CA2118324A1 - Substituted indolizino¬1,2-b|quinolinones - Google Patents

Abstract

The present invention provides a method of treating viral infections by using antiviral substituted indolizinol[1,2-b]quinolinone compounds, and pharmaceutical compositions thereof.

Description

wo 93/20818 ,~ 1 1 ;} ~ Pcrtusg3/03s96 SUBSllTU'TE,D INDOLIZINO[ 1 ,2--b]QUINOLINONE,S

Th,is application is a continuation-in-part of U.S. Serial No. 07/870,649, filed on April 17, 1992, which is a continuation-in-part of U.S. Serial No.
07n83.063. filed on Octo,ber 25, 1991, which is a continuation-in-part of U.S.
Serial No. 07/606,216, filed on, October 31, 1990.
~ Sco~e of the Invention 'This invention relates to methods of treating v*al infections, antiviral compounds, and pharmaceutical çompositions thereof. More specifically, this 16 invention relates to a method of treating viral infections, certain indolizino[I,2-b]quinolinyl derivatives which have antiviral activity and 1.
pharmaceutical compositions thereo~.
',~
Back,~round -Certain lH-pyrano[3',4':6,?~indolizino[1,2-b]quinolinones are known tO have cytotoxic and antiviral activity. Carnptothecin is an example of such compounds. lt -is a water-insoluble, cytotoxic alkal,oid produced by Campto~eca acuminata treesindigenous to China ,and Notha,~,od,vtes f~tida trees indigenous to India.
25 Cam~to~he~i~and its~close congeners are known to inhibit eukaryotic topoisomerase I. In-fact, the cytotoxic and andtumor activity of carnptoth,ecin and its close congeners results from inhibition of eukaryotic topoisomerase I (Ca,ncer Res. 19,~, 48, 1722, Mo,lec. Phar,macol. 1988, 34, 755). Compounds that are related in structure to c~m,ptoth,ecin but do not inhibit eukaryotic topoisomerase I are not 30 cy~otoxic to mammalian cells and have no antitumor activity (J. Med. Chem. 1988, 32,:~15;~Cancer Res. 1989, 49, 1465; Cancer Res. 1989, 49, 4358).
A number of investigators have shown that camptothecin possesses antiviral acivity. However, although camptothecin has demonstr~ted antiviral activity in in vitro tissue culture systems. camptothecin and its close analogs that have a 3~ hydroxylactone moiety cannot be considered as useful in ~ivo antiviral agents W O 93/20818 21 1 ~32 1 PC~r/US93/03S96 because they undesirably inhibit mammalian topoisomerase I, as well as host cellDNA replication, and are cytotoxic to mammalian cells. Furthermore, camptothecinis not an attractive candidate for drug development as an antiviral agent because of L
unacceptable dose-limiting toxicity, unpredictable toxicity, and poor aqueous solubility, andlor unacceptable shelf life stability.
There is a need for new antiviral agents. Substituted indolizino[1,2-b]quinolinones that lack the a-hydroxylactone moiety oÇ
camptothecin have been shown to be non-cytotoxic to mammalian cells and to lack antitumor activity (Ann. Rev. Pharmcol. Toxicol. 1977, 17, 117; J. Med. Chem.
1989, 32, 715). This is because these compounds do not contain the essential structural features re~uired to inhibit eukaryotic topoisomerase I. However, recently we have found that certain substituted indolizino[1,2-b]quinolinones lacking the a-hydroxylactone moiety do have antiviral activity but not the undesirable cytotoxicity of camptothecin. Thus, such substituted indolizino[1,2-b]quinolinones are usefulfor treating viral infectlons.

S~,J~IAR,~I~ INVENTIQN

One aspect of the present invention provides a method for treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharrnaceutically acceptable salt thereoÇ, alone or in combination with a calTier -g , R R

R ` ~ ~y I
whcrein:

R7 is -H, -CN, Iower alkyl or -(CH2)nCH2V where n=0-3;

wo 93/20818 ~ 3 ~ Pcr/us93/o3596 R9 IS -H, -OR, -NRRl, -CN, -(CH2)nCH2V where n=0-3; -R10is-H,-OR,-NRRl,-CN,-COR12,-CH(OH)R12,-0-(CH2)1 sCH2NRR1, -OC(O)NRRI, 1,4' bipiperidine-1'-carboxy, -(cH2)ncH2v where n~0-3;

Y is -OH, -oCoR14 OP(O)(OH)R15 or -NRR1; -R11 is -H or -OR;

R12 is -H or lower alkyl;

R13 is loweralkyl; ~:

R and R1 are independently selected from the group consisting of -H, -C
1~ alkyl, and, when R and R1 are substituted on nitrogen, R and R1 can be ¦ ~ ~
taken together to form a 5-7 membered saturated heterocyciic ring - .
containing the nitrogen; : :

R14 iS CR12R16R17;
-(CH2)nCH2Rl7 (where n=1-33; ;~

~J;

2~

3 ( ~H2R

..
- (where n=0 or 1, and CH2R17 can be substituted on the 30 phenyl at the 2, 3, or 4 position);

wo 93/20818 Pcr/us93to3s96

- 4 -o(CH2)nCH2R17 (where n = 1-3);
-NRR1;
6 -NH(CH2)nCH2R17 (where n = 1-3);
R15 is OH, OR18 or CH2NH2;

R16 is H or the side ehain of any naturally occuring a-amino acid;

R17 is NRR1 ~) N~N --N3N~
where X is any pharmaceutically acceptable anion;
i R18 is lower alkyl;
16 ~O

X is -CH(OH)CH(OH)CH3, ~CHR3R4 or 6 Y is -CH3 or -CH20R2;

_ R2 is -H, -C(O)H, -CoR14~ or -P(O)(OH)R1S;

- ~-~ ~ R3 is -OH, -oCoR14, or -oP(o)(oH)R15;
, R4 is -H, lower alkyl, or -OR; and R6 is -H or lower alkyl.

- provided that: -a) if one of R7, R9, R10 or R11 is other than -H, only one of the others may be other than -H;
b) only one of R7, R9, R10 or R1 I may be -NRR1;

WO93/20818 21 t ~ i! PCl'~US93/03596 c) when X is -CHR3R4 and R4 is -OR, R3 is -OH;

d) when Y is -CH20R2, X is R

This invention also provides compounds having the formula of Formula I as described hereinabove, except that: ;

a~ when R7, R9, R10, and Rl l are all -H and Y is -CH3, then X is not -C(O)H, -CH20H, -C(O)CH2CH3. or-CH(OH)CH2CH3; and b) when R7, R9, R10 and Rl 1 are all -H ar~d Y is -C~20C(O)H, then X
is not -C(O)CH2CH3.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier or excipient. ¦
In yet another aspect, the present invention relates to processes for making a compound of Forrnula I.
.
DETALED DESCRIPllON OF THE INV~NTION
, 2û The following definitions are used throughout this patent application._ _ !
"Aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains ¦
where both double and triple bonds may be present in any combina~ion. The phrase"lower alkyl" and "C1 6 alkyi'~ refer to an alkyl group of l to 6 carbon atoms in any isomeric form, but particularly the normal or linear forrn. "Lower alkoxy" meansthe group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo. "Acyl"
means the radical having a terminal carbonyl carbon.
The phrase "5-7 membered saturated heterocyclic ring containing the nitrogen" is intended to include saturated rings such as piperidine, pyrrolidine, molpholine, piperazine, and~N-alkyl piperazine.

wo 93~20818 Pcr/us93/~3596 The ~erm " l ,4'-bipiperidine- l '-carboxy" is used to identify the following radical:

~ ~N~ N--C--O--Salts of any sort may be made from these compounds, provided that an acidic group or a sufficiently basic nitrogen is present in the compound. Particularly preferred are the phamnaceutically acceptable salts of the instant compounds. These salts are defined as those which are acceptable in their application to a 10 pharmaceutical use, meaning that the salt will retain the biological activity of the parent compound and that the salt wi1l not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are propared in a standard manner. The parent compound, in a suitable solvent, is reacted with an excess of an organic or 15 inorganic acid in the case of acid addition salts of a base moiety; or an excess of organic or inorganic base in the case where the parent contains an acid group.
Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, màleic acid, succinic acid and methanesulfonic acid.
Cadonic salts are readily prepared from alkali metals such as sodium, potassium,- 20 calcium, magnesium, zinc, copper or the like as well as ammonia. Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, and the like.
- _ - The chemic~l nomenclature used tbroughout this patent application to name the compounds of the present invention is in accordance with the structural formula 25 rèpresented as Formula II.

y ' ~ ~

6 7 II ~

WO93/20818 f l 3 ', ci 2 ~': PCI/US93/03596 In the event that some combination of substituents creates a chiral center or another form of an isomeric center in a compound of this invention, all fonns of such ;
isomer(s) are considered to be aspects of the present inventions. When a compound of the present invention contains a chiral center, the present invention includes the ~ -racemic mixture, the pure enantiomers, and any enantiomerically enriched mixturethcreof.
The present invention provides a method of treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I as described hereinabove, or a phannaceutically acceptable salt thereof, alone or in combination with a carrier or excipient.
The present method is useful for treating viral infections in animals, particularly mammals, most pàrticularly humans, caused by a broad vanety of DNA
replicating animal viruses. The present method is particularly useful in treating viral infechons caused by herpes simplex virus, particularly herpes simplex virus typc 1 (HSV1 ) and herpes simplex virus type 2 (HSY2), varicella zoster virus ¦ ~
(VZV), or cytomegalovirus (CMV) when the infected host is a mammal, ~ -par~icuiarly when the infected host is~human.
A preferred method of treating viral infections according to the present invention uses compounds of Formula IM1 20 _ "
~ y ~0 X is -CH(OH)CH(O~)(~H3, -CHR3R4, or R; and Y is -CH3 or -CH20R2, 25 Fo~mula IMl co~esponding to Folmula I wherein R7, R9, R10, and R1 } are each -H and X and Y arc as ~esclibed herein. A more preferred method uses compounds of Forrnula IMl~wlrere X is CHR3R4 where R3 is -OH, oCOR14 or ~0 oP(o)(oH)R~5 and Y is -CH3, where X is R where R6 is -H or lower alkyl and Y is -CH3 or -CH20R2, or where X is -CH(OH)CH(OH)CH3 and Y is -CH3.

WO 93/20818 1 8 - P~r/US93~03596 ~ "

Ano~her preferred method for ~eating viral infections according to the present invention uses compounds of Formula IM2 R

Formula IM2 corresponding~to Formula I wherein R7, R9, and Rl 1 are each H, R10 :~
is as defined hereinabove for Fo~nula I except that R l0 is not -H, and X and Y are ~:
as defined hereinabove in Fonnula I. A more preferred method uses compounds of Formula IM2 where R10 is -OR, -CN, COR12, or -(CH2)nCH2V; or X is -CHR3R4 where R3 is -OH. oCORl4 or OP(O)(OH)Rl5 and R4 is -H or lower alkyl and Y is -CH3. or X is R where R6 is -H or lower alkyl and Y is -CH3 or CH20R2.
Yet another preferred method of use according to the present invention uses compounds of Pormula IM3 R

Y

.
, .
- - Fonnula IM3 corresponding to Formula I wherein R7 and Rl 1 are each I :
- 20 -H, R9 and R10 are as defined hereinabove for Fo~nula I except that R9 and R10 ~ j :
=- - are each not -H, and X and Y are as defined hereinabove in Formula I. A more preferr~d method uses compounds of Formula IM3 wherein R9 is -(CH2)nCH2V, Rl0 is -OR, X is CHR3R4 where R3 is -OH, oCORl4 or OP(O)(OH)Rl5 and R4 is Wo 93/20818 '~ Pcr/uss3/o3~96 _~0 -H or lower alkyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2.
Another prefeIred method of use according to the present invention uses compounds of Formula IM4 C, '~`

IM4 -~

Fonnula IM4 co~esponding to Formula I wherein R9, R10 and Rl 1 are each -H, R7 10 is as defined hereinabove except that R7 is not -H, and X and Y are as defined hereinabove in Fo~mula 1. A more prefe~red method uses compounds of Formula IM4 where R7 is lower alkyl, -CN, or -(CH2)nCH2V; X is CHR3R4 where R3 is -OH, oCOR14 or OP(O)(OH~R15 and R4 is -H or lower alkyl, or X is R
where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2.
Yet another prefe~ed method of use according to the present invention uses compounds of Fonnula IM5 ~0 Formula IM5 corresponding tO Formula l wherein R7, R10 and Rl 1 are wo93~2û818 21 ~ /13 PCr/US93/03596 -H, R9 is as defined hereinabove for Forrnula I except that R9 is not -H, and X and Y are as defined hereinabove in Forrnula I. A more preferred method uses compounds of Fonnula IM~ where R9 is -OR, X is CHR3R4 where R3 is -OH, ~0 oCOR14 or OP(O)(OH)Rl5 and R4 is -H or lower alkyl, or X is R where R6

5 is -H or lower alkyl, and Y is -CH3 or CH20R2 Still another preferred method of use according to the present invention uses compounds is represented by Fonnula IM6 ~" J `~ y Fonnula IM6 corresponding to FoImula I wherein R7, R9 and R10 are each H, Rl 1 is -OR, and X and Y are as deflned hereinabove in Fonnul~ I. A more prefeIIed method uses compounds of Formula IM6 where R11 is OR, X is CHR3R4 where R3 ¦ -~0 15 is -OH, oCORl4 or OP(O)(OH)R15 and R4 is -H or lower alkyl, or X is R
where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2. - ~ :;
The present invention also provides compounds having antiviral activity, and pharmaceutically acceptable salts thereof, said compound having the structure -~
- --represented by Forrnula I hereinabove except that:
2~ ~ ~ a) when R7, R9, Rl0, and R l 1 are all -H and Y is -CH3, then X is not -C(O)H, -cH2oH~ -CH(OH)CH(OH)CH3, -C~O)CH2CH3, or -CH(OH)CH2CH3; and b) when R7, R9, R10 and Rl 1 are all -H and Y is -CH20C(O)H, then X
is not -C~O)CH2CH3. ~ . .
- , wo 93/20818 ~ Pcr/uss3/o3s96 Prefe~Ted compounds of the present invention include those of Formula IN1 I ~ y

6 IN1 Formula IN1 corresponding to Formula I wherein R7, R9, R10 and Rl 1 are each -H, ~0 X is R where R6 is -H or lower alkyl, and Y is CH3 or CH20R2 (provided R6 is not -CH2CH3 when Y is -CH3) or X is CHR3R4 where R3 is -OH, oCORl4 10 or OP(O)(OH)R lS and R4 is -H or lower alkyl (provided that R4 is not -CH2CH3 when R3 is OH), and Y is -CH3.
Compounds of Formula IN2 are also preferred according to the present invennon o ~ "1 ~

- Foiniula IN2 colTesponding to Formuia I wherein R7, R9 and Rl 1 are each -H, R 10 is as desc~ibed hereinabove for Forrnula I except that R10 is not -H, and X and Y
are as defined hereinabove for Formula I. More prefe~Ted compounds of Fonnula ~2 include those-where-R1~ is -OR, -CN, -COR12, or ^(CH2)nCH2V, and X is CHR3R4 where R3 is -OH, oCOR14 or OP(O)(OH)R15 and R4 is -H or lower Q, alkyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3 or CH20R2.
Another pFeferred group of compounds of the present invention is represented by Forrnula IN3 wo 93/20~18 Pcr/us93/03~96 21~ 8 ` ~

R ~ 12-Formula I~3 co~responding to Formula I wherein R7 and R l l are each -H, R5~ and5 R10 are as descnbed hereinabove for Formula I except that R9 and R 10 are not -H, and X and Y are as defined hereinabove for Formula I. More prefe~red compounds of Fo~mula IN3 include those where R9 is -(CH2)nCH2V, R10 is -OR, X is CHR3R4 where R3 is -OH, oCOE~l4 or oP(o)(oH)R15 and R4 is -H or lower ;-~6 1 ~-yl, or X is R where R6 is -H or lower aL~cyl, and Y is -CH3 or CH;~OR2.
S~ll another prefeTred group of inven~ve compounds is represented by Fonnula IN4 :
R

IN4 :~
.

