VI): R is -CH2CH=NOH, ?0 Compound of formula (VI): R is -CH2CH2NH2, Compound of formula (VI): R is -CH2CH2NHCH2-Phenyl, Compound of formula (VI): R is -CH2CH2NHCH?-(4-pyrdidyl), Compound of formula (VI): R is -CH2CH2NHCH2-(4-quinolyl), wo ~sio99~s ~crms~nssos Compound of formula (VI): R is -CH~CH(OH)CN, Compound of formula (VI): R is -CH2CH2NHCH(C02CH3)CH2-Phenyl, Compound of formula (VI): R is -CHZCN, Compound of formula (VI): R is -CH2CH=CH-(4-methoxyphenyl), S Compound of formula (VI): R is -CHZCH=CH-(4-chlorophenyl), - Compound of formula (VI): R is -CH2CH=CH-(4-fluorophenyl), Compound of formula (VI): R is -CH2CH=CH-(3-quinolyl), Compound of formula (VI): R is -CH2CH=CH-(8-quinolyl), and Compound of formula (VI): R is -CH2CH2NHCHZCH2-(2-chlorophenyl).
Another embodiment of the invention is the process for preparing a compound having the formula - o Rc NMe2 t 1 0~..
R ~ o (V) o ;

wherein R and R~ are as defined previously and Rb is selected from the group consisting of hydroxy, -O-C(O)-NH2 and -O-C(O)-imidazolyl;
the method comprising:
(a) treating a compound having the formula O R R' NMe2 .O 0~~.
HO~,,.
~''~ O
HO O
'.
I 'O
O
O
wherein R~ is a hydroxy protecting group and R is as previously defined with a reagent combination selected from WO 98/09978 PCT/US97l1S506 ( 1 ) an alkali metal hydride and a phosgene reagent selected from phosgene, diphosgene and triphosgene under anhydrous conditions, followed by aqueous base catalyzed decarboxylation, and (2) reaction with methanesulfonic anhydride in pyridine, followed by treatment with an amine base, to give the compound of formula V wherein Rb is hydroxy;
(b) optionally treating the compound of formula V of step (b) wherein Rb is hydroxy with an alkali metal hydride base and carbonyldiimidazole to give the compound of formula V
wherein Rb is -O-C(O)-imidazolyl;
(c) optionally treating the compound of formula V of step (a) wherein Rb is -O-C(O)-imidazolyl with an amine to give the compound of formula V wherein Rb is -O-C(O)-NH12;
and (d) cpt~~onal!y deprotect;ng and iscl4ti:,g tike desired-compound.:- _ Definitions As used throughout this specification and the appended claims, the following terms have the meanings specified.
, The terms "CI-C3-alkyl", "C1-C6-alkyl", and "Cl-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 C1-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, examples of C~-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, ~a-butyl, tert-butyl, neopentyl and n-hexyl. Examples of C1-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 "C~-C6-alkoxy" as used herein refers to an C1-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
Examples of C1-C6-alkoxy, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term "Cl-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-I-yl, and the Like.
The term "C1-C12-alkynyl" 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, l,l-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The term "C1-C3-aikylamino" as used herein refers to one or two C1-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of Ci-C3-alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
1o The term "oxo" denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl 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, 1 i5 hydrvCarvvu5; Such aS-hexaite ai~d-iOiuEiiG, foi example, halogenated i5ydrocarbans, Slll;ll 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 20 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 Physical Properties and Methods of Purification, 4th ed., edited by John A.
25 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 30 groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, ac:ytamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
35 The term "C3-C~~-cycloalkyl" denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single 7_ WO 98!09978 PCTlUS97l15506 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 -NR'R" wherein R' and R" are independently selected from alkyl, as previously defined.
Additionally, R' and R" taken together may optionally be -(CH2)~- where k is an integer of from 2 to 6 Examples of dialkylamino include, dimethylamino, diethylaminocarbonyl, methylethylamino, piperidino, and the Like.
The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is e~cemplified by such groups as chloromethyl, bromoethyl, trifluo:omeLhyl; u~;~ th.°, like. . . ~: . _ ..
The term "alkoxycarbonyl" represents an ester group; i.e. ari allcoxy 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.
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 -CONHR'R"
wherein R' and R" are independently selected from hydrogen or alkyl, or R' and R" taken together may optionally be -(CH2)k- 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, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl; and the like.
The term "heterocycloallcyl" 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 heterocycloallcyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include, Gut 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-methylphenyl)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,I-dimethylethoxycarbonyl)piperazine, 4-(2-(bis-{2-propenyl)amino)ethyl)piperazine, 4-(2-(diethylamino)ethyl)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-methox_yphPryl)piperazine; 4-(2-metl:ylphen~rl)piYeraz::r~, 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-trimethoxyphenyl)piperazine, 4-(3,5-''S 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-fluorophenyljpiperazine> 4-(4-methoxyphenyl)piperazine, 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-S-yljmethyl)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, l,?,3,4-wo 9sio~ms pcriusmnsso6 tetrahydroquinoline, azacyclooctane, decahyd~roquinoline, piperazine, piperidine, pyrrolidine, thiomorpholine, and triazole.
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-grotecting.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 Organic 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 methoxymethyl, and esters including acetyl benzoyl, and the like.
IS , yThe term "ketone protecting gro~!p",as used herein;-ref=ers 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, cf., for example, T.H.
Greene and P.G.M. Wuts, Protective Groups in Organic Synthe~is. 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:
Oreanic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vo(. 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, C1-C3-alkyl, Ct-C6-alkoxy, Ct-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, 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 t0 atoms thereon with Cl, Br, F, l, OH, CN, C1-C3-alkyl, Ct-C6-alkoxy, Ct-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, 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 W group, as defined-above, substituted by independent replacemeclt of one; two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C~-C3-alkyl, Ct-C6-alkoxy, Ci-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substitutent may be an aryl, heteroaryl, or heterocycloalkyl group.
20 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. iVt. Serge, et al, describe 3t pharmaceutically acceptable salts in detail in 1. Pharmaceutical Sciences.
66: 1-19 (1977).
The salts can be prepared ira sing 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, maleie acid, tartaric acid, citric acid, suecinic 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, naphthalenesulfonate, nicodnate, nitrate, oleate, oxalate, palrnitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
1~ Representative alkali or alkaline 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.
1 ~ As used herein, the term "pharmaceuticallyacceptable ester" refegs 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 allcanedioic acids, in which each alkyl or alkenyl moiety 20 advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pharmaceutically 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 2i with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefidrisk 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.
3t) Higuchi and V. Stella, Pro-drugs ~s Novel Delivery Svstems, Vol. 14 of the A.C.S.
Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drua Design, American Pharmaceutical Association and Pergamon Press, 1987.
3, Antibacterial Activitv Representative compounds of the present invention were assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous CA 02564020 2006-10-31 . ________ .._..._ _ dilutions of the test compound mixed with 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-O1-5) 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 S 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 to 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 15 control. The results of t his assay, shown below in T able 2 demonstrate the antibacterial activity of the compounds of the invention.

WO 98/09978 PC1YU89'1/I~S~
Table 1 Antibacterial Activity(MIC'sl of Selected Compounds Microoreanism Orb Er_ v. _A

code standard 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 Stieptococcus.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 PP 0.2 Escherichia coli JUHL QQ > 100 Escherichia coli SS RR 0.78 Escherichiacoli DC-2 SS >100 Candida albicans CCH 442 TT >100 Mycobacterium smegmatis UU 3.1 Nocardia Asteroides ATCC9970W 0.1 Haemophilis Influenzae DILL.WW ' 4 AMP R

Streptococcus Pneumonia XX 0.06 Streptococcus Pneumonia YY 0.06 Streptococcus Pneumonia ZZ >128 Streptococcus Pneumonia ZZA 16 Table 1, continued Organism Exam Exam Exam Exam Exam Exam 1e 1e 1e 1e 1e Ex_ 1e ample code 1 AA 12.5 3.1 25 6.2 3.1 25 3.1 BB 50 3.1 >I00 6.2 3.1 25 1.56 CC >100 >100 >100 >100 >100 >100 >100 L SO 1 100 12.5 3.1 6.2 6.2 DL .

EE 6.2 1.56 25 12.5 3.1 6.2 0.78 FF 25 3.1 25 12.5 3.1 50 3.1 GG >100 >100 >100 >100 >100 >I00 >100 HH 5p 6.2 50 6.2 3.1 100 3.1 12.5 6.2 25 6.2 1.56 6.2 0.78 JJ 25 3.I 25 1.56 0.78 3.1 0.05 . . T1 T7 ~ 1.56 25 I .5o u.78 6.2 0.39 ~

~,ri . 1 100 3.l 1.56 6.2 0.39 * 3 _ .

MM >100 >100 >I00 >100 >100 >100 >100 NN 12.5 3.1 100 6.2 3.1 I2.5 0.78 pp 3.~1 1.56 12.5 0.78 0.39 6.2 0.2 pp 6.2 3.1 100 6.2 1.56 i 2.5 0.78 >100 >100 >100 >100 >100 >100 25 RR 12.5 3.1 50 6.2 3.1 6.2 0.39 S S > 100 > 100 > 100 > 100 I 00 > 100 25 'pI' >100 >100 >100 >100 >100 >100 >100 U U > 100 25 100 > 100 100 I 00 6.2 W ~6.2 0.2 12.5 6.2 0.78 12.5 0.2 ~ >128 - - >128 - - 16 8 - - 0.25 4 - - 0.25 ZZ >128 - - >128 - - >64 8 _ - 16 - - 4 * missin g data -"
is indicated by "

Vw'O 9RN14~'JR p~T1I1~17t15iQ6 Tahlr, I. c~~tinue,l C?~ >misnt~ l~~pr~rrl~T'actom~~ m Exam 'xaro Fxvrn re Ir; J

:IT . ~ (~ ~ 17 fi.2. G.2 1.5f~ fi_2 I,~fi i.$~, 1).Z

1313 ~S_2 3,1 l.5fi ~.2 1.5f~ I . (~_2 S~

C~ :~1t1(~~lOl? :~2i1r1X100 >llrilStn ~ltltl UI7 6.2 fs.2 3.l fi_2 1,S(i 1_Sfi E~ fi.2 ~.2 3.1 fi.2 l,5fi J.Sb 11.2 F1-~ fi.~ (i.2 3.i ~.2 1_~fi ~,5f> (~_2 ..

Cit i ~ t ~ 1 ~ I '~ 10~J~ I SU ~ I
(~ {)t) 1)r) Ijr) (1(l 1111 ~.2 12..5 J,Sfi fr.2 I.5(i 1_it~ 0.2 T1 6,2 1_~~ 0,~$ I.~6 0.7$ 1_5t; 0,2 a.T 0.2 t).2 0,2 U.2 17.Z (1.'~~) hiC I,$~ fl.~t~ t1.2 U,2 fy.3~)CJ.'18 r1,2 L1, C~..~4tl.3~J U,39 11.~t) 0.3~ 11.7Ft ~).2 nil ~IC7c>>~r~ ~o uu~ >loo zi ;I~I~

NN I.s~, i.Sfs tt.~~l:~.1 i1.7~ 0,78 ir.l ~.1L~ JJ.2~ fJ_a'~ tl.a'~U.78 ()_2 ~J.3~! -I'P I,fib ().7Y1 U,7~i 3,1 fl.~'$1).7X fl.~

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NN cl.7H U.2 ~).7~cta.~~ :!, 1.5t, 0.2 t cx) 1.5~ r).il~ U.7R 1).i)2 ~.2 ~)"~9 E).t)1 PP 3.1 (?.I t.5(i . tE.3~)~5 i?.7$ X1_1 :~1(14~>E~u :.1r)(!:yltla >lt~n ~loc~ tcJa ~il~ 6.2 (J.2 1.56 tl.~~ 2;5 12.$ (J.3sl SS > I >1~)U :x > ll?U ~ I40 ~ 1f)(71{)i) U(1 Ii40 TT ~1Q~) >1(~f) ~kfl(~;~ItH~ ~Tt7(I ~EfIQ ~lf)f1 ut) 12.5 t~,~ 12.s t1.39 ~lt)(J 6.~. 3. U

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Y'S' ~T.S U.03 t . 0.25 2 4.5 U.(1i >~z~ r28 ~lz,~ ~t~~ :}12x 32 >Tz~s 77~A i1.3 0.~.~ 2 ~ ~ 2 E)_5 .g WO 98/09978 PGT/iTS97/15506 Table 1. continued Organism Ex~le Example Ex. ExampleExampleExample Example ample code 186 187 188 189 190 191 192 AA 0.1 0.1 0.1 0.2 0.05 0.05 0.1 BB 0.01 0.1 U.l C.1 0.05 0.05 0.1 ' CC >100 >100 >100 >100 >100 >100 >100 DD 0.1 0.1 0.1 0.2 0.05 0.05 0.1 EE 0.1 0.1 0.2 0.1 0.02 0.1 0.2 FF 0.01 0.1 0.1 0.1 0.02 0.05 0.1 G G >100 >100 >100 >100 >100 >100 >100 H H 0.1 0.1 0.2 0.2 0.05 0.0 0.1 D 0.05 0.02 0.05 0.05 0.02 0.05 0.02 JJ <=0.005<=0.005<=0.005 <=0.005<=0.005- 0.01 KK 0.01 0.02 <=0.005 <=0.005<=0.005- 0.05 0.01-LL 0.01 0.01 0.01 <=0.005<=0.0050.02 0.01 NIIVt 3.1 25 25 50 12.5 3.I 50 N N 0.1 0.1 0.1 0.2 0.1 0.1 0.1 00 <=0.0050.01 0.02 ~ 0.02 0.01 0.01 0.01 P P 0.1 0.0 0.2 0.1 0.1 0.1 0.2 QQ >100 100 >100 100 100 50 >100 RR 0.39 0.39 0.78 0.39 0.2 0.2 0.2 S S >100 >100 >100 50 100 100 100 TT >100 >100 >100 >100 >100 >100 >100 UU 0.2 0.78 0.78 0.78 0.78 0.39 3.1 W 0.1 0.1 0.39 0.05 0.1 0.02 0.1 XX 0.03 0.03 0.03 0.125 0.06 0.03 0.03 YY 0.015 0.03 0.03 0.06 0.03 0.03 0.03 ZZ >128 >16 >64 >32 >128 2 >128 2'ZA 1 0.25 1 0.5 0.5 0.25 0.25 WO 98/fr9978 PCT/US97/15506 Table 1, continued Orb Exampl_e ExampleExam Exam ExampleExample Ex 1e 1e 1e code 193 194 195 196 197 198 199 AA 0.05 0.05 0.05 0.1 0.1 0.05 0.1 BB 0.1 0.05 _ - 0.I 0.05 0.1 CC >100 >100 >100 >100 >100 >100 >100 DD 0.1 0.05 0.05 0.1 0,1 0.05 0.1 EE 0.1 0.1 0.05 0.1 0.2 0.05 0.1 FF 0.1 0.05 0.05 0. i 0.2 0.02 0.1 G G >100 >100 >100 >100 >100 >100 >100 H H 0.I 0.05 0.05 0.2 0.1 0.1 0.1 Il 0.02 0.02 0.05 0.05 0.05 0.02 <=0.05 JJ 0.01 <=0.0050.01 <=0.005 <=0.005<=0.005 <=0.05 K K 0.01 0.01 0.05 <=0:005 <=0.005<=0.00 <=0.05 S

LL <=0.005 0.01 0.02 <=0.005 <=0.005<=0.005 -MM 25 0.78 1.56 >100 100 0.39 50 N N 0.05 0.05 0.1 0.2 0.1 0.1 0.1 00 0.01 0.01 0.01 ' 0.01 0.02 <=0.005 0.05 P P 0.1 0.1 0.1 0.1 0.2 0.1 0.1 QQ 100 50 50 >100 100 50 100 RR 0.2 0.39 0.2 0.39 0.2 0.1 0.39 S S >100 100 50 >100 100 50 >100 TT >100 >100 >100 >100 >100 >100 >100 ULT 0.39 0.78 0.39 0.2 1.56 0.39 0.78 W 0.05 <=O.OOS0.05 0.1 O.I 0.02 0.1 XX 0.03 <=0.0040.03 ~ 0.03 0.03 <=0.004 0.008 YY 0.015 <=0.0040.015 0.03 0.03 <=0.004 0.008 ZZ >128 64 4 >128 64 4 >128 ZZA 0.25 0.25 0.25 0.25 0.5 0.125 0.25 WO 98/09978 ~ . PGT/US97115506 Table I, continued Organism ExampleExample Example ExampleExampleExample Example code 200 201 202 203 204 205 206 AA 0.1 0.1 - 0.2 0.1 - 0.7 8 BB 0.1 0.1 - 0.39 0.1 - 0.39 CC >100 >I04 - >100 >100 - >100 DD 0. I 0.1 - 0.2 0. I - 0.78 EE 0.1 0, t - 0.2 0.1 - 0.?8 FF 0.1 0.1 - 0.39 0.1 - 0.78 .

GG >t00 >100 - >100 >100 - >I00 HH 0.1 0.1 - 0.2 0.1 - 0.78 II 0.02 0.05 - 0.2 0.05 - 0.39 JJ Ø0I 0.01 - <=0.005 O.OI - 0.I

KK 0.02 0:01 - 0.0I 0.01 - 0.39 LL - 0.01 - 0.01 0.01 - 0.39 MM 50 1.56 - 1.56 3.1 - >100 NN 0.2 0.2 - 0.39 0.2 - 1.56 00 0.01 0.05 - 0.02 0.02 - 0.2 PP 0.2 0.1 - 0.39 0.1 - 1.56 QQ 50 50 - 100 > I00 - > 100 RR 0.39 0.2 - 0.39 0.78 - 25 S S 12. 5 50 - 100 > 100 - > 100 TT >100 >I00 - ~>100 >100 - >I00 UU 0.78 6.2 - 6.2 0.78 - 3.1 W 0.1 0.2 - 0.39 0.1 - 3.1 WW 2 2 4 4 >128 XX <=0:004 0.03 0.03 0.03 0.06 0.03 0.5 YY <=0.004 0.03 0.03 0.03 0.06 0.06 0.5 ZZ >128 16 32 16 8 >64 >I28 ZZA 0.25 1 2 2 0.5 4 4 -6.2_ Table 1, continued Organism Example ExampleExample Example Ex- Ex_ Ex~
ample amvle ample code 207 208 209 210 211 212 213 AA 0.1 0.1 0.05 0.1 0.05 0.39 0.2 BB 0.1 0.39 - ~ 0.05 ~u.39 G.2 CC >100 >100 >100 >100 >100 >100 >100 DD 0.1 0.2 0.1 0.1 0.1 0,39 0.2 EE 0.1 0.2 0.1 0.1 0.1 0.39 0.2 FF 0.1 0.2 0.1 0.1 0.1 0.39 0.2 G G >100 >100 >100 >100 >100 >100 >100 H H 0.1 0.2 0.1 0.1 0.05 0.39 0.2 II 0.02 0.1 0.02 0.02 0.01 0.1 0.1 JJ <=0.0050.01 0.01 <=0.005 0.01 <=0.0050.05 KK <=0.0050.01 0.01 <=0.005 0.01 0.~1 0.0~

LL 0.01 0.01 0.01 O.OI 0.01 0.05 0.02 MM 1.56 0.78 3.1 0.78 3.1 25 100 NN 0.2 0.39 0.1 0.2 0.1 0.39 0.39 00 0.01 0.01 0.01 0.02 0.01 0.05 0.05 P P 0.1 0.1 0.2 0.2 0.1 0.39 0.2 QQ 25 25 100 50 25 >100 100 RR 0.2 0.39 0.2 0.2 0.2 0.39 0.39 S S 50 50 >100 >100 50 >100 >100 TT >100 >100 >100 >100 >100 >100 >100 UU 0.39 0.78 0.78 0.78 0.39 0.78 0.39 W 0.02 0.2 0.02 0.02 0.05 0.2 0.39 XX 0.015 0.03 0.03 O.OIS <=0.0040.125 0.03 YY 0.015 0.03 0.03 <=0.004 <=0.0040.25 0.03 ZZ 64 4 4 4 16 128 >128 ZZA 0.5 1 0.5 0.25 0.25 1 i i wo 9sio9ms rc r~us9~nsso6 Table 1. continued Organism Example Exam ExampleExampleExamvle ExampleExample 1e code 214 215 216 217 218 219 221 AA 6.2 0.05 0.2 0.2 0.1 0.2 . 0.2 BB 25 0.1 0.2 0.39 0.1 0.2 0.39 - .

CC >100 >100 >100 >100 >100 100 >100 DD 12.5 0.1 0.2 0.39 0.1 0.2 0.39 -EE 12.5 0.1 0.2 0. I 0.2 0.2 FF 12.5 0.1 0.2 0.2 0.1 0.2 0.2 G G > 100 > 100 > 100 > 100 > 100 100 > 100 HH 25 0.1 0.2 0.39 0.1 0.2 0.2 II 25 0.05 0.05 0.2 0.05 0.05 0.05 JJ 6.2 0.01 0.01 0.02 0.01 <=0.005<=0.005 R ~ 3.1 0.01 0.02 0.02- 0.01 0:02 x:02-LI. 1.56 0.01 0.02 0.02 0.01 0.02 0.01 MM 12.5 0.78 0.78 0.78 6.2 3.1 >100 NN 25 0.1 0.2 0.78 0.2 0.2 0.39 00 12.5 0.01 0.05 0.1 0.05 0.05 0.02 PP 12.5 0.2 0.1 0.39 0.05 0.2 0.2 QQ > 100 25 100 50 50 100 12.5 RR 3.1 0.2 0.39 0.39 0.39 0.78 0.1 SS >100 >100 >100 >100 >100 >100 12.5 TT >100 >100 >100 >100 >100 >100 >100 UU 100 0.78 0.78 12.5 0.78 0.39 3.1 W 50 0.02 0.1 0.78 0.05 0.05 0.2 XX 1 0.015 0.015 ~ 0.03 0.015 0.03 0.03 YY 1 <=0.004 0.015 0.03 0.015 0.03 0.06 ZZ >128 16 0.5 2 4 2 >128 ZZA 32 0.25 U.25 2 0.25 0.25 2 wo 9gro~8 ~crnls9~nsso~
Table I, continued Organism Example Exam ExampleExampleExample Example Exam 1e 1e code 222 223 224 225 226 227 228 AA 0.2 0.2 0.39 0.2 0.1 0.2 0.39 BB O.I 0.2 0.2 0.39 0.1 0.2 0.78 CC >100 >100 >100 >100 >I00 >100 >100 - DD 0.39 0.2 0.2 0.39 0.1 0.2 0.78 EE 0.2 0.2 0.2 0.39 0.1 0.2 0.78 FF 0.2 0.2 0.2 0.2 0.1 0.2 0.78 GG >100 >I00 >100 >100 >100 >100 >100 1-IH 0.2 0.39 0.39 0.2 0.1 0.2 0.78 II 0.02 0.05 0.01 0.05 0.05 0.05 0.1 JJ <=0.005 <=0.0050.01 0.01 0.01 <=0.005 0.02 KK 0.02 <=0.005<=0.0050.01 0.02 0.05 <=0.005 LL <=0.005 <=0.0050.01 0.01 0.01 0.02 0.0-I

MM >100 >100 >100 >100 6.2 50 25 NN 0.39 0.1 0.2 0.39 0.39 0.39 0.78 00 0.01 0.05 0.02 0.02 0.02 0.05 0.2 PP 0.2 0.2 0.2 0.2 0.1 0.39 0.39 -QQ 25 50 25 12. 6. 2 6. 2 > 100 RR 0.1 0.2 0.2 0.2 0.2 0.2 0.78 S S 25 100 25 12.5 12.5 25 > 100 TT >100 >100 >100 >100 >100 >100 >100 UU 0.78 3.1 3.1 3.1 0.78 1.56 3.I

W 0.2 0.2 0.1 0.2 0.05 0.05 0.78 XX 0.03 0.03 0.03 0.03 0.03 0.03 0.125 W 0.06 0.03 0.03 0.06 0.03 0.03 0.125 ZZ >128 >128 >128 >I28 >128 >64 >128 ZZA 2 0.5 2 2 2 2 I

r' WO 98/09978 PG"T/~JS97/1~
Table 1, continued Organism ExampleExam ExampleExample ExampleExample Ex_ ample 1e code 229 230 231 232 233 234 235 AA 0.2 0.1 0.1 0.1 0.1 0.1 0.2 B B 0.2 0.1 0.1 0.1 0.1 0.1 0.2 CC >100 >100 >100 >100 >100 >100 >I00 DD 0.2 0.1 0.1 0.2 0.2 0.2 0.2 EE 0.2 0.1 0.1 0.2 0.2 0.2 0.2 F F 0.2 0.2 0.05 0.1 0.1 0.1 0.2 G G >100 >100 >100 >100 >100 >100 >100 H H 0.2 0.1 0.2 ' 0.2 0.2 0.1 0.2 II 0.05 0.05 0.02 0.02 0.05 0.05 0.05 JJ <=0.005 <=0.0050.02 0.02 0.02 <=0.0050.01 KK 0.02 <=0.0050.02 0.02 0.02 0.05 0.01 LL 0.01 <=0.0050.02 0.02 0.02 0.01 ~ 0.01 MM 50 >100 100 >100 100 100 25 N N 0.2 0.0 0.1 0.2 0.1 0.2 0.2 00 0.02 0.05 0.02 0.02 0.02 0.01 0.05 PP 0.05 0.2 0.1 0.2 0.2 0.1 0.39 QQ >100 100 100 25 50 50 >100 RR 0.39 0.39 0.39 0.39 0.39 0.39 0.78 S S >100 >100 I00 >I00 50 50 >100 TT >100 >100 >I00 >100 >100 >100 >100 L'U 1.56 0.78 0.78 0.39 0.78 0.78 0.78 W 0.2 0.05 0.05 0.05 0.05 0.1 3.1 WW 2 2 '_' 2 2 2 4 X X <=0.004 0.03 0.03 0.03 0.03 0.03 0.03 YY <=0.004 0.015 0.03 0.03 0.03 0.03 0.03 ZZ >128 128 >128 >128 64 >128 32 ZJ~A 0.125 0.25 0.5 0.5 0.25 0.25 0.5 CVO 98/09978 PCT/US97/1350Cc Table 1, continued Organism Example Example ExampleExample ExampleExam Example 1e code 236 237 238 239 240 241 242 AA 0.2 0.39 0.2 6.2 3.1 3.1 0.2 . BB 0.2 0.39 0.2 6.2 3. i - -CC >100 >100 >100 >100 >100 >100 >1U0 DD 0.2 0.39 0.39 6.2 6.2 6.2 0.2 EE 0.2 0.39 0.39 6.2 3.1 6.2 0.2 FF 0.2 0.39 0.39 6.2 3.1 6.2 0.2 G G 100 >100 >100 >100 >100 >100 >100 HH 0.2 0.39 0.39 . 6.2 3.1 6.2 0.39 II 0.05 0.1 0.05 1.56 0.78 1.56 0.1 JJ 0.05 0.05 0.02 0.39 0.39 0.39 0.02 KK 0.05 0.05 0.02 0.39 0.39 1.56 0.05 LL 0.01 0.05 0.02 0.39 0.39 0.78 0.01 MM 25 >100 >100 >100 >100 >100 >100 N N 0.2 0.2 0.2 1.56 0.78 6.2 0.2 00 0.05 0.05 0.05 0,39 0.39 0.78 0.05 PP 0.2 0.39 0.2 1.56 1.56 3.1 0.39 QQ 50 >100 100 >100 >100 >100 >100 RR 0.39 0.39 0.39 6.2 3.1 1.56 0.78 S S >100 >100 >100 >100 >100 >100 >100 TT >100 >100 >100 >I00 >100 >100 >100 UU 0.39 0.78 0.2 50 6.2 100 0.78 W 0.2 0.3 9 0.1 3.1 1.56 6.2 0.39 XX 0.03 0.03 0.03 0.25 0.25 0.5 0.03 YY 0.03 0.03 0.03 0.25 0.25 0.25 0.03 ZZ 32 >128 >64 >128 >128 >128 >128 ~ZA 0 0.5 0.25 1 1 4 0.25 WO 98/099?8 PGT/US9?/15506 Table 1, continued Organism Example Example Example Example Example Example Example code 243 244 245 246 247 248 249 pA 0.05 0.1 0.1 0.78 0.05 0.05 0.1 BB 0.05 0.2 0.2 0.78 0.05 0.05 0.1 CC >100 >100 >100 >100 >104 >100 >100 DD 0.05 0.2 0.2 0.78 0.05 0.05 0.2 EE 0.1 0.2 0.2 0.78 0.05 0.05 0.2 FF 0.05 0.1 0.2 0.78 0.05 0.02 0.1 G G > 100 > 100 > 100 > 100 > 100 > 100 > 100 HH 0.1 0.2 0.1 0.78 0.05 0.05 0.1 11 0.02 0.05 0.05 0.2 0.02 0.02 0.05 J J 0.02 0.01 0.05 0.1 <=0.0050.02 0.01 K K 0.02 <=0.005 0.02 0.2 0.01 <=0:005-. 0.02 LL 0.02 0.02 0.02 0.2 0.01 <=0.0050.02 MM 6.2 1.56 0.78 >100 0.39 0.39 100 N N 0.1 0.2 0.1 0.39 0.1 0.1 0.1 Op 0.02 0.02 0.05 0.2 0.01 0.02 0.01 PP 0.02 0.2 0.2 0,78 0.02 0.1 0.1 QQ 50 50 50 >100 25 50 100 RR 0.2 0.1 0.05 0.78 0.2 0.39 0.39 S S 50 25 25 > 100 25 50 > 100 TT >100 >100 >100 >100 >100 >100 >100 UU 0.39 0.78 0.78 50 0.39 0.39 0.39 W 0.05 0.02 0.05 0.78 0.01 0.02 0.1 XX 0.03 0.03 . 0.03 0.25 <=0.0040.03 0.03 YY 0.03 0.03 0.03 0.125 <=0.0040.03 0.03 ZZ 128 6~ 64 >128 4 4 >128 P, 0.25 0.5 0.5 0.5 0.25 0.25 0.25 vvo 9sro~s pcrn~rs~nss~~
Table 1, continued Organism Exam Example ExampleEx, ampleExampleE_ xamuleE_ xarrr~le 1e code 2_~ 251 252 253 254 255 256 AA 0.2 0.1 0.1 0.05 0.1 0.1 0.05 BB 0.2 0.1 0.1 0.05 0.1 0.2 0.05 .

