CA2095219A1 - Substituted indolizino[1,2-b]quinolinones - Google Patents

Abstract

The present invention provides a method of treating viral infections with substituted indolizino[1,2-b]quinolinone antiviral compounds, certain novel substituted indolizino[1,2-b]quinolinone compounds having antiviral activity, and pharmaceutical compositions thereof.

Description

~W092/07856 ~ 219 PCT/US91/08028 SUBSTITUTED INDOLIZINO[1,2-b]QUINOLIMONES
This application is a continuation-in-part of U.S.
Serial No. 07/606,216, filed on October 31, 1990.
~coDe of the Inyen~inn ~ his invention relates to methods of treatlng viral infections, antiviral compounds, and pharmaceutical compositions thereof. More specifically, this invention relates to a me~hod of treating viral infections, certain indolizino[1,2-b]-quinolinyl derivatives which have an~iviral activity and pharmaceutical compositions thereo-.
1~) R,_~~gr'o~
Certain lH-pvrano[3',4':6,7]indolizino [1,2-b]quinolinones are known to have cytotoxic and antiviral activity. Camptothecin is an example of such compounds. It is a water-insoluble, cytotoxic alkaloid produced by Ca~tothe~a ~s~mi~d~a trees indigenous to China and Not~apo~ytes f~ trees indigenous to India.
Camptothecin and a few close congeners are the only class of compounds known to inhibit eukaryotic topoisomerase I.
In fact, the cytotoxic and antitumor activity of camptothecin and its close congeners results from inhibition of eukaryotic topoisomerase I (Cancer Res.
1988, 48, 1722; Molec. Pharmacol. 1988, 34, 755).
Compounds that are related in structure to camptothecin but do not inhibit eukaryotic topoisomerase I are not cytotoxic to mammalian cells and have no antitumor activity ~J. ~ed. Chem. 1988, 32, 715; Cancer Res. 1989, g9, 1465; Cancer Res. 1989, 49, 4358).
A number or investigators have shown that camp~othecin possesses antiviral activity. However, although camptothecin has demonstrated antiviral activity in in vitro tissue culture sys~ems, camptothecin and its close analogs that have an E-ring hydroxylactone moiety canno~ be considered as useful in vivo antiviral agents SUBSTITUTE~ S~EE~

:,, - :
. ; :

W092/07856 ~ 9 ~ ~ 9 PCT/US91/08028 -because they undesirably inhibit mammalian topoisomera3e I, as well as host cell DNA repllcation, and are cytoto~.ic to mammalian cells. Furthermore, camptothecin iQ not an attractive candidate for drug development as an antiviral agent because of unacceptable dose-limiting toxicity, unpredictable toxicity, and poor aqueous solubility, and/or unacceptable shelf life stability.
There is a need for new antiviral agents.
Substituted indolizino[1,2-~]quinolinones that lack tne E-ring a-hydroxy lactone moiety of camptothecin have bee-.
shown to be non-cytotoxic to mammalian cells ar.~ ~o lack antitumor activity (Ann. Re~. Pnarmcol . Toxico ' . ~ 377, 17, 117; J. Med. Chem. 1989, 32, 715). This ls because these compounds do not contain the essential structural features required to inhibit eukaryotic topoisomerase I.
However, recently we have found that certain substituted indolizino[l,2-b]quinolinones lacking the E-ring hydroxylactone moiety do have antiviral activity but not the undesirable cytotoxicity of camptothecin. Thus, such substituted indolizino[1,2-b]quinolinones are useful for treating viral infections.
SUMM~RY OF TH~ lNVEN~TON
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 pharmaceutically acceptable salt thereof, alone or in combination with a carrier Rll ~ (I) ;. 30 v - wherein:
R7 is -H, -NO2, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH2Ar, -C aCCH2NRR1, -CH=CHCH2NRR1~ ~(CH2)nCH2V where SU8S~TUTE S! IEF~

, ~ .