Formula IN4 corresponding to Formula I wherein R9, R10 and Rl 1 are each -H, R7 ~;
is as desc~ibed hereinabove for Formula I except that R7 is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN4 include those compounds where R7 is lower aL~cyl, -CN, or -(CH2)nCH2V; X is CHR3R4 where R3 is -OH, oCOR14 or oP(o~(oH)R15 and R4 is -H or lower ~
20 aLtcyl, or X is R where R6 is -H or lower alkyl, and Y is -CH3.

WO 93/20818 r~ ~ PCI /US93/03596 Another preferred group of compounds according to the present invention is represented by Formula IN5 _~Y

~ IN5 -, .
Formula IN5 corresponding to Fonnula 1 wherein R7, R10 alld R11 are each -H, R9 is as described hereinabove for Formula I except that R9 is not -H, and X and Y are :~
as defined hereinabove for Formula I. More prefe~ed compounds of Formula IN5 j :
include those compounds where R9 is -OR, X is CHR3R4 wh`ere R3 is -OH, oCOR14 or OP(O)(OII)R15 and R4 is -H or lower aLIcyl, or X is R where R6 , ~
is -H or lower alkyl, and Y ls -CH3 or CH20R2 ~ `
Yet a further group of preferred compounds is represented by Formula IN6 R ~ ~ Y
=
- - - - X

Formula I~6 correspondmg to ~ormula I wherein R7, R9 and Rl0 are each -H, R
is -OR, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN6 ar-e compounds where R 1 1 is -OR, X is CHR3R4 where R3 is -OH, oCOR14 or oP(o)(o~)R15 and R4 is -H or lower aLkyl, or X is R where R6 is -H or~lower alkyl, and Y is -CH3 or CH20R2 WO 93/20818 PCr/US93/03596 f`~ 3 2 ~;

The following compounds are particularly preferred:

7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino[172-b]quinolin-9(1 1~)-one;

5 7-[1-[(3-arnino- 1-oxopropyl)oxy]propyl]-8-methylindolizino [ 1 ,2-b]quinolin-9( 1 lH)-one;

8-methyl-7- [ 1 -[(2-pyITolidinylcarbonyl)oxy]propyl]indolizino -[1,2-b]quinolin-9(1 lH)-one; ~-' ''''''' 7-[1 -~2-amino-3-( lH-imidazol-4-yl)- 1 -oxopropyl]oxy]propyl]-8-methylindolizino[ 1 ,2-b]quinolin-9( 1 lhr)-one; ~:

7-[1-[(2-arnino-3-methyl- 1 -oxobutyl)oxy]propyl]-8-methylindolizino . -: 15 [1 j2-b]quinolin-9(1 1H)-one;

7-[1-[(2-amino-2-methyl-1-oxopropyl)oxy]propyl3-8-me~hylindolizino[1 ,2-b]quinolin-9(1 lH)-one; j 20 7-[1-~(aminoacetyl)oxy]propyl]-2-cyano-8-methylindolizino-[1,2-b]quinolin-9(1 l*')-one;

8-methyl-7-[ 1 -[[(2-pyrrolidinylcar~onyl)aminoacetyl]oxy]-propyl]indolizino[ 1 ,2-b]quinolin-9( 1 1H~-one;
8-methyl-7-[ 1 -~[(dimethylamino)acetyl]oxy]propyl]indolizino[ 1 ,2-b]quinolin-

9(1 lH)-one;

- - 7-[1-[[(1 ,4'-bipiperidin- 1 '-yl)acetyl]oxy]propyl]-8-methylindolizino[ 1 ,2-b]quinolin-30~ 9(1 lH)-one;

- ~ 8-methyl-7-[1 -[(4-morpholinylace~yl)oxy]propyl]indolizino[1,2-b]quinolin-9(1 lH)-one;

WO93/20818 `~J ~ '' PCl/US93/035~6 8-methyl-7-[1 -[[(4-methylpiperazin-l-yl)acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(1 IH)-one;

7-~l-[[(l-imidazolyl)acetyl]oxy]propyl]-8-methylindolizino~1,2-b]quinolin-9 5 one;

8-methyl-7-[1-1(pyridinioacetyl)oxy]propyl]indolizino~1,2-b]quinolin-9(llH)-one , iodide;

7-[1-[[4-~(dimethylamino)methyl]benzoyl]oxy]pro~yl]-8-methylindolizino[1,2-b]quinolin-9(llH)-one; :
~.
8-Methyl-7-~1-[[4-(pyridiniomethyl)benzoyl]oxy]propyl]indolizino[1,2-b]quinolin- ~ ~-9(1 lH)-one trifluoroacetate;
- I :~
8-~[(~morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one;
i , 7-~1-[~(aminomethyl)hydroxyphosphinyl]oxy]propyl~-8-methylindolizino [1,2-b]quinolin-g(l 1H)-one;

12-[~(arninoacetyl)oxy~methyll-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one; ~ -8-methyl-12-[[~4-morpholinoacetyl)~xy]méthylr-7-~1-oxopropyl)indolizino [1,2-b]quinolin-9(1 lH)-one; - ~ ~

8-methyl-7-[ 1 -[(phosphono)oxy]propyl]inodlizino[ 1 ,2-b]quinolin-9(1 lH)-one; and 8-[t(dimethylaminoacetyl)oxy]methyl]-7-( 1 -ox~propyl)indolizino[ 1 ,2-b~quinolin-9(11H)-one. -=~

Some compounds used in the method for treating viral infections according to the present invention are known. The publications listed herein discussing the `

wo 93/20818 PCr/US93/03596 21 ~ 3 ~ ~

preparation of such compounds are incorporated herein by reference. The compounds of the present invention can be prepared by several means from known starting materials or by adding the appropriate substituent to the starting materials ;
used in published synthetic methods for making camptothecin. The preferred 5 synthetic methods for preparing the inventive compounds are outlined in the following reaction flow charts.
In general, the inventive compounds are prepared by opening the lactone ring of carnptothecin or a camptothecin derivative which may have the desired R7 - ' -R11 substituenttoobtainan8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin- ! :-9(11H)-one. Alternatively, the lactone ring may be opened and then the R7 R1 1 ¦ -substituents introduced. In yet another alternative method, an existing R7 R1 1 ` i group is modified to obtain the desired compound. Once the lactone ring is opened, : :
the resulting X and Y groups may be further modified as needed to make the subject compounds.
Starting materials are commercially available or can be made by published ¦ -methods. Carnptothecin, 10-hydroxycamptothecin and 9-hydroxycamptothecin are natural products. Camptothecin and 10-hydroxycamptothecin are available from sources in the People's Republic of China. A 9-hydroxycamptothecin compound which can be used as starting material for making some of the inventive compounds -is described in Published Japanese Patent Application No. 59-51,289. The syntheses of 9- and 12-nitrocamptothecins are described by Wall, et al. (J. Med. Chem. 1986, 29, 2358). A total synthesis of camptothecin is described by Wall, et al., J. Med. -Chem 1980, 23, 554. The 1980 Wall, et al. synthesis can be used as a means to int~oduce one or more R7 - R 11 substituents into the compounds of Formula I. This involve~ m~if-9ing the Wall synthesis at the appropriate step in a manner which puts in place the desired substituent, then continuing with the desc~ibed synthesis.
The ring-opening reaction is illustrated by Scheme 1. For the sake of convenience7 all reaction schemes shown herein are illustrated with compounds which are substitutcd with -H at R7 - R 11. However, these methods also apply tocompounds of the present invention having any other combination of R7 - R l 1 subsd~uenrs as dcfined herein above, including compounds in which one or more subsdtuents may rcquire protection during chemical reactions and deprotection thercafter, as is well-known to those of ordinary skill in the art.

wog3t~0818 ;~ I 1 8 ~ Pcr/US93~03596 Scheme 1 /~ 2 ~o Compounds of formula 1 are converted to compounds of formula 2 by ~`
heating the compounds in a high boiling, preferably unreactive, solvent such as N,N-dimethylformamide or triglyme (tIiethylene glycol dimethyl ether).
As shown in Scheme 2 the keto group of compounds of formula 2 can be reduced to give the corresponding hydroxy compounds 3 from which the halo compounds 4 can be derived. The keto group also can be converted to an oxime (compounds 5) which can In turn be reduced to give the primary amino compounds ¦
6. The keto group also can be convened to a ketal group such as a 1,3-dioxolane - (compounds 7~ which are useful intermediates for further transformations). The hyd~oxyl group of compounds 3 can also be acylated to produce esters, carbonates, - and carbamates (8) or phosphorylated to produce phosphates and phosphonates (9) ;~
wherein~R20 and R21 are groups convertible into R14 and R15 respectively, by either deprotection or further elabora~on by well-known methods.

- -- - -- .
.

, ' . _ .

.

WO 93/20818 PCr/US93/03596 ;f 1 1 ~ 3 2 i - 18 - :
Scheme 2 2 ~' ~ 3~il- .;~

~--OH R = hab ~R

NOH ~--NH2 ~7 ~
',, 3 ~ ~N
8 ~ 20 ~OOOR

~OP(O)~OH)R
- - _ wo 93/20818 i~ ~ 1. 8 .? '' ~ PcrtlJsg3/03sg6 .
As illustrated in Scheme 3, dehydration of alcohols 3 gives alkenes 10 which can be hydroxylated ts:) diols 11. Oxidative cleavage of the diols generates aldehydes 12 which may be covalently solvated by water or an alcoholic solvent tO
produce compounds of formula 13. Hydride reduction of compounds of formula 12 5 and 13 give the primary alcohols 14.

Scheme ., 3 ~,r~ ~

,;/ ~)H j H~

R o 0 a~2 OH

Also derived from carnptothecins are the a-hydroxy acids 15 which are formed by hydrogenolytic cleavage of the lactone ring as shown in Scheme 4.
. . .

WO 93/208l~ P~r/US~3~03~96 -- .
Schemç 4 ~ COOH ~

OH .~ ., Some ring subs~ituents may be labile tO the conditions used in the preferred ~.
5 method of making compounds 2 as given in Scheme 1. To make compounds which are unstable under ~hose conditions, ~he sequence set out in ~cheme S can provide ..
access to certain of those compounds or provide intermediates for making other compounds. :-' . .:
Scheme.5 ~ o ~ o ~ o 16~ 1~ HJ~ ¦ -~
R' 2 R ~ R I ~:
HO~ H~

More specifically~ th~c~rbonyl group of compounds 16 is first protected as a 15 ketal ~17), and then the pyridine-ring is reduced to give compounds 18, for exarnple with sodium cyanoborohydride in an acidic solvent such as acetic acid. Finally, oxidation of compounds 18, for example by iodobenzene diacetate, gives the 2-hydroxy ketals 19 which along with the keto compounds 20 derit~ed from the ketals by acid hydrolysis can be used to make compounds with other substituents as 20 illustrated in Scheme~-WO 93/20818 ~ 1 ~ 3 J ; '-~ PCr/US93/03596 Schem~

RO~ o W~N~
,~0 R COQ
20 ..~ ~_ t2~
13 ~ R
R 05 ~(0)0 R' 2~
RR NC(Op~, ~ o 20 ~ ~N~--~0 CF,S03 S R

W~ 93/~0818 PCr/US93/03596 ~:
~l83~

S~heme 6~on'~!
H2 NC~2~ 0 2 2~ o 28~ ~N~
Rt 2 o~ Rt 2 25 ~ X --25 = ~ r I ~

32 ~

~----~ - O-- - OHC

R O
, -25 _`~[;r~_COI~

R

WO93/20818 ;f i ~ ' P~tUS93/035~6 Sç~e~ç 6 (cQn't) H~N~ ~ o H,N ~ ~ ~

R NH

H~ ~ ~ o R S02 NH

qO ~ W~4N4~4 R O
R.2 ¦

R CONH~ o R" CON

46----~ 0~
F~ O ~ 2 The compounds in Scheme 6 are prepared either by alkylation (compounds 21) or acylation (compounds 22, 23, and 24) of the 2-hydroxy ketones 20 or by replacement of the 2-hydroxy group in the ketals (19) via the triflates (25).
Cyanation of the triflates following the method of Kosugi, M, et ai, Chem. Lett.1981, 69 gives compounds 26 which are hydrolyzed to compounds 2T - (~atalytic hydrogenation of the cyano group of compounds 26 gives aminomethyl ketals 28 which upon hydrolysis gives the ketones 29.
Alte~atively, starting with the ~iflates (25), a carbonyl group can be introduced onto the ring, for example by the procedure of Cacchi, S, et al, W O 93/20818 PC~r/US93~03596 ~
,`.~183~-J --' , Tetrahedron Lett. 1986, 27, 3931. If an amine or alcohol is used, the corresponding amides (30) or esters (32) are obtained which are then hydrolyzed to the respective keto compounds 31 and 33. Reduction of the esters 32 with a hydride gives the primary alcohols 34 which upon hydrolysis produce the keto alcohols 35 which can5 be acylated to give carboxylates, carbonates and ca}bamates or phosphorylated to give phosphates or phosphonates by methods similar to those used for prepanng such derivatives from compounds 3. Aldehydes (compounds 36) can be made by oxidizing the alcohols 34 using a mild oxidant which gives the aldehyde in preference to the acid (for example, MnO2). Deprotection gives the keto aldehydes

10 37-Similarly, the triflates are converted to vinyl ethers 38 following the method of Cabri, W., et al. (J. Org. Chem. 1990, 55, 3654), and then compounds 38 are .
hydrolyzed to diketones 39. Selective hydrolysis of the enol ether function in compourids 38 produces the 2-keto compounds that can be reduced to secondary 16 alcohols from which the ketal groups can be removed and the alcohol function acylated or phosphorylated as described for compounds 3.
Introduction of an amino group at the 2-position is accomplished by hydrolyzing esters 32, conver~ing the resulting acids to acid halides (acid chlorides), treating the acid halides vith sodium azide and heating those products followed by ! :
20 ~eatment with water to form the amines (40) which upon deblocking gives compounds 41. These arnines can be alkylated (42), sulfonylated (44), or acylated (46) by known means and then deprotected to compounds 43, 45, and 47, ~;
respectively. - ~
Compounds with a substituent at the 1-position that cannot be made by the 25 method of Scheme 1 can be made by USilfg the activating effect of the 2-hydroxy group in compounds 19; the hydroxy group may be retained in the product or removed. These preparations are illustrated in Scheme 7.

wo 93/20818 ,; ~ ~. " 3 ? ~1 Pcr/us93/o3s96 Scheme 7 ~, o HO~
~N

R ~ halo CN ~
CN

4i(1R~) HO~ ~

2 ~ ~

RR ~ RR N~

~R G~
R _.
Halogenation of compounds 19 is accomplished by stan~ard means to 6 praduce 1-halo ketals 48 which are cleaved to the corresponding ketones 49. Cyano ketals 50 are prepared using the iodides (48) in the cyanation reaction described for the synthesis of compounds 26. Cleavage of compounds 50 giw~corn-pounds ~1, or alternatively, the hydroxy function can be removed from 50 by converting the compounds to the co-~responding triflates 52 and then reducing them to compounds0 5~ L~, the method of . acchi, S. et al., Te~rahedron L:e~t. 1986, 2-7~5541. Hydrolysis of ketals ~3 gives ketones 54.
The conversion of compounds 19 to compounds 5~is accomplished using tetramethyldiaminomethane and an acid. The dioxolane protec~ing group can then be hydrolyzed to obtain the keto compounds 56.