CC >100 >100 >100 >100 >100 >100 >100 - DD 0.2 0.1 0.1 0.05 0.1 0.2 0.05 EE 0.2 0.1 0.1 0.1 0.1 0.2 0.05 FF 0.2 0.1 0.1 0.05 0.1 0.2 0.02 G G 100 >100 >100 >100 >100 >100 >100 H H 0.2 0.1 0.1 0.05 0.1 O.I 0.1 II 0.05 0.1 0.05 0.05 0.02 0.05 , 0.02 JJ 0.01 0.02 0.02 ~ 0.02 <=0.0050.02 0.01 KK 0.01 0.05 0.02 0.02 0:~vi 0.02 0.02 LL 0.01 0.05 0.05 0.01 0.01 0.02 0.01 ' MM 6.2 6.2 3.1 0.78 0.78 50 25 N N 0.2 0.2 0.1 0.05 0.1 0.2 0.2 00 0.1 0.02 0.02 0.01 0.02 0.05 0.01 P P 0.2 0.2 0.2 0.1 0.1 0.2 0.1 QQ 100 >100 >100 , 50 25 100 100 RR 0.39' 1.56 0.78 0.2 0.2 0.2 0.2 S S >100 >100 >100 50 100 >100 >100 TT >100 >100 >100 >100 >100 >100 >100 U U 0.78 0.2 0.2 0.2 0.78 3.1 1.56 W 0.1 0.05 0.05 0.02 0.01 0.05 0.05 XX 0.03 0.125 0.03 0.015 <=0.0040.03 0.03 YY 0.03 0.25 0.03 0.03 <=0.0040.03 0.03 ZZ 16 >128 4 1 2 16 16 L~A 0.5 1 0.25 0.25 0.25 0.25 0.25 wo 9sio~~s porn ,rsr~nsso6 Table 1. continued Organism Example ExampleExample ExampleExample Ex-ample Example code 257 258 259 260 261A 261B 262 AA 0.2 0.78 6.2 25 6.2 3.1 0.78 BB 0..2 0.39 6.2 25 . 6.2 3. 1w 0.?8 ~ .-_ .

CC >100 >100 >100 ->100 >100 >100 >100 DD 0.2 0.78 12.5 25 12.5 6.2 0.78 EE 0.2 0.39 6.2 25 12.5 3.1 0.78 FF 0.2 0.78 6.2 25 12.5 3.1 0.78.

GG >100 >100 >100 >100 >100 >100 >100 HH 0.2 0.78 6.2 25 6.2 6.2 0.78 II 0.1 0.39 0.78 3.1 1.56 0.78 0.39 11 0.01 0.05 0.39 0.78 0.39 0.39 <=0.005 KK 0.05 0.1. 0.78 ._ 0.7R0.39 0,39 0.05 LL 0.01 0.05 0.39 0.78 0.39 0.39 0.1 MM 100 >100 >100 >100 >100 >100 >100 NN 0.2 0.2 1.56 12.5 1.56 0.78 0.78 00 0.05 0.1 0.78 1.56 0.78 0.39 0.1 PP 0.2 0.39 1.56 3.1 3.1 1.56 0.39 QQ >I00 >100 >100 >100 >100 >100 >100 RR 0.78 0.78 1.56 6.2 6.2 6.2 1.56 SS >100 >100 >100 >100 >100 >100 >100 TT >100 >100 >100 >100 >100 >100 >100 UU 0.39 12.5 12.5 >100 25 25 6.2 W 0.2 0.39 3.1 50 6.2 6.2 0.39 XX 0.125 0.03 1 . 2 1 0.5 0.03 YY 0.125 0.03 1 1 1 0.5 0.03 ZZ 128 >128 >128 >64 >128 >128 >128 7~A 0. 5 0.12 5 4 16 2 I 0.5 Table 1. continued Organism Example Example ExampleEx 1e ExampleExample Example code 263 264 265 266 26? 268 2C~9 AA 0.1 0.01 0.1 0.2 0.05 0.39 -BB 0.1 C.01 G.l 0.2 0.~5 0.39 -CC >100 >100 50 >100 >100 25 -DD 0.1 0.01 0.1 ~ 0.2 0.05 0.39 -EE 0.1 0.01 0.1 0.2 0.05 0.39 -FF 0.05 0.01 0.1 0.2 0.05 0.39 GG >100 >100 25 >100 >100 25 -HH 0.1 0.05 0.1 0.2 0.05 0.39 -. II 0.02 0.01 0.05 0.1 0.05 0.2 -JJ . 0.01 <=0.005<=0.005 0.01 <=0.005 0.1 -KK 0.02 0.01 <-0.005 ~.01 <=0:005 0. i LL 0.02 0.01 0.01 0.01 <=0.005 0.1 -MM 50 3.1 6.2 6.2 1.56 25 -. NN 0.2 0.2 0.1 0.2 0.1 0.39 -00 0.02 <=0.0050.01 0.02 <=0.005 0.1 PP 0.2 0.1 0.05 0.2 0.05 0.39 -QQ >100 100 >100 >100 25 >100 -RR 0.78 0.1 0.78 0.78 0.2 3.1 -S S > 100 100 > 100 ~ > 25 > 100 -TT >100 >100 50 >100 >100 >100 -UU 0.78 0.78 0.2 0.39 0.39 0.39 -W 0.2 0.01 0.2 0.1 0.02 0.39 -XX 0.015 0.03 x.015 0.06 0.03 0.125 0.06 YY 0.015 0.015 0.015 0.03 0.03 0.125 0.06 ZZ >128 >128 32 2 8 8 2 ~A 0.25 0.5 0.25 0.25 0.25 1 0.5 ~-gyp 9g~pg97g PGT/I1S97/15506 Table 1, conrinued Oreanism Example ExampleExample ExampleExamvle ExampleExample _ ~

code 270 271 272 273 274 275 276 AA 0.1 0.3 0.2 0.2 0.1 0.2 0.39 w BB 0.1 0.78 O.l - 0.2 0.1 0.2 0.?8 .

CC >100 >100 100 >100 >100 >100 50 DD 0.1 0.39 0.2 0.2 0.1 0.2 0.39 EE 0.2 0.78 0.2 0.2 0.1 0.2 0.78 FF 0.1 0.39 0.1 0.2 0.05 0.2 0.78 GG >100 100 50 >100 >100 >100 25 H H 0.1 0.3 0.2 0.2 0.1 0.2 0,78 II 0.05 0.39 0.05 0.1 0.05 0.1 0.2 JJ 0.05 0.1 0.02 0.02 0.01 0.01 0.02 lc~._ .. 0.05 , 0.2 0.02. 0.02 0.01 0.05 0.1 LL 0.05 0.1 0.05 0.05 0.01 0.02 0.02 I~llVI 3.1 6. 2 3.1 . 12.5 6. 2 12.5 25 NN 0.2 0.39 0.2 0.39 0.1 0.2 0.39 00 0.02 0.2 0.05 0.05 0.01 0.02 0.1 PP 0.2 0.78 0.2 0.39 0.1 0.2 0.39 QQ 50 >100 >100 >100 >100 >100 >100 RR 0.39 3.1 0.78 0.78 0.2 0.78 6.2 S S 50 >100 >100 >100 >100 >100 >100 TT >100 >100 >100 >100 >100 >100 100 U(J 0.39 1.56 0.2 0.78 0.78 0.39 0.78 W 0.1 0.78 0.2 0.39 0.05 0.2 1.56 XX 0.03- 0.25 0.03 0.03 <=0.004 0.03 0.125 YY 0.03 0.25 0.03 0.03 <=0.004 0.03 0.125 Z.LA 0.25 1 0.25 0.5 0.25 0.5 0.5 wo 9so9ms pcr~s~nsso6 Table I. continued ' Organism Example Example Example Examvle Example Example Example code 277 278 279 2A0 281 282 283 _. AA 1.56 0.05 0.39 0.39 0.78 0.2 0.1 BB 1.56 0.05 0.39 0.39 0.78 0.1 0.1 CC >100 >100 50 50 >100 100 100 DD 1.56 0.05 0.78 O.:i9 0.78 0.2 0.1 EE 1.56 0.05 0.39 0.39 0.78 0.2 0.1 FF 1.56 0.05 0.39 0.39 0.78 0.1 0.1 G G > 100 > 100 50 25 > 100 100 50 HH 1.56 0.1 0.39 0.39 0.78 0.2 0.2 Il 0.78 0.05 0.2 0.2 0.39 0.05 0.05 JJ 0.39 0.01 0.05 0.05 0.05 O.OI 0.01 1K ' 0.2- O.OI 0.02 0.05 0.1 <=0.0050.02 LL 0.2 <=0.005 - 0.1 0.1 <=0.005<=0.005 MM 50 1.56 25 . 12.5 50 25 3.1 NN 1.56 0.2 0.39 0.39 0.39 0.1 0.2 00 0.39 0.01 0.05 0.1 0.2 0.05 0.01 PP 3.1 0.1 0.39 0.78 0.78 0.2 0.2 QQ >100 25 >100 >100 >100 >100 >100 RR 6.2 0.39 1.56 1.56 3.1 0.78 0.78 SS >100 12.5 >100 >100 >100 >100 >100 TT >100 >100 >100 >100 >100 >100 >100 UU 3.1 0.78 0.78 3.1 3.1 1.56 0.39 W 3.1 0.02 0.78 6.2 3.1 0.2 0.2 WW > 128 4 8 8 32 8 2 XX 0.5 0.03 0.03 ~ 0.06 0.25 O.U3 <=0.004 W 0.5 0.03 0.03 0.06 0.25 0.03 <=0.004 ZZA 4 0.5 0.5 1 I 0.25 0.125 Table 1. conrinued Oreanism Ex_ ampleExampleExam Example ~ 1e Exam Exam 1 1e code 2 4 285 2$6 287 288 289 AA 0.2 3.1 6.2 0.1 0.1 0.2 w BB 0.2 3.1 6.2 0.1 0.2 0.2 CC 50 >100 >100 >100 >100 >100 DD 0.2 3.1 6.2 0.1 0.39 0.2 EE 0.2 3.1 6.2 O.I 0.39 0.2 FF 0.2 3.1 6.2 0.02 0.39 0.2 GG 50 >100 >100 >100 100 >100 HH 0.2 3.1 6.2 0.1 0.39 0.2 0.05 0.39 1.56 0.05 0.39 0.2 JJ . 0.02 0.2 0.39 0.02 0.01 0.02 KK . 0.02 0.2 . 0.2 x.02 0.02 0.1 z.
, LL, <=0.005 0.05 4.78 0.02 0.1 0.1 MM 25 100 100 3 .1 12.5 > 100 .

NN 0.2 0.78 1.56 . 0.1 0.39 0.39 pp 0.05 0.39 1.56 0.02 0.02 0.05 pp 0.2 0.39 3.1 0.2 0.39 0.39 QQ >100 >100 >100 50 >100 >100 RR 1.56 12.5 12.5 0.39 3.1 3.1 SS >100 >100 >100 >100 >100 >100 TT 50 >100 >100 >100 >100 >100 UU 0.2 6.2 25 0.39 0.39 1.56 W 0.78 1.56 12.5 0.05 0.39 0.39 WW 4 >128 128 2 8 64 XX 0.03 0.25 - 1 0.03 0.125 0.25 YY 0.03 0.25 0.5 0.03 0.125 0.25 ZZ 32 64 64 4 16 >128 7~A 0.25 1 2 0.5 1 1 wo 9s~o~~a ~cTnrs~n Table 1, continued Organism Example Example Example Example code 290 291 292 293 AA 0.1 0.05 0.1 0.39 BB 0.1 O:OSw 0_ ~ G.39 CC 50 >100 >100 >100 DD 0.1 0.05 0.1 0.39 EE 0. I 0.05 0.1 0.39 FF 0.1 0.05 0.1 0.39 GG 25 >100 >100 >100 HH 0.1 0.05 0.05 0.39 II 0.05 0.02 0.02 0.1 JJ <=0.005 <=0.005 <=0.0050.02 r_c ~ <=0,005 <=0.005 - 0:02 0.0~ . .

LL 0.01 <=0.005 0.01 0.02 MM 6.2 3.1 12.5 > 100 N N 0.1 0.1 0.05 0.7 8 00 0.01 <=0.005 0.02 0.05 PP 0.05 0.05 0.1 0.2 QQ >100 25 50 >100 RR 0.78 0.1 0.2 0.78 SS >100 50 100 >100 TT 50 >100 >100 >100 UU 0.2 0.39 0.78 12.5 W 0.2 0.01 0.02 0.78 XX 0.015 <=0.004 0.03 0.03 YY 0.015 <=0.004 0.03 0.03 ZZ 32 1 16 > 128 TLA 0.25 0.125 0_25 0.5 WO 98!09978 PGT/I1S97/155~6 Pharmaceutical Compositions 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 !U 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 1S solutions; as w2il aS ou5er non-toxic cot~lpatibi2 iubflCants such as Sodlum iauryi 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 2U 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, 25 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, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and 30 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 35 wetting agents and suspending agent.S. 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 he dissolved or dispersed in sterile water or other sterile injeetable 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 tum, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a Yarenterall;~ ad:rinistered ding form rs-accomplished by di~so;ving or suspendiZrg the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in 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 2S excipients or earners 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 Ieast 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 3i starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, fj absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as _77 _ WO 98/09978 PCT/LTS97/L~06 kaolin and bentonite 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 1o 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 milk sugar as well as high is . molecular weight~olethylene glyeols 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 20 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 farms may also comprise buffering agents. They may ~5 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 30 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, eyd ns are also contemplated as being within the scope of this invention.
35 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, _7g_ WO 98I09~78 PCT/US97I15 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 polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluor ohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving ar dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the to 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 15 the patient a therapeutically effective amount of a campcu~~d 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 2o usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. 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, 25 general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment;
v 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 30 other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from O.l .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) 35 of this invention per day in single or multiple doses.

WO 98!09978 PGT/US9?115506 Abbreviations Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: AIBN for azobisisobutyronitrile; Bu3SnH for tributyltin hydride;
CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DEAD
for diethylazodicarboxylate; DMF for dimethylformamide; DMSO for dimethylsulfoxide; DPPA
for diphenylphosphoryl azide; Et3N for triethylamine; .EtOAc for ethyl acetate; -Et20 for diethyl ether; EtOH for ethanol; HOAc for acetic acid; MeOH for methanol;
NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMMO for N-methylmorpholine N-oxide; TEA for ' -_ triethylamine; THF for tetrahydrofuran; and TPP for triphenylphosphine.
S~rnthetic Methods The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes I-VI (to be found following the text describing the schemes) which illustrate the methods by which the compounds of the .
invention may be prepared. The compounds of tl:e present inrentier. are prepa.rcd by the -representative methods described below. The groups A, B, D, E, W, X, Y, Z, Ra, Rb, R~, and Rd are as defined above unless otherwise noted below.
The preparation of the compounds of the invention of formula VIII from erythromycin A is outlined in Schemes Ia and Ib. 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.
Also 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-R3 or =N-O-C(R8)(R9)-O-R3 where R3 is defined above and Rg and R9 are each independently ?S selected from the group consisting of (a) hydrogen, (b) unsubstituted CI-C12-alkyl, (c) CI-C12-alkyl substituted with aryl, and (d) CI-C12-alkyl substituted with substituted aryl, or R9 and RIO taken together with the carbon to which they are attached form a C3-C12-cycloalkyl ring). An especially preferred carbonyl protecting group V is O-(1-isopropoxycyclohexyl) 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 Organic Synthesis, 2nd ed., John Wiley & Son, Inc., 1991, which is incorporated by reference. Hydraxy protecting groups include, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, or a trialkylsilyl 3S 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 _g0_ WO 98/09978 PCTIiJ597/15506 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.
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 3_ where RP is-a hydroxy protecting group. A preferred protecting group RP is trimethylsilyl.
The 6-hydroxy group of compound 3 is then alkylaterl 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-propenyl phenyl sulfone, 3-bromo-l-trimethylsilyl-I-propyne, 3-bromo-2-octyne, 1-bro!ro-2-bury.~.e, ?-pical,~l chl~rid;., 3-picolyi chloride, 4-picoiyl chloride, 4-bromomethyl quinoline, bromoacetonitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-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, potassium hydride, potassium isopropoxide, potassium tent-butoxide, potassium isobutoxide and the like.
The deprotection of the 2'- and 4"-hydroxyl groups is then carried out according to methods described in literature, for example, by T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Son. Inc., 1991, which is incorporated herein by reference. The conditions used for the deprotection of the 2'- and ~"-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-R3 or =N-O-C(Rg)(R9)-O-R3 where R3, Rg and R9 are as defined above to =N-OH.) If this is not the case, the conversion is carried out in a separate step.
_81_ The deoximation reaction can be carried out according to the methods described in.
the literature, for example by Greene (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 metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite and --the like. Examples of the solvents used are protic solvents such as ware., 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 oat in the presence of an organic acid such as formic acid, acetic acid and trifluoroacetic acid.
The amount of acid used is from about I to about 10 equivalents of the amount of compound 5_ used. In a preferred embodiment, the deoximation is carried out using an organic acid such as formic acid in ethanol and water to give the desired product 6.
The conversion of the 6-substituted erythromycin derivative to the 6-substituted ketolide is described in scheme I b. The cladinose moiety of macrolide 6 is removed either by mild aaueous acid hydrolysis or by enzymatic hydrolysis to give ,7.
Represenrad~~e acids -include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or ti-ifluoroacetic 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. The 2'-hydroxy group of 7 is 2o protected using a suitable hydroxy protecting reagent such as acetic anhydride, benzoyl anhydride, benzyl chloroformate or trialkylsilyl chloride in an aprotic solvent, as defined above, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or a mixture thereof. A particularly preferred protecting group RP is benzoate.
It is possible to reverse the order of the steps for removing the cladinose and protecting the hydroxy groups without affecting the yield of the process.
The 3-hydroxy group of 8 is oxidized to the ketone 9 using a modified Swern oxidation procedure. Suitable oxidizing agents are N-chlorosuccinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In a typical example, 8 is added into a pre-formed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent such as methylene chloride at -10 to 25 °C. After being stirred for 0.5-4 hours, a tertiary amine such as triethylamme or Hunig's base is added to produce the corresponding ketone. The 2' hydroxy protecting group of 9 is then removed by standard methods to give the desired ketolide VIII. 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 trialkylsilyl group, the compound may be deprotected by treatment with fluoride in THF or acetonitrile.
The oxime derivative may then be prepared by reaction of compound VaI wherein X
is O with hydroxylamine hydrochloride in the presence of base, or hydroxylamine in the -g2_ .: -presence of acid as described in US Pat. No. 5.274,085, to form the compounds wherein R1 is H. Reaction with the substituted hydroxylamine RiONH2, results in the formation of compounds in which Rt is other than H. Alternatively, compounds wherein R1 is other than H may be prepared by initial formation of the unsubstituted oxime as described above followed by reaction with RiX' wherein X' is a suitable leaving group such as halogen.
The preparation of the compounds of this invention of formula f DC) wherein L
is CO
and T is -NH- or -N(W-Rd)- is outlined in Schemes lc and 4. According to Scheme lc, the 6-O-substituted compound 6 is first protected with a suitable hydroxy protecting group to give compound 6A, by the procedures referenced above. Compound 6A is then treated with sodium hexamethyldisilazide and carbonyldiimidazole to give compound 6B. In particular, treatment of compound 6B, with aqueous ammonia results in formation of the cyclic carbamate 6C wherein Re is H. Likewise, reaction of compound 6B with an amino compound of the formula H2N-W-R~ results in formation of the cyclic carbamate in which Re is -W-Rd.
1_5 Alternate or additional procedures may be-used to preps.=e cempet~ds o~
ft7rrr~ula (IX) wherein L is CO and T is -N(W-Rd)-. For example, treatment of a compound wherein Re is H with an alkylating agent having the formula Rd-halogen, wherein Rd is as defined previously, gives a compound 6C wherein Re is W-R~, W is absent and Rd is as defined previously.
Reaction of compound 6B with a hydrazine compound of the formula H2N-NH-Rd results in formation of the cyclic carbamate gives a compound 6C wherein Re is W-Rd, W is -NH- and Rd is as defined above. When unsubstituted hydrazine is the reagent the final product is a compound 6C wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2).
Treatment of a compound 6C wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2) with an alkylating agent having the formula Rd-halogen, wherein Rd is as defined previously, gives a compound 6C wherein Re is W-Rd, W is -NH- and Rd is as defined previously.
Treatment of compound 6C with an acylating agent selected from the group consisting of Rd-C(CO)-halogen or (Rd-C(CO)-O)2 gives a compound 6C wherein Re is W
is -NH-CO- and Rd is as defined previously Treatment of a compound 6C wherein Re is -N(W-Rd)- wherein (W-Rd) is (NH2) with an aldehyde Rd-CHO, wherein Rd is as defined previously gives a compound wherein W is -N=CH- and Rd is as defined previously.
Treatment of a compound of formula (IX) wherein L is CO and T is -N(W-Rd)-3~ wherein (W-Rd) is (NI-h), with an alkylating agent having the formula Rd-halogen, wherein Rd is as defined previously, gives the compound formula (IX) wherein L is CO, T is -N(W-Rd)-, W is absent and Rd is as defined.

Reaction of compound 6B with a hydroxylamine compound of the formula H2N-O-Rd results in formation of the cyclic carbamate in which Re is -O-R~.
Removal of the cladinose moiety by acid hydrolysis as described previously gives the compound 6D wherein Z' is H. Compound 6D is then oxidized to 6E by the modified Swern oxidation procedure described for Scheme 1 b above for converting compound 8 to ketone 9.
Deprotection of the 2'-hydroxy group as described above provides the desired ketolide IX.
According to the alternate procedure shown in Scheme 1 d, the compound 2A, which 1o is the 9-oxime compound of erythromycin A, is subjected to acid hydrolysis with dilute mineral or organic acid as described previously to remove the cladinose moiety and give compound 7A. The oxime compound 7A is then converted to the protected oxime compound 7B wherein V is =N-O-R1 (shown) or =N-O-C(RS)(R6)-O-R~ where R1, RS
and R6 are as defined previously, by reaction with the appropriately substituted oxime protecting r~a_gent. T_he '~ and:2'-hydroxy groups of ?L are then protested as described pre-piously, preferably with a trimethylsilyl protecting group, to give compound 7C.
Compound 7C is then alkylated as described previously for Scheme la to give compound 7D, and compound 7D is first deoximated as described above for Scheme 1 a then the deoximated product is converted to the compound 7E by the procedures described for preparation of compound 6C
from compound 6A in Scheme lc. Compound 7E is then deprotected and oxidized to the 3-ketolide derivative compound of formula IX, wherein X is O, L is CO and T is -NH- or -N(W-Rd)- by procedures described previously.
_gq.._ >~cr/~rs9'ns~
VVO 98/09978 _ Scheme la O i NMe2 V i i NMe2 0,, ,, , .,oH o,,. ,,... ,,o HO,,, ' 6 .,ft HO,,,.
HO ' O _ HO ..
_ ~.~,..
O
,...
O,'.~ O
O
O .~' O- H O .~' O- H
.''OMe .~~OMe NMe2 H NMe2 R V
V I RPO. I
~O
t : O t,,~.
,.. HO,,.. 6 HO,,,. g .,~t ,~~t O
HO O HO
.---- v.,~~. ~1 ,.. ~
I 0,,..
w Oi,,.
O
O
O ''~~ ORP O .,~ ~~~' ORa ' ~~OMe home OH . O R H NMez I
I . R H NMe2 ~ 0,,,.
I ,,,, ,.
HO,,,. 6 'w~ O
O
HO
I _ 0.., O
O ~'~ O- H
O 'n ~ H . home .~~OMe WO 98/09978 PCT/US9'1/15506 Scheme 1b O R i NMe2 O R ~ NMe2 _ I O 0...
,. ~,,._ ,.
.... ,.
HO,,, HO .
HO,,, g 6 .", O
HO O --.
~ ~
O
O
O ., ~~~ O- H O
home R RP NMep R RP NMe2 O 0~.. O 0....
HO ~~~~ HO ~~~
6 ..~~ O ~ ~~. 6 .
HO O HO
..,; . ~ _.--I 'O 1 'OH
O O

OR' I R NM'e2 NMe2 N ~ 1 p R HO,,, ,~O
r~,. .~ HO~... ~ 6 HO,,,. g ,,~~ O --, HO
HO
,,~~'' ~ 1 '- o '-0 0 O VIII, X = NORI
VIII, X = O

wo 9sio9ms pc~r~s~~n Scheme lc O R ~ NMe2 O R Rp NMe2 O 0~.. O 0~..
''~~. .' ''~' .' HO~,, g HO~~.. 6 _ HO . ...~ O HO ..,~ O
'~,,.- _.,r '~,,..
O _ O''~., O _ O'~~.
O ~~~ O- H O .~~ O- RP
6_ .home ~A .~~OMe O R RP NMe2 I
/~ O
N~ / 6 ,.
O
R Rp Nivie2 O I O
Re O Oi'. On O
O
w~' 6 O O O ~~'' O_ R p v''~ ~B . ~~OMe I ' O-Z' O
O
6C. Z' is 4"-acetyl-cladinose 6D. Z' is H
O R Rp NMe2 a '~~. ,'O O'~.
O~ N'~. 6 ~
O . ~~i~ O p' ' R H NMe2 Re O I O
v i... o'O i'' O ' O ~.. O~ w.' 6 O O
O