. W092~07856 2 5 ~ ~ 2, 1 9 PCT/US91/08028 n=0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -oCooR13, -OCONRRl, -NRRl, or -CN;
R9 iS -H, -OR, -NO2, -NRR1, -CN, halo, -(CH2)nCH2V where n=0-3 and v is -OH, -OC1-6alkyl, -OCOR12, -oCooR13, -OCONRR1, -NRR1, or -CN;
R10 is -H, -OR, -NO2, -NRR1, -CN, -COR12, -CH(OH)R12, -OC(O)R12, -OC(O)OR12, -OC(O)CH2CH2CooRl3, -O-(CH2)1-sCH2NRR1, -OC(O)NRR1, 1,4'-bipiperidine-1'-carbo~y, -(CH2)nCH2V where n=0-3 and V is -OH, 3~12, -ocoo~13, _ocoNRRll _N~R1 or -CN
R11 is -H, -CN, or -OR;
: 15 R12 is -H or lower alkyl;
; R13 is 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 Rl can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;
X is -H, -OH, -CN, -SOR, -CH(OH)CH(OH)CH3, -CHR3R4, :~ ~ R5 -C -CCH2NRR1, -CH2CH2CH2NRR1, lower alkyl, R
\o CH3 or -c(cH2cH3)(oH)cooH;
Y is -H, -CH3, -CH20R2;
R2 is -H, -C~O)H, -C(O)C1-5alkyl, -C(O)C1-4alkylCOOH
or -C(O)C1-4alkylNRR1;
. 35 R3 is -OH, halo, or -NH2;
- R4 is -H, lower alkyl, or -OR;
Q R5 is =O, =NOH, or =CHR;
R6 is -H, lower alkyl, o~ -NRR1; and :;' SUBSrlTUTE SHEET

';- .

W092/07~56 2 ~ 3 ~ 2 1 9 PCT/US91/0802X ~

Ar is phenyl, monosubstituted phenyl, disubstituted phenyl, 3-pyridyl, monosubstituted 3-pyridyl, or disubstituted 3-pyridyl, where substitutents can be -CN or lower alkoxy;
provided that:
a) if one of R7, R9, Rl0 or Rll is other thar. -H, only one of the others may be other than -H;
b) only one of R7, R9, Rl0 or Rll may be -NO2 o~
-NRRl;
c) when X is -CHR3R4 and R4 iS -OR, R3 is -OHi d) when R6 is -NRRl, R5 iS =O;
e) when R5 is =CHR, R6 is -H;

f) when X is ~ 3, R10 is -OH, and R7, R9, and Rll are -H, and Y is -CH3; and g) when Y is -CH2OR2, X is R6, R5 is =O, and R6 is -H or lower alkyl.
This invention also provides compounds having the formula of Formula I as described hereinabove, except that:

a) when R7, R9, Rl0, and Rll are all -H and Y is -CH3, then X is not -H, -C(O)H, -CH2OH, -CH(OH)CH(OH)CH3, -C(O)CH2CH3, or -CH(OH)CH2CH3;
b) when R7, R9, Rl0 and Rll are all -H and Y is ~ -CH2OC(O)H, then X is not -C(O)CH2CH3;
; 30 c) when R7, R9, Rl0, Rll, and Y are all -H, then X
; is not -CH2OH, -C(O)H, -CH2Br, -OH, or -H; and d) when R7 is -OCH3, then X and Y are not -H.
Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier or excipien~.

SUBSllTUTE SHEET

.: ~
;. ~

W092/07856 2 ~ 9 3 219 PCT/US91/08028 In yet another aspect, the present inventlon relates to processes for making a compound of Formula I.
DET~IT ~.D DE!:;CRIP'rTON OF T~l~. TNVENT~
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 do-_~le ar.d trip'e bonds may be present in any co~n_.ior.. ~he ph_ase "lowe- alXyl" refers to an alkyl group of l .o 6 carbon atoms in any isomeric form, but particularly ~ne normal or iinear form. "Lower alkoxy"
means the 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, morpholine, piperazine, and N-alkyl piperazine.
The term "l,4'-bipiperidine-l'-carboxy" is used to identify the following radical:

C C

Salts of any sort may be made from these compounds, provided that an acidic group or a sufficiently basic nitrogen in the acid or base. Particularly preferred are the pharmaceutically acceptable salts of the instant compounds. These salts are defined as those which are acceptable in their application to a pharmaceutical use, -~ meaning that the salt will retain the biological activity of the parent compound and that the salt will not have untoward or deleterious effecls ir. its application and use in treating diseases.

'~ SU8SmU~E S~
, : ` ~, .' ' ', . ' ::- , : , : .

2 ~ 2 ' 9 Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound, in a sultable solvent, is reacted with an excess of an organic or inorganic acid in the case of acid addition salts o~ 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, maleic acid, succinic acid and methanesulfonic acid. Cationic salts are readily prepared from alkali metals such as soàium, potassium, calcium, magnesium, zinc, copper or the like 2S well as ammonia. Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, and the like.
The chemical nomenclature used throughout this patent application to name the compounds of the present invention is in accordance with the structural formula represented as Formula II.
1 12 1l N ~9 ` 3 ~ N~ ~ (Il) X
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 forms of such isomer~s) are considered to be aspects of the present inventions. When a compound of the present invention contains a chlral center, the present invention includes the racemic mixture, the pure enantiomers, and any enantiomerically enriched mixtu-e thereof.
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 hereinab3ve, or a pharmaceutically S1~ JTE SHE~T

.