W O 93~20818 PCT/US93/03596 :~
2 i I i~

Methods for making compounds with different groups at the 7-position are illustra~ed in Scheme 8. :~
~h~me Ps ~0~ o ~o S2 a~3 58~ ~O

CN

~OF~ ' U~ C~ ~ ;

63 ~

- OH
Sa ~ r, ~

- NRR
NNR

sa ~ 3~

wo 93~208i8 ~ PCr/USg3/û3596 Scheme 8 (con't) s~ ~ ~o NPIR

R '0~ CH20H

~ ~, ~0 R,J,s R~3,s0 The hydroxy compounds 57 are made as described by Sugasawa, T., et al., Ch~m. Pharm. Bull. 1974, 22, 771. The ~iflates (58~ are prepared in the usual manner. Reduction to compounds 59 is ca~Tied out by the same method used for compounds S2. Cyanation of the triflates tO give compounds 60 uses the method employed tO prepare compounds 26. Alkoxyvinylation of ~he triflates to give compounds 61 is carried out as in the preparation of compounds 38; acid hydrolysis of the vinyl ethers gives the ketones 62 which upon reaction with diazome~hane by the method of Kametani, T., et al. (Heteroc~cles 1975, 3, 167) give methyl derivatives 63 which are reduced by hydrides to the alcohols 64. Coupling of the _ triflates with 3-dialkylaminopropyne by the method of Echavarren, A. M.~an~Stil!e, J. K. (J. Am. Chem. Soc. 1988, llO, 15573 gives compounds 65 which are catalytically hydrogenated to compounds 66. Vinylation of the triflates by the procedure of Chen, Q-Y. and Yang, Z-Y. (Tetratledron Lett. 1986, 2~, 1171) givescompounds 67 which are catalytically hydrogenated to ethyl compounds 68~
Carbonylation of the triflates in the prescnee of an amine or an alcohol by t~e 20 pr~ccdure used to make compounds 30 and 32 leads to amides 69 and ester~ 70, - respectively. As descnbed for compounds 62, compounds 70 are methylated with dhzomethane to give derivatives 71 which then are reduced to alcohols 72 by hydrides~ Displacement of the ~iflate function from compounds 58 by thiols givessulfides 73 which are oxidized to sulfoxides 74.

.. . ~ . , , ~ ,, . ! . ' , . , ' ,: . . .. .

W O 93/20B18 P ~ /US93/03596 21 ~

Compounds with substituents in the 12-position are prepared as illustrated in Scheme 9. ' Scheme 9 R " R

R R ~-~ O ,~ O

R ' 2 o~ 17 NHCHzAr - NHCHzAr ~ ~o ~
R1 2 o~ R1 2 ~ ~

W0 93/208l8 ,~ Pcr/US93~03596 Scheme 9 (con't) _ R
C~2 NH2 C~l~ N~2 fH2 NRR R, ~,NRR ~NRR

R
NRR ~,NRR -~5 \~

WO93/20818 ;. ~ , PCr/US93/03596 Sch~me 9 (con't) CH2 Os02 R 2 CN . CH2 CN
~ O ~ o ~ o ':

99 ~ 00 ~H2 fNH2 ; i 100 > ~_ ~, ~N~

2 O~ ~
R R

CH2oR~3 CH2~13 i 99 ~N~ ~N~ ¦

~Xo~ R

Wo 93/208~8 PC~/US93/03596 12-Hydroxymethyl compounds 76 are prepared by the method of Miyaska, T. et al. (~eterocycles 1981,16,1713) using ferrous sulfate, hydrogen peroxtde and methanol with sulfuric acid. These alcohols are acylated or phosphorylated as described for compounds 3 to produce carboxylates, carbonates and carbamates, orphosphates and phosphonates. Sirnilarly, 12-alkyl compounds 77 are prepared by the method of Miyasaka, T. et al. (IJ.S. Pat. No. 4,399,282). Oxidation of compounds 78, for example, with hyd~ogen peroxide in acetic acid, gives the N-oxides 79 which upon heating with tosyl chloride in N,N-dimethylformamide gives the 12-chloro compounds 80 that can be converted to many other compounds.
Heating of the chloro compounds with arylols, such as phenol, gives the 12-aryloxy compounds 81 which upon deprotection give the ketones 82; i~, however, an aminomethylarene is included in the reaction, the products are compounds 83 which upon hydrolysis give keto compounds 84. Ille chloro substituent of compounds 80 can be replaced with an iodo group (85) by heating with potassium iodide in acetic acid containing some acetic anhydride. The iodo derivatives are easily used in various coupling reactions similar to those carried out with tnflates 25 and 58.Cyanation gives compounds 86 which are deblocked to ketones 87 or are reduced toaminomethyl compounds 88 which give ketones 89 upon hydrolysis. Likewise, propynylamines 90 can be produced and then deprotected to compounds 91 or catalytically hydrogenated to compounds 92 and 94 which are hydrolyzed to keto compounds 93 and 95, respectively. Heating compounds 85 with sodium acetate in acetic acid giYes the 12-hydroxy compounds 96 which can be aLkylated using ei~her base and alkyl halides or diazoalkanes to give 12-alkoxy compounds 97 which upondeprotecdon afford ketones 98. The 12-hydroxymethyl compounds 76 can be protected and then activated for displacement reactions by conversion to a s~lfonate-~
(99), for example, a mesylate. Cyanide displacement on compounds 99 giYes the ketals 100 which upon hydrolysis give 12-cyanomethyl ketones 101. The cyano ketals can also be redu~ed to aminoethyl compounds 102 that give ketones 103 after hydrolysis. Treatment of sulfonates 99 with alcohols in the presence of bases gives ethers 104 which can be converted to keto ethers 105.
The reactions illustrated in Scheme 9 for the 12-hydroxymethyl c~p-ounds 76 could likewise be applied to hydroxymethyl compounds 34 to produce denvatives co~csponding to compounds 99 through 105.
As shown in Scheme 10, compounds 107, the open nng form of compounds 106, which are described in co-pending U.S. Ser. No. 071839,823, are acylated or wo93~20818 ,'. ~ S J ~ PCI/US93/0359~ ~.

phosphorylated as describe~d for compounds 3 to give compounds ~08 and 109, respectively. ~-Sçheme 10 ~N ~ CH2 OH
0~ ~0 1~ ~
123H 12~=
R R

O
107 ~ W~N~CH20COR 8 1 08 ~z~cO
R

~, O
07 ~ W` ~CH~OP(O)(OH)R

R

The compounds of the present invention exhibit antiviral activity and are generally useful in treating DNA rcplicating animal virus infections, particularly those caused by viruses in the herpes farnily. More specifically, these compounds 10 are useful in treating infections caused by the following human pathogens:

Herpes Simplex v~rus types 1 and 2;
Cytomegalovirus;
Varicella Zoster virus;
Epstein Ba~r virus; and Papilloma virus (multiple types) Infections caused by the following animal pathogens may also be treated w~th thepresent ~ompounds:

wo s3/20818 '~ PCr/US93/û3596 Equine Herpes virus;
Porcine Herpes ~n~s;
Marek's disease virus;
Feline Rhinotracheitis virus; and 6 Bovine Herpes virus.

Assa~ys The assay used to test the compounds of the present invention for antiviral 10 activity was taken from the literature and was modified in well-known ways to adapt it to currentiy available technology. A generalized descliption of the assay follows.

~ssay Procedure Well plates were seeded with the appropriate cells at a concentration of 15 lxlO5 cells per well suspended in 0.5 mL of Earle's Minimum Essential Medium (EMEM) containing 10% fetal bovine serum (~BS) and antibiotic and antimycotic soludon. After- cells were 8~90% confluent (24 hours), old medium was removed and washed with Hank's buffered saline solution (HBSS). CelIs were then infectedfor 1 hour at 37C with 100-200 plaque fonning units per well of a he~pes simplex 20 virus suspended in 250 mL HBSS. Following adsorption, the following were added:

A) 250 m~Jwell 2 x EMEM containing Human IgG
(ca 0.1 mg/mL; Sigma No. G-67633;
B) Z50 mL/well EMEM containing 10% FBS and antibiotic/antimycotic solutioh;
C) 250 nL/well HBSS containing appropriately - ~
diluted compound.

i After 24 48 hours ~optimum time determined by examination of the plaques under microscope), old medium was aspirated off. Each well was stained with a `~
selected stain solution (0.5% crystal violet in MeOH:H20 7:3) and then rinsed with water and air dried and plaques counted. Compound effectiveness was evaluated in -` -~
tenns of percent plaque reduction as compared to untreated, infected controls.
This procedure can be used to test compound efficacy against many viruses 3~ besides he~pcs simplex by simply modifying the cell type used in the first step to --wo 93~20818 PCr/US93/03596 h :1 '. 8 3 ~ ~

match the virus being tested and following the procedure outlined above. Other cell types which could be used in this assay include mouse mammary tumor cells, human lung fibroblasts, sheep chorioplexus cells, and green monkey kidney cells.Other assays which are useful for determining the antiviral activity of the 5 present compounds include the following types: cell count, clonogenic, cytopathic effect, dish-colony formation, microtiter-growth inhibition, thymidine incorporation and yield reduction. Each of these well-known assays is in the literature and selected assays are available cornmercially.

10 Pharmaceutical Com~ositions and Method of Treatment The present invention provides a broad variety of compositions prepared from compounds of the present invention. Such composieions have u~ility for human and veterinary antiviral use, and for treating viral infections in plants, e.g., agricultural or ornamental seeds and plants. Such compositions comprise a caITier 15 which is acceptable for the intended end use together with at least one inventive compound. Por example, in veterinary use, the carrier may be a liquid, or spray, or may be formulated in a solid, non-degradeable or degradeable form for inser~ion in the rumen. Por agricultural use, the compound can be mixed with a fertilizer, other microbiocides such as fungicides, or insecticides and the like. The present 20 compounds may also be forrnulated in powders or sprays for application to plant surfaces.
The pharmaceutical compositions of this invention comprise one or more compounds of the present invention in admixture with an inert pharmaceutically acceptable camer or diluent. Compositions may contain an effective amount of the25 inventive compound in one unit, such as in a single pill, capsule, or pre-measlLred intravenous dose or pre-filled syringe for injection, or, as is frequently the case, the composition may be prepared in individual dose forms where one unit, such as a pill, contains a sub-optimal dose with the user being instructed to take two or more unit doses per treatment. When the composition is presented as a cream, it contains 30 a discrete amount of drug and the user applies an effective amount of the cream one or more ~mes until the disease is in remission or hasbeen~ffectively treated.
Concentrates for latcr dilution by the end user may also be prepared, for instance for IV formuladons and muld-dose injectable formulations.
CarTiers or dilucnts contemplated for use in these compositions are generally 35 hlown in the pharmaceutical formulary arts. Reference to useful materials can be .

.;

W0 93~2~818 ~ PCl /US93/~3~96 found in well known compilations such as Re~n~ PhaIm,aceutical Sciences, Maclc Publishing Co., Easton, PA, 18042, USA.
The nature of the composition and the pharmaceutically acceptable camer or diluent will, of course, depend upon the intended route of administration, for exampls, by intravenous and intramuscular injection, parenterally, topically, orally, or by inhalation.
For parenteral administration the phannaceutical composition may be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
For topical administration the pharmaceutical composition may be in the form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for administration to the skin, eye, ear, nose or genitalia.
For oral administration the pharmaceutical composition may be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
1~ The pharmaceutically acceptable carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, kaolin, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, mannitol, steasic acid and the like.
Ex~mples of appropriate pharmaceutically acceptable liquid carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water. For aerosol systems, phannaceuticallyacceptable car~iers include dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carTier or diluent, the instant compositions may include other ingredients such as stabilizers, andoxidants, preservatives, lubricants, suspending agents, viscosity modifiers and -the li~e, provided that the additional ingredients do not have a detnmental effect on the therapeutic action of the instant compositions. Similarly, the carrier or diluent may include time delay materials well known to the art, such as glyceryl -m~nostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
To obtain a stable water soluble dose form, a pharmaceutically acceptable ~
salt of a compound of the present invention is dissolved in an aqueous solution of an ~
organic or inorganic acid or base. If a soluble salt form is not available, the inwntive compound may be dissolved in a suitable co-solvent or combinations thercof. Examples of such suitable cosolvents include, but are not limited to, wo 93/20818 PCr/US93/03596 ~ 1 1 8 3 ~ ~

alcohol, pr~pylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
It will be appreciated that the actual preferred dosages of the compounds of the present invention used in the pharrnaceutical and other compositions of thisinvention will vary according to the par~icular complex being used, the particular ~-composition formulated, the mode of adrninistration and the particular site, host and disease being treated. These compounds are active in the concentration ranges oftwo commercial antiviral drugs, Cytovene (ganciclovir) and Zovirax (acyclovir).
For example, thc latter is manufactured in 200 mg capsules with instructions fortreating herpes simplex viruses by taking one capsule every 4 hours, but not to I ~ -exceed 5 capsules per day.