O
O
IX, L is CO, T is -NH- or -N(WR4)-_g7_ I
I
WO 98f09978 Scheme 1d H NMe2 , , . N H NMe2 ''~ ,~'O 0~~~ O'~.
HO,, . _ HO - '~n p __ - _ ,,,.. O
w n O'''~. / O\ ~ _ O y ~~ O- H 0 OMe V is N-OH i N- H
Rz is Rz NMez I I ~ i R NMe2 . . /,, O 0~~.
. ~ . ~ . ~ 0,,, ;
. "0',I '' ' H~O ' '''' HO,,~
O HO . ..n O O
O_ ORz ORZ
0 n ZC O
V~1' is N- R1 g~isH
protecting r m V R RZ NMez R Rz NMe2 I ~ Re I O
O,,~ ~ ~,,~ ,'O
'~~.
''~ ~'O N
NO''~' ~~ ~ ~" O O
O 0 . 0 'o,~w ---..,...
ORZ ~- ,., ORZ
O O
LD, 7E
V is N- Rl, RZ is hardrozv rotecting er" oun IX, X is O, Re is H or WR4 _$$_ The preparation of the compounds of this invention of formula (IBC) wherein L
is CO
and T is O and compounds of formula VI is outlined in Scheme 2. In Scheme 2, the preparation follows the procedure described by Baker et al., J. Org. Chem., 1988, 53, 2340, which is incorporated herein by reference. In particular, the 2' protected ketolide derivative 9, prepared as described in Scheme 1 above, is converted to the cyclic carbonate by reaction wit~'~ carbonyldiimidazole and sodium hexamethyldisiiazide:
Deprotection as described above gives compound IX wherein L is CO and T is O.
Compounds of formula VI are prepared from 9 by reaction with sodium hydride or lithium hydride and phosgene, diphosgene or triphosgene under anhydrous conditions 10 followed by aqueous work up (aqueous base catalyzed decarboxylation).
Alternatively, 9 is converted to its corresponding mesylate by reaction with methanesulfonic anhydride in pyridine. The mesylate is then converted to 11 by treatment with an amine base such as DBU or dimethylaminopyridine in acetone or acetonitrile. The 2' protecting group is the removed as described above to give compound Vl.
~ s Compounds of formula VI are also prepared frcm -1-00 by treatment with an amine base such as 1,8-diazobicyclo[5.5.0]undec-7-ene (DBU) or 4-dimethylaminopyridine (DMAP) in a solvent such as benzene or acetonitrile, or by reaction with sodium or lithium hydride in tetrahydrofuran or N,N-dimethylformamide (DMF) to give 11 which is then deprotected as described above to give the desired compound.
Compounds of formula VII are prepared as described in Schemes 3a and 3b. In accordance with Scheme 3a, ketolide 11, prepared as in Scheme 2, is converted to 12 by reaction with carbonyldiimidazole and an alkali metal hydride base, such as sodium hydride, lithium hydride or potassium hydride in a suitable aprotic solvent at from about 0 °C to ambient temperature. Compound 12 may also be prepared by reaction of diol 9, or cyclic carbonate 10, prepared as described in Scheme ? above. by reaction with carbonyldiimidazole and sodium or lithium hydride under similar conditions.
Compound 12 is then reacted with diamine 13 having substituents A, B, D and E as defined above. in a suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF, to give the bicyclic compound 14. Compound 14 is then eyclized by treatment with dilute acid, such as acetic acid or HCl in a suitable organic solvent such as ethanol or propanol and deprotected as described above to give the tricyclic ketolide VIl. Alternatively, the 2'-protecting group of the bicyclic ketolide 14 may be removed prior to cyclization using the methods described in Scheme 1. Compounds of formula IV or VII may be reduced to compounds of formula IV-A by treatment with a reducing agent selected 'from hydrogen in the presence of palladium catalyst, alkyl borohydride and lithium aluminum hydride in a suitable organic solvent.
Scheme 3b illustrates an alternative preparation of compounds of formula VII.
Starting material 12 is reacted with a beta-aminoalcohol 1 ~ (Y=OH) in a suitable solvent system such as aqueous acetonitrile, DMF or aqueous DMF at 0 - 70 °C to give _1ø which is converted to the azide with a Mitsunobu reaction using triphenylphosphine and diphenylphosphoryl azide and DEAD in tetrahydrofuran. Alternatively, the hydroxy group in ~ may be activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride S or trifluoromethanesulfonic anhydride in an aprotic solvent. The activated hydroxy group is then converted to the corresponding azide by reaction viith lithium azide or sodium azide in an aprotic solvent. The 2'-protecting group is then removed as described above; and the azide is reduced to the amine ~. Suitable reducing reagents are triphenylphosphine-water, hydrogen with a catalyst, sodium borohydride, or dialkylaluminum hydride in the t0 appropriate solvent for these reactions, as is well known in the art.
Compound ~ is then cyclized as described in Scheme 3a above.
Compounds of formula IX wherein L is CO and T is NH or N-W-Rd are prepared as shown in Scheme 4. The preparation follows the procedure described by Baker et al., J.
Org. Chem., 1988, 53, 2340, which is incorporated herein by reference. In particular, 15 treatment of compound-l~; prepareu as des.,~ibed in Scheme 3 above W th aqueous ammonia results in formation of the cyclic carbamate _1$ wherein Re is H.
Likewise, reaction of compound 12 with an amino compound of the formula H2N-W-Rd results in formation of the cyclic carbamate in which Re is -W-Rd.
Deprotection of the 2'-hydroxy group as described above provides the desired ketolide IX.
20 In particular, treatment of compound 6B, with aqueous ammonia results in formation of the cyclic carbamate f~C wherein Re is H. Likewise, reaction of compound 6B with an amino compound of the formula H2N-W-Rd results in formation of the cyclic carbamate in which Re is -W-Rd.

WO 98/09978 l~rnJS~nsso~
Scheme 2 - .. RP NMe2 I
O,,~
C - - Rp NMe2 O' O
O
O

O

i . . .
R~ NMe2 I
O,,~
- ~ NMe2 10,,~, O
J
O

O
IX,L=CO,T=O
R ~JM62 J
O t~'~0~,, CH3 ~~n C
O
O

wo 9sio~a >QCr~s9~nsso~
Scheme 3a RP NMe2 O R Rp NMe2 I
0.., O 0....
H3C ,~~
N~ N / 6 ~~~~ O
O
O ~~,1'. _ O O

E~~..
A
B~~~~ NH2 D NH2 R RP NMe2 E ~... O I I
O Oo.
,,, H3Ci~.. ,.
D O~o~...- 6 O
E~~.. N OH NMe2 :' A \ ~ HO,,~. ~ O
H3C~~., ~~
Na... 6 O~ ~~~~ O O 14 O
O
o D H
V1I E~,,, ~ Of.~ NMe2 A I
H3Cn.. ~ O HO,,,,.
N~~.. 6 "" o O

O
1V-B, Rb is H

CA 02564020 2006-10-31 ' r~
wo 9sio~~s ~rius9~nsso~
Scheme 3b o RP NMe2 . 0~...
N~ N D
O
O D
Y
E rr..
- A I~
O ,~ 8 ''.. NH2 D Y O R Rp NMez Err.. ,''~ Oi.,.
A
H3Crr..
Nn..
O
O . ~'r O
~ O
O
1: Y - OH ---~ Y ~ N3 2: deprotect 3: Y=N3 ---' Y=NHZ
D
E rr.. E NMe2 D NHZ R NMe2 O HO~,, Err.. O
B '''~ H3Crr.. v A O HO'~..
Nrr.. 6 .,~r ~~ . H3Crr..
O O O B ' Nn,.
O _ O~O l.~r O O
~O
o o ~ y i ~-r wo ~o~~s pc~rnls~nsso6 Scheme 4 o RP NMe2 N~N ~ ._..._ - _ O
NH40H or O 12 HZ~a O ~ RP NMe2 0~..
R~ Hs~~., .'O _...
~ N,m..
O~ .I~~ O
O
.:
~O
O
O

Re=HorWRa NMe2 O
O HO,,, R ~ H3~''~~ v O~ Nip".
--' O O
w 'O
O
O
IX: L = CO, T = NH
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.
Representative examples of further elaboration of the 6-position are shown in Scheme 5.
For example, compound 20 where R is 6-O-CH2CH=CH2 and M' represents the macrolide i WO 98f09978 PCT/US97/15506 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 27; (b) treated with osmium tetroxide to give the 2,3-dihydroxypropyl compound 31 which in turn may be functionalized, such as by esterification with an acylating agent such as an acyl halide or acyl anhydride, at each oxygen atoms to give 32; (c) oxidized with m-chloroperoxybenzoic acid in an aprotic solvent to give the epoxy methyl compound 29 which can be opened with nucieophilic compounds, for example, amines or N-containing heteroaryl compounds, to give compounds with N-containing side chains 30; (d) oxidized under blacker conditions as described by Henry in "Palladium Catalyzed Oxidation of Hydrocarbons", Reidel 1o Publishing Co., Dordrecht, Holland (1980), to give the 6-O-CH2-C(O)-CH3 compound 28;
and (e) ozonized to give the aldehyde 21 which can in turn be ( 1 ) converted to oximes 22 and 24 by reaction with H2NOR3 or H2NOH respectively, or (2) 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 23. Reaction of the oxime 15 24 with diisopropyl carbodiimide in an aprnr~c sot Vpnt in the presence of CuCl gi;res use nitrile 25. Reaction of 20 with an aryl halide under Heck conditions (Pd(II) or Pd(O), phosphine, and amine or inorganic base, see Organic Reactions,1982, 27, 345-390) gives 26. Reduction of the double bond in 26, for example using H2 and palladium on carbon gives 33.
2o Scheme 6 describes alternate procedures for preparing compounds of formula XI
wherein L is CO, T is -NH- or -N(W-Rd)- and R is substituted alkenyl. The 6-O-allyl erythromycin compound 33 is converted to the compound of formula XI wherein L
is CO, T is -NH- or -N(W-Rd)- and R is allyl by removing the cladinose and oxidation of the 3-hydroxy group as described in earlier Schemes. Subsequent reaction of the compound of 25 formula XI wherein L is CO, T is -NH- or -N(W-Rd)- and R is allyl with a compound having the formula R**-halogen, wherein R** is aryl, substituted aryl, heteroaryl or substituted heteroaryl, under Heck conditions with (Pd(II j or Pd(O), phosphine, and amine or inorganic base, (see Organic Reactions, >i982, 27, 345-39C) gives the desired product of formula XI wherein L is CO, T is N(Rd) and R is substituted alkenyl.
3o Alternately, compound 33 is converted to the 6-O-(substituted alkenyl) compound of formula 34 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 34 may then be converted to the desired product of formula XI wherein L is CO, T is -NI-I- or -N(W-Rd)-, and R
is 3i substituted alkenyl by removing the cladinose and oxidation of the 3-hydroxy group as described in earlier Schemes.

Scheme 5 PCT/~6 OR
M'- O OH
M
t OH R' H
O
_O
\ M~--O
M ~'- O OH
CHs ~ O
M - O/ ' M ._ O ----.~- -M' H3 ~Z

Ar /O ~ N-O
--~
M-O ~ M'-O ~ M.-O
Ar M- O ~ / N- OH
---~ ~-- C= N
NHRs M' M,- O
M ,._ O

VV~ 98/09978 ~~'1'/IJS9'7Ig5 Scheme 6 I I
Rp NMe2 RP NMe2 I ' I
On. R 0,,, O~ . O
O ~ O ~
O O
XI. R is allvl 6C. R is allvl.
Z' is 4"-aceyl-cladinose R~ is H .or W-R~
n..
R"

RP NMe2 . RP NMe2 O I I
a R 0,,, R 0,,, ~~. ~~O
N,,, O~O . ..n0 O O~ 7 O
v''. -r O-Z' O O
~4 XI. R is substituted a11~
6C. R is substituted allvl.
Z' is 4"-acetyl-cla_dinose Representative examples of still further elaboration of the 6-position are shown in Scheme 7. The desired 6-O-substituted compound may be prepared by chemical modification of an initially prepared 6-O-propargyl compound. For example, compound 35 where R is 6-O-CH2-C---CH and M' represents the macrolide ring system can be further derivatized. The triple bond of the alkyne compound 35 can be treated with an aryl halide, a substituted aryl halide, an 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 36. Compound 35 may also be treated with a boronic acid derivative HB(ORZZ), wherein RZZ is H or CI-CIp-alkyl, in an aprotic solvent at 0 °C to ambient temperature to give compounds 37, which are then treated with _97_ Pd(triphenylphosphine)4 and an aryl halide, a substituted aryl halide, an heteroaryl halide or substituted heteroaryl halide under Suzuki reaction conditions to give compounds 38.
Compound 35 may also be treated with N-halosuccinimide in acetic acid to give compounds 39. Also, compound 35 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 the presence of an organic amine, such as triethylamine, to give the appropriately substituted compounds 41.
Further, compound 36 can be selectively reduced to the corresponding eis-olefin compound 40 by catalytic hydrogenation in ethanol at atmospheric pressure in the presence of 5% PdBaS04 1O and quinoline (Rao et al., J. Org. Chem., (1986), 51: 4158-4159).
Scheme 8 describes alternate procedures for preparing compounds of formula X1 wherein L is CO, T is -NH- or -N(W-Rd)-, and R is substituted alkynyl. The 6-O-propargyl erythromycin compound 42 may be converted to the compound of formula XI
wherein L is CO; T is N(Rd) and R is propargyl by removing the cladinose and oxidation of the 3-hydroxy group as described in earlier Schemes: SLbsequert reaction-of ~he-eorrtpound of formula XI wherein L is CO, T is N(Rd) and R is propargyl with a compound having the formula R**-halogen, wherein R** is aryl, substituted aryl, heteroaryl or substituted heteroaryl, in the presence of Pd(triphenylphosphine)2C12 and CuI in the presence of an organic amine, such as triethylamine, gives the desired product of formula XI
wherein L is 2U CO, T is -NH- or -N(W-Rd)-, and R is substituted alkynyl.
Compound 42 is converted to the 6-O-(substituted alkynyl) compound of formula by reaction with a compound having the formula R**-halogen, wherein R** is aryl, substituted aryl, heteroaryl or substituted heteroaryl, in the presence of Pd(triphenylphosphine)2C12 and CuI in the presence of an organic amine, such as triethylamine, as just described. Compound 43 is then converted to the desired product of formula XI wherein L is CO, T is -NH- or -N(W-Rd)-, and R is substituted alkynyl by removing the cladinose and oxidation of the 3-hydroxy group as described in earlier Schemes.

dv~ 9s~~s rcrrtJSrrn Scheme '7 Aryl /---ArYI
M'- O ~ M'- O
3(~ Rae ~8'ReB
M'-O M'- O
35 ~ 37 Halogen M'- O
Aryl j ~-Aryl M'-O
M'- O

wo 9sio~rrs pcrrtls9~nsso6 Scheme 8 - RP NMe2 O RP NMe2 t R 0,~~ Re O O .
y.. ,~~
O \ O~ Nn. 6 7 O O . ..~~ O
O
'.
O
O O
42 XI. R is nronarevl 6C. R is nrooarevl.
Z'is 4"-acetyj-cladinose.
Rg i~, ~I or W-R~ _ . .
R" R.:
RP NMez Rp NMe2 O I I
Re O Oi.. R 0...
\ ~i,, y v O~N~.. 6 O
"O O
O
v'' ~ O-Z' O
O O
XI. R is substituted orooarevl fiC. R is substituteC~propar~ ~Ll.
Z' is 4"-acetyl-cladinose -1~0-wo 9sio99~s ~crnrs~nsso~
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.
Example 1 Compound of Formula (VIIn: X is O, R is allvl Step la: Compound 4 from Scheme la; V is N-O-(1-isopropoxycyclohexyl). R is allvl. Ri?
is trimethvlsil ~~1.
To a 0 °C solution of 2',4"-bis-O=trimethylsilylerythromycin A 9-[O-(1-isopropoxycyclohexyl)oxime (1.032 g, 1.00 mmol), prepared according to the method of U.S. Pat. No. 4,990,602 in 5 mL of DMSO and ~ mL of THF was added freshly distilled allyl bromide (0.73 mL, 2.00 mmol). After approximately 5 minutes, a solution of potassium tent-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 1S washed with water and, brine. The organic phase was copcentrated i_n_ vacuo to give d:e desired compound (1.062 g) as a white foam.
Step 1b: Compound 5 from Scheme la; V is NOH, R is allyl.
To a solution of the compound resulting from step la (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 at ambient temperature, 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 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: Compound 6 from Scheme la: 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 ~tL) and warmed at 86 °C for 2.~
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 (2x), dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by column chromatography eluting with 1 % MeOH in methylene chloride containing 19o ammonium hydroxide to give 686 mg WO 98109978 PC'TlUS97/15506 (57%) of the title compound. 13C NMR (CDC13) 8 219.3 (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-11 ), 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)> 11.9 (C-10 CH3), 10.1 (C-IS), 8.9 (C-4 CH3). MS
(FAB)+ m/e 774 (M+H)~, 812 (M+K)+.
Steg Id- Compound 7 from Scheme 1b: R is ally!.
To a suspension of the compound prepared in step lc (7.73 g, I0.0 mmol) in ethanol (25 rriL) and water (75 mL) was added aqueous 1 M HCl ( 18 mL) over 10 minutes.
The reaction mixture was stirred for 9 hours at ambient temperature and then was left standing in the refrigerator overnight. Aqueous 2 M NaOH (9 mL, I 8 mmol) which resulted in the formation of a white precipitate. The mixture was diluted with water and :5 filter. :: T he soliW vas washed -with vivater'and dried 'under vacuum to give the des-cladinosyl compound 7 (3.11 g).
Step le~ Compound 8 from Scheme 1b: R is ally!. R~ is benzovl.
To a solution of the product of step 1d (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.
Aqueous 5% sodium carbonate was added and the mixture was stirred for 20 minutes. The mixture was 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.
Step 1f: Compound 9 from Scheme I b: R is all~R is benzovl:
same as Compound of Formula (II), R~ is OH. R~ is benzovl 3o To a -10 °C solution under N2 of N-chlorosuccinimide (0.68 g, 5.07 mmol) in dichloromethane (20 mL) was added dimethylsulfide (0.43 mL, 5.92 mmol) over 5 minutes. The resulting white slurry was stirred for 20 minutes at -10 °C and then a solution of the compound resulting from step 1e (2.43 g, 3.38 mmol) in dichloromethane (24 mL) was added and the reaction mixture was stirred for 30 minutes at -10 to -5 °C.
Triethylamine (0.47 mL, 3.38 mmol) was added dropwise over 5 minutes and the reaction mixture was stirred for 30 minutes at 0 °C. The reaction mixture was extracted with dichloromethane. The organic phase was washed twice with aqueous 5% sodium I
j-, bicarbonate and once with 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 (2.27 g) as a white foam.
Step 1 e: Compound of Formula (VIII): X is Os R is allvl.
A solution of the compound resulting from step if (7i9 mg~ ~r:0 mmol) in methanol (20 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 desired compound (577 mg) as a white foam. )3C
NMR
(CDCI3) 8 219.2 (C-9), 206.0 (C-3), 169.8 (C-1 ), 135.3, 117.5, 102.8, 78.4, 78.0, 75.9, 74.4, 70.3, 69.5, 69.0, 65.9, 64.6, 50.6, 45.4, 45.1, 40.2, 38.6, 37.8, 31.6, 28.4, 21.8, 21.3, 20.3, 18.1, 16.5, 14.7, 12.8, 12.3, 10.6. MS (FAB)+ m/e 614 (M+H)+.
Example 2 Compound-of Formula ;~'III~: X is l'jOH. R is aIlvl: .
To a solution of the compound resulting from Example 1 (122 mg, 0.2 mmol) in ethanol was added hydroxylamine hydrochloride (76 mg, 1.1 mmol) and triethylamine (56 p.L, 0.4 mmol) and the reaction mixture was stirred overnight at 80 °C.
The reaction mixture was concentrated and the residue was taken up in ethyl acetate. The organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) gave the E oxime (42 mg) and the Z oxime (38 mg) as white foams. 13C
NMR
(CDC13) b 206.3 (C-3), 170.1 (C-9), 169.8 (C-I), 136.1, 116.5, 102.7, 78.6, 78.2, 75.5, 74. I , 70.3, 70.2, 69.4, 65.9, 64.7, 50.6, 45.2, 40.2, 37.3, 33.1, 28.4, 25.4, 21.9, 21.3, 2~ 20.3, 18.6, 16.5, 14.9, 14.7, 12.8, 10.7. MS (FAB)+ m/e 629 (M+H)+.
Example 3 Compound of Formula (VFI11: X is O, R is propyl.
A solution of the compound resulting from Example 1 (122 mg, 0.2 mmol) in 3o ethanol was flushed with nitrogen and 10% palladium on carbon (20 mg) was added. The mixture was then flushed with hydrogen and the reaction mixture was stirred overnight under positive hydrogen pressure. The reaction mixture was filtered and concentrated in vacuo to give a glass. Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) gave the title compound as a white solid. 13C N1VIR (CDCl3) 8 220.2 (C-9), 35 206.5 (C-3), 169.9 (C-1), 102.7, 78.1, 77.7, ?5.7, 74.I, 70.3, 69.4, 65.9, 64.5, 50.6, 45.4, 44.7, 40.2, 38.8, 37.5, 28.4, 22.3, 21.9, 21.3> 20.3, 18.3, 16.5> 14.9, 14.7, 12.4, 10.6, 10.2. MS (FAB)+ m/e 616 (M+H)+.

wo ssio~~s pcrms~nssos Example 4 Compound of Formula VIII): X is O, R is -CH~CHO.
Step 4a: Compound of Formula (VIII): X is O. R is -CH~CHO N-oxide.
Ozone was passed through a -78 °C solution in dichloromethane ( 100 mL) of the - -compound resulting from Example 1 (2.45 g, 4.0 mmol) for 45 minutes. The reaction mixture was then flushed with nitrogen for 10 minutes. Dimethyl sulfide ( 1.46 mL, 20 =
mmol) was added at -78 °C and the reaction mixture was stirred for 30 minutes at 0 °C. The reaction mixture was concentrated in vacuo to give a white foam (2.78 g) which was used .
without further purification.
Std 4b: Compound of Formula (VIII): X is O, R is -CH~CHO.
The desired compound was prepared by heating a solution in THF (40 mL) of the compound resulting from step 4a (2.78 g, 4.0-mmol) and-triphe:~yphospht.~.~
(2_62 g, 10:0 rnmol) at 55 °C for 2.5 hours. The reaction mixture was concentrated in vacuo to give a white foam. Chromatography on silica gel ( 1:1 acetone-hexane, then 75:25:0.5 acetone-hexane-triethylamine) gave the desired compound ( 1.29 g) as a white solid. MS
(FAB)+
m!e 616 (M+H)+.
Example S
Compound of Formula (VIII): X is O, R is -CH~CH=NOH.
To a solution in methanol (5 mL) of the compound prepared in Example 4 (46 mg, 0.08 mmol) was added triethylamine (31~.L, 0.225 mmol) and hydroxylamine hydrochloride (7.7 mg, 0.112 mmol) and the reaction mixture was stirred for 6 hours at ambient temperature. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo to give a clear glass. Chromatography on silica gel (95:x:0.5 dichloromethane-methanol-ammonia) gave the title compound (29 mg) as a white solid. MS (FAB)+
m/e 631 (NI+H)+.
Example 6 Compound of Formula IVITI): X is NOHLR is -CH~CH=NOH.
The title compound (7.0 mg) was obtained from the chromatography described in Example 5. MS (FAB)+ m/e 631 (M+H)+. MS (FAB)+ m/e 645 (M+H)+.