W092/07856 2 G ~J ~ 2 1 9 PCT/US91/08028 acceptable salt thereof, alone or in combination with a carrier or excipient.
The present method is useful for treati.ng vlral infections in animals and plants caused by a broad variety 5 OI viruses. The present method is particularly useful in treating viral infections caused by herpes simplex virus, particularly herpes simplex virus type l (HSVl) and herpes simplex vlrus type 2 (HSV2), or cytomegalovirus when the lnfectec' hos~ is a mzmmal, ~articularly when the infected host is human.
~ - ?referre~ mer:.oà of .rea-ing viral infections according to the present invention uses compounds of Formula IMl ~Y

: l5 X IMl ,,Rs `. where X is -CN, -SOR, -CH(OH)CH(OH)CH3, -CHR3R4, R6 or .~, ~~\

: ~ 3; and Y is -CH3 or -CH2OR2, Formula IMl corresponding to Formula I wherein R7, R9, Rl0, and Rll are each -H and X and Y are as described herein. A more preferred method uses compounds of Formula IMl where X is ~ Rs CHR3R4 where R3 is -OH and Y is -CH3, where X is R6 where R5 is -0 and 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.
. Another preferred method for treating viral infections according to the presen~ invention uses compounds of Formula I~12 R10 ~

.~

: SUBSTITUTE SHEET
, . , , . ` . . ` . . .
.: ` . ` , `` . :... ` , ~ ` : . . . ' ~. - . ' `. .

W092/078~6 2 ~ 2 ~ 9 PCT/US91/08028 Formula IM2 corresponding to Formula I wherein R7, R9, and Rll are each H, Rl0 is as defined hereinabove for Formula I except that Rl0 is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM2 where Rl0 is -OR, -CN, CORl2, or -(CH2)nCH2V, X is -CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, or R6 where R5 is =0 and R6 is -H or lower alkyl and Y is -CH3.
Yet another preferred method of use according to the present invention uses compounds of Formula IM3 R10 ~

Formula IM3 corresponding to Formula I wherein R7 and R
: are each :: -H, R9 and Rl0 are as defined hereinabove for Fomula I
except that R9 and Rl0 are each not -H, and X and Y are as .:~, defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM3 wherein R9 is ~(CH2)nCH2V, Rl0 is -OR, X is CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, or R6 where R5 is =0 and R6 i-s -H or lower alkyl, and Y is -CH3.
Another preferred method of use according to the present invention uses compounds of Formula IM4 ~$Y

~ IM4 SUE3g~ SHEET

~ ~ .
. ~:

W092/07856 2 ~ , 2 1 9 PCT/US91/08028 Formula IM4 corresponding to Formula I wherein R9, Rl0 and Rll are each -H, R7 iS as defined herelnabove except that R7 is not -H, and X and Y are as de~ined hereinabove in Formula I. A more preferred method uses compounds o~
Formula IM4 where R7 is lower alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar, X is CHR3R4 where R3 is -OH and R4 is -H or ~R5 lower alkyl, or R6 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3.
Yet another preferred me~hod of use according to the preser.- inver.tlon uses compounas is represented by Formula ~$Y

Formula IM5 corresponding to Formula I wherein R7, Rl0 and Rll are -H, R9 is as defined hereinabove for Fomula I except that R9 is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM5 where R9 is -OR, X is CHR3R4 where R3 is -OH
,R5 and R4 is -H or lower alkyl, or R6 where R5 is -0 and R6 is -H or lower alkyl, and Y is -CH3 Still another preferred method of use according to the present invention uses comoounds is represented by Formula IM6 R~ y SUBSTiTUT' SltEE, , , . . . .:
, :. ; : : , ,, .. . .