In the following Examples, temperature is in degrees Centigrade (C).
Unless othe~wise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in ¦ -the art can, using the preceding description, utilize the present invention to its fullest - extcnt. These Examples are given to illustrate the inYention, not to limit its scope.
Rcferencc is made to the claims for what is reserved to the inventors hereunder. ¦

~xam~
fi)-1-Methoxv-7~ hydroxy~rQ~y~:~nethylindolizinorl.2-blquinolin-9(1 lH)-one - A solution of 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b~quinolin-9(1 1H)-one (5.0 mg, 15 11mol) in a mixture of MeOH (0.2 mL), CH2C12 (0.6 mL) and THF (0.2 mL) was treated with a single portion of sodium b~rohydride (4.0 mg, liO ~mol). After sti~Ting at room temperature-for ~3 h, therçaction mixture was concentrated under reduced pressurç. The residue was treated with 10% aqueous NH4Cl (350 pL) and allowed to stand at 4C overnight. The solid which formed was collected by filtration, washed sparingly with H20 and dried to afford the ~tle compound. lH NMR (CDC13/MeOH-d4) d 8.77 (s, lH), 7.69 (m, 2H), 7.59 (s, lH), 6.92 (dd, J = 6.8, 1.7 Hz, lH), 5.23 (br s, 2H), 4.89 (m, lH), 4.05 (s, 3H), 2.24 (s,3H), 1.79 (m, 2H), 1.03 (t, J = 7.4~~, 3EI).- ~
.

WO 93~208]8 ~ J~ Pcr/us93/o3s96 Exam,?le,.~
f~ 2-Cvano-7-f1-hydroxv~ro~"vl)-8-~hy~ Qlizino~1~2-b~q~l~-9(1lH~-one The title compound was prepared according to the procedure in Example 1 except using 2-cyan~8-methyl-7-(1-oxopropyl)indolizino~1,2-b]quinolin-9(11~)-onc. lH NMR (CDC13/MeOH-d4~ d 8.29 (s, 1H), 8.32 (d, J=1.7 Hz, lH), 8.20 (d, J
= 8.9 Hz, lH),7.92 (dd, J = 8.8, 1.8 Hz, lH), 7.67 (s, lH), 5.30 (br s, 2H), 4.91 (m, lH), 2.26 (s, 3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for C20H17N32 H2O: C, 68-75; H, 5.48; N, 12.03, Found: C, 68.97; H, 5.26; N,

11.72.

Exam~le 3 ~m~11-8-methvlindolizino~ 1.2-b]quino~i~n-9( l lH~-one Hydrot~i~Qaçetate 3A. (+)-8-Methyl-7-rl-~[(1.1-dimethylethoxv)carbonyllamino3-acetvlloxvlvro~yllindolizinoLl,2-b~quinolin-9!1:1H)-one To a suspension of N-[(1,1-dimethylethoxy)carbonyl]glycine (1.15 g, 6.6 rnmol) in CH2C12 (50 rnL) under an argon atmosphere was added 1,3-dicyclohexylcarbodiim~ide (1.35 g, 6.5 mmol). After stirring at room temperaturefor 0.5 h, (i~-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(l lH)-one(1.0 g, 3.3 rnmol) was added followed by a few mg of 4-dimethylaminopyridine.
The resulting mixture was allowed to stir at r~om temperature overnight and tbenwas filtered. The filtrate was washed successively with 2.5% aqueous NaHCO3 2~ (100 mL), 0.1 N HCl (100 mL) and H20 (100 rnL), dried over sodium sulfate and concentrated in vacuo. The solid residue was p~ified by column chromatography on silica gel clu~ng with a solvent gradient of 0-2% MeOH/CH2C12 tO provide the title compound. lH NMR (CDCl3) d 8.34 (s, lH), 8.21 (d, J = 8.8 Hz, lH),7.91, I
(d, J = 8.3 Hz, lH), 7.81, (m, lH), 7.63, (m lH), 7.32 (s, lH), 5.96 (apparent br t, J
= 7.0 Hz, lH), 5.25 (s, 2H), 5.03 (br s, lH), 4.15-3.94 (m, 2H), 2.36 (s, 3H), 2.04- `
1.84 (m, 2H), 1.44 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). Anal. Calcd for C26H29N3O5-1/8 H20: C, 67.04; H, 6.33; N, 9.02. Found: C, 66.95; H, 6.54; N, 8.83.

wo 93~20818 Pcr/us93/03596 r~ l L ~ ?) ", .

3B. fi)-7-r 1-~(Ar~unoacetvl)oxyl~ vll-8-methvlindolizinor L2-b~quinolin-9(1 l~)-one Hvdro~ifluoroaçetate To a stiIring suspension of (i)-8-methyl-7-[1-[[[[(1,1- , dimethylethoxy)carbonyl]amino]acetyl~oxy~propyl]indolizino~ 1 ,2-b]quinolin-9(11~)-one (1.15 g, 2.5 mmol) in 1,3-dimethoxybenzene (12 mL) under an argon atmosphere was added trifluoroacetic acid (13 mL). After stirring for 1.5 h at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in H20, extracted with Et20, filtered and lyophilized to afford the title compound as a pale yellow solid. lH NMR (DMSO-d6) d 8.68 (s, lH~, 8.24 (m, lH~, 8.13 (m, lH), 7.86 (apparent br t, lH), 7.70 (apparent br t, lH), 7.19 (s, lH), S.91 ~apparent br t, lH), 5.26 (s, 2H), 4.02 (br s, 2H), 2.25 (s, 3H), 2.06-1.81 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H). ~ Anal. Calcd for C2lH2lN3o3- CF3C02H 9/4 H20: ;
C, 53.33; H, 5.16; N, 8.11. Found: C, 53.09; H, 4.91; N, 7.74.

Exam~lç 4 (i)-7-rl-r(3-Amino-l-oxoprogvl~oxYlgrogYl!-8-methvlindolizino~l .2-b~quinolin-9(1 lH)-one Hvdroacetate 4A. (~ethvl-7-rl-rr3-rr(l.l-~ethylethoxY)çarbonvllaminol-L
oxogro~ylloxvl~ro~vllin~olizinor 1 .2-bl~uinolir~-9( 1 1 H)-one A mixture containing (:t)-7-(1-hydroxypropyl)-8-methylindolizino[ 1,2-b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 rnmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-dichloroethane (S mL) under an argon atmosphere was heated~at reflux-for S d.
Thin layer chromatographic analysis at this time indicated that the reaction wasincomplete, so the mixture was transferred to a pressure bottle and heated at 90-95C for 1 d. Afterwards, additional 4-nitropbenyl 3-~[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mgt 0.80 rn~nol) and dry triethylamine (222 rnL, 1.60 mmol) were added, and heating was continued for 13 d. Thc mixture was then purified by flash chromatogEaphy-ehl~ng with a solvent gradient of 0-3% MeOH/CH2C12. The material tnat was i-soIated was recrystallizedfrom Et20 and dried in vacuo to afford the title compound, mp 15S-8~C. lH NMR
(CDCl3) d 8.35 (sl lH), 8.22 (d, J = 8.6 Hz, lH), 7.91 (d, J = 7.2 Hz, lH), 7.81 ~m, lH), 7.63 (m, lH~, 7.32 (s, lH), S.90 (dd, J = 7.7, 6.1 Hz, lH), 5.26 (s, 2H), 5.02 WO93~20818 ff ,~ ,i, ;?` ~ PCr/US93/03596 (br s, lH), 3.44 (m, 2H~, 2.66 (q, J = 5.8 Hz, 2H), 2.02- 1.80 tm, 2H), 1.38 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C27H31N3Os- 1/5 H20: C, ~7.40; H, 6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35.

4B. fi)-7-rl-r(3-Amino-l-oxopropvl)oxy~propyll-8-methvlindolizino~1.2-bl~uinolin-9(l lhn-one Hvdroacetate The title compound was prepared according to the procedure in Example 3B
except using ~+)-8-methyl-7-[1-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(l lH)-one with the product being purified by reversed phase chromatography on Partisil 40 ODS-3 elu~ing with a gradient of ~100% MeOH in H20 containing 1% ace~c acid. lH NMR
(CDC13/MeOH-d4) d 8.42 (s, IH), 8.20 (d, J = 8.4 Hz, lH), 7.96 (d, J - 8.3 Hz, lH), 7.84 (m, lH), 7.67 (m, lH),7.43 (s, lH), 5.92 (dd, J= 7.7, 6.0 Hz, lH), 5.28 (s, 2H), 3.02 (br s,2H),2.69 (apparent br t, J = 5.9 Hz, 2H), 2.36 (s, 3H)~ 2.02 (s, 3H), 2.02-1.82 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). CIMS f~NH3, m/e, rel. int.) 378 (100) [(M+H)+]. AnaL Calcd for C22H23N3O3-C2H4O2-13/4 H2O: C, 58.11; H, 6.81; N, 8.47. Found: C, 58.22; H, 6.13; N, 8.10.

Exan~
8-Methvl-7-rl-r(-2-py~ dinylca~b-oDy~ o~ylpropyl]i~idolizino[l~-blquinolin- ! ,'`.
9(11~)-one Hvdrotrifluoroacetate and Separation of Isome~
: .
~
~A.~ (R.S~8-Methyl-7-[l-~rrS)l-~ unç~ethoxy~carbonyll-2- ~
. ~
~vrrolidinvlcarbonvl~oxv~ropyl~indo~i~L2-bl~iuinolin-9f l lH)-gnç
The title compound was prepared according to the procedure in Example 3A ~ ~ ~-exceptusing N-[(l,1-dimethylethoxy)carbonyl~-L-proline,N,N'- - -diisopropylcarbodiimide and (~)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.
. ~, 58. (R~.s~-8-Methyl-7-rl-r(fs)-2-pvrrolidinvlcalbonvl)oxylpropvllindolizino ,i;
.2,-bl~uinolin-9(11~-one Hvdrotrifluoroacetate ~ - - ;
To a mixture rontaining (R,S)-8-methyl-7-[1-[[(S)l-[(l,1- ~ -dimethylcthoxy)carbonyl~-2-pyrrolidinylcarbonyl]oxy~propyl]indolizino [1,2-b]quinolin-9(1 lH)~ne (1.66 g, 3.3 mmol) in CH2C12 (50 mL) was added t~ifluoroacetic acid (10 mL). The resulting mixture was allowed to stir at room WO 93/2081 8 PCl /US93/03596 temperature for 1.5 h and then was concentrated under reduced pressure. The residue was dissolved in H20 (150 rnL) and lyophilized to afford th~ title compound as a mixture of diastereomers. lH NMR (D2O) d 7.68 and 7.64 (2 s, lH), 7.45 and 7.36 (two d, lH), 7.33-6.95 (m, 3H), 6.94 and 6.91 (two s, lH), 5.93 (m, lH), 4.9-4.6 (m obscured by HOD peak), 4.2-3.9 (m, 2H), 3.S2 and 3.43 (overlapping m and t, 2H), 2.73-2.55 (m, lH), 2.45-1.95 (m, SH),2.12 and 2.06 (two s, 3H), 1.08 (m, 3H). Anal. Catcd for C24H2sN3O3- 11/4 CF3CO2H: C, 49.41; H, 3.90; N, 5.86. Found: C, 49.84; H, 4.16; N, 6.00. ~-SC. (S)-8-Methyl-7-rl-rf(S~-2-~Yrrolidinvlcarbonvl)oxyl~ro~YIlindQlizino rl.2-blQuinolin-9(11H~-one Hvdrotrifluoroacetate The diastereomeric n~ixture of (R,S)-8-methyl-7-[1-~((S)-2-pynolidinylcarbonyl)oxy]propyl]indolizino[ l ,2-b]quinolin-9(1 lH)-one was purified by preparative chromatography (JY column packed with 2 kg 15-20 mm Vydac C 18 RP silica), eluting with 0.1/25n5 TFA/CH3CN/H20. The title compound was the first to elute and was obtained after solvent removal under reduced pressure andlyophiliza~ion. lH NMR (D2O) d 7.99 (s, lH), 7.75 (d, J = 8.5 Hz, lH), 7.57 (m, lH), 7.51 (d, J = 8.2 Hz, lH), 7.33 (m, lH), 7.20 (s, lH), 6.09 (dd, J - 7.9,5.6 Hz, lH), 4.9-4.7 (m obscured by HOI) peak), 4.52 (d, J = 18.9 Hz, lH), 4.40 (d, J -18.8 Hz, lH), 3.53 (t, J = 7.3 Hz, 2H)~ 2.75 (m, lH~, 2.45-2.08 (m, 5H), 2.30 (s, --- 3H), 1.19 (t, J = 7.4 Hz,3H). Anal. Calcd for C24H25N3O3-2 CF3C02H 1/4 H2O:
C, 52.88; H, 4.36; N, 6.61. Found: C, 52.76; H, 4.50; N, 6.64.
SD. (R-)-8-Methyl-7-rl-r((S~-2-~vrrolidinYlcarbonvl)ox~l~ro~vllindolizino [1.2-blquinotin-9(11~)-one Hvdrotrifluoroace~ate The remaining fracdons from the separation process in Exampl~5C- were combined and concentrated under reduced pressure. The title compound was obtained after an additional pre~arative chromatographic separation using the condinons in Example 5C. lH NMR (D2O) d 8.00 (s, lH), 7.68 (d, J = 8.5 Hz, lH), 7.5~7.49 (m, 2H),7.32 (m, lH), 7.19 (s, lH), 6.09 (dd, J - 8.0, 5.2 Hz, lH), 4.93-4.67 9m obscured by HOD peak), 4.49 (d, J = 18.9 Hz, lH), 4.40 (d, J = 19.0Hz, lH),3.66-3.57 (m, 2H), 2.78 (m, lH), 2.47 (m, lH), 2~9 (~ 2H), 2.24 (s, 3H),2.15 (m, 2H), 1.17 (t,3H). Anal. Calcd for C24H2sN3o3- 7 CF3C02H-4 H20: C, 35.83; H, 3.17; N, 3.30. Found: C, 35.86; H,3.24; N, 3.64.