wo 9sror~~s >PC~r~s9~nss~
Ex~n~le 7 Compound of Formula fVII1): X is O. R is -CH~CN.
To a solution under nitrogen of the compound prepared in Example 5 ( 168 mg, 0.267 mmol) in THF (5 mL) was added diisopropylcarbodiimide (83 ltL, 0.534 mmol) and CuCl (2.7 mg, 0.027 mmol) and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo to give a clear glass. Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) gave the title compound (63 mg) as a white solid. I3C NMR (CDCl3) $
219.5(C-io 9), 205.6 (C-3), 169.9 (C-1), 103.4, 81.3, 78.2, 77.4, 77.1, 74.0, 70.2, 69.7, 69.1, 65.9, 51.1, 48.6, 46.7, 44.3, 40.2, 38.0, 37.6, 28.2, 23.5, 21.2, 19.7, 17.8, 16.1, 14.4, 11.9> 10.5, 10.5. MS (FAB)+ mJe 613 (M+H)~.
Example 8 IS Compound of Formula IVIIII:.._X is OL,R is -CH2CH2TIH~.
To a solution in methanol (10 mL) of the compound prepared in Example 4 (170 mg, 0.276 mmol) was added ammonium acetate (212 mg, 2.76 mmol) and the mixture was cooled to 0 °C. Sodium cyanoborohydride (34 mg, 0.553 mmol) was added and the reaction mixture was stirred for 30 hours at 0 °C. The reaction mixture was taken up in 20 ethyl acetate and washed with aqueous 5% sodium carbonate, aqueous 2% , tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (90:10:0.5 dichloromethane-methanol-ammonia) gave the title compound (90 mg) as a white solid. 13C NMR (CDC13) 8 217.0 (C-9), 206.3 (C-3), 170.6 (C-1), 102.7, 78.9, 78.5, 75.1, 74.9, 70.3, 69.4, 67.8. 65.9.
25 63.1, 50.8, 45.8, 44.9, 41.7, 40.3, 38.8, 38.2, 28.4, 22.2, 21.3, 20.7, 19.2, 16.6, 14.9, 12.8, 12.4, 10.9. MS (FAB)+ m!e 617 (M+H)+.
Example 9 Compound of Formula (VIII): X is O. R is -CH~CH~NHCH2-Phenvl.
30 To a 0 °C solution in methanol ( 10 mL) of the compound prepared in Example 4 ( 121.3 mg, 0.200 mmol) was added acetic acid ( 114 ~.L, 2.00 mmol) and benzylamine (218 ~,L, 2.00 mmol) and the mixture was stirred for 10 minutes. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) was added and the reaction mixture was stirred for I6 hours.
Additional sodium cyanoborohydride (24.8 mg, 0.400 mmol) was then added and stirring 35 was continued for 5 hours. The reaction mixture was taken up in ethyl acetate and washed with aqueous S% sodium carbonate, aqueous 2% tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo.
Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) followed by a second chromatography (50:50:0.5 acetone-hexanes-triethylamine) gave the title compound (82 mg) as a white foam. 13C NMR (CDC13) 8 216.6 (C-9), 206.3 (C-3), 170.5 (C-I), 139.0, 128.6, 128.3, 126,9, 102.4, 78.9, 78.4, 75.1, 74.8, 70.2, 69.4, 67.8, 65.9, 61.7, 53.2, 50.7, 48:2, 45.6, 44.8, 40.2, 38.8, 38.0, 28.3, 21.9, 21.3, 20.6, 18.8, 16.6, 14.6, 12.6, 12.3, 10.7. MS (FAB)+ m/e 707 (M+H)+. ' -, Example 10 Compound of Formula (VIII): X is O. R is -CH~CHZNHCHZCH2-Phenvl.
1U To a 0 °C solution in methanol (10 mL) of the compound prepared in Example 4 ( 121.3 mg, 0.200 mmol) was added acetic acid ( 1 I 4 p.L, 2.00 mmol) and phenethylamine (218 p.L, 2.00 mmol) and the mixture was stirred for 10 minutes. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) and the reaction mixture was stirred for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5%
sodium carbonate, aqueous 2% tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (90:10:0.5 dichloromethane-methanol-ammonia) gave the title compound (60.1 mg) as a white foam. MS (FAB)+ m/e 721 (M+H)+.
Example 11 Compound of Formula (VIII): X is O. R is -CH~CH~NHCHICO?CHY)CH~-Phenvl.
To a 0 °C solution in methanol (10 mL) of the compound prepared in Example 4 (121.3 mg, 0.200 mmol) was added L-phenylalanine methyl ester hydrochloride (129 mg, 0.600 mmol) and the mixture was stirred for lOminutes. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) and the reaction mixture was stirred for 22 hours. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium carbonate, aqueous 2%
tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) gave the title compound (60.1 mg) as a white foam. 13C NMR (CDC13) 8 217.8 (C-9), 206.4 (C-3), 170.5 (C-1), 170.4, 137.5, 129.4, 128.2, 126,4, 102.4, 78.8, 78:4, 75.2, 74.9, 70.2, 69.4, 68.5, 65.9, 63.1, 61.6, 51.4, 50.7, 47.1, 45.5, 44.7, 40.2, 39.?, 38.4, 28.4, 21.8, 21.2, 20.6, 18.7, 16.6, 14.7, 12.6, 12.2, 10.7. MS (FAB)+
m/e 779 (M+H)+.
Example 12 Compound of Formula 1VIII): X is O, R is -CH~CH~NHCH~-(4~yrid ~/' i~VO 98109978 PCT/US97l15506 The desired compound was prepared according to the method of Example 10, except substituting 4-aminomethylpyridine for phenethylamine. 13C NMR (CDCl3) 8 217.8 (C-9), 206.2 (C-3), 170.6 (C-1), 149.7, 148.2, 123.3, 102.5, 78.9, 78.4, 75.0, 74.9, 70.2, 69.5, 68.4, 65.9, 61.7, 52.4, 50.7, 48.7, 45.7, 44.8, 40.2. 39.2, 38.5, 38.2, 28.4, 21.8, 21.3, 20.6, 18.7, 16.6, 14.6, 12.6, 12.2, 10.7. MS (FAB)+ m/e 708 (M+H)+.
Exam.,ple 13 Compound of Formula IVIII): X is O. R is -CHCCH2NNCH~-f4-quinolyl).
To a solution of the compound prepared in Example 8 (90 mg, 0.15 mmol) in methanol (2 mL) was added 4-quinolinecarboxaldehyde (23 mg, 0.15 mmol), acetic acid. .
(8.6 N,L, 0.15 mmol), and sodium cyanoborohydride (9.4 mg, 0.15 mmol) and the reaction mixture was stirred for 15 hours. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium carbonate, aqueous 2%
tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, arid concentrated in vacuo. Chromatography on silica gel (-90:1:0.5 dichlflrometlvane-methaiiol ammonia) gave the title compound (32 mg) as an off white solid. MS (FAB)+ m/e ( M+H)+.
Example 14 Compound of Formula (VIIII: X is O.'R is -CH~CH=CH-Phenyl.
Step 14a: Compound 9 from Scheme 2: X is O. R is -CHZCH=CH-Phenyl. Rp is benzoyl.
To a solution under nitrogen of the compound prepared in Example 1, step 6, (717 mg, 1.00 mmol), palladium(II)acetate (22 mg, 0.100 mmol), and triphenyphosphine (52 mg, 0.200 mmol) in acetonitrile (5 mL) was added iodobenzene (220 p,L, 2.00 mmol) and triethylamine (280 p.L, 2.00 mmol) and the mixture was cooled to -78 °C, degassed, and sealed. The reaction mixture was then warmed to 60 °C for 0.5 hours and stirred at 80 °C
for 12 hours. The reaction mixture was taken up in ethyl acetate and washed twice with aqueous 5% sodium bicarbonate, once with aqueous 2%
tris(hydroxymethyl)aminomethane, and once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (95:5:0.5 dichloromethane methanol-ammonia) gave the title compound (721 mg) as an off-white foam.
Step 14b: Compound of Formula (Vlll): X is O, R is -CH2CH=CH-Phenyl.
Deprotection of the compound prepared in step 14a was accomplished by heating in methanol according to the procedure of Example 1, step g. 13C NMR (CDCI3) S
219.4 (C-9), 206.0 (C-3), 169.8 (C-I), 137.0, 132.6, 128.3, 127.3, 126.7, 126.6, 102.7, 78.4, -10?-78.2, 75.9, 74.3, 70.3, 69.5, 69.1, 65.9, 64.2, 50.6, 45.4, 45.3, 40.2, 38.7, 37.7, 28.3, 21.9, 21.2, 20.3, 18. I , 16.5, 14.6, 13.0, 12.3, 10.8. MS (FAB)+ m/e 690 (M+H)+.
Example 15 Compound of Formula (VIII): X is O, R is -CH C~ H~CH~-Phenyl. ' A solution of the compound prepared in Example 14 ( 170 mg, 0.247 tnmol) in ' -.
methanol (10 mL) was flushed with nitrogen. 10% Palladium on carbon (50 mg) was added and the mixture was flushed with hydrogen and stirred for 18 hours under positive hydrogen pressure. The reaction mixture was~filtered through celite and the filter cake was rinsed with dichloromethane. The filtrate was concentrated in vacuo to give a colorless .
glass. The glass was taken up in ether, hexane was added and the solvents were removed in vacuo to give the title compound (67 mg) as a white solid. 13C NMR (CDC13) 8 220.2 (C-9), 206.5 (C-3), 170.0 (C-1), 142.3, 128.4, 128.1, 125.4, 102.6, 78.2, 78.0, 75.6, 74.2, 70.3, 69.5, 69.4, 65.9, 62.1, 50.6, 45.4, 44.6, 40.2, 38.8, 37.5, 32.1, 30.3, 28.4, 21.9, t5 21.3, 20.2, 18.4; 1-6.5, 14.9, 12.4, 10.6.- M-S (FAB)+ mEe 592 (M+H)~. - -_- _ _ Example 16 , Compound of Formula (VIII): X is O, R is -CH2CH=CH-(4-methoxyphenvl).
The desired compound was prepared according to the method of Example 14, except substituting 4-iodoanisole for iodobenzene. MS (FAB)+ m/e 720 (M+H)+.
Example 17 Compound of Formula (VIII): X is O. R is -CH~CH=CH-(4-chlorophenyl).
The desired compound was prepared according to the method of Example 14, except substituting I-chloro-4-iodobenzene for iodobenzene. 13C NMR (CDCl3) 8 219.6 (C-9), 206.0 (C-3), 169.8 (C-1), 139.6. 135.5, 131.3, 128.5, 127.9, 127.3, 102.7, 78.4, 78.2, 75.9, 74.2, 70.3, 69.5, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2, 38.6, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0, 12.2, 10.8. MS (FAB)+ m/e 724 (M+H)+.
Example 18 Compound of Formula (VIII): X is O, R is -CH~CH=CH-f3-quinolvl).
Step 18a: Compound 9 from Scheme 2: X is O, R is -CH~CH=CH-(3-auinolvl). Rn is benzovl.
A mixture of the compound prepared in Example l, step f, (1.80g, 0.25 mmol), palladium(II)acetate (11 mg, 0.05 mmol), and tri-o-tolylphosphine (30 mg, 0.10 mmol) and 3-bromoquinoline (68 p.L, 0.5 mmol) in acetonitrile (2 mL) was cooled to -78 °C, degassed, WO 98/09978 PCT/U8~7/15506 and sealed. The reaction mixture was then warmed to 50 °C for 2 hours and stirred at 80'°C
for 16 hours. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium carbonate, aqueous 2% tris(hydroxymethyl)aminomethane, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel S (98:2 dichloromethane-methanol) gave the title compound ( 186 mg) as an off white foam.
MS (FAB)+ m/e 845 (M+H)+.
Step 18b: Compound of Formula (VIII)- X is O R is -CH~CH=CHl3-auinol Deprotection of the compound prepared in step 18a was accomplished by heating in methanol according to the procedure of Example 1, step g. 13C NMR (CDCI3) b 219.7 (C'.-9), 205.9 (C-3), 169.8 (C-1 ), 1 X2.1, 150.0, 147.5, 140.2, 132.6, 130.0, 129.2, 129.1, 128.8, 128.1, 127.9, 126.5, 102.8, 78.5, 78.2, 75.9, 74.2, 70.2, 69.4, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2, 38.7, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0, 12.2, 10.8. MS (FAB)+ m/e 741 (M+H)+. .
Using the procedures described in the preceding examples and schemes and methods known in the synthetic organic chemistry art, the following compounds of Formula VIII
wherein X is O can be prepared. These compounds having the R substituent as described in the table below are of the formula O R NMe2 I
O H 0,,, H3C.,,,. ,'CH3 H 0,,, H O ' .~~ O O CH3 L'13C~~.. O CHs O

O
Ex. No. substitutent 19 R is -CH2CH~CH20H

20 R is -CH~C(O)OH

21 R is -CH2CH2NHCH3 22 R is -CH2CH2NHCH20H

23 R is -CH2CHZN(CH3)2 24 R is -CH2CH2(1-morpholinyl) R is -CH2C(O)NH2 26 R is -CH2NHC(O)NH2 27 R is -CH2NHC(O)CH3 28 R is -CHZF

WO 98J09978 ' J PCT/US97/1 29 R is -CH2CH20CH3 30 R is -CH2CH3 31 R is -CHZCH=CH(CH3)2 32 R is -CH2CH2CH(CH3)CH3 33 R is -CH2CH20CH2CH20CH3 34 R is -CH2SCH3 35 R is -cyclopropyl 36 R is -CH20CH3 37 R is -CH2CHZF

38 R is -CH2-cyclopropyl 39 R is -CH2CH2CH0 40 R is -C(O)CH2CH2CH3 4I R is -CH2-(4-nitrophenyl) 42 R is -CH2-(4-chlorophenyl) 43 R is -CH2-(4-methoxyphenyl) 44 R is -CH2-(4-cyanaphenyl) 45 R is -CHZCH=CHC(O)OCH3 46 R is -CH2CH=CHC(O)OCH2CH3 47 R is -CH2CH=CHCH3 48 R is -CHZCH=CHCH2CH3 49 R is -CH2CH=CHCH2CH2CH3 50 R is -CH2CH=CHS02-phenyl 51 R is -CH2C~C-Si(CH3)3 52 R is -CH2C-CCH2CH2CH2CH2CH2CH3 53 R is -CH2C=CCH3 54 R is -CH2-(2-pyridyl) 55 R is -CH2-(3-pyridyl) 56 R is -CH2-(4-pyridyl) 57 R is -CH2-(4-quinolyl) 58 R is -CH2N02 59 R is -CH2C(O)OCH3 60 R is -CHZC(O)-phenyl 61 R is -CH2C(O)CH2CH3 62 R is -CH2Cl 63 R is -CH2S(O)2-phenyl 64 R is -CH2CH=CHBr 65 R is -CH2CH=CH-(4-quinolyl 66 R is -CH2CH2CH2-(4-quinolyl 67 R is -CH2CH=CH-(5-quinolyl 68 R is -CH2CH2CH2-(5-quinolyl 69 R is -CH2CH=CH-(4-benzoxazolyl 70 R is -CH2CH=CH-(7-benzimidazolyl Example 71 Compound of Formula (IXI: L is CO, T is O, R is -CH~CH=CHI
Step 71 a: Compound 10 from Scheme 2: R is R is -CH?LH=CHI. R~ is benzoyl.
To a -35 °C solution under nitrogen in THF (60 mL) of the compound prepared in Example l, step f, (3.58 g, 5.00 mmol) was added sodium hexamethyldisilazide (1.0 M in THF, 5.5 mL, 5.5 mmol) and the resulting white suspension was stirred for 30 minutes. A

~N~ 98/09978 PCT/US97/15506 solution of carbonyldiimidazole (4.05 g, 25 mmol) in THF (40 mL) was added dropwise over 20 minutes at -35 °C and then the cold bath was removed and the reaction mixture was stirred for 30 minutes. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on silica gel (30% acetone-hexane) gave the title compound (2.6 g) as a white foam. MS (FAB)+ m/e 744 (M+H)+.
Step 71b: Compound of Formula (IXl: L is CO. T is O. R is -C'.H~CH=CHI.
Deprotection of the compound prepared in step 71 a was accomplished by heating in methanol according to the procedure of Example l, step g. 13C NMR (CDCI3) 8 212.1 (C-9), 205.0 (C-3), 168.9 (C-1), 153.8, 134.4, 118.4, 103.1, 84.7, 80.5, 78.7, 77.1, 76.9, 70.3, 69.5, 65.9, 64.8, 50.8, 46.5, 44.1, 40.2, 38.8, 38.1, 28.4, 22.7, 21.2, 20.5, 18.3, 14.5, 13.6, 12.6, 10.6. MS (FAB)+ m/e 640 (M+H)+.
Example 72 Compound of Formula (IXI: L is CO, T is O. R is -CH~CH=CH-Phen ~LI.
Step 72a: Compound 10 from Scheme 2: R is -CH2CH=CH-Phenyl. R~ is benzovl.
A solution of the compound prepared in Example 14, step a (150 mg, 0.20 mmol) in 20 THF (5 mL) was cooled to -35 °C and flushed with nitrogen. Lithium hexamethyldisilazide ( 1.0 M in THF, 0.22 mL, 0.22 mmol) over 2 minutes at -35 °C. The reaction mixture was stirred for 10 minutes at -35 °C and then a solution of carbonyldiirnidazole ( 162 mg, 1.00 mmol) in THF (3 mL) was added dropwise over 2 minutes. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The reaction mixture was cooled to 0 25 °C and aqueous 0.5 M KHZP04 was added. The mixture was extracted with ethyl acetate and the organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel (30alo acetone-hexane) gave the title compound (87 mg) as a white solid. MS (FAB)+ m/e 820 (IvI+H)+.
3o Step 72b: Compound of Form_ula~IX~: L is CO T is O R is -CH~CH=CH-Phenyl.
Deprotection of the compound prepared in step 72a was accomplished by heating in methanol according to the procedure of Example I, step g. 13C NMR (CDCI3) 8 212.4 (C-9), 205.2 (C-3), 168.3 (C-1), 153.3, 136.4,.134.9, 128.3, 127.6, 127.0, 124.7, 103.2, 84.5, 80.8, 78.7, 78.0, 70.3, 69.6, 65.9, 64.5, 50.9, 46.9, 44.4, 40.2, 39.1, 37.8, 28.3, 35 23.0, 21.2, 20.4, 18.1, 14.8, 14.4, 13.7, 12.6, 10.8. MS (FAB)+ m/e 716 (M+H)+.
Example 73 Compound of Formula (IX): L is CO, T is O, R is -CH2CH2CH~-Phenyl.
Step 73a: Compound 8 from Scheme 1b; R is -CH~CH~~CH~-Phenyl, Rp is benzoyl.
The desired compound was prepared by reaction of the compound of Example 15 with benzoic anhydride according to the procedure of Example l, step e.
Step 73b: Compound 10 from scheme 1 b; R is -CH~CH~CH~-Phenyl, R~ is benzoyl.
A solution of the compound prepared in step 73a (104 mg, 0.13 mmol) in THF (5 mL) was cooled to -35 °C and flushed with nitrogen. Sodium hexamethyldisilazide (1.0 M
1 a in THF, 0.16 mL, 0.16 mmol) over 1 minute at -35 °C. The reaction mixture was stirred for IU minutes at -35 °C and then a solution of carbonyldiimidazole (105 mg, 0.65 mmol) in THF (3 mL) was added dropwise over 1 minute. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless glass.
Chromatography on silica gel (30% acetone-hexane) gave the title compound (63 mg) as a white solid. MS
(FAB)+ m/e 822 (M+H)+.
Step 73c: Com-pound of Formula (IX): L is CO. T is O, R is -CH2CH~CH2-Phenvl.
Deprotection of the compound prepared in step 73b was accomplished by heating in methanol according to the procedure of Example 1, step g. 13C NMR (CDCl3) 8 21 l.8 (C-9), 205.1 (C-3), 169.6 (C-1 ), 153.6, 141.x, 128.5, 128. I , 125.5, 102.7, 84.6, 80.5, 78.3, 76.(1, 70.2, 69.5, 65.9, 62.4, 50.7, 45.5, 44.5, 40.2, 38,6, 37.9, 31.9, 30.4, 28.4, 22.6, 21.2, 20.3, 18.5, 14.6, 13.4, 13.3, 12.6, 10.4. MS (FAB)+ m/e 718 (M+H)+.
Example 74 Compound of Formula (IXI: L is CO, T is O. R is -CH~CH=CH-(4-chloroDhenvll.
Step 74a: Compound 10 from Scheme 1 b: R is -CH~CH=CH-l4-chlorophen 1~P is benzovl.
A solution of the compound of formula 10 (R is -CH2CH=CH-(4-chlorophenyl), Rp is benzoyl), prepared as in Example I7, (165 mg, 0.20 mmol) in THF (5 mL) was cooled to -35 °C and flushed with nitrogen. Lithium hexamethyldisila~ide (1.0 M in THF, 0.22 mL, 0.22 mmol) over 2 minutes at -35 °C. The reaction mixture was stirred for 10 3S minutes at -35 °C and then a solution of carbonyldiimidazole (105 mg, 0.65 mmol) in THF
(3 mL) was added dropwise over 2 minutes. The cold bath was removed and the reaction mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo to give a colorless glass (219 mg) which was used without further purification. MS (FAB)+ m/e 854 (M+H)+.
Step74b: Compound of Formula (IX): L is CO, T is O, R is -CH~CH=CH-(4-_ chlorophenvll.
Deprotection of the compound prepared in step 74a was accomplished by heating in methanol according to the procedure of Example 1, step g. i~C NMR (CDC13) 8 212.4 (C-9), 205.1 (C-3), 168.6 (C-1 ), 153.3, 135.0, 133.5, 133.2, 128.5, 128.3, 125.5, 103.2, 84.5, 80.7, 78.8, 78.0, 70.3, 69.6, 66.0, 64.3, 50.9, 46.9, 44.4, 40.2, 39.1, 37.8, 28.4, 23.0, 21.2, 20.4, 18.1, 14.8, 14.4, 13.6, 12.6, 10.7. MS (FAB)+ m/e 750 (M+H)+.
Example 75 Compound of Formula ~IXI: L is CO. T is O, R is -CH~CH=CH-(3-quinolyl).
The compound formula 10 (R is -CH2CH=CH-(3-quinolyl), Rp is benzoyl), prepared as in Example 18, was converted to the title compound using the procedure of Example 71, steps a and b. 13C NMR (CDC13) b 212.4 (C-9), 205.2 (C-3), 168.7 (C-1), 153.4, 150.3, 147.6, 132.7, 131.1, 129.6, 129.0, 128.9, 128.4, 128.1, 127.7, 126.6, 103.2, 84.5, 80.6, 78.9, 77.5, 77.0, 70.3, 69.6, 65.9, 64.3, 50.9, 46.9, 44.5, 40.3, 39.0, 37.8, 28.4, 22.8, 21.2, 20.4, 18.1, 14.7, 14.4, 13.5, 12.6, 10.6. MS
(FAB)+ m/e 767 (M+H)+.
Using the procedures described in the preceding examples and schemes and methods known in the synthetic organic chemistry art, the following compounds of Formula IX
wherein L is CO and T is O can be prepared. These compounds having the R
substituent as described in the table below are of the formula O R NMe2 'O I-I 0,,..
HaC~,.
0,,, O

H3C.. ~ ~CH3 'O
O

O
Ex. No. Substituent 76 R is -CH2CH~CHz.

77 R is -CH2CH2NH~.

78 R is -CH2CH=NOH.

79 R is -CH2CH~CH~OH

80 R is -CH2F

81 R is -CHZCH2-phenyl 82 R is -CH2CH2-(4-ptTidyl) 83 R is -CH2CH~-(4-quinolyl) 84 R is -CH2CH(OH)CN

85 R is -CH(C(O)OCH3)CH2-phenyl 86 R is -CH2CN

87 R is -CH2CH=CH-(4-methoxyphenyl) 88 R is -CH2CH=CH-(4-fluorophenyl) 89 R is -CH2CH=CH-(8-quinolyl) 90 R is -CH2CH~NHCH~_-phenyl 91 R is -CH2-phenyl 92 R is -CH2-(4-pyridyl>

93 R is -CH2-(4-quinolvl) 94 R is -CHZCH=CH-(4-pyridyl) 95 R is -CH~CH2CHd-(4-pyridyl) 96 R is -CH2CH=CH-l,4-quinolyl) , 97 R is -CH2CH2CH~_-(4-quinolyl) 98 R is -CH2CH=CH-(~-quinolyl) 99 R is -CH2CH~CH~-('~-quinolyl) 10()R is -CH2CH=CH-(4-benzoxazolyl) 101 R is -CH2CH=CH-(.~-benzimidazolyl) Example 102 Compound of Formula (IXI: L is CO, T is NH. R is -CH~CH=CH2.
Step 102a: Compound 11 from Scheme 2: R is -CH~CH=CH2. R~ is benzovl.
To a solution of compound 10 (R is -CH2CH=CH2, RP is benzoyl), prepared as in Example 71. step a, (2.59 g, 3.48 mmol) in benzene (100 mL) was added 1,8-diazabicyclo(5.4.0]undec-7-ene (DBU, S.U mi,, 34 mmol). The reaction mixture was flushed with rd~ogen, warrr-~ed to 80 °C, and stirred for 3:5 hoofs.
TiaC reaction mixture was cooled to 0 °C and aqueous 0.5 M NaH2P04 ( 100 mL) was added. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with 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 (1.74 g) as a white solid. MS
(FAB)+ rr>!e 700 (M+H)+.
yep lU2b: Compound 12 from Scheme 3a: R is -CH~CH=CHI. R~ is benzovl.
A solution in THF (30 mL) of the compound prepared in step 102a (1.74 g, 2.49 mmol) was cooled to -10 °C and flushed with nitrogen. Sodium hydride (80% in mineral oil, 150 mg, 5.00 mmol) was added and the reaction mixture was stirred for 10 minutes. A

solution of carbonyldiimidazole (1.22 g, 7.50 mmol) in THF (20 mL) was added over 10 minutes at -10 °C. The cold bath was removed and the reaction mixture was stirred for 1 hour. The reaction mixture was extracted with ethyl acetate and 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 (1.58 g) as a white solid. MS (FAB)+ m/e 794 (M+H)+.
Step 102c: Compound i 8 from Scheme 4; R is -CH~CH=CH?;R~ is benzovl.
The compound prepared in step 102b (1.19 g, 1.5 mmol) was dissolved in THF (2 mL) and acetonitrile (20 mL) and the solution was flushed with nitrogen.
Agueous ammonium hydroxide (28%, 21 mL) was added and the reaction mixture was stirred under nitrogen for 24 hours. The reaction mixture was extracted with ethyl acetate and 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 (0.56 g) as a white solid. MS
(FAB)+ m/e 743 (M+H)+. .
Step 102d: Compound of Formula (IX): L is CO, T is NHyR is -CH2CH=CHI
The tide compound was prepared by deprotection of the compound prepared in step 102c by heating in methanol according to the procedure of Example 1, step g.

(CDC13) b 216.9 (C-9), 205.3 (C-3), 169.5 (C-1), 158.0, 134.4, 118.2, 102.8, 83.7, 78.4, 77.1, 76.1, 70.2, 69.5, 65.9, 64.7, 57.8, 50.8, 45.9, 45.1, 40.2, 38.9, 37.3, 28.3, 22.6, 21.2, 20.2, 18.1, 14.5, 13.8, 13.7, 10.6. MS (FAB)+ m/e 639 (M+H)+.
Example 103 Compound of Formula (IX): L is CO. T is NH, R is -CH~CH=CH-Phenyl The desired compound was prepared using the procedure of Example 18, except substituting the compound prepared in Example 102, step c, (which is the compound 18 of Scheme 4, wherein R is allyl and RP is benzoyl) for the compound of Example 1, step f, used therein, and substituting iodobenzene for 3-bromoquinoline. 13C NMR
(CDC13) s 217.1 (C-9), 205.3 (C-3), 169.5 (C-1), 157.4, 136.5, 133.7, 128.6, 127.8, 126.5, 125.4, 102.9, 83.4, 78.4, ?7.7, 76.4, 70.3, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1, 40.2, 39.1, 37.3, 31.5, 28.3, 22.8, 21.2, 20.3, 18.1, 14.4, 14.2, 13.7, 10.8. MS
(FAB)+ m/e 715 (M+H)+.
Example 104 Compound of Formula (IX): L is CO T is NH R is -CH~CH=CH-(3-quinolyl) The desired compound was prepared usilig the procedure of Example 18, except substituting the compound prepared in Example 102, step c, (which is the compound 18 of Scheme 4, wherein R is allyl and RP is benzoyl) for the compound of Example 1, step f, used therein. 13C NMR (CDCl3) S 217.4 (C-9), 205.3 (C-3), 169.6 (C-1 ), 157.7, 149.7, s 147.6, 132.5, 129.9, 129.6, 129.2, 129.1, 128.6, 128.1, 126.7, 102.9, 83.5, 78.8, 77.5, 76.5, 70.2, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1, 40.2, 39.1, 37.4, 28.2, 22.6, 21.2, 20.2, 18.1, 14.4, 14.2, 13.7, 10.7. MS (FAB)+ m/e 766 (M+H)+.
Using the procedures described in the preceding examples and schemes and methods known in the synthetic organic chemistry art, the following compounds of Formula IX
wherein L is CO and T is NH can be prepared. These compounds having the R
substituent as described in the table below are of the formula:

NMe2 O
O H 0.,.
H~ H3C,,, ,,.
O~ N...

H3C~~ ~ O'CH3 O

O
Ex. No. Substituent 105 R is -CH2CH2CH3.

106 R is -CH2CH2NH2.

107 R is -CH2CH=NOH.

108 R is -CH2CH2CH20H

109 R is -CH2F

110 R is -CH2CH2NHCH2-phenyl 111 R is-CHiCH~Ie'HCH2-(4-pyridyl) 112 R is -CH2CH2NHCH2-(4-quinolyl) 113 R is -CH2CH(OH)CN

114 R is -CH(C(O)OCH3)CH2-phenyl 115 R is -CH2CN

116 R is ,CH2CH=CH-(4-chlorophenyl) 117 R is -CHZCH=CH-(4-fluorophenyl) 118 R is -CH2CH=CH-(4-methoxyphenyl) 119 R is -CH2CH2CH2-(4-ethoxyphenyl) 120 R is -CH2CH=CH-(3-quinolyl) 121 R is -CIIzCH2NHCH2CH2-(2-chlorophenyl) 122 R is -CH2-phenyl 123 R is -CHZ-(4-pyridyl) 124 R is -CH2-(4-quinolyl) 125 R is -CH2CH=CH-(4-pyridyl) 126 R is -CH2CH2CH2-(4-pyridyl) 127 R is -CH2CH=CH-(4-quinolyl) 128 R is -CH?CH2CH2-(4-quinolyl) 129 R is -CH?CH=CH-(5-quinolyl) 130 R is -CH2CH?CH2-(5-quinolyl) 131 R is -CH2CH=CH-(4-benzoxazolyl) 132 R is -CH2CH=CH-(4-benzimidazolyl) 133 R is -CH2CH=CH-(8-quinolyl) Example 134 Compound o Formula (VII): A. B. D, and E are H. R is all-yl.
S Std 134a: Compound of Formula 14 (Scheme 3a): A, B, D, and E are H, R is allvl, Rp is benzo~
To a solution under nitrogen of a compound of formula 12 (R is allyl, Rp is benzoyl, 385 mg, 0.485 mmol), prepared as in Example 102, step b, in acetonitrile was added ethylenediamine (291 mg, 4.85 mmol) and the reaction mixture was stirred for 67 hours. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and concentrated in vacuo to give the title compound (401 mg) as colorless oil which was used without further purification.

15 Step 134b: Compound of Formula (VII): A. B, D, and E are H, R is allyl.
The crude oil prepared in step 134a was dissolved in methanol (5 mL), acetic acid (60 pL) was added, and the reaction mixture was stirred for I 5 hours at ambient temperature. The reaction mixture was extracted with ethyl acetate and the organic phase was washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate, and 2o concentrated in vacuo to give a slightly yellow glass (347 mg).
Chromatography on silica gel (95:5:0.5 dichloromethane-methanol-ammonia) gave the title compound (126 mg) as a white foam. MS rri/e 664 (M+H)+.
Using the procedures described in the preceding examples and schemes and methods 25 known in the synthetic organic chemistry art, the following compounds of Formula VI1 wherein A, B, D and E are H can be prepared. These compounds having the R
substituent as described in the table below are of the formula:

WO 98!09978 PCT/LTS97/15506 N R NMe2 ~O HO~,,, Nln. ''~I O
H3C''''~ ''' CH3 H C~~ ~ ~ CH3 CH3 ~ ' CH3 O
Ex. No. Substituent 135 R is -CH2CH2CH3.