wo s3J2o8 1 8 ~ 1 ~ pcr/ Us93/o3~g6 5E. (R.S)-8-Methvl-7-rl-rrfR)-I-r(1.1-dimethvlethoxv)carbonyll-2-~lidinylcarborly~ yl~ro~~ zino~l.2-blquinolin-9~1 lH)-one To a mixture of N-l(1,1-dimethylethoxy)carbonyl]-D-proline (6.74 g, 31.3 mmol) in CH2Cl2 (47 mL) under an argon atmosphere was added dicyclohexylcarbodiimide (3.22 g, 15.6 mmol). After stirring at room temperaturefor 2 h, the mixture was filtered and concentrated under reduced pressure to afford N-[(l,l-dimethylethoxy)carbonyl]-D-proline anhydride. This was added to a suspension of (i)-7~ hydroxypropyl)-8-methylindolizino[ 1 ,2-b]quinolin-9( 1 lH)-one (1.S0 g, 4.9 mmol) and 4-dimethylaminopyridine (609 mg, 5.0 mmol) in CH2Cl2 (450 mL), and tbe mixture was allowed to stir at room temperature under an argon atmosphcre overnight. The reacdon mixture was washed with H20 (2x), dried ovcr potassium carbonatc and concentrated under reduced pressure. The rcsidue was purified by flash chromatography eluting with a solvent gradient of 0-2% McOH/CHCl3 to afford tbc titlc compound.
:15 ! -, ~E. (R.s3-8-Methyl-7-rl-!((0-2-~vrrolidinyl~bonyl3oxvl~ropvllindolizino . ~' ~1.2-b~qi~in-9(11H)-one Hydrotnfluo~s~
Thc titlc compound was prepared according to the procedurc in Example SB
except using (R,S)-8-methyl-7-~1-[[~R)-l-[(l,l-dimethylethoxy)carbonyl~-2-20 pslr~lidinylcarbonyl]oxy~propyl]indolizino[l,2-blquinolin-9(11H)-one. lH NMR
was cssentially identical to that of the compound of Exarnple SB. Anal. Calcd for C241{25N303 2 CF3co2H:- C, 53.25; H, 4.31: N, 6.65. Found: C, 53.07; H, 4.68;
N, 7.02.
..
25 SG. fR3-8-Mctl~yl-7-rl-r((R)-2-~ oxvl~ro~vllindolizl~o rl~2-bl~uinolin-9f~ -onc Hvdrotrifluoroacetate - ~ ~
The title compound was obtaincd by separation of the diastereomers of (R,S3-8-methyl-7-[1-[((R)-2-pynolidinylcarbonyl30xy~propyl]indolizino~1,2-b]quinolin-9(1 lH)-one according tO - ~ , .;.
thc p ocedu~ in Example SC. Anal. Calcd for C24H25~303-3 CF3C02H H20: _ ¦
C, 47.19; H, 3.96; N, 5.50. Found: C, 47.24; H, 4.30; N, 5.83.

(S~-8-Methyl-7-r1-~ -2-~y~rolidinvlcarbonvl)~xy~o~vllindolizino no~ un-one Hvdrotrifluoroacetate '..:

W O 93/20818 PC~r/~S93/03S96 ~ 1 1 3 3 ~?'~

The title compound was obtained by separa~on of the diastereomers of ~;
(R,S)-8-methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino [1,2-b]quinolin-9(l lH)-one according to the procedure in Example SC. Anal. Calcd for C24H25N3O3-8/3 CF3CO2H-H2O: C, 48.56; H, 4.12; N, 5.79. Found: C, 48.61;H,4.53;N,6.10.

Exam~le 6 (R.S)-7-rl-rr(S)-2-Amino-3-(lH-imidazol-4-vl)-1-oxopro~vl]oxylpro~vll-8-methvlindolizjnQ~ ~lin-9(1 lH)-one Hv~o~ifluoro~te 6A. (R.S)-8-Methvl-7-rl-rr(S)-2-r~(1.1-dimethvlethoxv)carbonvlla~inol-3-(lH-imidazol~-vl)- 1 -oxopropylloxvlpropvl~i7r~dolizinor l .2-b]quinQlin-9r l l hr)-one The title compound was prepared according to the procedure in Example 3A
except using N,1-bisl(l,l-dimethylethoxy)carbonyl]-L-histidine, N,N'-diisopropylcarbodiimide and (+)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(l lH)-one. 7 f~ ~R.S)-7-~1-rr(S~-2-Amino-~-(lH-imidazQI-4-yl~-l-oxo~ro~vlloxvlpro~vll-8-~thvlindolizino[1.2-blquinolin-9(11H)-one Hvdrotrifluoroacetate ~-~
The title compound was prepared according to the procedure in Example 5B
except using (R,S)-8-methyl-7-[1-[~(S)-2-[[(1,1-dimethylethoxy)carbonyl~amino]-3-(lH-imidazol-4-yl)-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(1 lH)-one and was purif1ed by preparadve MPI,C eluting first with 0.1 % TFA/H2O followed by a solvent gradient of 20-50% MeOH in H20 containing 0.1% TFA. lH NMR
(D2O) d 8.64 and 8.35 (two s, lH), 8.22 (d, lH), 7.90 (d, lH), 7.70 (m, 2H), 7.45 (m, 2H), 7.20 (s, lH), 6.04 (m, lH), 4.9-4.6 (m obscured by HOD peak), 3.68-3.47(m, 2H), 2.23 and 2.19 (two s, 3H), 2.15-1.96 (m, 2H), 1.04 and 0.96 (two t, 3H).
An'al. Calcd for C~5H25N503-2.8 CP3CO~H: C, 48.18; H, 3.67; N, 9.18. Found:
C, 48.29; H, 3.93; N, 9.15.
3û
_ W~93/20818 ~.i $ ~ i PCr/US93/03596 Exam~le 7 (:t)-7-rl-~(2-Amino-3-methvl-1-oxobutvl)oxvlDropvll-8-methvlindolizinor1.2-~lquinolin-9(11H)-one Hvdrotrifluoroa~etate 7A. (~ 8-Methvl-7-rl-rr2^rr(1.1-dimethylethoxv)carbonvll~ninol-~-methvl-1-oxobut~lloxy]~ro~yllipdolizinorl.2-b~quinolin-9(11H)-one The title compound was prepared according to the procedure in Example 3A
except using N-[(l,1-dimethylethoxy)carbonyl~-L-valine and (i)-7-(1- ~ -hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. lH NMR (CDCl3) d 8.34 (s, lH), 8.22 (m, lH),7.91 (d, J = 8.2 Hz, lH),7.80 (m~ lH), 7.62 (m, lH)9 7.34 (two s, lH), 5.94 (m, lH), 5.26 (s, 2H), S.04 ~two br d, J - 9.3 Hz, lH), 4.36 (two d, J = 4.5 Hz, lH), 2.36 (s, 3H), 2.4-2.2 (m, lH), 2.1-1.8 (m, 2H), 1.44 and 1.38 (two s, 9H), 1.00 (overlapping t and d, 9H).

7B. ~i)-7-rl-r(2-Amino-3-methvl-1-oxobutvl)oxvlpropvll-8-methvlindolizinorl.2-bl~uinolin-9(11H)-one HYdro~ifluoroacetate The ~itle compound was prepared according to the procedure in Example 3B
except using (t)-8-methyl-7-~1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutyl]oxy]propyl]indolizino[1,2-b]quinolin-9(llH)-one. lH NMR
(CDCl3, MeOH-d4) d 8.3g and 8.35 (two s, lH3, 8.20-8.13 (m, lH), 7.94-7.81 (m, 2H), 7.66 (apparent br t, lH),7.41 (two s, lH), 6.0~ (m, lH), 5.25 (s, 2H), 3.98(two d, J = 4 4 Hz, lH), 2.55-2.36 (m, lH), 2.33 (s? 3H), 2.14-1.90 ~m, 2H), 1.15- -;
1.01 (m, 9H). Anal. Cald for C24H27N303-CF3C02H-7/4 H20: C, 56.67; H, 5.76; N, 7.63. Found: C, 56.65; H, 5.62; N, 7.29.
~5 --- -.
Exam~le 8 (i~-7-r 1 -~(2-Amino-2-methvl- 1-oxo~ro~vl)oxvl~r~vll-8-methvlindolizinor 1 2-b]quinolin-9(11~f)-one Hvdrotnfluoroa~etate `~
, 30 ~A. (i~-8-Methvl-7-rl-rr2-rr(1.1-dimethvlethoxY)carbonYlLaminol-2-m~hvl-1-oxoDropvlloxvlpro~Yllindolizi~lor 1.2-bl~uinoli~-9f 11 H)-one To a mix~ure containing 2-methyl-2-[N-~dimetbylethoxy)carbonyl~aLmino]propionic acid (406 mg, 2.0 mmol) and dicyclohexylca~bodiimide (432 mg, 2.0 mmol) in CH2C12 (3 mL) under an argon 35 atrnosphere were added (i)-7-(1-hydroxypropyl)-8-methylindolizino wo 93/20818 Pcr/us93/03596 t J 1 .L 8 3 [1,2-b]quinolin-9(llH)-one (153 mg, 0.5 mmol) and 4-dimethylaminopyridine (25 mg). The resulting mixture was allowed to stir at room temperaturc for 4 d and then was poured into CH2Cl2, washed successively with 5% aqueous NaHCO3, 0.5 N
HCl and H20, and dried over sodium sulfate. Removal of the solvent in vacuo and 5purification of the residue by column chromatography (silica gel) eluting with a ~;
solvent gradicnt of 1.5-5% MeOHlCH2C12 afforded the ti~le compound as an off-white solid. lH NMR (CDC13) d 8.33 (s, lH), 8.20 (d, J = 8.9 Hz, lH), 7.90 (d, J = ;
8.3 Hz, lH), 7.80 (m, lH), 7.62 (m, lH), 7.33 (s, lH), 5.92 (dd, J = 7.5, 6.3 Hz, lH), 5.25 (s, 2H), 5.10 (br s, lH), 2.38 (s, 3H), 2.08-1.82 (m, 2H), 1.56 (s, 3H), 101.55 (s, 3H), 1.41 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). ;

(~-7-rl-r(2-Amino-2-mothvl-1-oxoprovvl)oxvl~ro~vll-8-~ethylindolizinorl.2-blquinolin-9(1 lH)-one Hvdrotrifluoroacetate Thc title compound was prepared according to the procedure in Example 3B
15cxccpt using (+)-8-methyl-7-[1-~[2-[[(l,l~imethylethoxy)carbonyl~aminol-2-methyl-1-oxopropyl~oxy~propyl]indolizinoll,2-b]quinolin-9(1 lH)-one. lH NMR
(DMSOLd6) d 8.67 (s, lH), 8.11 (m, 2H), 7.84 (m, lH), 7.70 (m, lH), 7.21 (s, lH), 5.85 (dd, J = 7.9, 5.8 Hz, lH), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 0.97 (t, J = 7.3 Hz, 3H). Anal. Calcd for 20C~sN303-CF3CO2H-2 H20: C, 55.45; H, 5.58; N, 7.76. Found: C, 55.85; H, .19;N,7.83.
-~ :
fi)-7~r 1 -r(Aminoacctvl)oxyl~ro~yll-2-cvano-8-meth~vlindolizinor 1 .2-blquinolin-9(1 lH~-one H~drotrifluoroaçetate 9A. (~:)-2-Cvan~8-methvl-7-r 1 -rrrr( 1.1-dim~thvlcthoxvkarbonvllaminolacetylloxvl~ vllindolizinor 1 .2-blquinolin-9(1 lH)-onc The title compound was prepared according to the procedure in Example 3A
cxcept using (:~2-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]~uinolin-9(1 lH)-one.

9B. (i)-7-r1-r(Aminoacetvl)oxvl~ro~Y11-2-cvano-8-35 m~~ zinorl~2-bl~uinolin-9(~ -one W093~208l8 ~ 1 ~ 3 ` ~. 1 Pcr/uss3/o3s96 The title compound was prepared according to the procedure in Exarnple 3B
except using (~ 2-cyano-8-methyl-7-[1-~[~[(1,1-dimethylethoxy)carbonyl~amino]acetyl]oxy3propyl]indolizino[ 1 ,2-b]quinolin-9(1 lH)-one. lH NMR (DMSO-d6) d 8.81 (d, J = 1.5 Hz, lH), 8.77 (s, lH), 8.27 f~d, J = 8.9 ~Iz, lH), 8.13 (dd, J = 8.9, 1.8 Hz, lH), 7.24 ~s, lH), 5.91 (apparent br t, J =
6.7 Hz, lH), 5.29 (s, 2H), 3.98 (br s, 2H), 2.26 (s, 3H), 2.05-1.81 (m, 2H), 0.96 (t, J
= 7.4 Hz, 3H). Anal. Calcd for C22H20N4O3-3/2 CF3C02H-H20: C, 52.00; H, 4.10; N, 9.70. Pound: C, 52.04; H, 4.32; N, 9.73.

~xample 10 f:t~-7-rl-r(Aminoacetvl)oxvl~ro~vll-12-cvano-8-methylindolizino~1.2-~lquinolin- -:
- 9(11~)-one Hydrotrif~uoroacetate 10A. (:~:)-12-Cvano-8-methvl-7-rl-rrrr(1.1- , ~-~im~l~hQ~carbonYllaminolacetylloxylpropyllindolizino~ 1 .2-b]quinolin- 1 -9fll~)-ol~.e The title compound was prepared according to the procedure in Example 3A
exceptusing (i~12-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin- , ~-9(1 lH)-one. lH NMR (GDC13) d 8.31 (d J = 8.5 Hz, lH), 8.27 (d, J = 8.3 Hz, lH), -7.95 (m, lH), 7.84 (m, lH), 7.32 (s, lH), 5.95 (apparent br t, J = 7.0 Hz, lH), 5.43 (s, 2H), 5.0 ~br s, lH), 4.03 (m, 2H), 2.38 (s, 3H), 0.99 (t, J = 7.4 Hz, 3H).

10B. (+)-7-rl-r(Aminoacetvl)oxvl~ropvll-12-cvano-8-methylindolizirlD~1.2-bl~inolin-9(1 lH)-one Hyd~otrifluoroacetate 25 - ~ - - ~ --:T~-e tIde compound was prepared according to the procedure in Example 3B
- except using (i)-12-cyano-8-methyl-7-[1-l[[[(1,1-dimethylethoxy)carbonyl]amino3acetyl~oxy]pr~pyl]indolizino[1,2-b]quinolin-9(1 IH~-one. lH NMR (CDCl3/MeOH-d4) d 8.28 (d, J = 8.5 Hz, lH), 8.22 (d, J =
- 8-.4 Hz, lH), 7.95 (m, lH), 7.82 (m, lH), 7.36 (s, lH), 6.00 (apparent t, J = 6.6 Hz, 1H), 5.41 (s, 2H), 3.92 (br s, 2H), 2.33 (s, 3H), 2.08-1.82 (m, 2H), 1.00 (t, J = 7.2 3~1). Anal. Calcd for C22H2oN4(:)3 3/2 CF3co2H 5/2 H20: C, 49.67; H, 4.42; N, 9.27. Found: C, 49.41; H, 4.23; N, 9.29.

..

wo 93/20818PCr/US93/03~96 f 1 18.-, ?, 1 -4~
Exam~le 1 1 (R.S)-8-Methvl-7-rl -rr(S~-(2-~vrrolidinvlcarbonvl)aIninQacetvlloxvl- -,Dro,Dyllindolizinorl.2-b]quinolin-9(1 lH~-one Hv~ro~rifluorQacetate 1 lA.fR.S~8-Methvl-7-r1-rrrr(S~1-rt1.1-dimethvle~oxv~carbQnyll-2-,Dyrrolidinvlcarbonvllarninolacetv!loxvl~yllindolizinor 1 .~-bl-quinolin-9f 1 1~- ~ ~
one ~:
The title compound was prepared according to tne procedure in Example SE
except using (i)-7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino ~1,2-b]quinolin-9(1 lH)-one.

1 lB. fR.S)-8-Methvl-7-rl-rr(S)-(2- :~
~vrrolidinvlcarbonyl~ami~oacetvlloxvlDro~vllindolizinor 1 .2-blquinolin-9( 1 1~)-Qne The dtle compound was prepared according to the procedure in Example 5B
except using (R,g)-8-methyl-7-11-[[[[(S)l-[(1,1-dimethyle~hoxy)carbonyl]-2-pyrrolidinykarbonyl]amino]acctyl]oxy]propyl]indolizino[l,2-~uinolin-9(1 lH)-one. Anal. Calcd for Ci6H2gN4o4 3/2 CF3C02~I-H20: C, 53.62; H, 4.89; N, 8.63. Found: C, 53.64; H, 5.29; N, 8.50. i E~LLe l2 (+)-8-Methvl-7-rl-rrfdimethvlamin~a~etvllox~o~vllindolizinorl.2-blquinolin-9(11H) one Hvdrochloride ~- 25 12A. (:0-7-r1-rrChloroacetyl)ox~opvll-8-methylindolizinQrl.2-blquinolin-- - - 9(1 lH)~n~
To a suspension of (t)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(1 lH)-one (306 mg, 1.0 mmol) in freshly distilled CHCl3 (45 mL) were added chloroacetic anhydride (205 mg, 1.2 mrnol), pyridine (80 mL, 1.0 mmol) and4 dime~hylaminopyridine (12.2 mg, 0.1 mmol). The resulting mixture, which became homogeneous aftcr 20 min, was allowed to stir at room temperature ov~night. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2C12, washed successively with H20 (2x), 0.1 N NaOH and H20 and dried over sodium sulfate. The solvent was removed in 1~acuo to afford 35 the title compound. lH NMR (CDCl3) d 8.35 (s, lH), 8.24 (d, lH), 7.93 (d, lH), WO 93/20818 ~f ~ 2 ~ PCI`/US93/03~96 47 :
7.85 (m, lH),7.65 (m, lH),7.33 ~s, lH), 5.99 (dd, lH), 5.28 (s, 2H), 4.19 (s, 2H), 2.40 (s, 3H), 2.12-1.95 (m, 2H), l.OO (t, 3H). Anal. Calcd for C21HlgClN2O3-1/2 H2O: C, 64.37; H, 5.14; N, 7.15. Found: C, 64.29; H, 4.86; N, 6.82. , `
.
5 12B. f+)-7-rl-r(lodoacetvl)oxyl~ yll-8-methYlindolizinorl.2-blquinolin-,9(1~ ,o"n,e -' To a mixture of (_)-7-[1-[(chloroacetyl)oxy]propyl]-8-methylindolizino[1,2-b3quinolin-9(l lH)-one (100 mg, 0.26 mmol) in acetone (10 mL) was added sodium iodide (150 mg, 1.0 mrnol), and the resulting solution was heated at reflux for 1 h.
10 Upon cooling, a solid precipitate appeared. The solvent was removed in vacuo, and thc residue was partitioned between CH2Cl2 and H2O. The organic extract was washed with H20 (3x), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. lH NMR (CDCl3) d 8.35 (s, lH), 8.22 (d, J= 8.2 Hz, lH),7.92 (d, J = 8.0 Hz, lH), 7.81 (rn, lH), 7.66 (m, lH),7.38 (s, lH), 5.91 (dd, J = 7.9, 6.0 Hz, lH), 5.26 (two s, 2H), 3.84 (d, J = 10.1 Hz, lH), 3.75 (d, I ~`
J = 10.1 Hz, lH), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C21H19IN203-1/2 H20: C, 52.19; H, 4.17; N, 5.80. Found: C,52.16;
H, 4.05; N, 5.39. ;~

12C. (i)-8-Methvl-7-rl-rr(dimethvlamino)ace~ylloxvl~ro~vllindolizinorl.2- `
b~uinolin-9(11H~-one Hvdrochloride A stream of dimethylamine was introduced into a solution containing (+)-7 [1-[(iodoacetyljoxy3propyl]-8-methylindolizino[1,2-b]quinolin-9( l lH)-one (50 mg, !
0.11 mmol) in anhydrous CH2C12 (15 mL). The resulting solution was allowed to stir for 2 h an~- then was-concentrated under reduced pressure. The residue was partidoned bctween CH2Cl2 and H20, and the organic layer was washed several i --times with H2O and dIied over sodium sulfate. Into this solution was bubbled a stream of HCl gas, and the resulting cloudy mixture was stirred for 15 min and then was concentrated in vacuo. The rcsidue was dissolved in H20 and Iyophilized to afford thc dtle compound as an orange solid. lH NMR (DMSO-d6) d 8.68 (s, lH), 8.15 and 8.1~ ro overlapping d, 2H), 7.86 (m, lH), 7.71 (m, lH),7.17 (s, lH), 5.96 (apparcnt br t, lH), 5.26 (s, 2H), 4.41 (s, 2H), 2.84 (br s, 6H), 2.26 (s, 3H), 2.20~1.86 (m, 2H),0.96 (t, J = 7.3 Hz, 3H). CIMS (NH3, m/e, rel. int.) 392 (100)~(M+H)+]. Anal. Calcd for C23H25N303-2HCI-13/8H20: C, 55.96; H, 6.18; N, 8.51. Found: C, 56.27; H, 6.03; N, 8.04.

wo 93/20818 PCr/VS93/03596 ~11 3~,?ii E~camPl~ 13 (*)-7-~l-rrtl~4~-Bi~i~endin-l~-vl!acetyl~Qxy~ yl]-8-methylindolizinQcl~2 blquinolin-9(1 1~)-nne Hvdroiodidç
To a suspension of (+)-7^[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(1 1hl)-one (50 mg, 0.11 mmol) in CH2Cl2 (4 mL) was added 4-pipendinopiperidine (17.6 mg, 0.11 mmol3. A~ter sti~ring at roomtemperature for 3.5 h, thin layer chromatographic analysis indicated that the reaction was incomplete,. Addi~ional 4-piperidinopiperidine (2.7 mg, 0.Q16 mmol) was added, and sti~ring was continued for 2 d. The mixture was concentrated under reduced pressure, and the residue was purified by eolumn chromatography eluting wi~ a solvent ~ient of 0-100% MeOH in H20 containing 1% HOAc. The title compound was obtained after lyophilization. lH NMR (CDC13~ d 8.35 (s, lH), 1~ 8.21 (d, J = 8.4 Hz, lH), 7.92 (d, J = 8.3 Hz, lH), 7.83 (m, lH~, 7.63 (m, lH), 7.34 (s, lH), 5.94 (apparent t, lH), 5.26 (s, 2H), 3.32 (s, 2H), 3.00- (br m, 2H), 2.37 (s, 3H), 2.~1.4 (m, 13H~, 0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C3 1H3gN4O3- 1/4HI-3/8 H2O: C, 67.28; H, 7.10; N, 10.12. Found: C, 67.67; H, 6.79; N, 9.69.

2~ Exam~le 14 $-Methvl-?-r1-r(4-mor~bolinylaççtyl)oxv~r~y~dolizino~1 .2-blquinolin-9(11H)-one Hyd~ochloride -The ~tle compound was prepared according to the proceduue in Example 13 - - 2~ except using (:t)-7-[1-[(iodoacctyl)oxy~propyl~-8-methylindolizino[1,2-b~quinolin-- - 9(1 lH)-one and morpholine. lH NMR (CDC13/MeOH-d4) d 8.51 (s, lH), 8.26 (d, J = 8.5 Hz, lH), 7.99 (d, J - 8.3 Hz, lH), 7.88 (m, lH), 7.70 (m, lH), 7.53 (s, lH), 5.98 (dd, J= 7.4, S.9 Hz, lH), S.30 (s, 2H), 4.29 (s, 2H), 4.02 (br s, 4H), 3.45 (br s partially obscured by HOD peak), 2.33 (s, 3H), 2.10-1.87 (m, 2H), 1.03 (t, J = 7.4 30 Hz, 3H). Anal. Calcd for C2sH27N3O4 2HCl H20: C, 57.25; H, 5.96; N, 8.01.
- - Found: C, 57.37; H, 6.28; N, 7.65.

W0 93/208]8 .~ PCr/US93/03596 Exam~l 1 5 (*)-8-Methvl-7- r 1 -r ~¢4-methvl~iper~in- 1 -yl2acetvll~ro~yllindolizinor 1.2-bJq~i~olin-9(1 1H)-on~Hydr~chl~ridç

The titlccompound was prepared according to the procedure in Example 13 `;
except using (i:)-7-~1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin- : `
9(11H) one and N-methylpiperazine. 1H NMR f~DMSO-d6) d 8.67 ~s, lH), 8.15 (m7 2H), 7.87 (m, lH), 7.72 (m, lH), 7.11 (s, lH), 5.84 (m, lH), 5.25 (s, 2H), 3.5-2.6 (m, 13H), 2.23 f~s, 3H), 2.04 1.82 (m, 2H), 0.95 (t, J - 7.5 Hz, 3H). Anal. Calcd for C26H30N403-2 HCl 9/2 H20: C, 52.00; H, 6.88; N, 9.33. Found: C, 52.12;
H, 9.1 1; N, 9.30. --(i)-7-rl-rrf l-Imida2;01vl)acetylloxv~ vl~-8-metbylindolizin~ -bl~luinolin-~(1 lH)^Q~ HvdrQ~hl~Lde The ~ide compound was prepared according to the procedure in Example 13 i :
except using [~ 7-[1-[~iodoacetyl)oxy]propyl]-8-methylindoliz:ino~1,2-bJquinolin-9(1 lH)-one and imidazole. lH NMR (CDC13/MeOH-d4) d 9.17 (s, lH), 8.60 (s, lH), 8.34 (d, lH), 8.04 (d, lH), 7.95 (m, lH), 7.75 (m, lH), 7.61 (s, lH), 7.51 (br s, lH), 7.41 (~r s, lH), 5.95 (m, lH), 5.65 (d, lH), 5.42 (d, lH), 5.33 (s, 2H), 2.36 (s, 3H~, 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C24H22N403-2 HCl- 11/4 H20: i -C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29.

2~ - : ~cam~le 17 8-MethYI-7-r 1 -rrpyridinioacet~)oxyl~r~vllindolizinor 1 .2-blquinolin-9( 1 1 H~ one iodide The title compound was prepared according to the procedur~ in Example 13 except using (+)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinoiin-9(11*')~ne and py~idine~ (CDCl3/hIeOH-d4) d 9.09 (d, J = S.S Hz, 2H), 8.65 (t~ J = 7.9 Hz, lH~, 8.Si (s, lH), 8.17 (m~ 3H), 7.99 (d, J = 8.1 Hz, lH), 7.89 (m, lH), 7.70 (m, lH), 7.50 (s, lH), 6.ûS (d, J = 17.2 Hz, lH), 6.02 (m, lH).5.87 (d, J = 17.2 Hz, lH), 5.30 (s, 2H), 2.31 ~s, 3H), 2.18-1.94 (m, 2H), 1.09 (t, J = 7.4 wo 93/20818 PCr/uSs3/03s96 2~ 1 3,,, ,~

Hz, 3H). Anal. Calcd for C26H24IN303- 1/4 H20: C~ 55.97; H, 4.43; N, 7.53.
Found: C, S5.72; H, 4.30; N, 7.26.

~xam~le 18 5 (i~-7-r 1-rr~r(Dimethvlamino)methvllbenzQyl!oxvl~ro~vll-8-methvlindolizinor 1.2-bl~uinolin-9(1 1H~-one Hvdrochlonde 18A. (t)-7-r1-rr4-(Chloromethvl)benzoylloxvl~ro~vll-8-methylindQlizinorl.2-bl~uinolin-9f11H)-one The title compound was prcpared according to the procedure in Example 3A
except using (i)-7-tl-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(1 1H)-one and 4-(chloromethyl)benzoic acid. lH NMR (CDCl3) d 8.33 (s, lH), 8.16 (m, 3H), 7.91 (br d, J = 7.3 Hz, lH), 7.78 tm, lH), 7.61 tm, lH), 7.51 (d, J = 8.3 Hz, ' 2H), 7.40 (s, lH), 6.11 (dd,J= 8.1, 6.1 Hz, lH), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s, 16 3H), 2.21-1.93 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Anal. Calcd for C27H23ClN2O3-1/2 H2O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16;
N, 6.02.
I
18B. (+~-7-rl-rr4-r(Dimethvlamino)methvllbenzovlloxvl~ro~yll-8-20 methvlindolizinorl.2-bl~uinolin-9fllH)-one Hvdrochloride A suspension containing (:~)-7-[1-[[4-(chloromethyl)benzoylloxy3propyl]-8-methylindolizino[l~2-b]quinolin-9(llH)-one (35 mg, 0.08 mmol) and sodium iodide (57 mg, 0.38 mmol) in dry acetone (50 mL) was heated at reflux for 1 h and then allowed to cool and s~r at room temperature overnight. Into this mixture 25 - dinlediyla-~nine was bubbled for several min, and the mixture was allowed to stir at - rooni temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between H20 and CH2C12. The organic layer was washed with H20 and dricd over sodium sulfate. The solvent was removed in ~-Yacuo, and the residue was purified by column chromatography eluting with a solvent gradicnt of 0-5% MeoHlcH2cl2! The isolated material was treated with 3 H20 and 0.3 mL 0.1 N HCl and lyophilized to afford the title compound as a beige solid. lH NMR (CDCl3JMeOH-d4) d 8.44 (s, lH), 8.26 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 8.6 Hz, lH), 7.96 (d, J - 8.~ Hz, lH), 7.82 ~m, lH), 7.74 (d, J = 8.4 Hz, 2H), 7.66 (m, lH), 7.55 (s, lH), 6.14 (dd, J = 7.9, 5.8 Hz, lH), 5.28 (s, 2H), 4.31 (s, 3~ 2H), 2.80 (s, 6H), 2.44 (s, 3H), 2.20-1.95 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H). Anal.

w0 93/20818 ~ ;q PC~/US93/03596 ':