136 R is -CH2CH2NH2.

137 R is -CH2CH=NOH.

138 R is -CH~CHZCH20H

139 R is -CH2F

140 R is -CHZCN

141 R is -CH2CH(OH)CN

142 R is -CH2-phenyl 143 R is -CH2-(4-pyridyl) 144 R is -CH2-(4-quinolyl) 145 R is -CH2CH=CH-(4-pyridyl) 146 R is -CH2CH=CH-(4-chlorophenyl) 147 R is -CH2CH=CH-(4-fluorophenyl) 148 R is -CH2CH=CH-(4-methoxyphenyl) 149 R is -CH2CH2CH2-phenyl 150 R is -CH2CH=CH-(4-pyridyl) 151 R is -CH2CH2CH2-(4-pyridyl) 152 R is -CH2CH=CH-(4-quinolyl) 153 R is -CH2CH2CH2-(4-quinolyl) 154 R is -CH2CH=CH-(S-quinolyl) 155 R is -CH2CH2CH2-(5-quinolyl) 156 R is -CHZCH=CH-(4-benzoxazolyl) 157 R is -CH2CH=CH-(4-benzimidazolyl) 1S8 R is -CH2CH=CH-(8-quinolyl) 159 R is -CH2CH2NHCH2-phenyl 160 R is -CH2CH2NHCH2-(4-pyridyl) 161 R is -CHZCH2NHCH2-(4-quinolyl) 162 R is -CH2CH2NHCH(CH2-phenyl)C(O)OCH3 163 R is -CH2CH2NHCH2CH2-{2-chlorophenyl) Example 164 Compound of Formula (VI11: A, B and E are H, D is benzyi, R is allyl.
Step 614a: 2-(R)-(BOC-amino)-3-phenvl-1-propanol.
To a 5.2 g (23.8 mmol) sample of di-t-butyl dicarbonate in 20 mL of methylene chloride held at 0°C was added (R)-2-amino-3-phenyl-1-propanol (3.0 g, 19.8 mmol, Aldrich), and the reaction mixture was stirred 1.5 hours at room temperature.
The solvent was removed, and the residue was dried under high vacuum and taken directly to the next step.
Step 164: 2-(R)-(BOC-amino)-i-O-methanesulfonyloxy-3-phen~propane.
The material from step 164a was dissolved in 20 mL of methylene chloride and 5 mL of THF, and the solution was cooled to (>°C. Triethylamine (4.1 mL, 29.4 mmol) was added, then methanesulfonyl chloride ( 1.9 mL, 24.5 mmol) was added slowly.
The mixture was stirred 45 minutes at room temperature, then the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried (Na2S0~) and filtered. The solvent was removed under vacuum to afford 6.38 g of the title compound. MS m/z (M+H)+: 330, MS m/z (M+NH4)+: 347.
Step 164c: 1-azido-2-(R)-(BOC-amino)-3-phenylpropane.
The compound from step 164b above (6.36 g, 193 mmol) was dissolved in 25 mL
of DMF, and 2.5 g (38 mmol) of NaN3 was added. The reaction mixture was stirred for 24 hours at 62°C. The solution was cooled to room temperature, then extracted with ethyl acetate. The organic extract was washed with water and brine, dried (Na2S04) and filtered.
The solvent was removed under vacuum to afford 4.34 g of the title compound.
MS m/z (M+H)+: 277, MS m!z (M+Nf-i~)+: 294.
Step 164d: 1-azido-2-(R)-amino-3-,ghenylpropane.
The compound from step 164c (4.3 g,15.6 mmol) was dissolved in 30 mL of 4 N
HCl in ethanol, and the reaction mixture was stirred for 1.5 hours at room temperature. The solvent was stripped and chased with ether. The residue was dissolved in water, NaCI was added, and the mixture was extracted with ethyl ether, which was discarded.
The aqueous layer was adjusted to pH 12 with K2C03, saturated with NaCI, then extracted with CHCI3.
The organic extract was washed with brine, dried (Na2S04) and filtered. The solvent was removed under vacuum to afford 2.17 g of the title compound. MS m/z (M+H)+:
177, MS
m/z (M+h'~-14)'': 194.
-l I9-Step 164e: l, 2-(R)-diamino-3=phen~pr~ane.
A sample of the compound from step 164d ( 1.2 g, 6.8 mmol) was hydrogenated (4 atm) in ethanol over 1.2 g of 10% Pd/C for 21.5 hours at room temperature. The mixture was filtered to remove the catalyst, and the solvent was removed to afford the title compound (1.055 g). MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168.
Step 164f: Compound 14 from Scheme 3a; A, B and E are H D is benzyl R is al)yl R~ is benzoyl The desired compound is prepared by stirring a solution of compound prepared as in Example 102, step b, (which is the compoundl2 from Scheme 3a, wherein R is allyl, Rp is benzoyl), and 1,2-(R)-diamino-3-phenylpropane, prepared as in step 164e above, in aqueous acetonitrile for an amount of time sufficient to consume substantially all of the starting material.
15 Step 164: Compound 14 from Scheme 3a~ A B and E are H D is benzvl R is allvl Rp is H.
The title compound is prepared by deprotection of the compound prepared in step 164f by heating in methanol according to the procedure of Example 1, step g.
2(? Step 164h: Compound of Formula (VII): A B and E are HtD is benzyl R is all The desired compound is prepared by heating a solution of the compound prepared in step 164g in ethanol-acetic acid.
Example 165 25 Compound of Formula (VII): A is benzyl B D and E are H R is allvl Step 165x: Compound 16 from Scheme 3b~ A is benzvl B D and E are H Y is OH R
is allvlrRta is benzovl.
The desired compound is prepared according to the method of Example 164, step f, 30 except substituting (S)-2-amino-3-phenyl-1-piopanol (Aldrich Chemical Co.) for 1, 2-(R)-diamino-3-phenylpropane.
Step 165b: Compound 16 from S h m . 3b~ A iS ben7yl R D and E are. H Y is N2, R is allvl, R,R is benzo ~~1.
35 The desired compound is prepared by treating a solution in THF of the compound of step 165a with triphenylphosphine, diethylazodicarboxylate, and diphenylphosphorylazide.

Step 165c: Compound 16 from Scheme 3b; A is benzyl, B, D and E are H, Y is N~, R is allvl, R~ is H.
The desired compound is prepared by.deprotection of the compound prepared in step 165b by heating in methanol according to the procedure of Example l, step g.
Step 165d: Compound 1? from Scheme 3b: R is allyl.
The desired compound is prepared by refluxing a solution in THF of the product of step 165d and triphenylphosphine.
Step 165e: Compound of Formula (VI1): A is benzvl, B, D and E are H, R is allyl.
The desired compound is prepared by heating a solution of the compound prepared in step 165d in ethanol-acetic acid.
ExamQle 166 15 Compound of Formula (VII): A and E are phenvl, B and D and are H. R is all,~rl.
The desired compound is prepared according to the method of Example 164, steps f h, except substituting 1,2-Biphenyl-1,2-ethylenediamine (Aldrich Chemical Co.) for 1, 2-(R)-diamino-3-phenylpropane.
2o Example 16?
Compound of Formula (VI1): A is methyl, B, D and E are H. R is allyl.
The desired compound is prepared according to the method of Example 165, except substituting (S)-'_'-amino-I-propanol (Aldrich Chemical Co.) for (S)-2-amino-3-phenyl-1-propanol.
Example 168 Compound of Formula (VIII: A and D are methyl, B and E are H, R is all~l.
Step 168x: meso-2,3-bis(methanesulfonyloxy)butane 3o Samples of meso-2,3-butanediol (10 g, 1 I 1 mmol, Aldrich) and triethylamine (92.8 mL, 666 mmol) were dissolved in methylene chloride. The solution was cooled to -?8°C, and methanesulfonyl chloride (25.8 mL, 333 mmol) was added dropwise. A
precipitate formed. The mixture was diluted with additional methylene chloride, and the mixture was stirred for 20 minutes at -?8°C and at 0°C for 2 hours. The reaction mixture was warmed to room temperature, diluted with additional solvent, and washed with H20, aqueous NaeIC03 and aqueous NaCI. The organic solution was dried over MgS04, and the solvent was removed to afford the title compound (25.01 g). 1H NMR (300 MHz, CDCI~) :
8 4:91 (q, 2H), 3.10 (s, 6H), 1.45 (d. 6H).
Ste~~ 168b: meso-2,3-diazidobutane.
A sample of the compound from step 168a (25 g) was dissolved in 250 mL of DMF, and NaN3 (40 g) was added. The mixture was stirred vigorously at 85°C for 24 hours, then cooled to room temperature. The mixture was diluted with 800 mL of ether, washed with H20, aqueous NaI~C03 and aqueous NaCI, then dried over MgS04. The solution was filtered and concentrated to afford the title compound (13.00 g).
~H NMR
(300 MHz, CDC13) : 8 3.50 (m, 2H). 1.30 (d. 6H).
Step 168c: meso-2,3-butanediamine.
A sample of the compound from step 168b (13.0 g, 125 mmol) was dissolved in ethanol and hydrogenated at 4 atm over 10% Pd/C for 20 hours at room temperature. The catalyst was removed by filtration, and the solvent was removed under vacuum to afford the title compound. 'H NMR (300 MHz. CDC13) : 8 2.70 (m, 2H), 1.45 (br, 4H), 1.05 (d, 6H).
MS (m/z) : 89 (M+H)+.
Sten 1684: Compound of Formula (VI1): A and D are methyl B and E are H R is ally The desired compound is prepared according to the method of Example 164, steps c-h, except substituting meso-2,3-butanediamine, prepared as in step 168c, for the 1, 2-(R)-diamino-3-phenylpropane thereof.
Example 169 Compound of Formula (VII): A and E taken together is -CH2CH2CH~- B and D are H
R
is allvl.
The desired compound is prepared according to the method of Example 168, except substituting 1,2-cyclopentane diol (Aldrich Chemical Co.) for meso 2,3-butanediol.
Example 170 Compound of Formula (VII): A B D and E are H R is -CH2CH-CH-(3-quinolyl) The desired compound was prepared by coupling 34bromoquinoli~ie with the product of Example 134 according to the method of Example 18. MS (FAB)+ m/e (M+H)+.

Example 171 Compound of Formula (VII): A. B, D, and E are H, R is -CH~CH~CH,~-(3-auinolyl).
To a sample of the compound from Example 170 ( 110 mg) in methanol ( 10 mL) flushed with nitrogen was added 1U% Pd/C (50 mg), and the mixture was stirred at room s temperature under 1 atm of hydrogen for 16 hours. The mixture was filtered and concentrated, and the residue was purified by chromatography on silica gel eluting with 95:5:0.5 to 90:10:0.5 dichloromethane/methanol/dimethylamine to give the title compound (1U6 mg). High Res. MS m/e (M+H)~ Calcd for f.'.44H~N40y: 793.4752; Found 793.4766.
to Example 172 Compound of Formula (VIII): X is O. R is CH~~3-iodoohenyl) Following the procedures of Example 1, except substituting 3-iodobenzyl bromide for the allyl bromide of step I f, the title compound was prepared. MS (FAB)+
m/e 949 (M+H)+.
Example 173 Compound of Formula (VIII): X is O. R is CHI-(2-n~hthyl) Following the procedures of Example l, except substituting (2-naphthyl)methyl 20 bromide for the allyl bromide of step la and acetic anhydride for the benzoic anhydride in step 1e, the title compound was prepared. MS (FAB)+ m/e 714 (M+H)+; Anal.
Calcd. for C4pH59NO~p: C, 67.30; H, 8.33; N, 1.96; Found: C, 66.91; H, 8.29; N, 1.64.
Example 174 25 Compound of Formula ~VII1): X is O. R is CHI-CH=CH-(4-fluoroDhenvl) Following the procedures of Example 172, except substituting 4-fluoro-1-1- iodobenzene for the iodobenzene of step 14a, the title compound was prepared.
Example 175 3o Compound of Formula (VIII): X is O. R is CHI-CH(OH)-CN
The title compound was obtained by chromatographic separation from the reaction mixture of the crude product of Example 8. MS (FAB)+ m/e 643 (M+H)+.

Example 176 Compound of Formula (IX): L is CO, T is NH, R is -CHI-(2-naphthyl) Step 176a. Compound 6 from Scheme la; R is -CHI-(2-naphthyl).
Following the procedures of Example 1, steps a-c, except substituting (2-naphthyl)methyl bromide for the allyl bromide of step 1 a, the title compound was prepared.
MS (FAB)+ m/e 874 (M+H)+.
Step 176b. Compound 6A from Scheme lc: R is -CHI-(2-na_phthyl), R_p is acetyl The compound from step 176a (2.0 g) was treated according to the procedure of Example 1 step e, except substituting acetic anhydride for the benzoic anhydride of that example. MS (FAB)+ m/e 958 (M+H)+.
Step 176c. Compound 6B from Scheme 1 c; R is -CHI-(2-naphthyll Rp is acet~
The compound of step 176b (500 mg) was treated with NaH and carbonyldiimidazole according to the procedure of Example 102 step b to afford the title compound (58 mg). MS (FAB)+ m/e 1034 (M+H)+.
Step 176d. Compound 6C from Scheme lc; R is -CHI-(2-naphthyl) Rp is acetyl Ra is H
2o The compound of step 176c (58 mg) was treated with ammonia in acetonitrile according to the procedure of Example 102 step c to afford the title compound.
MS (FAB)+
m/e 983 (M+H)+.
Step 176e. Compound of formula (IX); L is CO T is NH R is -CHI-(2-naphthyl) 2S The compound of step 176d was treated according to the procedures of Example 1 steps 1d, if and 1g, to give the title compound. MS (FAB)+ m/e 739 (M+H)+.
Example 177 Compound of Formula (III): Rc is acetyl, L is CO T is NH R is -CH~CH=CH2 Step 177a. Compound 6A from Scheme Ic~ R is -CH~CH=CH2 R~ is ace 1 To a sample of the compound from Example I step c (405.2 g, 528 mmol) in dichloromethane (20 mL) was added dirnethylaminopyridine(0.488 g, 4 mmol) and acetic anhydride (3.39 mL, 36 mmol), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with methylene chloride, then washed with 5%
aqueous sodium bicarbonate and brine and dried over Na2S04. The residue was dried and recrystallized from acetonitrile to give the title compound (491 g). MS m/e 857 (M+H)+.

WO 98/09978 PCT/(JS97115506 Step 177b. Compound 6B from Scheme lc; R is -CH~CH=CH2, R~ is ace 1 To a sample of the compound from step 177a (85.8 g, l()0 mmol) in dry THF (S00 mL) cooled to -40 °C and flushed with nitrogen was added sodium bis(trimethylsilyl)anude ( 125 mL, 125 mmol) over 20 minutes, and the mixture was stirred at -40 °C for 40 minutes.
To this mixture was added a solution of carbonyldiimidazole (3.65 g, 22.56 mmol) in 5:3 THF/DMF (800 mL) under nitrogen at -40 °C over 30 minutes, and the mixture was stirred at -20 °C for 30 minutes. The mixture was stirred at room temperature for 27 hours, then diluted with ethyl acetate. The mixture was washed with 5% sodium bicarbonate and brine, dried over Na2S04, and concentrated to give the title compound (124 gj, which was taken directly to the next step.
Step 177c. Compound 6C from Scheme Ic: R is -CH~CH=CH2, R~ is acetvl, Rsl is H
The compound from step 177b (124 g) was dissolved in 9:1 acetonitrile/T'HF
(1100 mL), ammonium hydroxide (28%, 200 mL) was added, and the mixture was stirred at room temperature under nitrogen for 8 days. The solvent was removed, and the residue was dissolved in ethyl acetate. This solution was washed with 5% sodium bicarbonate and brine, dried over Na2S04, and concentrated to give the title compound. MS
(FAB)+ m/e 882 (M+H)+.
Step 177d. Compound 6D from Scheme 1 c; R is -CH~CH=CHI, RL~ is acetyl. Ra is H
To a sample of the compound from step 177c (69.0 g, 78.2 mmol) suspended in ethanol (200 mL) and diluted with water (400 mL) was added HCl (0.972 N, 400 mL) dropwise wer 20 minutes. The mixture was stirred for 4 hours, and additional HCl was added (4 N, 100 mL) over 20 minutes. The mixture was stirred for 18 hours, cooled to 0 °C, then NaOH (4 N, 200 mL) was added over 30 minutes to approximately pH 9. The title compound was isolated by filtration (35.56 g) Step 177e. Compound 6E from Scheme 1 c: R is -CH~CH=CH~;R~ is acet~, R~ is H:
!Compound of Formula !III); Rc is acetyl. L is CO. T is NH. R is -CH C~ H=CHI
To a -10 °C solution under nitrogen of N-chlorosuccinimide (2.37 g, 17.8 mmol) in dichloromethane (80 mL) was added dimethylsulfide (1.52 mL, 20.8 mmol) over 5 minutes. The resulting white slurry was stirred for 10 minutes at -10 °C, a solution of the compound from step 177d (8.10 g, I 1.9 mmol) in dichloromethane (60 mL) was added and 3i the reaction mixture was stirred for 30 minutes at -10 to -5 °C.
Triethylamine (1.99 mL, i4.3 mmolj was added dropwise over 10 minutes and the reaction mixture was stirred for 1 hour at 0 °C. The reaction mixture was 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 (eluting with 50:50:0.5 acetone/hexanes/ammonium hydroxide) gave the title compound (8.27 g) as a white foam. Anal. Calcd. for C35H56N201 ~: C, 61.75; H, 8.29; N, 4.1 I; Found:
C, 62.25; H, 8.50; N, 4.28.
Example 178 alternate preparation of Compound of Formula (IX): L is CO, T is NH, R is -CH~CH=CH-(3-quinolxll Step 178a. (Compound of Formula (III): Rc is acetyl, L is CO, T is NH, R is -CH,~CH=CH-(3-quinolyl )) A mixture of the compound from Example 177 (46.36 g, 68.2 mmol), palladium(II)acetate (3.055 g, 13.6 mmol), and tri-o-tolylphosphine (8.268 g, 27.2 mmol) is in acetonitrile (400 mL) was flushed with nitrogen. To this solution was added 3-bromoquinoline ( I 8.45 mL, 136 mmol) and triethylamine ( 18.92 mL, 13.6 mmol) via syringe . The reaction mixture was heated at 50 °C for 1 hour and stirred at 90 °C for 4 days. The reaction mixture was taken up in ethyl acetate and washed with aqueous 5%
sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in 2U vacuo. Chromatography on silica gel (eluting with 50:50:0.5 acetone/hexanes/ammonium hydroxide) gave the title compound (46.56 g) as a white foam. MS m/e 808 (M+H)+.
Step 178b: Compound of Formula (IX): L is CO, T is NH, R is -CH~CH=CH-(3-uinol 1 .
25 Deprotection of a sample of the compound prepared in step 178a (42.43 g) was accomplished by stirring overnight in methanol according to the procedure of Example 1, step g to give the title product (32.95 g). MS m/e 766 (M+H)+.
Example 179 30 Compound of Formula (IX): L is CO, T is N(CH~1, R is -CH~CH=CHI
Step 179a: Compound 18 from Scheme 4~ R* is methvl R is -CH~CH=CH~;R>? is benz~v _ _ A sample of the compound from Example 102, step 102b (Compound (12) from 35 Scheme 3a; R is -CH2CH=CH2, RP is benzoyl, 320 mg, 0.400 mmol) was dissolved in acetonitrile (10 mL) and the solution was flushed with nitrogen. Aqueous methylamine (40%, 0.344 mL) was added and the reaction mixture was stirred under nitrogen for 4 days.

The reaction mixture was extracted with ethyl acetate and 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 (277 mg) as a white solid. MS m/e 757 (M+H)+.
Step 179b. Compound of Formula (IX): L is CO, T is N(CH~), R is -CH~CH=CHI
Deprotection of a sample of the compound prepared in step 1?9a (110 mg) was accomplished by stirnng overnight in methanol according to the procedure of Example 1, step g, to give the title product (48 mg). Anal. Calcd. for C34H56N201p: C, 62.56; H, 8.65; N, 4.29; Found: C, 62.23; H, 8.72; N, 4.13 Example I80 Compound of Formula (IX): L is CO, T is N(CH~), R is -CH~CH=CH-(3-quinolvl) Following the procedure of Example 178, except substituting the compound of 15 Example 179 step a for the starting material compound therein (from Example 177), the title compound was prepared.
Example 181 Compound of Formula (IX): L is CO, T is N(CH~CH~N(CH~~~), R is -CH~CH=CHI
Step 181a. Compound 18 from Scheme h; R* is 2-(dimethylamino)ethyl, R is -CH2CH=CH2, R>? is benzoyl.
Following the procedures of Example 179, except substituting N,N-dimethylethylenediamine for the methylamine thereof, the title compound was prepared (285 mg). MS m/e 814 (M+H)+.
Step 181 a. Compound of Formula (IX): L is CO. T is N(CH~CHZN(CH~~ R is -CHiCH=CHI
Deprotection of a sample of the compound prepared in step 181a (110 mg) was 3o accomplished by heating overnight in methanol according to the procedure of Example 1, step g, to give the title product (28 mg).

Example 182 Compound of Formula (IX): L is CO, T is N(CHZCH2N(CH~~~I. R is -CH~CH=CH-(3-uinol 1 Following the procedures of Example 178, except substituting the compound of Example 181 step a ( 162 mg) for the starting material compound therein (from Example 177), the title compound was prepared (33.4 mg).
Example 183 Compound of Formula (IX): L is CO, T is N(CH2CH=CHI), R is -CH2CH=CH2 ~ t) Step I 83a. Compound 18 from Scheme 4; R* is -CH~CH=CHI, R is -CH7CH=CHI. R~
is benzovl.
Following the procedures of Example 179, except substituting allylamine for the methylamine thereof, the title compound was prepared .
1, Step 183b. Compound of Formula (IX): L is CO, T is N(CH2CH=CH R is -CH2CH=CHI
Deprotection of a sample of the compound prepared in step 183a (78 mg) was accomplished by heating overnight in methanol according to the procedure of Example l, 20 step g, to give the title product (33 mg).
Example 184 Compound of Formula (IX): L is CO, T is T is N(CH~CH=CH-(3-auinolvl)), R is -CH~CH=CH-(3-~c uino_lyl) 25 Following the procedures of Example 178, except substituting the compound of Example 183 step a for the starting material compound therein (from Example ~
77), the title compound was prepared. H. Res. M.S. Calcd. for C54H69N4~10~ 933.5014; Found 933.5052.
Examples 185-219 Following the procedures of Example 178, except substituting the reagent below for the 3-bromoquinoline of Example 178, the compounds 185-219 shown in the table below the following compounds I 85-219 shown in the table below were prepared. These compounds of Formula IX wherein L is CO and T is O having the R substituent as described in the table below are of the formula O R NMe2 H~ H3C.,, ,O H 0~,, O~ N ~~..
"" O

H3C~~~. O CH3 O

Examples 185-219 Ex. reagent substituent data _No.

185 3-bromopyridineR is -CH2CH=CH-(3-pyridyl)MS 716 (M+H)+

186 2-bromonaphthaleneR is -CH2CH=CH-(2-naphthyl)MS 765 (M+H)+

187 4-bromoisoquinolineR i~ -CH2CH=CH-(4-isoquinolinyl)H. Res. M.S.

Calcd. for C42H60N3~10=

766.4279; Found 776.4271.

188 4-bromo-1,2- R is -CH2CH=CH-(3,4- H. Res. M.S.

methylenedioxy-methylenedioxyphenyl) Calcd. for benzene C40H58N2~12~

759.4068; Found 759.4083.

189 8-bromoquinolineR is -CH2CH=CH-(8-quinolyl)MS 766 (M+H)+

190 5-bromoindole R is -CH2CH=CH-(5-indolyl)H. Res. M.S.

Calcd. for C41 H59N3~ 10~

754.4279; Found 754.4294.

191 3-bromo-6-chloro-R is -CHZCH=CH-(6-chlcro-3-H. Res. M.S.

quinoline quinolyl) Calcd. for C42H58N3~10-800.3889; Found 800.3880.

192 3,4-ethylenedioxy-R is -CH2CH=CH-(3,4- H. Res. M.5.

benzene ethylenedioxyphenyl) Calcd. for C41H60N3~12~

773.4225; Found 773.4204.

193 1-iodo-3- R is -CH2CH=CH-(3-nitrophenyl)H. Res. M.S.

nitrobenzene Calcd, for C39H58N3~12:
.

760.4020; Found 760.4004.

194 6-bromoquinolineR is -CH2CH=CH-(6-quinolyl)MS 766 (M+H)+

195 3-bromo-6- R is -CH2CH=CH-(6-nitroquinolyl)H. Res. M.S.

nitroquinoline Calcd. for C42H59~4012~

811.4129; Found 81 1.4122.

196 5-bromoquinolineR is -CH2CH=CH-(5-quinolyl)H. Res. M.S.

Calcd. for C42H60N3010~

766.4279; Found 766.4281.

197 2-methyl-6- R is -CH2CH=CH-(2-methyl-6-Anal. Calcd. for bromoquinoline quinolyl) C43H61~'3010~

C, 66.22; H, 7.88; N, 5.39;

Found: C. 66.43;

H, 8.12; 1\ , 5.18.

198 3-bromoquinolineCompound of Formula (III): H. Res. M.S.
* L is CO, T is NH, R~ is acetyl; R Calcd. for is -CH2CH=CH-{3-quinolyl) C44H61 N3010~

808.4379; Found 808.438 I .

199 5-bromoisoquinolineR is -CH2CH=CH-(5-isoquinolyl)H. Res. M.S.

Calcd. for C42H59N3010~

766.4279; Found 766.4301.

200 6-bromo-7-vitro-R is -CH2CH=CH-(7-vitro-6- H. Res. M.S.

quinoxaline quinoxalinyl) Calcd. for C44H57N5012~

812.4082: Found 812.4064.

201 6-amino-3- R is -CH2CH=CH-(6-amino-3- H. Res. M.S.

bromoquinoline quinolyl) Calcd, for C42H60N4010:

781.4388; Found 781.4386.

202 3-bromo-1,8- R is -CH2CH=CH-(1,8-naphthyridin-H. Res. M.S.

, naphthyridine 3-yl) Calcd. for C41H58N4~10:

781.4388; Found 781.4386.

203 6-(acetylamino)-3-R is -CH2CH=CH-(6-(acetylarnino)-3-H. Res. M.S.

bromoquinoline quinolyl) Calcd. for C~H62N40I 1 823.4493; Found 823.4479.

204 3-bromocarbazoleR is -CH2CH=CH-(3-carbazolyl)H. Res. M.S.

Calcd. for C45H61 N3010~

804.4435; Found 803.4437.

~~ 9/09978 PC1'/US97/15506 205 5- R is -CHZCH=CH-(5-benzimidazolyl)H. Res. M.S.

bromobenzimidazole Calcd. for C4oHs~N4Clo~

755.4231;
Found 755.4224.

206 7-bromo-3-hydroxy-R is -CH~CH=CH-(-3-hydroxy-2-(N-H. Res. M.S.

N-(2- (2-methoxyphenyl)amido)-7-naphthyl)Calcd. for methoxyphenyl)-2- C51 H67N3013:

napthylamide 930.4752;
Found 930.4754.

207 6-bromoquinoxalineR is -CH2CH=CH-(6-quinoxalinyl)H. Res. M.S.

Calcd. for C41H59N4~13~

767.4231;
Found 767.4236.

208 3-bromo-6- R is -CH2CH=CH-(6-hydroxy-3-H. Res. M.S.

hydroxylquinolinequinolyl j Calcd, for C42H60N3~11 ?82.4228;
Found 782.4207.

209 3-bromo-6- R is -CH~CH=CH-(6-methoxy-3-H. Res. M.S.

methoxyquinolinequinolyl) Calcd. for C43H62N3~11 796.4384;
Found 796.4379.

210 3-bromo-5- R is -CH2CH=CH-(5-nitro-3-quinolyl)H. Res. M.S.

nitroquinolin e Calcd. for C42H59N4~12~

811.4129;
Found 811.4146.

211 3-bromo-8- R is -CH2CH=CH-(8-nitro-3-quinolyl)Anal. Calcd.
for nitroquinoiine C42HS8N4~12~

C, 62.21;
H, 7.21; N, 6.91;

Found: C, 62.56;

H, 7.48; N, 6.61.

212 2-chloroquinolineR is -CH2CH=CH-(2-quinolyl)MS (M+H)+
766.

213 4-chloroquinolineR is -CH2CH=CH-(4-qui:.olyl)MS 766 (M+H)+

214 3-bromoquinoline-6-R is -CH2CH=CH-(4-carboxyl-3-MS (M+H)+
810.

carboxylic acid quinolyl) 215 3-bromo-6- R is -CH2CH=CH-(6-fluoro-3-Anal. Calcd.
for fluoroquinoline quinolyl) C42H58~3C10~

C, 64.35;
H, 7.46; N, 5.36;

Found: C, 64.53;

H, 7.69; N, 5.18.

216 3-bromoquinoline-6-R is -CH2CH=CH-(6- MS (M+H)+
824.

carboxylic acid methoxycarbonyl-3-quinolyl) methyl ester 217 3-bromoquinoline-6-R is -CH2CH=CH-(6-aminocarbonyl-N1S (M+H)+
809.

carboxamide 3-quinolyl) 218 3-bromo-6- R is -CH2CH=CH-(6-cyano-3- MS (M+H)+ 791.
cyanoquinoline quinolyl) 219 3-bromo-6- R is -CH2CH=CH-(3-bromo-6- MS (M+H)+ 844.
iodoquinoline quinolyl) * without deprotection step Examgle 220 Compound of Formula (IX): L is CO, T is NH, R is -CH2C(O)H
The compound from Example 102 ( 14.0 g) was dissolved in CH2CI2 (200 mL) and the solution was cooled to -78 °C under a nitrogen atmosphere. Ozone was then bubbled through the solution until a blue color persisted. The reaction was then purged with N~ until colorless and dimethylsulfide ( 14 mL) was added, and the reaction mixture was warmed to 0 °C. After stirring for 90 min, the reaction mixture was concentrated under reduced pressure to give a light-yellow foam. This material was dissolved in THF (300 mL) and treated with triphenylphosphine (8 g) at reflux for 6 hours, then the reaction mixture was concentrated under reduced pressure. Chromatography ( l :1 acetone/hexanes to 3:1 acetone/hexanes with 0.5% TEA) gave the product (6.6 g) as an off-white foam.
MS(CI) m/e 641 (M+H)+.
Example 221 Compound of Formula (IX): L is CO, T is NH, R is -CH~CH~NHCH~Phenyl The compound from Example 220 (120 mg, 0.187 mmol) and benzylamine (40 ~,L, 0.366 mmol, 2 equiv) were dissolved in 3 mL of dry dichloromethane. Molecular sieves (4A) were added and the reaction was stirred overnight. The reaction was then filtered and concentrated under reduced pressure. The resulting imine was dissolved in MeOH
(5 mL), a catalytic amount of 10% Pd on carbon was added, and the reaction was stirred rapidly under 1 atm of H2 pressure for 20 hours. The mixture was then filtered through a Celite pad, and the solution concentrated under reduced pressure. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NI-I40H) gave the desired material (84 mg) as a white solid. 13C NMR (CDCl3) 8 218.3, 205.6, 170.3, 157.9, 140.2, 128.2, 126.8, 102.4, 83.5, 78.2, 76.9, 75.1, 70.1, 69.5, 65.9, 62.0, 58.4, 53.8, 50.6, 48.2, 45.3, 44.8, 40.1, 39.0, 37.4, 28.2, 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3. MS(CI) m/e 732 (M+H)+.
Example 222 Compound of Formula (IX): L is CO, T is NH, R is -CH~CH2NHCH~CH~Phenvl The title compound was prepared from the compound of Example 220 ( 108 mg, 0.169 mmol) and phenethylamine (42 ~tL, 0.334 mmol, 2 equiv) using the procedure described for Example 221. Chromatography (Si0?, 5% MeOH/dichloromethane with 0.5% NH40H) gave the desired material (82 mg) as a white solid. /3C NMR
(CDC13) 8 218.1, 205.5, 170.3, 158.0, 140.2, 128.8, 128.2, 125.8, 102.4, 83.6, 78.3, 76.9, 75.1, 70.1, 69.5, 65.9, 61.9, 58.3, 51.5, 50.6, 48.8, 45.2, 44.9, 40.1, 38.9, 37.4, 36.5, 28.2, 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.4, 12.8, 10.3. MS(CI) m/e 746 (M+H)+.
Anal Calcd for C4pH63N301p. Found C 64.26, H 8.47, N 5.43.
Example 223 Compound of Formula (IX): L is CO. T is NH. R is -CH2CH~NF1CH~CH2CH~Phenvl The title compound was prepared from the compound of Example 220 ( 100 mg, 0.156 mmol) and 3-phenyl-1-propylamine (40 pL, 0.282 mmol, 1.8 equivj using the procedure described for Example 221. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.5% NH40H) gave the desired material (45 mg) as a white solid. »C NMR
(CDC13) 8 218.6, 205.7, 170.4, 158.1, 142.3, 128.4, 128.2, 125.6, 102.4, 83.7, 78.3, 77.0, l5 75.2, 70.2, 69.5, 65.9, 62.0, 58.4, 50.6, 49.2, 49.0, 45.3, 44.9, 40.2, 39:0, 37.5, 33.7, 31.7, 28.2, 22.4, 21.2, 20.?, 18.3, 14.6, 13.6, 13.5, 12.8, 10.3. MS(CI) m/e (M+H)~. Anal Calcd for C4tH6sN3010.
Example 224 Compound of Formula SIX): L is CO, T is NH, R is -CH~CH~NHCH2CHZCH~CH~Phenvl The title compound was prepared from the compound of Example 220 ( 170 mg, 0.266 mmoI) and 4-phenyl-1-butylamine (68 pL, 0.431 mmol, 1.6 equiv) using the procedure described for Example 221. Chromatography (5i02, 5%
MeOH/dichloromethane 25 with 0.2% NH40H) gave the desired material (87 mg) as a white solid. 13C
NMR (CDCI3) 8 218.6, 205.6, 170.4, 158.1, 142.6, 128.4, 128.1, 125.5, 102.4, 83.7, 78.3, 77.0, 75.2, 70.2, 69.5, 65.9, 61.9, 58.4, 50.6, 50.0, 49.0, 45.3, 44.9, 40.2, 39.0, 37.5, 35.8, 29.7, 29.1, 28.2, 22.4, 21.2, 20.7, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3. MS(CI) m/e 774 (M+H)+. Anal Calcd for C4?H67N301p. Found C 64.80, H 8.63, N 5.35.
Example 225 Compound of Formula IIXI: L is CO. T is NhI, R is -CH~CH~NHCH2CH~CH~-~3-quinolyl) The compound from Example 220 (135 mg, 0.211 mmol) and 3-(3-quinolyl)-1-propylamine (70 mg, 0.376 mmol, 1.8 equiv) were dissolved in 4 m/. of dry dichloromethane. Molecular sieves (4~1) were added and the reaction was stirred overnight.
The reaction was then filtered and concentrated under reduced pressure. The resulting imine was dissolved in MeOH (5 mL) and treated with NaCNBH3 (about 100 mg) and enough AcOH to turn bromocresol green indicator from blue to yellow. After stirring for 4 hours, the reaction mixture was poured into saturated NaHC03 solution and extracted into dichloromethane. The organic portion was washed with saturated NaHC03, HBO and brine, dried (Na2S04) and concentrated under reduced pressure. Chromatography (Si02, 5% MeOH/dichloromethane with 0.5% NH40H to 10% MeOH/dichloromethane with 1%
I~'H40H) gave the desired material (71 mg) as a white solid. 13C NMR (CDCI3) b 218.8, 205.7, 170.5, 158.2, 152.2, 146.8, 135.0, 134.2, 129.1, I 28.4, 128.2, 127.4, 126.4, 102.5, 83.8, 78.4, 77.2, 75.2, 70.2, 69.6, 65.9, 62.0, 58.4, 50.7, 49.5, 49.1, 45.4, ~0 44.9, 40.2, 39.1, 37.6, 31.4, 30.9, 28.3, 22.6, 21.3, 20.7, 18.3, 14.7, 13.6, 13.5, 12.8, 10.3. MS(CI) m/e 81 I (M+H)+. Anal Calcd for C44H66N4010~ Found C 65.50, H 8.S
I , N 6.66.
Example 226 ~5 Compound of Formula (IX): L is CO, T is NH, R is -CH~CH~NHCH2f3-q_uinolvl) The title compound was prepared from the compound of Example 220 ( 150 mg, 0.234 mmol ) and 3-(aminomethyl)quinoline ( 100 mg, 0.633 mmol, 2.7 equiv) using the procedure described for Example 225. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.5% NH40H) gave the desired material (82 mg) as a white solid. 13C NMR
(CDCl3) 20 8 218.8, 205.5, 170.4, 158.1, 151.6, 147.3, 134.5, 133.0, 129.0, 128.7, 128.0, 127.6, 126.3, 102.4, 83.7, 78.3, 76.9, 75.1, 70.1, 69.4, 65.8, 61.8, 58.4, 51.3, 50.5, 48.5, 45.3, 44.8, 40.1, 39.0, 37.4, 28.2, 22.3, 21.2, 20.6, 18.2, 14.6, 13.6, 13.4, 12.7, 10.2.
MS(CI) m/e 783 (M+H)+. Anal Calcd for C42H62N4010. Found C 64.32, H 8.01, N
7.11.
25 The 3-(aminomethyl)quinoline reagent was prepared as follows:
Step 226a~hvdroxymethyl)quinoline Quinoline 3-carboxaldehyde (1.0 g, 6.37 mmoI) was dissolved in 20 mL of EtOH
and treated with NaBH4 (70 mg). After stirring for 1 hour, the solution was treated with 2 30 mL of 1 N HCI, and after stirring for 10 min the reaction mixture was treated with enough 1 N NaOH to make the solution basic. The reaction mixture was extracted with Et20 and the organic portion was washed with H20 and brine. The organic portion was dried over Na2SOq and concentrated under reduced pressure to give the title compound.
MS(CI) m/c 160 (M+H)+.

d6'0 98/09978 PCTlUS97/15506 'rep 226b. 3~azidomethvl)quinoline 3-(hydroxymethyl)quinoline (0.36 g, 2.26 mmol) and triphenyl phosphine (621 mg, 2.37 mmol, 1.05 equiv) were dissolved in 10 mL of dry THF followed by cooling to 0 °C.
The reaction mixture was treated with diphenylphosphoryl azide (570 ~L. 2.63 mmol, 1.16 equiv) followed by the dropwise addition of diethylazodicarboxylate (405 ~tL, 2.57 mmol, 1.14 equiv). The reaction mixture was allowed to warm to room temperature overnight.
The reaction mixture was then concentrated under reduced pressure.
Chromatography {Si02, 2:1 Hexanes/EtOAc) gave the desired material (35U mg) as a colorless oil. MS(CI) m/e 185 (M+H)+.
Step 226c. 3-(aminomethyl)quinoline 3-(azidomethyl)quinoline (250 mg, 1.36 mmol) and triphenylphosphine (880 mg, 3.36 mmol, 2.5 equiv) were dissolved in 10 mL THF. The reaction mixture was treated with 0.5 mL of HBO and refluxed for 6 hours. The reaction mixture was cooled and partitioned between Et~O and 1 N HCI. The aqueous portion was then treated with 11\' NaOH until basic and extracted into EtOAc. The organic portion was dried over Na2S04 and concentrated under reduced pressure to give the title compound (104 mg) as a brown oil. MS(C1) m/e 159 (M+H)+.
Example 227 Compound of Formula (IX): L is CO. T is NH. R is -CH~CH~NHCH2l6-quinolyl) The title compound was prepared from the compound of Example 220 (116 mg, 0.181 mmol) and 3-(aminomethyl)quinoline (40 mg, 0.25 mmol, 1.4 equiv) using the procedure described for Example 221. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.5% NH40H) gave the desired material (62 mg) as a white solid. 13C NMR
(CDCl3) 8 218.7, 205.6, 170.4, 158.1, 149.8, 147.8, 138.9, 136.0, 130.3, 129.4. 128.3, 126.2, 121.0, 102.5, 83.7, 78.4, 77.0, 75.2, 70.2, 69.5, 65.9, 62.1, 58.5, 53.7, 50.6, 48.6, 45.4, 44.9, 40.2, 39.1, 37.5, 28.3, 22.4, 21.3, 20.7, 18.3, 14.7, 13.7, 13.5, 12.8, 10.3.
MS(CI) m/e 783 (M+H)+. Anal Calcd for C42H62N4010~
The 6-(aminomethyl)quinoline reagent was prepared as follows:
Step 227a. 6-(hvdroxymethyl)ctuinoline Quinoline 6-carboxylic acid (1.73 g, 10.0 mmol) was suspended in 40 mL of THF, under N2 at 0 °C, and treated with N-ethyl morpholine ( 1.3 mL, 10.2 mmol, 1.02 equiv) followed by the dropwise addition of ethyl chloroformate (1.1 mL, 11_5 mmol, 1.15 equiv). After stirring for 15 min, the solution was filtered, and the resulting salts were rinsed with additional THF. The filtrate was then added to a rapidly stirring solution of NaBH4 (760 mg, 20 mmol) in H20 (50 mL). After stirring for 20 min, the reaction mixture was quenched with saturated NH4C1 solution and extracted with EtOAc (2 x 50 mL). The organic portion was washed with brine, dried over Na2S04, and concentrated under reduced pressure. Chromatography (SiO~, 1:3 Hexanes/EtOAc) gave the desired material (1.03 g) as a colorless oil. MS(C1) m/e 160 (M+H)+.
Step 227b. 6-~zidometh.~quinoline 6-(hydroxymethyl)quinoline (0.51 g, 3.21 mmol) and triphenyl phosphine (880 mg, 3.36 mtnol, 1.05 equiv) were dissolved in 15 rnL of dry THF followed by cooling to 0 °C.
The reaction mixture was treated with diphenylphosphoryl azide (0.81 mL, 3.74 mmol, to 1.16 equiv) followed by the dropwise addition of diethylazodicarboxylate (0.57 mL, 3.62 mmol, 1.13 equiv). The reaction mixture was allowed to warm to room temperature overnight, then concentrated under reduced pressure. Chromatography (Si02, 30%
EtOAelHexanes) gave the desired material (32() mg) as a colorless oil. MS(CI) m/e 185 (M+H)+. .
Step 227c. 6-(aminomethvl)quinoline 6-(azidomethyljquinoline (320 mg) and triphenylphosphine (880 mg) were dissolved in 7 mL THF. The reaction mixture was treated with 0.5 mL of H20 and refluxed for 7 hours. The reaction mixture was cooled and partitioned between Et20 and 1N HCI.
The aqueous portion was then treated with 1N NaOH until basic and extracted into EtOAc.
The organic portion was dried over Na2S04 and concentrated under reduced pressure to give the title compound (70 mg) as a brown oil. MS(CI) m/e 159 (M+H)+.
Example 228 Compound of Formula fIX): L is CO. T is NH R is -CH2CH=NO(phenyl) The compound from Example 220 (200 mg, 0.313 mmol) and O-phenylhydroxylamine~HCl (138 mg, 0.948 mmol, 3.0 equiv) were dissolved in 4 mL
of MeOH. Triethylamine (I 18 ~L, 0.847 mmol, 2.7 equiv) was added and the reaction was stirred at reflux for 3 hours. The reaction was cooled and quenched with saturated NaHC03 solution. The reaction mixture was extracted with dichloromethane (2 x 25 mL) and the combined organic portions were washed with H20 and brine. The organic portion was dried over Na2S0~ and concentrated under reduced pressure. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH40H) gave the desired material (150 mg, 3:2 mixture of oxime isomers) as a violet-colored solid. 13C NMR (CDCl3) b 218.1, 217.4, 205.0, -169.9, 169.8, 159.1, 159.1, 157.9, 157.6, 152.9, 150.8, 129.1, 129.0, 122.2, 122.1, 114.8, 114.6, 103.2, 103.1, 83.5, 83.4, 79.8, 79.6, 77.1, 77.0, 76.9, 70.2;
69:6; 65:8; .
60.3, 58.1, 58.0, 58.0, 50.9, 50.9, 46.6, 46.6, 44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 37.4, 28.2, 22.2, 22.1, 21.1, 21.1, 20.5, 20.1, 18.0, 17.9, 14.6, 14.5, 14.5, 14.4, 13.5, 13.5, 1 U.4, 10.2. MS(CI) m/e 732 (M+H)+. Anal Calcd for C3gHS~N301 ~. Found C
62.30, H
7.76, N 5.74.
Example 229 Compound of Formula (IXI: L is CO. T is Nl-I. R is -CH~CIy- =NOCH_ h n 1 The title compound was prepared from the compound of Example 220 (201 mg, 0.314 mmol) and O-benzylhydroxylamine~HCl (150 mg, 0.940 mmol, 3.0 equiv) using the procedure described for Example 228. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH40H) gave the desired material (170 mg, 2:1 mixture of oxime isomers) as a n> white solid. 13C NMR (CDCl3) 8 218.1, 2I 7.2, 205.1, 170.0, 169.8, l 58.0, 157.9, 150.5, 147.8, 138.1, 137.8, 128.4, 128.0, 127.8, 103.3, 103.3, 83.7, 83.7, 79.6, 79.5, 77.5, 77.3, 77.0, 76.9, 76.1, 76.0, 70.4, 69.7, 66.0, 60.5, 58.2, 58.1, 58.0, 51.0, 51.0, 46.8, 46.5, 45.0, 44.9, 40.3, 38.9, 38.7, 37.6, 28.4, 22.5, 22.4, 21.3, 20.6, 20.2, 18.2, 1$.l, 14.8, 14.7, 14.6, 14.4, 13.7, 13.7, 10.6, 10.5. MS(C1) m/e 746 (M+H)+.
Anal Calcd for C39H59N3011. Found C 62.89 H 8.04, N 5.42 Example 230 Compound of Formula (IXO L is COT is NH R is -CH~CH=NOCH~(4-NO~- h~en~
The title compound was prepared from the compound of Example 220 (200 mg, 0.313 mmol) and O-(4-nitrobenzyl)hydroxylamine~HCl (192 mg, 0.938 mmol, 3.0 equiv) using the procedure described for Example 228. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH40H) gave the desired material (184 mg, 2:1 mixture of oxime isomers) as a white solid. 13C NMR (CDCl3) 8 218.2, 217.3, 205.0, 169.9, 169.7, 157.8, 151.2, 148.7, 147.4, 145.7, 145.5, 128.4, 128.1, 123.6, 123.5, 103.2, 83.6, 83.5, 79.6, 79.4, 77.1, 76.9, 76.8, 74.5, 74.3, 70.2, 69.6, 65.8, 60.2, 58.0, 57.9, 57.8, 51.0, 50.9, 46.8, 46.6, 44.9, 44.7, 40.2, 38.7, 38.5, 37.5, 37.4, 28.2, 22.4, 22.2, 21.2, 21.2, 20.5, 20.1, 18.1, 17.9, 14.8, 14.5> 14.4, 13.5, 10.5, 10.3. MS(C1) a-n/P 791 (M+H)+.
Example 231 Compound of Formula IIXO L is CO T is NH R is -CH~CH=NOCH {4-~uinol~l) The compound from Example 220 {200 mg, 0.313 mmol) and O-(4-quinolyl)methylhydroxylamine (200 mg, 0.86 mmol, 2.7 equiv) were dissolved in 4 mL of MeOH. Catalytic pTSA~H20 was added and the reaction was stirred at reflux for 2 hours.
The reaction was cooled and quenched with saturated NaHC03 solution. The reaction mixture was extracted with dichloromethane (2 x 25 mL) and the combined organic portions were wasi~ed with H20 and brine. '~1'he organic portion was dried over Na2S04 and concentrated under reduced pressure. Chromatography (Si02, 5%
MeOH/dichloromethane V1'O 98/09978 PCT/US97/15506 with 0.2% NH40H) gave the desired material (226 mg, 2:1 mixture of oxime isomers) as a white solid. 13C NMR (CDCI3) 8 218.1, 217.3, 205.0, 205.0, 170.0, 169.8, 158.0, 1 X7.9, 151.3, 150.3, 148.7, 148.0, 143.2. 143.2, 130.1, 130.0, 129.1, 129.1, I 26.7, 1?6.2, 126.2, 123.4, 123.3, 119.9, 119.6. 103.2, 83.7, 83.6, 79.7, 79.5, 77.4, 77.2, 77.1, 77.0, 76.9, 72.6, 72.3, 70.3, 69.6, 65.8, 60.3, 58.1, 58.0, 57.9, 51.0, 50.9, 46.8.
46.6, 44.9, 44.8, 40.2, 38.8, 38.5, 37.5, 37.5, 28.2, 22.4, 22.2, 21.2, 21.2, 20.5, 20.2, 18.1, 18.0, 14.9, 14.6, 14.5, 13.6, 13.6, 10.6, 10.3. MS(CI) m/e 797 (M+H)+.
Anal Calcd for C42H6pNq01 ~. Found C 63.46, H 7.80, N 6.$7.
The O-(4-quinolyl)methylhydroxylamine reagent was prepared as follows:
Steg231a. N-l4-quinolyl)methoxvphthalimide 4-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (2.27 g, 8.66 mmol, 1.15 equiv) and N-hydroxyphthalimide (1.42 g, 8.71 mmol, 1.15 equiv) were dissolved in 40 mL of dry THF. Diethylazodicarboxylate ( 1.44 mL, 9.15 mmol, 1.21 equiv) was then added dropwise and the reaction was stirred overnight . The reaction mixture was then diluted with 50 mL of Et~O and filtered. The resulting solid was dissolved in dichloromethane and washed with 1N NaOH, H20 and brine. The organic portion was dried over Na2S04 and concentrated under reduced pressure to give the title compound (2.03 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Step 231 b. O-(4-quinolyl)methylhydroxylamine N-(4-quinolyl)methoxy phthalimide (2.00 g) was suspended in 95% EtOH and hydrazine (0.30 mL) was added. The reaction mixture was stirred for 3 h and then filtered.
The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.44 g) as a yellow oil. MS(CI) m/e 175 (M+H)+. y Example 232 Compound of Formula (IX): L is CO. T is NH R is -CH2CH=NOCH,~(2-quinol~
The title compound was prepared from the compound of Example 220 (206 mg, 0_322 mmol) and O-(2-quinolyl)methylhydroxylamine (120 mg, 0.681 mmol, 2.1 equiv) using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH40H) gave the desll'ed material (185 mg, 3:1 mixture of oxime isomers) as a white solid. 13C NMR (CDC13) 8 217.9, 217.2, 204.9, 204.9, 169.9, 169.8, 159.0, 158.9, 157.8, 151.0, 148.7, 147.6, 136.5, 129.3, 129.2, 129.0, 127.5, 126.1, 126.0, 119.8, 119.6, 103.1, 83.5, 79.6, 79.4, 77.3, 77.0, 76.9, 76.9, 76.8, 76.7, 70.2, 69.5, 65.8, 60.4, 58.0, 58.0, 50.9, 46.5, 46.4, 44.8, 44.7, 40.1, 38.7, WO 98109978 ~ PCT/US97/15506 38.5, 37.4, 3?.4, 28.2, 22.3, 22.2, 21.2, 21.1, '_'U.5, 20.1, 18.1, 18.0, 14.5, 14.4, 14.3, 13.5, 10.4, 10.3. MS(CI) m!e 797 (M+H)+.
The O-(2-quinolyl)methylhydroxylamine reagent was prepared as follows:
Step 232x. N-(2-quinolyl)methoxvphthalimide 2-(hydroxymethyl)quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (1.00 g, 6.29 mmol, 1.05 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate ( 1.09 mL, 6.93 mmol, I
.10 equiv) was then added dropwise and the reaction was stirred overnight . The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et20. Th;s was combined with the original solid and recrystallization from EtOH gave the desired pr oduct ( 1.53 g) as a fluffy white solid.
MS(CI) m/e 305 (M+H)+.
Step 232b. O-(2-q-uinolyl)methvlhYdrox ~Llanune N-(2-quinolyl)methoxy phthalimide (1.53 g> was suspended in 95% EtOH and hydrazine (0.30 mL) was added. The reaction mixture was stirred for 5 h and then filtered.
The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.91 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 23 3 Compound of Formula (IXI: L is CO T is NI-l. R is -CH,~CH=NOCH~(3-quinol~
The title compound was prepared from the compound of Example 220 (250 mg, 0.391 mmol) and O-(3-quinolyl)methylhydroxylamine (160 mg, 0.909 mmol, 2.3 equiv) using the procedure described for Example 231. Chromatography (Si02, 5%
MeOHr'dichloromethane with 0.2% NH~OH) gave the desired material (202 mg, 2:1 mixture of oxime isomers) as a white solid. 13C NMR (CDC13) S 217.9, 217.1, 205.0, 169.9, 169.7, 157.9, 157.8, 151.0, 150.9, 150.8, 148.4, 147.8, 135.4, 135.2, 130.6, 130.5, 129.3, 129.2, 128.0, 127.9, 127.9, 126.6, 126.5, 103.2, 83.6, 83.5, 79.5, 79.4, 77.2, 76.9, 76.7, 73.7, 73.4, 70.3, 69.6, 65.9, 60.3, 58.1, 57.9, 51.0, 50.9, 46.7, 46.4, 44.9, 44.7, 40.2, 38.8, 38.6, 37.5, 28.2, 22.4, 22.2, 21.2, 20.4, 20.1, 18.1, 18.0, 14.7, 14.6, 14.4, 14.3, 13.6, 13.5, 10.5, 10.3. MS(CI) m/e 797 (M+H)~. Anal Calcd for C42H60N4011 ~ Found C 63.00 H 7.56 N 6.79.
The O-(3-quinolyl)methylhydroxylamine reagent was prepared as follows:

Step 233a. N-(3-q_uinolyl)methoxyphthalimide 3-(hydroxymethyl)quinoline (400 mg, 2.52 mmol), triphenyl phosphine (692 mg, 2:64 mmol, 1.05 equiv) and N-hydroxyphthalimide (430 mg, 2.64 mmol, 1.05 equiv) were dissolved in 10 mL of dry THF. Diethylazodicarboxylate (0.44 mL, 2.80 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight . The reaction mixture placed in a freezer for 2 hours, and then filtered to give the desired product (0.69 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Step 233b. O-(3-ctuinol~rl)methvlhydroxvlamine N-(3-quinolyl)methoxy phthalimide (0.69 g) was suspended in 95% EtOH and hydrazine (0.10 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.42 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 234 Compound of Formula (IX): L is CO. T is NH. R is -CH~CH=NOCH~(6-quinolyl) The title compound was prepared from the compound of Example 220 ( 120 mg, 0.186 mmol) and O-(6-quinolyl)methylhydroxylamine (92 mg, 0.529 mmol, 2.8 equiv) using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH~OH) gave the desired material (89 mg, 3:1 mixture of oxime isomers) as a white solid. 13C NMR (CDC13) 8 217.9, 217.1, 204.9, 169.8, 169.6, 157.8, 157.7, 150.6, 150.1, 148.0, 147.8, 136.1, 136.1, 129.6, 129.4, 129.3, 128.0, 126.6, 126.3, 121.0, 103.0, 83.5, 83.4, 79.4, 79.3, 77.4, 77.0, 76.8, 76.7, 76.6, 75.5, 75.3, 70.1, 69.5, 65.7, 60.2, 58.0, 57.9, 57.8, 50.8, 46.6, 46.3, 44.8, 44.6, 40.1, --38.6, 38.4, 37:3;-28.1; 22:3;-22.1; 21.1;-20:4;-20:0,~18.0,-i7:8; 14:7;
14_.5; x14.3, ~3.4;w' v 10.4, 10:2. MS(CI) m!e 797 (M+H)+. Anal Calcd for C42H6pN4011. Found C 63.03 H
7.60 N 6.69.
The O-(6-quinolyl)methylhydroxylamine reagent was prepared as follows:
Sten 234a. N-f6-quinolyl)methoxyphthalimide 6-(hydroxymethyl)quinoline (520 mg, 3.27 mmol), triphenyl phosphine (900 mg, 3.44 mmol, 1.05 equiv) and N-hydroxyphthalimide (560 mg, 3.43 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (574 ~L, 3.63 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight . The reaction mixture filtered to give a white solid. The filtrate was concentrated and a second crop of material was obtained by triturating with Et20. This was combined with the original solid and recrystallization from EtOH gave the desired product (782 mg) as a fluffy white solid.
MS(C1) m/e 305 (M+H)+.
Step 234b. O-!2-quinolyl)methylhydroxylamine N-(2-quinolyl)methoxy phthalimide (782 mg) was suspended in 95% EtOH and hydrazine (0.15 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (480 mg) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Example 235 Compound of Formula (IX): L is CO, T is NH. R is -CH2CH=NOCH~II-naphthvl) The title compound was prepared from the compound of Example 220 ( 117 mg, I5 0.183 mmol) and D-(1-naphthyl)methylhydroxylamine (80 mg, 0.462 mmol, 2.5 equiv) using the procedure described for Example 231. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.1% NH40H) gave the desired material (112 mg, 2:1 mixture of oxime isomers) as a white solid. 1-~C NMR (CDCl3) 8 217.8, 217.0, 205.0, 169.9, 169.7, 157.9, 157.8, 150.3, 147.7, 133.7, 133.1, 131.8, 128.7, 128.6, 128.4, 127.1, 20 126.8, 126.2, 125.6, 125.3, 124.1, 103.1, 103.1, 83.6, 79.5, 79.3, 77.2, 77.0, 76.9, 74.7, 74.3, 70.3, 69.6, 65.9, 60.5, 58.1, 58.0, 51.0, 50.9, 46.6, 46.3, 44.9, 44.8, 40.2, 38.8, 38.6, 37.5, 28.3, 22.4, 22.3, 21.2, 20.5, 20.0, 14.6, I 4.5, 14.1, 13.6, I 0.5, I 0.3.
MS(CI) m/e 796 (M+H)+. Anal Calcd for C43H61N3O11. Found C 64.91 H 7.80 N
5.06.
The O-(1-naphthyl)methylhydroxylamine reagent was prepared as follows:
step 235a. N-!I-naphthyl)methoxyphthalimide 1-(hydroxymethyl)naphthalene (I.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.f0 moral, 1.04 equiv) and I'r'-hydroxyphthalir~de (1.08 g, 6.63 rntnol, i.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight . The reaction mixture was diluted with 25 mL of Et20 and placed in a freezer for 2 hours.
The reaction mixture was then filtered to give a white solid. Recrystallization from EtOH
gave the desired product (1.21 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
Step 235b. O-!1-naphthyllmethyl~droxylamine N-(I-naphthyl)methoxy phthalimide (1.21 g) was suspended in 95% EtOH and hydrazine (0.20 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (480 mg) as a colorless oil. MS(CI) m/e 174 (M+H)+.
S Example 236 Compound of Formula (IXI: L is CO. T is NH. R is -CH2CH=NOCH~(2-naphthvll The title compound was prepared from the compound of Example 220 ( 122 mg, 0.191 mmol) and O-(2-naphthyl)methylhydroxylamine (62 mg, 0.358 mmol, 1.9 equiv) using the procedure described for Example 231. Chromatography (5i02, 5%
MeOH/dichloromethane with 0.1% NH40H) gave the desired material (100 mg, 3:1 mixture of oxime isomers) as a white solid. 13C NMR (CDCl3) 8 217.8, 217.0, 204.9, 169.8, 169.6, 157.8, 157.7, 150.3, 147.8, 135.4, 135.1, 133.2, 132.9, 128.0, 127.9, 127.9, 127.5, 127.0, 126.7, 126.1, 125.8, 125.7, 125.7, 125.6, 103.1, 83.5, 83.5, 79.4, 79.3, 77. I , 76.9, 76.8, 76.1, 75.9, 70.2, 69.5, 65.8, 60.3, 58.0, 57.9, 57.9, 50.9, 46.6, 46.3, 44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 28.1, 22.3, 22.1, 21.1, 20.4, 20.0, 18.0, 17.9, 14.6, 14.5, 14.4, 14.2, 13.5, 10.4, 10.2. MS(CI) m/e 796 (M+H)+. Anal Calcd for C43H61N3011. Found C 64.59 H 7.72 N 5.14.
The O-(2-naphthyl)methylhydroxylamine reagent was prepared as follows:
Step 236a. N-(2-naphth~lmethoxyphthalimide 2-(hydroxymethyl)naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) were dissolved in 25 mL of dry THF. Diethylazodicarboxylate (1.09 mL, 6.93 mmol, 1.09 equiv) was then added dropwise and the reaction was stirred overnight . The reaction ?5 mixture was placed in a freezer for 2 h and then filtered, rinsing with Et20, to give the product (1.38 g) as a white solid. MS(CI) m/e 321 (M+NH4)+.
- Step 236b. G-(2-naphth 1)y methylhvdroxvlamine N-(2-naphthyl)methoxy phthalimide (1.38 g) was suspended in 95% EtOH and hydrazine (0.25 mL) was added. The reaction mixture was stirred overnight and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (821 mg) as a colorless oil. MS(CI) m/e 174 (M+I-I)+.