-- : ~
Calcd for C2gH2gN303-3/2 HCl-712 H20: C, 59.51; H, 6.46; N, 7.18. Found: C, 59.91; H, 6.85; N, 6.85.
- ':.
Exam~le 19 (*~-8-Methvl-7-r l-rr4-~vndiniomethvl~benzovlloxylpro~vllindolizino~ 1.2-bl~ginolin-9(11H~-one t~ifluoroacetate .
To a suspension of (~)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]~uinolin-9(1 lH)-one and (77 mg, 0.25 mmol) in py2idine (8 mL) under an argon atmosphere was added 4-(chloromethyl)~enzoic acid (250 mg, 1.3 mmol). The resulting mixture was iallowed to stir at room temperature for 2.5 d and then was concentrated under reduced pressure. The residue was par~tioned between H20 and -CH2C12. and the phases were separated. The aqueous phase was adjusted to pH 7.5 by the addition of 5% iaqueous NaHC03 iand re-extracted with CH2C12. The 16 aqueous layer was concentrated under reduced pressur~, iand the residue was applied to a RP1g column and eluted with a solvent gradient of H20 to MeOH. The material that was isolated was chromatographed two additional times on a RP1g column, eluting with a solvent gradient of 0.1% TFA/H20 to 0.1% TFA/MeOH to afford, ~ter lyophiliza~on, the ti~e compound. IH NMR (CDCl3/MeOH-d4) d 9.07 (d, J = 5.7 Hz, 2H), 8.46 (m, lH), 8.39 (s, lH), 8.23 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.6 Hz, lH), 8.05 (m, 2H), 7.93 (d, J - 8.5 Hz, lH), 7.81 (m, lH~, 7.65 (m, lH), 7.59 ~d, J = 8.2 Hz, 2H), 7.49 (s, lH), 6.13 (dd, J = 7.8, 5.9 Hz, lH), 6.00 (s, 2H), 5.27 (s, 2H), 2.42 (s, 3H), 2.2-2.0 (m~-2H), 1;08 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C34H2gF3N30s-5/2 CF3C02H 5/2 H20: C, 49.53; H, 3.78; N, 4.44.
Found: C, 49.53; H, 3.31; N, 4.27. - ~

(i:)-7-rl-rr((~hLoromethYl)hydrox~hos~hinvlloxYlpro~yll-8-methYlindolizinQ~l~2 b~uino!in-9~1 l~)-one 'r~ie~vlamine Salt _ ~o a suspension of (+)-7-(1-}~ydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(1 1H)-onc (92 mg, 0.3 mmol) in CH2C12 (5 mL) under an argon atmosphere was added Et3N (42 mL, 0.3 mmol) followed by chloromethylphosphonic dichloride (31 mL, 0.3 mmol). The resulting mixture was allowed to stir at room temperature for 2.5 d, and ~en Et3N (42 mL) and MeOH

WO 93/20818 PCI'/US93/03596 2 ~ , ? ,~

(200 mL) were added and stiITing was continued overnight. The mixture was concentrated under reduced pressure, and the residue was par~tior.. d between H20 and CH2C12. The organic layer was washed with H20 (2x), and the combined aqueous extracts were Iyophilized. The material that was obtained was applied to a RP1g column, eluted with a solvent gradient of H20 to MeOH and lyophilized to afford the title compound. lH NMR (CDCl3) d 8.27 (br s, lHj, 8.13 (m, lH), 7.9-7.5 (m, 4H), 5.60 (m, lH), 5.19 (br s, 2H), 3.49 (br d, J = 10.2 Hz,2Hj, 3.05 (m, ~3H), 2.0-1.8 (m, 2H), 1.28 (t, J --7.3 Hz, ~5-6H)1.00 (t, J = 7.2 Hz~ 3H). Anal.
Calcd for C29H20ClN2O4P-1/2 C6H1sN-7/4 H20: C, 55.15; H, 6.24; N, 6.99.
Found: C, 54.94; H,5.81; N, 6.92.

Exam~le 21 f+)-7-r 1 -r(2-Cyanoethoxv)hvdroxy~hos~hinvl)oxvlyro~vll-8-methvlindolizinor1.2- b~ Qlin-9(l lH)-one Sodium Salt (+)-7-(1-Hydroxyp~opyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (153 mg, 0.50 mmol),2-cyanoethyl phosphate (derived from 322 mg, 1.0 mmol of the barium salt by the procedurc of Moffatt, J.G., J. Am. Chem. Soc. 1963, 85, 1118), and N,N'-dicyclohexylcarbodiimde (462 mg, 2.24 mmol) in dry pyridine (4.0- 29 mL) were heated at 45C for 24 h with exclusion of moisture. Water and MeOH
were added to the reaction, and the solvents were all stripped off in vacuo.
Additional H20 and MeOH were added along with NaOAc (1.02 g), an insoluble soli~was removed by fil~a~on, and the solvents were stripped off again. The residue was applied as an aqueous soludon to a reversed phase column of Partisil 40 ODS-3~and eluted with a gradient of 0-100% MeOH/H20 to give the ~itle compound. lH NMR (MeOH-d4) d 8.58 (s, lH), 8.19 (d, J = 8.1 Hz, lH), 8.05 (dd, J = 8.1, 1.0 Hz, lH),7.86 (m, lH), 7.71 (s, lH), 7.68 (m, lH), 5.54 (m, lH), 5.29 (s, 2H), 3.98 (m, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H), 2.07-1.88 (m, 2H), 1.10 (t, J = 7.4 ~z, 3H). Anal. Calcd for C22H21N3NaOsP- 15/4 H20: C, 49.96; H, 5.43, N,-7.94. Found: C, 49.95; H, 5.22; N, 7.63.

.

WO 93/20818 ~ PCr/US~3/03596 -53- ~-Examl~le 22 -8-Me~hvl-7-r1-r(phos~hono~o~vlpro~Yllindolizin~[l~ir.olin-9(11H)-one TnmethYlamine Salt To (~ 7-~1-[(2-cyanoethoxy)hydroxyphosphinyl)oxy]propyl~-8- ~:
methylindolizino[1,2-b]quinolin-9(11H)-one sodium salt (89.4 mg, 0.19 mmol) in MeOH (1.0 mL) was added lN NaOH (1.65 mL), and the reaction mixture was stirred under argon for 7 h at room temperature. The reaction was acidified with lN
Ht 1 (1.75 rnL), stripped and redissolved in H20. This solution was applied of areversed phase column of Par~sil 40 ODS-3 and eluted with a gradient of 0-100%
MeOHlH20. After some of the dtle compound eluted as a sodium salt, another ~rac~on came off as mostly the free acid. The acid fraction was dissolved in MeOH, and ~CH3)3N in MeOH was added to raise the pH to app~oximately 10. The MeOH
was stripped off, H2O was added and the solution was lyophilized to give the title j ~-1~ compound as a partial sodium salt. lH NMR (MeOH-d4D20) d 8.58 (s, lH), 8.16(d, J = 8.5 Hz, lH), 8.04 (d, J = 8.3 Hz, lH), 7.85 (m, lH), 7.74 (s, lH), 7.68 (m, lH), 5.50 (br dd, lH), 5.26 (s, 2H), 2.92 (s, ~6.5H), 2.33 (s, 3H), 1.gS (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). Anal. Calcd for C19H1 gN20sP-3/4 C3HloN- 1/4 Na 9/2 H20: , C, 49.35; H, 6.72; N, 7.45. Found: C, 49.41, H, 6.43; N, 7.02.

., _ am~le ~3 :`~
(i)-7-rl-rr(Aminomethvl)hvdrox,vphQ~binylloxvlpropvll-8-m~thvlindolizinorlæ-b~uinolin-9(1lh~)-one 23A. (+)-7-~1-rrrrr(9-nuorenvlmethoxv~carbonvll~uninolmethyllhvdroxy~hosphinvlloxY~ro~vll-~-m~do~izinorl.2-bl~uinolin-9fl 1~)-one T~e title compound was prepared according to the procedure in Example 21 exceptusing (+)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b~quinolin-9(11H)-oneand[[[(9-~uorenylmethoxy)carbonyl]amino]methyl]phosphonicacid. Anal. !
Calcd for C35H32N306P-9/8 H20 C, 65-~49;-H, -5.38; N, 6.55. Found: C~ 65.83;
H,5.28;N,6.14.

~B. (il-7-r1-rr(Aminomethyl)hydrox~hosphinvlloxvlpro~11-8^
methvlindoli~inQfl~-bl~uinolin-9(1 lH)-one r~s~

wo 93/20818 P~r/US93/03596 h 1 1 3 ~ 2 `1 A mixture of Et2NH (10 mL) and (~ 7-[1-[[[[[(9-fluorenylmethoxy)carbonyl]arnino]methyl]hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(llH)-one (328 mg, 0.51 m~nol) was stirred at room temperature in a capped vial for 3h. The reaction m~xture was str~pped to 5 dryness, and H20 was added. The this partial solution was extracted with EtOAc, filtered and lyophilized to give a viscous oil which was triturated with CH3CN to produce a golden solid. The solid was dissolved in H20 and lyophilized to give the title compound as a par~al Et2NH salt. lH NMR (FDCl3/MeOH-d4) d 8.49 (s, lH), 8.12 (d, J = 8.7 Hz, lH), 8.00 (d, J = 8.3 Hz, lH), 7.84 (m, lH), 7.69 10 (overlapping s and m, 2H), S.S9 (dd, J = 14.9, 6.5 H z, l H), 5.27 (s,2H), 2.98 (q,J
= 7.2 Hz, ~1.lH), 2.85 (dd, J = 12.7, 2.6 H z, 2H), 2.31 (s, 3H), 2.02-1.83 (m, 2H), 1.31 (t, I - 7.3 Hz, -1.8H), 1.05 (t, J = 7.4 Hz, 3H). Anal. Calcd for C20 H 22 N 3 O 4P-1/4 C4 H ll N-S H 2 O: C, 49.68; H, 6.90; N, 8.97. Found: C,50.08;
H, 6.49; N, 8.46.

~IP.le...24

12-rr(AminoacetYl~oxYlmethvll-8-methyl-7-(1-oxo,~ro~vl)indolizinorl .2-bl~uinolin-9f 11H)-one HvdrofluorQacetate 24A. 8-Methvl-12-rrrrr(1.1-dimethvlethoxv)carbonvllaminolacetylloxvlmethvll-l-(l-oxo~ vl)indolizinorl.2-blquinolin-9(l lH)-one The title compound was prepared according to the procedure in Example SE
.. .
exceptusing 12-(hydroxymethyl)-8-methyl-7-(1-oxopropyl)indolizino[1,2-b~quinolin-9(11H)-one and N-[(l,1-dimethylethoxy)carbonyl]glycine.
.4B. 12-rr(ArninoacetvnoxYlmeth~rll-8-methY1-7-(1-oxo~ro~vl~indolizinorl~2-blquinolin-9(l lH)-one Hvdrotnfluoroacetate The title compound was prepared according to the procedure in Example 5B
except using 8-methyl-12-[[[[[(1,1-30 dimetnylethoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(1-oxopropyl)indolizino~1,2-bJquinol~n-9~1H)-one. lHNMR (D2olDss) d 7.6-7.3 (m, 4H), 6.64 (s, lH), 5.58 (s, 2H), 4.58 (s,2H), 4.20 (s,2H), 2.92 (q, J = 7.2 Hz, 2H~, 1.94 (s, 3H),1.22 (t, J =
7.2 Hz, 3H). Anal. Calcd for C22H21N304-CF3C02H-H20: C, 55.07; H, 4.62; N, 8.03. Found: C, 55.32; H, 4.69; N, 7.98.

W O 93/2081~ f~ PC~r/US93~b3596 .
Exam~le ~5 8-Methyl-12-rr(4-morpholinoa~e~l)oxvlmethvll-7-(1-oxQDro~vl)indolizino~1.2- .
hl~uinolin-9(1 lH)-on~Hv~rochlolide To a suspension of 12-hydroxymethyl-8-methyl-7-(1-oxopropyl)indolizino[l,2-b]quinolin-9(1 lH)-one (523 mg, 1.56 mmol) in anhydrousCH2C12 (58 mL) at room temperature under an argon ahnosphere was added snhydrous pyIidine (130 yL, 1.61 mmol) and 4-dimethylaminopyridine (19 mg, û.16 mmol). The reaction was stirred for 10 min and then was treated with iodoacetic anhydride (554 mg, 1.57 mmol) in one portion. After 1 h the turbid orange soludon was treated with morpholine (815 yL, 9.4 mmol) and stirred for 1 h.
The reaction rnixture was filtered to remove morpholine hydroiodide, and the filtrate was concentrated in vacuo at 15C and punfied by flash chromatography eluting with 2% MeOH in CHCl3 to give, after removal of solvent, a yellow powderwhich was suspended in H20 (10 mL~ and ~eated with 0.1N HCl (16 mL) to give a pH of 1.7. The resulting slu~ry was ~lltered and washed with MeCN followed by Et20 to give the ti~le compound as yellow f~akes(, mp. 148-150C ~dec.). lH NMR
(CDC13) d 8.22 (d, J = 8.6 Hz, lH), 8.11 (d, J = 8.6 Hz, lH), 7.84 (m, lH), 7.70 (m, lH), 7.25 (s, lH), 5.77 (s, 2H), 5.50 (s, 2H), 3.73 (m, 4H), 3.33 (s, 2H), 2.92 (q, J = -7.6 Hz, 2H), 2.58 (m, ~H), 2.31 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H). Anal. Calcd for C26H27N305 HCl l/2 H20: C, 61.60; H, 5.77; N, 8.29. Found: C, 61.62; H, 5.~4; N, 8.25.
~, ~m~le 26 8-rr(IXmethYlaminoacetvl)QxYlmethYll-?-(l-~2xoDro~yl)indolizinor~ bl~inQlin 9(1 IH~-one HvdrochloFide ~

26A. 8-rr(Iodoa~etvl)oxvlmethvll-7-(1-oxopropvliindolizinorl.2-blquinQlin-9(1 1H)-one To a suspension of (t)-3-ethyl-1,1 1-dihydr~3-hydroxy-3H,13H-3a furo[3',4':6,7]indolizino[1,2-b]quinolin-13-one (320 mg, 1.00 mmol) in dIy CH2C12 (20 ~) under argon was added over 4 min diIsobu~ylaluminum hydride (1.10 rnL
of 1.0M in CH2C12). After 15 min iodoace~ic anhydride (530 mg, 1.~0 mmol) was added in one portion. After 2 h, MeOH (10 mL) was added to the reac~ion, and after sti~ing 20 min, the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and chromatographed on silica gel eluting with a gradient of 0-5%

O 93/20818 PCr/US93/03596 r~

= -56-MeOEVCH2C12 to give the title compound and some unreacted star~ng material.
lH NMR (CDC13) d 8.42 (s, lH), 8.24 (d, J = 8.4 Hz, lH), 7.96 (d~ J = 8.3 Hz, lH), 7.85 (m, lH), 7.69 (m, lH), 7.29 (s, lH), 5.33 (s, 4H~, 3.70 (s, 2H~, 2.99 (q, J = 7.2 Hz, 2H), 1.28 ~t, J = 7.2 Hz, 3H). CIMS (NH3, mJe, rel. int.~ 489 (100) [(M+H)+~.
5 Anal. Calcd for C21H17IN2O4-1/2 H2O: C, 50.72; H, 3.65; N, 5.63. Found: C, 50.53; H, 3.35; N, 5.45.