WO 98!09978 PCT/US97l15506 Example 237 Compound of Formula (IX): L is CO. T is NI-I, R is -CH~CH2NHOCH~,(phenvl) The compound from Example 229 (120 mg, 0.161 mmol) was dissolved in MeOH
(5 mL) and treated with NaCNBH3 (about 120 mgj and enough AcOH to turn bromocresol green indicator from blue to yellow. After stirring for 20 hours, the reaction mixture was poured into saturated NaHC03 solution and extracted into dichloromethane. The organic portion was washed with saturated NaHC03, H20 and brine, dried (Na2S04) and concentrated under reduced pressure. Chromatography (Si02, 5%
MeOH/dichloromethane with 0.2% NH40H) gave the desired material (51 mg) as a white solid. 13C NMR
(CDC13) 8 219.0, 205.7, 170.5, 157.8, 138.3, 128.1, 127.5, 102.5, 83.6, 78.6, 77.0, 75.6, 75.2.
70.2, 69.5, 66.0, 58.8, 58.3, 51.4, 50.7, 45.3, 45.0, 40.2, 39.1, 37.7, 28.3, 22.4, 21.3, 20.7, 18.2, 14.7, 13.7, 13.5, 12.8, 10.3. MS(C1) m/e 74i; (M+H)+.
Example 238 t5 Compound of Formula (IX): L is CO, T is NH. R is -CH~CH~NI-30CH~(4-NO~~henyl) The compound from Example 230 (64 mg) was dissolved in MeOH (3 mL) and treated with NaCNBH3 (about 100 mg) and enough HCl to turn methyl orange indicator red. After stirring for 20 hours, the reaction mixture was poured into saturated NaHC03 solution and extracted into dichloromethane. The organic portion was washed with H20 20 and brine, dried (Na2S04) and concentrated under reduced pressure.
Chromatography (Si02, 5% MeOH/dichloromethane with 0.2% NH40H) gave the desired material (35 mg) as a white solid. 13C NMR (CDCI3) 8 219.5, 205.5, 170.5, 157.8, 147.2, 146.8, 128.3, 123.4, 102.4, 83.6, 78.6, 76.8, 75.0, 74.3, 70.1, 69.5, 65.8, 58.4, 58.1, 51.3, 50.6, 45.3, 45.0, 40.1, 38.9, 37.7, 28.2, 22.2, 21.2, 20.7, 18.1, 14.6, 13.5, 13.3, 12.8, 10.2.
25 MS(CI) m/e 793 (M+H)+.
Example 239 Compound of Formula !IX): L is CO, T is NH, R is -CH2C(O)-phenyl 30 Sten 239a. Compound of Formula (IX~ L is CO, T is NH._ R is -CH~C(OH)-phenyl The compound from Example 220 (550 mg, 0.8? mmol) was dissolved in 16 mL of dry THF and cooled to 0 °C under nitrogen. Phenylmagnesium bromide (3.0 M solution in Et20, 3.0 mL, 6.0 mmol, 6.9 equiv) was then added dropwise via syringe. The reaction was stirred for 50 min, then quenched by addition of saturated NI-I4C1 solution. The 35 reaction mixture was extracted with EtOAc and the organic portion was washed with H20 and brine, dried (Na2S04) and concentrated under reduced pressure.
Chromatography (SiO', 5% MeOH/dichloromethane with 0.2% NH40Hj gave the desired material (295 mg) as a white solid. MS(CI) m/e 719 (M+H)+.

Step 239b. Compound of Formula (18, Scheme 4): R* is H, R>? is Ac, R is -CH~C(OH)-hp envl.
The compound from the previous step (180 mg. 0.250 mmol) was dissolved in 5 mL of dry dichloromethane and treated with acetic anhydride (25 p.L, 0.269 mmol, 1.08 equiv). After stirring overnight, then reaction was quenched by addition of saturated NaHC03 solution. The reaction mixture was extracted with dichloromethane and the organic portion was washed with brine, dried (Na2S04) and concentrated under reduced pressure to give the desired material (160 mg) as a white solid. MS(CI) m/e 761 (M+H)+.
Step 239c. Compound of Formula (18, Scheme 4): R* is H, RP is Ac, R is -CH~C(O)-hp end.
DMSO (145 ~.L, 2.04 mmol, 14 equiv) was added to a cooled (-78 °C) solution of oxalyl chloride ( 145 mL, 1.32 mmol, 9 equiv) in 4 mL of dichloromethane under a nitrogen atmosphere. The compound from, the previous step (113 mg, 0.149 mmol) was dissolved in 2 mL of dichloromethane and added to the reaction, via cannula, over 15 min. After stirring for 1 hour. Et3N (0.37 mL, 2.65 mmol, 18 equiv) was added to the reaction mixture and the temperature was slowly raised to -20 °C. The was quenched by addition of 5%
KH2P04 solution and extracted with dichloromethane. The organic portion was washed 2o with 5% KHZP04, H20, and brine, dried (Na2S0~) and concentrated under reduced pressure. Chromatography (Si02, 1:1 acetone/hexanes) gave the desired material (42 mg) as a white powder. MS(CI) m/e 759 (M+H)+.
Step 239d. Compound of Formula (IX): L is CO. T is NH R is -CH~C(O)-phenyl The compound from the previous step was dissolved in 5 mL of MeOH and left to stirred overnight. The reaction mixture was concentrated under reduced to give the title compound (3.8 mg) -as a white solid. ~3C 1~,:'VIR (C-DCl3) 8 215.4; 206.1,-194.4, 169:6, 157.7, 135.5, 133.0, 128.5, 127.6, 103.0, 83.8, 79.6, 77.1, 77.1, 70.2, 69.5, 65.9, 65.4, 57.6, 50.9, 46.0, 44.6, 40.2, 38.9, 37.9, 28.4, 22.4, 21.3, 20.2, 18.9, 14.9, 13.9, 13.7, 13.6, 10.5. MS(CI) rn/e 7I7 (M+H)+.
Example 240 Compound of Formula (IX): L is CO T is NH R is -CH~CIOy-(4-F-phenyl) The title compound was prepared from the compound of Example 220 and 4-fluorophenylmagnesium bromide using the reaction sequence of Example 239.
13C ~R (CDC13) 8 215.3, 206.0, 192.8, 169.6, 165.7, 157.7, 131.5, 130.2, 115.6, 103.1, 83.8, 79.7, 7?.3, 76.8, 70.3, 69.6, 65.8, 65.1, 57.6, 50.9, 46.0, 44.6, 40.2, WO 98!09978 PCTlUS97/15506 38.8, 37.8, 28.3, 22.4, 21.3, 20.2, 18.8, 14.8, 13.9, 13.7, 13.5, 10.4. MS(CI) m/e 735 (M+H)+.
Example 241 s Compound of Formula IIXI: L is CO, T is NH, R is -CH~CH=NNHC(O)phenyl The compound from Example 220 (100 mg, 0.156 mmol) and benzoic hydrazide (50 mg, 0.370 mmol, 2.4 equiv) were dissolved in 3 mL of dry dichloromethane.
Molecular sieves (4A) were added and the reaction was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure.
Chromatography (Si02, to 5% MeOH/dichloromethane with 0.2% NH40H) gave the desired material (29 mg) as a white solid. 13C NMR (CDCl3) S 216.9, 204.2, 169.6, 164.3, 159.0, 148.8, 133.4, 131.2, 128.0, 127.7, 103.2, 83.9, 79.6, 77.6, 76.5, 70.1, 69.5, 65.7, 62.7, 57.8, 50.b, 46.9, 44.4, 40.0, 38.4, 37.3, 28.1, 21.9, 21.1, 20.7, 17.8, 15.0, 14.2, I 3.3, 13.1, I 0Ø
MS(CI) m/e 759 (M+H)+.
15 Example 242 Compound of Formula (IX): L is CO. T is NH, R is -CH~CH~CH~(3-quinol~, A mixture of the compound from Example 104 (230 mg) and 10 % Pd/C (50 mg) in 30 mL of methanol and 15 mL of ethyl acetate was flushed with nitrogen and stirred under I
atm of hydrogen at room temperature for 22 hours. The mixture was filtered, and the filtrate 20 was concentrated under reduced pressure. Chromatography on silica gel (5%
MeOH/dichloromethane with 0.5% NH40H) gave the desired material (175 mg) as a white solid. Anal Calcd for C42H65N3010~ C~ 65.35; H, 8.49; N, 5.44. Found C, 65.73;
H, 8.77; N, 5.17.
25 Example 243 Comgound of Formula !IX): L is CO,~ T is NH, R is -CH~12-(3-quinol~cyclopro~Yll To a solution of diazomethane (0.64 M, 3.12 mL, 2.00 mmol) in ether was added a solution of the compound from Example 104 (153 mg, 0.200 mmol) in dichloromethane (5.
0 mL) at 0 °C under nitrogen. A small amount (2 mg) of palladium acetate was added, and 30 the mixture was stirred for 20 minutes. Another portion of diazomethane (3 mL) was added, and the mixture was stirred for another hour. The solvents were evaporated, and the residue was purified by chromatography on silica gel (5% MeOH/dichloromethane with 0.5% NH40H) to give the title compound (100 mg) as a white solid. Anal Calcd for C43H61N3010: C, 66.22; H, 7.88; N, 5.39. Found C, 66.05; H, 8.08; N, 5.02.

Example 244 Compound of Formula (III): R~ is proQanoyl, L is CO, T is NHj R is -CH~CH=CH(3-quinolyl) To a solution of the compound from Example 104 (152 mg) in dichloromethane was added propionic anhydride (52 p,L) and triethylamine (56 p.L), and the mixture was stirred for 24 hours at room temperature. The mixture was diluted with ethyl acetate, and this was washed with 5% NaHC03 solution and brine, dried (Na2S0~) and concentrated under reduced pressure. The residue was chromatographed on silica gel (I:1 acetone/hexanesj to 0 give the title compound(119 mgj as a white foam. Anal Calcd for C45H63N30~
I: C, 65.75;
H, 7.72; N. S.11. Found C, 65.67; H, 7.92; N, 4.77.
Example 245 Compound of Formula (III): R~ is ethvlsuccinovl, L is CO. T is NH, ~5 R is -CHcCH=CH(3-quinolyl) To a solution of the compound from Example 104 (153 mg, 0.200 mmol) in dichloromethane (10 mL) at 0 °C was added ethyl succinyl chloride (29 p.L) and triethylamine (56 pL), and the mixture was stirred for 24 hours at room temperature. The 20 mixture was diluted with ethyl acetate, and this was washed with S% NaHC03 solution and brine, dried (Na2S04) and concentrated under reduced pressure. The residue was chromatographed on silica gel (1:1 acetone/hexanes) to give the title compound(110 mg) as a white foam. Anal Calcd for C4gH6~N3013~H20 C, 63.21; H, 7.63; N, 4.61. Found C, 63.08; H, 7.50; N, 4.20.
Example 246 Compound of Formula (IX): L is CO, T is NH. R is -CHI-C---C-H
Sten 246x. Compound 4 from Scheme 1~~ V is N-O-(1-is~ropoxvcvclohexvl), R is -CH~-C=-C-H. R~ is trimethylsilyl.
To a solution under nitrogen of 2',4"-bis-O-trimethylsilylerythromycin A 9-[O-(1-isopropoxycyclohexyl)oxime (100 g, 96.9 mmol, prepared according to the method of U.S.
Pat. No. 4,990,602) in THF (200 mL) was added anhydrous DMSO (200 mL) and the mixture was cooled to 0 °C. To this solution sticrCd under a N2 atmosphere was added propargyl bromide (27 mL, 240 mmol, 80 wt. % in toluene), followed by a solution of dry KOH (13.6 g, 24o mmol) in anhydrous DMSO (300 mL) over 25 minutes, and the mixture was stirred vigorously for 1 hour at 0 °C. Additional KOH (10.9 g, 190 mmol) and WO 98!09978 PCT/US97/15506 propargyl bromide (21 mL, 190 mmol) was added, and the mixture was stirred at 0 ~C
under N2 for 1.5 hours. This addition of KOH and propargyl bromide was repeated 3 more times at 1.5 hour internals. The mixture was then extracted with ethyl acetate, and the organic phases were washed with water and brine and dried (MgS04). Removal of the S solvent under vacuum gave the crude product (108 g), which was taken directly to the next step.
Step 246b: ComDOUnd 5 from Scheme la; R is -CHI-C~C-H
To the compound from Step 246a (108 g) in CH3CN (300 mL) was added water ~ 0 ( 150 mL j and acetic acid (glacial, 200 mL), and the mixture was stirred at room temperature for about 20 hours. The solvent was then removed under vacuum at 40 ~C, and the residue was taken up in EtOAc and washed successively with ~% Na2C03 and brine . The organic phase was then dried over MgS04, filtered and concentrated to give the title compound (74 g) as a brown foam, which was taken directly to the next step.
step 246c: Compound 6 from Scheme 1 a: R is -CHI-C---C-H
The compound from Step 246b (74 g) was dissolved in ethanol (550 mL) and diluted with water (550 mL). To this solution was added sodium nitrite (33 g, 0.48 mol), and the reaction mixture was stirred at room temperature for 15 minutes. Next was added 4M HCl (125 mL, 0.48 mol) at ambient temperature over 15 minutes, the mixture was heated to 70 ~C for two hours, then cooled to room temperature. The mixture was extracted with ethyl acetate, and the organic phase was washed with 5% Na2C03 and brine, then dried over MgS04, filtered and concentrated. The crude product was purified by chromatography on silica gel, eluting with I % methanol/dichloromethane containing 0.5%
ammonium hydroxide. The compound was crystallized from acetonitrile to give the title compound (27 g).
Sten 246d~ Compound 6A from Scheme lc' R~is acetyl. R is-CH2-CC-H
To a solution of 19 grams (246 mmol) the compound from Step 246c in anhydrous 3o dichloromethane (100 mL) was added 4-dimethylaminopyridine (105 mg) and triethylamine (7.16 mL, 52 mmol). The mixture was cooled to about 15 °C in a cold water bath, and acetic anhydride (5.5 milliliters, 59 mmol) was added over 5 minutes. After stirring at I S °C
for 5 minutes, the cold water bath was removed, and the reaction was stirred at ambient temperature for 4 hours. The mixture was diluted with ethyl acetate and washed successively with 5% aqueous sodium carbonate (twice), water (twice) and brine. The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo .
Drying to constant weight with high vacuum provided the title compound (21 g).

Step 246e: Compound 6B from Scheme Ic; RP is acetyl. R is -CHZGC-H
To a 0 °C solution of the compound from Step 246d (21 g, 24.5 mmol) in THF (128 rnL) and dimethyl sulfoxide (48 mLj was added 1,1'-carbonyldiimidazole (14.3 g, 88.3 mrnol). After stirring for 5 minutes, sodium hydride (60% dispersion in mineral oil, 1.3 g, 32.5 mmol) was added portionwise over 1 hour under a nitrogen atmosphere.
After complete addition, the cooling bath was removed, and the mixture was stirred at ambient temperature for 3.5 hours. The reaction was recooled to 0 °C, diluted with ethyl acetate 0400 mL), and quenched with 5% aqueous sodium bicarbonate (50 mL). The organic layers were washed successively with water and brine, then dried over magnesium sulfate.
The solution was filtered and the filtrate was concentrated in vaccu~. and dried to constant weight to afford the title compound (23 g), which was taken directly to the next step.
Step 246f: Compound 6C from Scheme 1 c~ R~ is acetyl, R is -CHI-C=C-H
A pressure vessel containing the compound from Step 246e (23 g, 24 mmol) in acetonitrile (250 mL) was cooled to -78 °C. An equal volume of liquid ammonia (250 milliliters) was condensed into the reaction vessel which was then sealed and allowed to warm to ambient temperature with stirring. After 20 hours the reaction was recooled to -78~C, the pressure vessel was opened and the reaction was allowed to warm to ambient temperature with stirring. When all the liquid ammonia had evaporated, the acetonitrile was removed in vacuo , and the residue was dried to constant weight to provide the title compound (21 g).
Step 246 : Compound 6D from Scheme lc~ R~ is acetyl, R is -CH2-C---C-H
To a 0 °C suspension of the compound from Step 246f (21 g) in 1:1 ethanol/water (200 mL) was added 4 M hydrochloric acid (125 mL) over 10 minutes. After removing the cooling bath, the reaction solution was stirred at ambient temperature for 26 hours. The mixture was diluted with water, cooled to 0 °C and made basic to pH 10 with 2N sodium hydroxide. The mixture was then extracted with ethyl acetate (400 mL), and the organic layers were washed with brine. The organic extracts were dried over magnesium sulfate, filtered, and concentrated ifa vacuo . Drying to constant weight provided 18 g of the crude product which was crystallized from ethyl acetate/hexanes to give the pure title compound (8.5 g).
Sten 246h: Compound 6E from Scheme lc' R~ is acetyl, R is -CHI-C---C-H
To a -10 °C solution of N-chlorosuccinimide (2.3 g, 0.017 moles) in dichloromethane (100 mL) was added methyl sulfide (1.47 mL, 0.021 moles) over minutes. The reaction was stirred at -IU °C for 10 minutes. A solution of the compound from Step.246g (8.3 g, 0.012 m) in dichloromethane (100 mL) was then added over 30 minutes, and the mixture was stirred for 25 minutes at -10 °C.
Triethylamine (1.6 mL, 0.021 mol) was added over 5 minutes, and the reaction was stirred at -10 °C for 50 minutes.
The reaction was then quenched with 5% aqueous sodium bicarbonate (50 mL), and extracted with dichloromethane (300 mL). The organic layers were washed with 5%
aqueous sodium bicarbonate followed by brine, dried over magnesium sulfate, filtered, and concentrated in vacuo . The crude product was purled on silica gel with column chromatography eluting sequentially with 30% acetone/hexanes followed by 50%
acetone/hexanes to provide the title compound (7.35 g).
Step 2461: Compound of Formula (IX): L is CO. T is NH. R is -CH -C-= -H
A sample (72 mg) of the compound from Step 246h was dissolved in methanol (8 mL) and stirred at ambient temperature for 18 hours. After concentrating under vacuum and 15 drying to constant weight under high vacuum 65 mg of the pure title compound was obtained. High Resolution FAB MS: calculated m/e for (M+H)*
C33H53N20~p=637.3700 Observed m/e =637.3718.
Example 247 2o Compound of Formula 1/X1 L is CO T is NH $,is -CHI-C_--C-f3-quinol~,) Step 247a Con-lpound 6E from S,~heme lc~ R is -CHI-C=C-(3-quinolyll A pressure tube equipped with a stir bar was charged with dic:~lorobis(triphenylphosphine)palladium(II) (6.2 mg), degassed triethylamine (2.5 mL), 25 degassed N,N-dimethylformamide (0.5 mL), then 3-bromoquinoline (93 ~.L and a sample of the compound from Step 246h (300 mg), and lastly copper (II) iodide (0.84 mg). The reaction was sealed under a nitrogen atmosphere and heated to 60 °C for 2 hours. After cooling to room temperature, the reaction was diluted with 1:1 ether/ethyl acetate and was washed three times with water and brine. The organic extracts were dried over magnesium 30 sulfate, filtered and concentrated in vacuo. Drying with high vacuum provided 374 milligrams of crude product. The crude product was purified with silica gel chromatography using 30% acetone/hexanes to give the title compound (280 mg,78%. MS
(APCI)+ m/e 806 (M+H)+.
35 Step 247b. Compound of Formula (/X1 L is CO T is NH R is -CHI-C- -f3;~uinolvll The compound form step 247a (270 mg) was dissolved methanol and was stirred at ambient temperature for 18 hours. After concentrating in vacuo and drying to constant weight under high vacuum 260 mg of crude product was obtained. Purification with silica gel chromatography eluting with 98:1:1 dichloromethane/methanol/ammonium hydroxide gave 221 mg of the title compound. High Resolution FAB MS: calculated m/e for (M+H)+
C4~HSgN301p=764.4122 Observed m/e =764.4121.
Example 248 Compound of Formula (TX): L is CO, T is NI--I, R is -CH2-C---C-(6-vitro-3~uinolyl) Following the procedure of Example 247, except substituting 6-vitro-3-bromoquinoline for 3-bromoquinoline, the title compound was prepared. High Resolution W FAB MS: calculated m/e for (M+H)+ : C42HS7N4012=809.3973 Observed m/e =809.3966 Example 249 Compound of Formula (IX): L is CO. T is NH R is -CH2-C---C-~henyl Following the procedure of Example 247, except substituting iodobenzene for 3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+
C39H57N201p=713.4013 Observed m/e =713.3998.
Example 250 Compound of Formula (IX): L is CO. T is NH, R is -CHI-C=C-naphthyl Following the procedure of Example 247, except substituting I-iodonaphthalene for 3-bromoquinoiine. High Resolution FAB MS: calculated m/e for (M+H)+
C43H59N201o=763.4170 Observed m/e =763.4161.
Example 251 Compound of Formula (IX): L is CO; T is NH, R is -CHI-C=C-(2-naphthyl) Following the procedure of Example 247, except substituting 2-bromonaphthalene for 3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+
C43H59N2010=763.4170 Observed m/e =76.4150.
Example 252 Compound of Formula (IXI: L is CO, T is NH. R is -CHI-C---C-(6-methoxl%-2-na~hthyl) Following the procedure of Example 247, except substituting 6-methoxy-2-bromonaphthalene for 3-bromoquinolinc. High Resolu~iun FAB MS: calculated m/e for (M+H)+ : C44H61N2011=793.4275 Observed m/e =793.4256.
3~

WO 98!09978 PCT/US97/15506 Example 253 Compound of Formula (IX): L is CO, T is NH. R is -CHIC-_-C-(6-chloro-2-na~hthyl) Following the procedure of Example 247, except substituting 6-chloro-3-bromoquinoline for 3-bromoquinoline. High Resolution FAB MS: calculated m!e for (M+H)+ : C42HS~N3O10C1=798.3732 Observed m/e =798.3743.
Example 254 Compound of Formula (IX~: L is CO, T is NH, R is -CH2-CSC-(6-quinolyl) Following the procedure of Example 247, except substituting 6-bromoquinoline for l0 3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+
C42HSgN3010=764.4122 Observed m/e =764.4116.
Example 255 ComRour~d of Formula (IX~: L is CO. T is NH. R is -CH2-C=C~2-meth~rl-6~uinolyl) '~ 5 Following the procedure of Example 247, except substituting 6-bromo-2-methylquinoline for 3-bromoquinoline. High Resolution FAB MS: calculated m/e for (M+H)+ : C~3H6oN3010=778.4279 Observed m/e =778.4282.
Exam-ple 256 20 Compound of Formula (IX): L is CO. T is NH, R is -CHIC-_-C-(5-(N-(2-p~~rl)amino)carbon~rl)furanyl) Following the procedure of Example 247, except substituting 5-bromo-furan-2-carboxylic acid pyridin-2-yl amide for 3-bromoquinoline. MS (FAB+):(M+H)+ @
m/e 823.
Example 257 Compound of Formula (IX): L is CO, T is NH. R is -CH2-C=C-( 1-~henyletheny~
Following the procedure of Example 247, except substituting alpha-bromostyrene for 3-bromoquinoline. MS (ESI) m/e 739 (M+H)+.
Example 258 Compound of Formula~IX~: L is CO. T is NH.'R is -CH2-C---C-Br Step 258a. Compound 6E from Scheme 1 c; R is -CH2-CSC-Br To a solution under nitrogen of the compound of Example 246, Step h (100 mg) in acetone (i mL) was added acetic acid (8.4 microliters) at ambient temperature.
A second solution containing N-bromosuccinimide (39 mg) and silver nitrate (2.5 mg) in 1 mL of acetone was prepared and then stirred at room temperature under nitrogen for ten minutes and was cooled to 0 °C. The first solution was then added to the second solution in one portion, the cooling bath was removed, and the resulting reaction mixture stirred at room temperature under nitrogen for 2 hours. The reaction was then diluted with ethyl acetate, s saturated aqueous sodium bicarbonate was added, and the mixture was stirred at room temperature overnight. The organic phase was separated, washed with brine and dried (MgS04). The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 40% acetone/hexanes to give the title compound (50 mg, 46 %).
t0 Step 258b. Compound of Formula (1XO L is CO T is NH R is -CHI-C---C-Br A sample (35 mg) of the compound from Step 258a was dissolved in methanol (2 mL) and stirred at ambient temperature for 16 hours. The solvent was removed, and the residue was purified by chromatography on silica gel, eluting, with 5:94:1 methanol/dichlormethane/1% NI~OH, to give the title compound (32 mg, 26 %). MS
1; (ESIj m/e 715 (M+H)+.
Example 259 Compound of Formula (IX): L is CO T is NI-1 R is -CHI-(2,2-dimethyl-1,3-dioxolan-4-Stev 259a. Compound 6D from Scheme lc' R is -CH2CHfOH)CH~OH, R>? is acetyl To a sample of the compound from Example 176, Step d (5.0 g, 7.32 mmol, Compound 6D from Scheme lc, R is -CH2CH=CH2, Rp is acetyl) and N
methylmorpholine N oxide (1.7 g; 14.5 mmol) in THF (25 mL) at room temperature was ~5 added Os04 (4 % in H20, 0.090 mL, 0.0147 mmol), and the mixture was stirred for 24 hours. The reaction was quenched with sodium bisulfite (1.5 g) and water (10 mL), and the solvents were removed under vacuum. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate, water and brine, and dried (Na2S04). The solvent was removed to give the title compound (3.17 g).
Step 259b. Compound 6D from Scheme lc~ R is -CH_~-(2,2-dimethyl-1,3-dioxolan-4-yl) R~ is acetyl, Rd is H
To a sample of the compound from Step 259a (500 mg, 0.70 mmol) and 2,2-dimethoxpropane (0.26 mL, 2.1 mmol) in toluene (7 mL) was added p-toluenesulfonic acid (160 mg, 0.84 mmol), and the mixture was stirred at 55 °C for 3 days.
The mixture was diluted with ethyl acetate, and this solution was washed with 10 % sodium carbonate solution, water and brine. The organic phase was dried (Na2S04), and the solvent was '~~ 98/09978 PCT/US97/15506 removed to give the crude product, which was purified by chromatography on silica gel, eluting with 2:97:1 methanol/chlorofoim/ammonium hydroxide to give the title compound (363 mg).
Step 259c. Compound 6E from Scheme lc: R is -CHI-(2,2-dimethyl-1,;-dioxolan-4-vl), R~ is acetyl, R~ is H
A sample of the compound from Step 259b (356 mg, 0.47 mmol) was oxidized with N-chlorosuccinimide and dimethylsulfide according to the procedure of Example l,Step f, to afford the title compound (371 mg).
Step 2594. Compound of Formula (IX): L is CO, T is NN, R is -CH~~?,2-dimeth, 1-dioxolan-4-yll A sample of the compound from Step 259c ( 100 mg, 0.13 mmol) was stirred in methanol (4 mL) overnight at room temperature. The solvent was removed, and the residue 1 ~ was purified by chromatography on silica gel, eluting with 0.9:98:1 methanol/chloroform/ammonium hydroxide to give the title compound (87 mg). MS
m/e 713 (M+H)+.
Example 260 Compound of Formula (IX): L is CO, T is NH. R is -CH~CH(OH)CH,~OH
A sample of the compound from Example 259 (100 mg, 0.13 mmol) was stirred at reflux with p-toluenesulfonic acid (35 mg, 0.18 mmol) in 4:1 THF/water (2.5 mL) for 3 hours. The mixture was diluted with ethyl acetate, and this solution was washed with 10 sodium carbonate solution, water and brine. The organic phase was dried (Na2S04), and 2~ the solvent was removed to give the crude product, which was purified by chromatography on silica gel, eluting with 2:97:1 methanol/chloroform/ammonium hydroxide to give the title compound (61 mg). MS m/e 689 (M+H)+.
Example 261 Compound of Formula (IX): L is CO, T is NI-I. R is -CH?CH(OH)-phenyl To a sample of the compound from Example 220 (550 mg, 0.87 mmol) in dry THF
( 16 mL) at 0 °C under nitrogen was added dropwise a solution of phenyl magnesium bromide (3.0 M, 2.0 mL, 6.0 mmol) in ether. The mixture was stirred for about I hour, and the reaction was quenched with saturated ammonium chloride solution. The mixture 3~ was extracted with ethyl acetate, and this solution was washed with water and brine and dried (Na2S04). The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 10:90:0.5 methanol/dichloromethane/ammonium hydroxide to give the title compound (235 mg) as two isomers. Isomer A: MS m/e (M+H)+. Isomer B: MS m/e 719 (M+H)+.
Example 262 S Compound of Formula (IX): L is CO, T is N(NH~) R is -CH~CH=CHI
To a sample of the compound from Example 102, Step b (793 mg, 1.0 mmol) in 9:1 acetonitrile/water (10 mL) was added hydrazine (85 % aqueous solution, 0.50 mL, 10.0 mmol), and the mixture was stirred at room temperature under nitrogen for 4 days. The mixture was diluted with ethyl acetate, and the organic phase was washed with water and brine and dried (Na2S04). The solvent was removed, and the residue was purified by chromatography on silica gel, eluting with 5:95:0.5 methanol/dichloromethane/ammonium hydroxide to give the title compound (91 mg). MS m/e 654 (M+H)+.
Example 263 15 Compound of Formula (IX): L is CO, T is N(NH~), R is -CH~CH=CH-f3-quinol~
Following the procedures of Example 178, except substituting the compound from Example 262 for the compound from Example 177, the title compound was prepared. MS
m/e 781 (M+H)+. High Resolution FAB MS: calculated m/e for (M+Hj+ of C42H59N3010:
781.4176; Found: 781.4188.
Example 264 Compound of Formula (IX): L is CO, T is N(NH~) R is -CH~CH~,CH2~quinolvl) Following the procedures of Example 3, except substituting the compound from Example 262 for the compound from Example 3, the title compound was prepared.
MS m/e 768 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of C42H61N3010~
768.4435; Found: 768.4437.
Example 265 Compound of Formula (IX): L is CO, T is NI~~, R is -CH2CH=CH-naphthyl Following the procedures of Example 178, except substituting 1-bromonaphthalene for the 3-bromoquinoline of Example 178, the title compound was prepared. MS
m/e 764 (M+H)+.

Example 266 Compound of Formula (IX): L is CO. T is NHS, R is -CH2CH=CH-(3-l2-furanvl)-6 uinol 1 A mixtwe of a sample of the 2'-acetylated derivative of the compound of Example 219 (acetylated by the procedure of Example 177, Step a) (177 mg, 0.200 mmol), (tributylstannyl)furan (78 pL, 0.200 mmol) and Pd(triphenylphosphine)4 (23 mg, 0.020 mmol) in dry toluene was heated in a sealed tube at 60 °C to 90 °C for 20 hours. The mixtwe was then diluted with ethyl acetate, which was washed with aqueous 5%
sodium bicarbonate and brine and dried (Na2S04). The solvent was removed, and the residue was pwified by chromatography on silica gel, eluting with 1:1 acetone/hexanes to give the acetylated title compound. This material was stirred with methanol for 48 hours, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 95:5:0.5 dichlormethane/methanol/dimethylamine to give the title compound ( 102 mg).
MS m/e 832 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of _ t5 C46H61N3011: 832.4384; Found: 832.4384.
Example 267 Compound of Formula (IX): L is CO. T is NHS R~~CH=CH-(8-chloro-3-quinolyl) Following the procedures of Example 178, except substituting 8-chloro-3-20 bromoquinoline for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m!e 800 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+
of C42HggCIN3010: 800.3889; Found: 800.3890.
Example 268 25 Compound of Formula (1X): L is CO. T is N>Fh, R is -CH~CH=CH-(4-chloro-2-trifluoromethyl-6-quinolyl) Following the procedures of Example 178, except substituting 6-bromo-4-chloro-trifluoromethylquinoline for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 868 (M+H)+.
Example 269 Com,~ound of Formula (IX): L is CO. T is NHS, R is -CH?CH=CH-(2-fluorenyl) Following the procedures of Example 178, except substituting 2-bromofluorene for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e (M+H)+.

WO 98!09978 PCT/LJS97/15506 Example 270 Compound of Formula (IX): L is CO, T is NHS. R is -CH2CH=CH-(9-fluorenone-2-yl) Following the procedures of Example 178, except substituting 2-iodo-9-fluorenone for the 3-bromoquinoline of Example 178, the title compound was prepared. MS
m/e 817 (M+H)+. Anal Calcd for C4~H6pN2011 C, 67.63; H, 7.40; N, 3.43. Found C, 68.1 I; H, 8.08; N, 3.21.
Example 271 Compound of Formula (IX): L is CO, T is NHS R is -CH~CH=CH-(6-benzoyl-2-l0 na hth 1 Following the procedures of Example 178, except substituting 6-benzoyl-2-(triouoromethylsulfonyloxy)naphthalene (prepared from 6-benzoyl-2-naphthol by reaction with trifluoromethylsulfonic anhydride) for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 869 (M+H)+.
Example 272 Compound of Formula (IX): L is CO, T is NHS, R is -CH~CH=CH-(7-methox~!-2 na hth 1 Following the procedures of Example 178, except substituting 7-methoxy-2-20 (trifluoromethylsulfonyloxy)naphthalene (prepared from 7-methoxy-2-naphthol by reaction with trifluoromethylsulfonic anhydride) for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 795 (M+H)+. Anal Calcd for C44H62N2011~'0.5 H20 C, 65.73; H, 7.90; N, 3.48. Found C, 65.62; H, 8.06: N, 3.49.
2, Example 273 ComQOUnd of Formula (IX): L is CO. T is NHS, R is -CH~CH=CH-(3-phenyl-6-q_uinol~
A mixture of a sample of the 2'-acetylated derivative of the compound of Example 219 (acetylated by the procedure of Example 177, Step a) (177 mg, 0.200 mmol), Pd(triphenylphosphine)4 (11.5 mg, 0.010 mmol), CuBr (1.43 mg) and 30 (tributylstannyl)benzene (78.3 p.L) in dioxane (2 mL) was heated in a sealed tube at 100 °C
for 15 hours. The mixture was then diluted with ethyl acetate, which was washed with aqueous 5% sodium carbonate and brine and dried (Na2S04). The solvent was removed, and the residue was purified by chromatography on silica gel to give the acetylated title compound (77 mg). This material was stirred with methanol for 48 hours, and the solvent 35 was removed. The residue was purified by chromatography on silica gel to give the title compound (54.2 mg). MS m/e 842 (M+H)+.

Example 274 Compound of Formula (IX): L is CO, T is NHS, R is -CH~CH=CH-l3-(2-~~yl)-6 uinol 1 Following the procedures of Example 273, except substituting 2-(tributylstannyl)pyridine for the 2-(tributylstannyl)furan of Example 273, the title compound was prepared. MS m/e 841 (M+H)+.
Example 275 Compound of Formula (IX): L is CO, T is NHS, R is -CH~CH=CH-(3-f2-thionhen I
uinol I
Following the procedures of Example 273, except substituting 2-(tributylstannyl)thiophene for the 2-(tributylstannyl)furan of Example 273, the title compound was prepared. MS m/e 848 (M+H)+.
15 Example 27b Compound of Formula f1X): L is CO. T is NH?, R is -CH~CH=CH-t4-meth~naphthyl) Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 1-bromo-4-methylnaphthalene for the 3-bromoquinoline of Example 178, the 20 title compound was prepared. MS m/e 779 (M+H)+. High Resolution FAB MS:
calculated m/e for (M+H)+ of C44H62N2010~ 779.4483; Found: 779.4495.
Example 277 Compound of Formula (IX): L is CO. T is NHS,, R is -CH~CHCH-(6-(3-D-25 ag lactopyranos,~I-2-naphthyl) Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 6-bromo-2-naphthyl-(3-D-galactopyranoside (obtained from Sigma Aldrich) for the 3-bromoquinoline of Example I78, the title compound was prepared. MS m/e 30 (M+H)+.
Example 278 Compound of Formula(IX): L is CO, T is NHS, R is -CH~CH=CH-(7-c~uinol~
Following the procedures of Example 178, except substituting the 2'-benzoylated 35 compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 7-(trifluoromethylsulfonyl)quinoline for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 766 (M+H)+.

WO 98!09978 PCTILTS97I15506 Example 279 Compound of Formula (IX): L is CO, T is 1\rH2. R is -CH~CH=CH-(4-fluoronaphth~
Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 1-bromo-4-fluoronaphthalene for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 783 (M+H)+. High Resolution FAB MS:
calculated m/e for (M+H)+ of C43HS9FN20tp: 783.4227; Found: 783.4223.
Example 280 Compound of Formula (IX): L is CO. T is NH7, R is -CH~CH=CH-(3-biphenyl) Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 3-bromobiphenyl for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 791 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of C45H63N2010: 791.4483; Found: 791.4492.
Example 281 Compound of Formula (IXI: L is CO. T is NHS. R is -CH2CH=CH-(5-nitronaphthyl) Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting I-bromo-S-nitronaphthalene for the 3-bromoquinoline of Example 178, the title compound was prepared.
Example 282 Compound of Formula (IXI: L is CO, T is NHS, R is -CH~CH=CH-(4-pyrrolvlyhen~
Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 1-(4-iodophenyl)pyrrole for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 780 (M+H)+. High Resolution FAB MS: calculated m/e for (M+H)+ of C43H~tN301p: 780 .4430; Found: 780 .4424.
Example 283 Compound of Formula (IX): L is CO. T is NHS. R is -CH~CH=CH-(b-methoxy-2-na hth l Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 2-bromo-6-methoxynaphthalene for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 795 (M+H)+. High Resolution FAB MS:
calculated m/e for (M+H)+ of C44H~2N2011: 795 .4426; Found: 795 .4426.
Example 284 Compound of Formula (IX): L is CO, T is NH~~R is -CH~CH=CH-(3,5-dichloronhen Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 1,3-dichloro-5-iodobenzene for the 3-bromoquinoline of Example 178, the title t0 compound was prepared. MS m/e 783 (M+H)+. High Resolution FAB MS:
calculated m/e for (M+H)+ of C39HS~C12N20~p: 783 .3390; Found: 783 .3392.
Example 285 Compound of Formula lIX): L is CO, T is NHS. R is -CHI-(3-iodonhenyl) 15 Following the procedures of Example I, steps a-f, except substituting the 3-iodobenzyl bromide for the allyl bromide of Example 1, Step a, to prepare the compound 9 from Scheme 1b, wherein R is 3-iodophenylmethyl and RP is benzoyl, then treating that compound according to the procedures of Example 102, the title compound was prepared.
MS m/e 815 (M+H)+.
Example 286 Compound of Formula (IX): L is CO. T is NHS, R is -CH2-(3-(2-furanvl)phenyl) Following the procedures of Example 266, except substituting the compound of Example 285 for the compound from Example 265, the title compound was prepared. MS
m/e 689 (M+H)~.
Example 287 Compound of Formula (IX): L is CO, T is NHS. R is -CH~CH=CH-(6-h~y-2 na hth 1 3o Following the procedures of Example 178, except substituting the 2'-benzoylated compound of Example 102, Step c for the 2'-acetylated compound of Example 177 and substituting 6-bromo-2-naphthol for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 781 (M+H)+.

Example 288 Compound of Formula (IX): L is CO, T is NHS, R is -CH2CH=CH-(6-(2-bromoethox~
2-naphthyl) Following the procedures of Example 178, except substituting 6-bromo-2-(2 bromoethoxy)naphthalene for the 3-bromoquinoline of Example 178, the title compound was prepared. MS m/e 887 (M+H)+.
Example 289 Compound of Formula (IX): L is CO, T is NHS, R is -CH~CH=CH-(6-(2-Stetrazolvl)ethoxv-2-naphthyl) To a sample of the compound from Example 288 (371 mg, 0.4 mmol) in acetonitrile (4 mL) was added tetrazole (138 mg, 2 mmol) and triethylamine (0.556 mL, 4 mmol), and the mixture was heated at 60 °C under nitrogen overnight. The volatiles were removed under vacuum, and the residue was dissolved'in ethyl acetate. This solution was washed with 5 % aqueous sodium bicarbonate and brine, dried (NazSOa), and concentrated. The residue was purified by chromatography on silica gel, eluting with 97:3:0.5 dichloromethane/methanol/ammonium hydroxide. This product was stirred in methanol at room temperature for 2 days, then the product was purified by chromatography on silica gel, eluting with 99:1:0.5 dichloromethane/methanol/ammonium hydroxide. MS m/e (M+H)+.
Examgle 290 Compound of Formula (IX): L is CO, T is NHS, R is -CH~CH=CH-naphtha Following the procedures of Example 178, except substituting 1-bromonaphthalene ?5 for the 3-bromoquinoline of Example 178, the title compound was prepared.
MS m/e xxx (M+H)+.
Example 291 Compound of Formula (IX): L is CO. T is NH, R is -CHI-C=C-(2-phen ley then~rl) Following the procedure of Example 247, except substituting beta-bromostyrene for 3-bromoquinoline. MS (ESI) m/e 739 (M+Ifi)+.
Example 292 Compound of Formula (IX): L is CO, T is NH, R is -CH2-CH=CH-(5-(3-isoxazolyl)-thiophenyl) Ste~292a. Compound 37 from Scheme 7 wherein RBB is OH

To 11.8 mL (11.8 mmol) borane-THF complex (1 molar solution in tetrahydrofwan) at -1(>°C was added 2-methyl-2-butene (2.7 mL, 24 mmol). The reaction was stirred at 0 °C for 2 hours and a separately prepared solution containing the compound from Example 246, Step h (Compound 6E from Scheme 1 c; RP is acetyl, R is -CH2-C---C-H, 2 g, 2.95 mmol) in 10 mL tetrahydrofwan was then added in one portion. The reaction was stirred at 0 ~C for 1 how and was warmed to ambient temperature. After 3 hours the reaction was recooled to 0 ~C and 5% aqueous sodium carbonate was added. The mixture was extracted with ethyl acetate, and the organic layers were washed with brine and dried over magnesium sulfate. Concentration and drying in vacuo gave 3.6 grams of crude product which was purified with silica gel chromatography eluting with acetone/hexanes ( 1:1 ) to provide the title compound (0.85 g, 40%).
Step 292b. Compound of .Formula (IX): L is CO, T is NH, Rc is acetvl, R is -CH_~-CI-1=CH-l5-(3-isoxazolyll-2-thio~hen~
> > A pressure tube equipped with a stir bar was charged with 100 mg (0.138 mmol) of the compound resulting from Step 292a , potassium carbonate (42 mg, 0.3 mmol) 2-bromo-5-(isoxazol-3-yl)thiophene (48 mg, 0.21 mmol), palladium (II) acetate (0.15 mg, 0.7 mmol), 0.75 mL acetone and 0.75 mL water. Two freeze-pump-thaw cycles were performed to degas reaction. The reaction tube was then sealed under nitrogen and heated at 65 ~C for 2 hours. The mixture was diluted with ethyl acetate and washed successively with water then brine. Organic extracts were dried over magnesium sulfate, concentrated in vacuo, and dried to constant weight with high vacuum to provide 140 mg of crude product.
Step 292c. Compound of Formula IIXI: L is CO, T is NH, R is -CHI-CH=CH-l5-~3-isoxazolvl)-2-thiophenyl) The compound resulting from Step 292b (140 mg) was dissolved in 5 mL methanol, and the solution was stirred at ambient temperature for 20 hours. The solution was concentrated in vacuo and dried to constant weight. The crude product was purified with silica gel chromatography eluting with 98: 1:l dichloromethane/methanol/ammonium hydroxide to give 34 mg of the title compound. High Resolution FAB MS:
calculated m/e for (M+H)+ : C4pHggN3011S: 788.3792 Observed: 788.3809.
Example 293 Compound of Formula (IX): L is CO, T is NFI. R is -CH2-CH=CH-f 1,3-dimethyl-2,4-dioxo-5-pyrimidinyl) Following the procedwes of Example 292, except substituting 5-bromo-1,3-dimethyiuracil for 2-bromo-5-(isoxazol-3-yl)thiophene, the title compound was prepared.

High Resolution FAB MS: calculated m/e for (M+H)+ : C39H~tN4012: 777.4286.
Observed m/e: 777.4291 Example 294 Compo nd of Formula (1X): L is CO, T is NH, R is -CHI-CH=CH-~5-(2-~~idyllaminocarbonyl-2-fura~ll Following the procedures of Example 292, except substituting 5-bromo-furan-2-carboxylic acid pyridin-2-yl-amide for 2-bromo-5-(isoxazol-3-yl)thiophene the title compound was prepared. MS (ESI)+:(M+H)+@ m/e 825.

Claims (21)

CLAIMS:

1. A compound of formula (V):

or a pharmaceutically acceptable salt thereof, wherein:
R b is selected from the group consisting of hydroxy, -O-C(O)-NH2, and -O-C(O)-imidazolyl;

R c is hydrogen or a hydroxy protecting group; and R is selected from the group consisting of (1) methyl substituted with a moiety selected from the group consisting of (a) -C .ident.N, (b) -F, (c) -CO2R10, where R10 is aryl-substituted C1-C3-alkyl or heteroaryl-substituted C1-C3-alkyl, (d) -S(O)n R10 where n is 0, 1 or 2 (e) aryl, (f) substituted aryl, (g) heteroaryl, and (h) substituted heteroaryl, (2) C2-C10-alkyl substituted with one substituent selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) -N3, (f) -NR13R14, where R13 and R14 are selected from the group consisting of:
(i) hydrogen, (ii) C1-C12-alkyl, (iii) C3-C12-alkenyl, (iv) C3-C12-alkynyl, (v) aryl, (vi) C3-C8-cycloalkyl, (vii) substituted aryl, (viii) heterocycloalkyl, (ix) substituted heterocycloalkyl, (x) C1-C12-alkyl substituted with aryl, (xi) C1-C12-alkyl substituted with substituted aryl, (xii) C1-C12-alkyl substituted with heterocycloalkyl, (xiii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xiv) heteroaryl, (xv) substituted heteroaryl, (xvi) 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 membered heterocycloalkyl ring which may be substituted with one substituent 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 (viii) C1-C3-alkoxy-C1-C3-alkyl, (g) -CO2R10, (h) =N-O-R10, (i) -CN, (j) -O-S(O)n R10, where n is 0,1 or 2, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C1-C12-alkyl substituted with heteroaryl, (p) heterocycloalkyl, and (q) substituted heterocycloalkyl, (3) C3-alkenyl unsubstituted or substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10, (d) -C(O)-R9, (e) -C(O)NR11R12, (f) -CN, (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 substituent selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10, (f) -C(O)NR11R12, (g) -NR13R14, (h) =N-O-R10 (i) -CN, (j) -O-S(O)n R10, where n is 0,1 or 2, (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 (r) -NHC(O)NR11R12, (s) =N-NR13R14, (t) =N-R9, (u) =N-NHC(O)R10, and (v) =N-NHC(O)NR11R12, (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, and (e) substituted heteroaryl;

wherein:
R9 is selected from the group consisting of:

(i) C1-C6-alkyl optionally substituted with a substituent selected from;
(aa) aryl, (bb) substituted aryl;
(cc) heteroaryl, and (dd) substituted heteroaryl;

(ii) aryl;

(iii) substituted aryl;
(iv) heteroaryl, (v) substituted heteroaryl; and (vi) heterocycloalkyl; and R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

2. A compound according to claim 1 of formula (VI).

or a pharmaceutically acceptable salt thereof, wherein R is as defined in claim 1.

3. A compound according to claim 2 selected from the group consisting of compound of formula (VI) wherein: R is -CH2CH=CH, compound of formula (VI) wherein: R is -CH2CH=CH-phenyl, compound of formula (VI) wherein: R is -CH2CH2CH2-phenyl, compound of formula (VI) wherein: R is -CH2CH2NH2, compound of formula (VI) wherein: R is -CH2CH2NHCH2-phenyl, compound of formula (VI) wherein: R is -CH2CH2NHCH2-(4-pyrdidyl), compound of formula (VI) wherein: R is -CH2CH2NHCH2-(4-quinolyl), compound of formula (VI) wherein: R is -CH2C.ident.N, compound of formula (VI) wherein: R is -CH2CH=CH-(4-methoxyphenyl), compound of formula (VI) wherein: R is -CH2CH=CH-(4-chlorophenyl), compound of formula (VI) wherein: R is -CH2CH=CH-(4-fluorophenyl), compound of formula (VI) wherein: R is -CH2CH=CH-(3-quinolyl), compound of formula (VI) wherein: R is -CH2CH=CH-(8-quinolyl), and compound of formula (VI) wherein: R is -CH2CH2NHCH2CH2-(2-chlorophenyl), or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 2 wherein: R is -CH2CH=CH, or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 2 wherein: R is -CH2CH=CH-phenyl, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 2 wherein: R is -CH2CH2NH2, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 2 wherein: R is -CH2CH2NHCH2-phenyl, or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 2 wherein: R is -CH2CH2NHCH2-(4-pyrdidyl), or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 2 wherein: R is -CH2CH2NHCH2-(4-quinolyl), or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 2 wherein: R is -CH2C.ident.N, or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 2 wherein: R is -CH2CH=CH-(4-methoxyphenyl), or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 2 wherein: R is -CH2CH=CH-(4-chlorophenyl), or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 2 wherein: R is -CH2CH=CH-(4-fluorophenyl), or a pharmaceutically acceptable salt thereof.

14. A compound according to claim 2 wherein: R is -CH2CH=CH-(3-quinolyl), or a pharmaceutically acceptable salt thereof.

15. A compound according to claim 2 wherein: R is -CH2CH=CH-(8-quinolyl), or a pharmaceutically acceptable salt thereof.

16. A compound according to claim 2 wherein: R is -CH2CH2NHCH2CH2-(2-chlorophenyl), or a pharmaceutically acceptable salt thereof

17. A pharmaceutical composition comprising a compound of formula (V), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

18. Use of a compound of formula (V), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for preparation of a medicament for controlling bacterial infection.

19. A compound of formula (V), according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in controlling bacterial infection.

20. An antibacterial pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (V), as defined in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

21. A process for preparing a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
R b is selected from the group consisting of hydroxy, -O-C(O)-NH2, and -O-C(O)-imidazolyl;
R c is hydrogen or a hydroxy protecting group; and 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, where R10 is aryl-substituted C1-C3-alkyl or heteroaryl-substituted C1-C3-alkyl, (d) -S(O)N R10, where n is 0, 1, or 2, (e) aryl, (f) substituted aryl, (g) heteroaryl, and (h) substituted heteroaryl, (2) C2-C10-alkyl substituted with one substituent selected from the group consisting of (a) halogen, (b) hydroxy, (c) C1-C3-alkoxy, (d) C1-C3-alkoxy-C1-C3-alkoxy, (e) -N3, (f) -NR13R14, where R13 and R14 are selected from the group consisting of:
(i) hydrogen, (ii) C1-C12-alkyl, (iii) C3-C12-alkenyl, (iv) C3-C12-alkynyl, (v) aryl, (vi) C3-C8-cycloalkyl, (vii) substituted aryl, (viii) heterocycloalkyl, (ix) substituted heterocycloalkyl, (x) C1-C12-alkyl substituted with aryl, (xi) C1-C12-alkyl substituted with substituted aryl, (xii) C1-C12-alkyl substituted with heterocycloalkyl, (xiii) C1-C12-alkyl substituted with substituted heterocycloalkyl, (xiv) heteroaryl, (xv) substituted heteroaryl, (xvi) 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 membered heterocycloalkyl ring which may be substituted with one substituent 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 (viii) C1-C3-alkoxy-C1-C3-alkyl, (g) -CO2R10, (h) =N-O-R10, (i) -CN, (j) -O-S(O)n R10, where n is 0,1 or 2, (k) aryl, (l) substituted aryl, (m) heteroaryl, (n) substituted heteroaryl, (o) C1-C12-alkyl substituted with heteroaryl, (p) heterocycloalkyl, and (q) substituted heterocycloalkyl, (3) C3-alkenyl unsubstituted or substituted with a moiety selected from the group consisting of (a) halogen, (b) -CHO, (c) -CO2R10, (d) -C(O)-R9, (e) -C(O)NR11R12, (f) -CN, (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 substituent selected from the group consisting of (a) halogen, (b) C1-C3-alkoxy, (c) oxo, (d) -CHO, (e) -CO2R10, (f) -C(O)NR11R12, (g) -NR13R14, (h) =N-O-R10, (i) -CN, (j) -O-S(O)n R10, where n is 0,1 or 2, (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, (r) -NHC(O)NR11R12, (s) =N-NR13R14, (t) =N-R9, (u) =N-NHC(O)R10, and (v) =N-NHC(O)NR11R12, (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, and (e) substituted heteroaryl;

wherein:

R9 is selected from the group consisting of:

(i) C1-C6-alkyl optionally substituted with a substituent selected from;
(aa) aryl;

(bb) substituted aryl;
(cc) heteroaryl, and (dd) substituted heteroaryl;

(ii) aryl;

(iii) substituted aryl;
(iv) heteroaryl, (v) substituted heteroaryl; and (vi) heterocycloalkyl; and R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

the process comprising:
(a) treating a compound of formula:

wherein R c is a hydroxy protecting group, with a reagent combination selected from the group consisting of:

(1) an alkali metal hydride and a reagent selected from the group consisting of phosgene, diphosgene, and triphosgene, under anhydrous conditions, followed by aqueous base catalyzed decarboxylation, and (2) reaction with methanesulfonic anhydride in pyridine followed by treatment with an amine base to give the compound of formula V, where R b is hydroxy;
(b) optionally treating the compound of formula V of step (b) with an alkali metal hydride base and carbonyldiimidazole to give the compound of formula V, where R b is -O-C(O)-imidazolyl;
(c) optionally treating the compound of formula V of step (a) with an amine to give the compound of formula V, where R b is -O-C(O)-NH2;
(d) optionally deprotecting and isolating the desired compound; and (e) when a salt of compound of formula V is required, converting a compound of fornula (V) obtained to a corresponding pharmaceutically acceptable salt thereof.