26B. 8-rr(Dimethvlaminoacetvl)o1~v!methYll-7-(1-oxo~ro~v~olizino~1.2-bl~uinolin-9(1 lH)-one Hvdr~chloride A suspension of 8-[[(iodoacetyl)oxy]methyl~-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(1 lH)-onc (48.8 mg, 0.098 mmol) in dry CH2C12 (5.0 n~) was covered by an atrnosphere of (CH3)2NH (balloon). Within a few min the solid had dissolved and after 5 min the reaction was strippcd to dryness. The residue was dissolvcd in CH2C12, washed first with 5% aqueous NaHCO3 and then with H20, and dried over Na2S04. The sohent was removed in vacuo, and the residue was suspended in H20 (20 rnL) to which was added lN HCl (100 ~1L) to dissohle most of the solid. After fil~a~ion, lyophilizauon gave the ~tle compound. lH NMR
(CDC131MeOH-d4) d 8.47 (s, lH), 8.23 (d, J = 8.3 Hz, lH), 7.98 (d, J = 7.5 Hz, lH), 7.87 (m, lH), 7.71 (m, lH), 7.44 (s, lH), 5.38 (s, 2H), 5.35 (s, 2H), 3.95 (s, 2H), 3.05 (s, 6H), 3.02 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). Anal. Calcd for C23H23N3O4 HCl 7/4 H2O: C, 58.35; H, 5.86; N, 8.88. Found: C, 58.26; H, 5.51;N,8.68. -!

Exam~le 27 8-rr(4-Mor~holiwace~vI~oxvlmethYll-7-fl-oxo~rogvl)indolizinorl.2-blquinolin-- - 9f 1 l~-one Hvdrochloride A suspension of 8-[~(iodoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino~1,2-b]quinolin-9(11~)-onc (138.2 mg, 0.278 2r~nol) in dry CH2C12 (18 mL) containing morpholine (75 ~, 0.86 mmol) was sti~red with moisture exclusion for 1.5 h, and thcn H2O was~cd and the layers separatcd. The organic layer was washed successively with H2O, 5% aqucous NaHCO3, and ~1nally H2O. After drying over Na2S04~ the o~ganic layer was stripped to dryness, and H20 (50 mL) and lN HCI
(284 ~) were added to dissolve all the residue. Lyophilization gave the title 35 compound. lH NMR (CDC13/MeOH-d4) d 8.50 (s, lH), 8.23 (d, J = 8.6 Hz, lH), WO 93/20818 ~ PCT/US93/03596 8.00 (d, J = 8.1 Hz, lH),7.88 (m, lH),7.72 (m, lH),7.47 (s, lH),5.37 (s,2H), 5.35 (s,2H),4.08 (br s,4H),3.99 (s,2H),3.50 (br s,4H),3.05 (s,6H)i 3.03 (q. J = `
7.1 Hz,2H),1.28 (t, J = 7.2 Hz,3H). An~. C~lcd for C25H25N305-5/4HCl-7/4 H2O: C,57.24; H,5.72; N,8.01. Found: C,57.17; H,5.33; N,7.62.

- -- = ::

Claims (65)

We claim:

1. A method for treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier I
wherein:
R7 is -H, -CN, lower alkyl, or -(CH2)nCH2V where n=0-3;
R9 is -H, -OR, -NRR1, -CN, -(CH2)nCH2V where n=0-3;
R10 is-H, -OR, -NRR1, -CN, -COR12, -CH(OH)R12, -O-(CH2)1-5CH2NRR1, -OC(O)NRR1, 1,4'-bipiperidine-1'-carboxy, -(CH2)nCH2V where n=0-3;
V is -OH, - OCOR14, OP(O)(OH)R15, or -NRR1;
R11 is -H or -OR;
R12 is -H or lower alkyl;
R and R1 are independently selected from the group consisting of -H, -C1-6 alkyl, and, when R and R1 are substituted on nitrogen, R and R1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;
R14 is -CR12R16R17, -(CH2)nCH2R17 (where n=1-3);
;
;

(where n=0 or 1, and CH2R17 can be substituted on the phenyl at the 2, 3, or 4 position);
-O(CH2)nCH2R17 (where n = 1-3);
-NRR1;
-NH(CH2)nCH2R17 (where n = 1-3);
R15 is OH, OR18, or CH2NH2;
R16 is H or the side chain of any naturally occuring a-amino acid;
R17 is NRR1, , , , where X
is any pharmaceutically acceptable anion;
R18 is lower alkyl;
X is CHR3R4 or ;
Y is -CH3, -CH2OR2;

R2 is -H, -C(O)H, -COR14, or -P(O)(OH)R15;
R3 is -OH, -OCOR14, or -OP(O)(OH)R15;
R4 is -H, lower alkyl, or -OR; and R6 is -H or lower alkyl;
provided that:
a) if one of R7, R9, R10 or R11 is other than -H, only one of the others may be other than -H;
b) only one of R7, R9, R10 or R11 may be -NRR1;
c) when X is -CHR3R4 and R4 is -OR, R3 is -OH; and d) when Y is -CH2OR2, X is .

2. The method of claim 1 wherein: R7, R9, R10, and R11 are each -H; X is -CHR3R4 or ; and Y is -CH3 or -CH2OR2.

3. The method of claim 2 wherein: X is -CHR3R4, where R3 is -OH; and Y is -CH3.

4. The method of claim 2 wherein: X is -CHR3R4, where R3 is OCOR14; and Y is CH3.

5. The method of Claim 4 wherein said compound is 7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

6. The method of Claim 4 wherein said compound is 7-[1-[(3-amino-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

7. The method of Claim 4 wherein said compound is 8-methyl-7-[1-[(-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

8. The method of Claim 4 wherein said compound is 7-[1-[(2-amino-2-methyl-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

9. The method of Claim 4 wherein said compound is 8-methyl-7-[1-[(4-morpholinylacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

10. The method of Claim 4 wherein said compound is 8-methyl-7-[1-[(pyridinioacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one iodide.

11. The method of Claim 4 wherein said compound is 7-[1-[[4-[(dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

12. The method of Claim 2 wherein: X is -CHR3R4, where R3 is OP(O)(OH)R15; and Y is CH3.

13. The method of Claim 12 wherein said compound is 8-methyl-7-[1-[(phosphono)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

14. The method of Claim 12 wherein said compound is 7-[1-[[(aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

15. The method of claim 1 wherein: X is and Y is CH2OR2 .

16. The method of claim 15 wherein said compound is 8-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

17. The method of claim 1 wherein: R7 is CH2OR2; X is ; and Y is -CH3.

18. The method of claim 17 wherein said compound is 8-methyl-12-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]qulnolin-9(11H)-one hydrochloride.

19. The method of claim 1 wherein: R7, R9, and R11 are each -H; provided that R10 is not -H.

20. The method of claim 18 wherein: R10 is -OR, -CN, -COR12, or -(CH2)nCH2V; and X is -CHR3R4, where R4 is -H or lower alkyl, or X is .

21. The method of claim 20 wherein: R10 is -(CH2)nCH2V; and X is where R6 is CH2CH3.

22. The method of claim 20 wherein said compound is 7-[1-[(aminoacetyl)oxy]propyl]-2-cyan-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

23. The method of claim 1 wherein: R7 is-H-, -R9 is -OR, NRR1, -CN, or -(CH2)nCH2V; R11 is -H;

24. The method of claim 23 wherein. R9 is -(CH2)nCH2V: R10 is -OR; X is -CHR3R4 where R3 is -OH and R4 is -H or- lower alkyl, or X is , and Y is -CH3.

25. The method of claim 1 wherein: R9, R10, and R11 are each -H; provided that R7 is not -H.

26. The method of claim 25 where R7 is lower alkyl, -CN, or -(CH2)nCH2V; X
is -CHR3R4 where R4 is -H or lower alkyl, or X is .

27. The method of claim 26 wherein said compound is 7-[1-[(aminoacetyl)oxy]propyl]-12-cyano-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

28. The method of claim 1 wherein: R7, R10, and R11 are each -H; provided that R9 is not -H.

29. The method of claim 28 wherein: R9 is -OR, X is -CHR3R4 where R4 is -H
or lower alkyl.

30. The method of claim 1 wherein: R7, R9, and R10 are each -H; and provided that R11 is not -H.

31. A compound of Formula I, or a pharmaceutically acceptable salt thereof I
wherein:
R7 is -H, -CN, lower alkyl, -(CH2)nCH2V where n=0-3;
R9 is -H, -OR, -NRR1, -CN, -(CH2)nCH2V where n=0-3;
R10 is -H, -OR, NRR1, -CN, -COR12, -CH(OH)R12, -O-(CH2)1-5CH2NRR1, -OC(O)NRR1, 1,4'-bipiperidine-1'-carboxy, -(CH2)nCH2V where n=0-3;

V is -OH, -OCOR14, -OP(O)(OH)R15, or -NRR1;
R11 is -H, or -OR;

R12 is -H or lower alkyl;

R and R1 are independently selected from the group consisting of -H, -C1-6 alkyl, and, when R and R1 are substituted on nitrogen, R and R1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;

R14 is -CR12R16R17, -(CH2)nCH2R17 (where n=1-3);

;

;
(where n=0 or 1, and CH2R17 can be substituted on the phenyl at the 2, 3, or 4 position);
-O(CH2)nCH2R17 (where n = 1-3);
-NRR1;
-NH(CH2)nCH2R17 (where n = 1-3);

R15 is OH, OR18, or CH2NH2;

R16 is H or the side chain of any naturally occuring a-amino acid;
R17 is NRR1, , , , where X
is any pharmaceutically acceptable anion;

R18 is lower alkyl;
X is -CHR3R4 or ;
Y is -CH3, or -CH2OR2;
R2 is -H, -C(O)H, -COR14, or -P(O)(OH)R15;
R3 is -OH, -OCOR14, or -OP(O)(OH)R15;
R4 is -H, lower alkyl, or -OR; and R6 is -H or lower alkyl;
provided that:

a) if one of R7, R9, R10 or R11 is other than -H, only one of the others may be other than -H, b) only one of R7, R9, R10 or R11 may be -NRR1;
c) when X is -CHR3R4 and R4 is -OR, R3 is -OH;
d) when Y is -CH2OR2, X is ;
e) when R7, R9, R10, and R11 are all -H and Y is -CH3, then X is not -C(O)H,-CH2OH, -C(O)CH2CH3, or-CH(OH)CH2CH3;

f) when R7, R9, R10 and R11 are all -H and Y is -CH2OC(O)H, then X
is not -C(O)CH2CH3; and g) when R7, R9, R10, R11, and Y are all -H, then X is not -CH2OH or -C(O)H.

32. A compound of claim 31 wherein: R7, R9, R10, and R11 are each -H; X is -CHR3R4 where R4 is -H or lower alkyl, or X is where R6 is -H or lower alkyl; and Y is -CH3 or CH2OR2.

33. A compound of claim 32 wherein said compound is 7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

34. A compound of claim 32 wherein said compound is 7-[1-[(3-amino-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

35. A compound of claim 32 wherein said compound is 8-methyl-7-[1-[(-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

36. A compound of claim 32 wherein said compound is 7-[1-[(2-amino-2-methyl-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

37. A compound of claim 32 wherein said compound is 8-methyl-7-[1-[[(2-pyrrolidinylcarbonyl)aminoacetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

38. A compound of claim 32 wherein said compound is 8-methyl-7-[1-[(4-morpholinylacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

39. A compound of claim 32 wherein said compound is 8-methyl-7-[1-[(pyridinioacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one iodide.

40. A compound of claim 32 wherein said compound is 7-[1-[[4-[(dimethlylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

41. A compound of claim 32 wherein said compound is 8-methyl-7-[1-[(phosphono)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

42. A compound of claim 32 wherein said compound is 7-[1-[[(aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

43. A compound of claim 1 wherein: X is ; and Y is CH2OR2.

44. A compound of claim 43 wherein said compound is 8-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

45. A compound of claim 1 whcrein: R7 is CH2OR2; X is ; and Y is -CH3.

46. A compound of claim 45 wherein said compound is 8-methyl-12-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one hydrochloride.

47. A compound of claim 31 wherein: R7, R9, and R11 are each -H; provided that R10 is not -H.

48. A compound of claim 47 wherein: R10 is -OR, -CN, -COR12, or -(CH2)nCH2V: X is -CHR3R4 where R4 is -H or lower alkyl, or X is .

49. A compound claim 48 wherein said compound is 7-[1-[(aminoacetyl)oxy]propyl]-2-cyano-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

50. A compound of claim 48 wherein: R10 is -(CH2)nCH2V; and X is , R6 is CH2CH3.

51. A compound of claim 31 wherein: R7 and R11 are each -H; provided that R9 and R10 are each not -H.

52. A compound of claim 51 wherein: R9 is -(CH2)nCH2V; R10 is -OR; X is -CHR3R4 where R4 is -H or lower alkyl, or X is ; and Y is -CH3 or CH2OR2.

53. A compound of claim 31 wherein: R9, R10, and R11 are each -H; provided that R7 is not -H.

54. A compound of claim 53 where R7 is lower alkyl, -CN, or -(CH2)nCH2V; X

is -CHR3R4 where R4 is -H or lower alkyl, or X is .

55. A compound of claim 54 wherein said compound 7-[1-[(aminoacetyl)oxy]propyl]-12-cyano-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

56. A compound of claim 31 wherein: R7, R10, and R11 are each -H; provided that R9 is not -H.

57. A compound of claim 56 wherein: R9 is -OR, X is -CHR3R4 where R4 is -H or lower alkyl.

58. A compound of claim 31 whaein: R7, R9, and R10 are each -H; provided that R11 is not -H.

59. A formulation comprising a compound of claim 31 in admixture with a carrier or excipient.

60. The formulation of claim 59 where the carrier is a pharmaceutically acceptable carrier or excipient.

61. The method of claim 1 wherein said viral infection is caused by a herpes simplex virus.

62. The method of claim 61 wherein said virus is herpes simplex type 1 and the infected host is a mammal.

63. The method of claim 61 wherein said virus is herpes simplex type 2 and the infected host is a mammal.

64. The method of claim 1 wherein said viral infection is caused by cytomegalovirus and the infected host is a mammal.

65. The method of claim 1 wherein said viral infection is caused by varicella zoster virus and the infected host is a mammal.