W092/07856 PCT/US91/08028 ^-~U~219 Formula IM6 corresponding to Formula I wherein R7, R9 and R10 are each H, R11 is -CN or -OR, and X and Y are as defined hereinabove in Formula I. A more pre~erred method uses compounds of Formula IM6 where R11 is -OCH3, X is CHR3R~ where R3 is -OH and R4 ~s -H or lower alkyl, or Rs R6 where R5 is =0 and R6 is -H or lower alkyl, and Y
is -C~3 Yet another preferred method of use according to the p~esent i~ventlons uses compounds of Formula IM7 ~0 Formula IM7 corresponding to Formula I wherein R7, R9, R10 and R11 are -H, X is -CN, -cH2cH3 or -CH=CH2, and Y is -H-The present invention also provides compounds having antiviral activity, and pharmaceutically acceptable salts thereof, said compound having the structure represented by Formula T hereinabove except that: .
a) when R7, R9, R10, and R11 are all -H and Y is -CH3, then X is not -H, -C(O)H, -CH2OH, -CH(OH)CH(OH)CH3, -C(O)CH2CH3, or -CH~OH)CH2CH3;
b) when R7, R9, R10 and R11 are all -H and Y is -CH2OC(O)H, then X is not -C(O)CH2CH3;
c) when R7, R9, R10, R , and Y are all -H, then X
is not -CH2OH, -C(O)H, -CH2Br, -OH, or -H; and d) when R7 is -OCH3, then X and Y are not -H.

Prefered compounds of the ~resent invention include those of Formula IN1 ~ ~$Y

SU8STITJTE S~EET

. . .

, ~W O 92/078~6 ~ 2 1 9 PC~r/US91/08028 Formula IN1 corresponding to Formula I wherein R7, R9, R10 ~ R5 and R11 are -H, X is -CN, -SOR, R6 where R5 i5 'O and R6 is -H or lower alkyl, or CHR3R4 where R3 is -OH and R4 is -H or lower alkyl (provided that R4 ls not -CH2CH3), and Y is -CH3.
Compounds of Formula IN2 are also preferred according to the pr-sent invention Rl ~ __~O

'' 10 Formula IN2 corresponding to Formuia I wherein R7, R9 and R11 are each -H, R10 is as described hereinabove for Formula I except that R10 is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN2 include those where R10 is -OR, : -CN, -COR12, or -(CH2)nCH2V, and X is CHR3R4 where R3 is -. OH and R4 is -H or lower alkyl, or R6 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3 Another preferred group o- compounds of the present invention are the compounds of Formula IN3 Il~

;:Formula IN3 corresponding to F~rmula I wherein R7 and R
`25 are each -H, R9 and Ri0 are as described hereinabove for ~`Formula I except that R9 and R10 are not -H, and X and Y
are as defined hereinabove fc- Formula I. More preferred compounds of Formula IN3 incl~-Q ~hose whe~e R9 is -(CH2)nCH2V, R10 is -OR, X is -HR3R4 where R3 is -OH and :, , .

S~J~S~
. : - . - . - ~

, : ,~, . ::

W092~07856 ~.~ 1 9 PCTt usg 1/08028 _~Rs R4 is -H or lower alkyl, or R6 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3.
Still another preferred group of inventive compounds are the compounds of Formula IN4 ~Y

Formula IN4 corresponding to Formula I wnerein R9, R10 and Riî are each -H, R7 is as described hereinabove for 10 Formula T 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 alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar, X is CHR3R4 ~ R5 where R3 is -OH and R4 is -H or lower alkyl, or R6 15 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3.
Another preferred group of compounds according to the present invention are the compounds of Formula IN5, Formula IN5 corresponding to Formula I wherein R7, R10 and Rl1 are each -H, R9 is as described hereinabove for Formula I except that R9 is no- -H, and X and Y are as : defined hereinabove for Formula I. More preferred 25 compounds of Formula IN5 include those compounds where R9 I is -OR, X is CHR3R4 where R3 is -OH and R4 is -H or lower .,, . .

:~`
:,' SUBSTITUTE SHEET

.

., , .. W092/07856 ~ 3 ~ ~ 1 9 PCT/US9l/08028 ~ R5 alkyl, or R6 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3 Yet a further group of preferred compounds is represented by Formula IN6 RllJ~Y
X I~6 Formula IN6 corres?or.ding ~o ~o-mul~ erein R~, ~9 and R10 are each -H, Rll is -C~ or -OR, and X and Y are as defined hereinabove ro- Formula I. ilore prererred compounds of Formula IN6 are compounds where Rll is -OCH3, X is CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, ~ R5 ; or R6 where R5 is =0 and R6 is -H or lower alkyl, and Y is -CH3.
Yet another preferred group of inventive compounds is represented by Formula IN7 ' ~$

Formula IN7 corresponding to Formula I wherein R7, R9, R10 and Rll are each -H, X is -CN, -CH2CH3, -CH2CH2, and Y is -H.
::' 2 The following compounds are particularly preferred:
8-methyl-7-(1-oxopropyl)indolizino~1,2-b~quinolin-9(llH)-o ne;
~+)-7-(1-hydroxypropyl)-8-meth;lindolizino~1,2-b]quinolin-9(llH)-one;
8-formyloxymethyl-7-(1-o~:opro~.l)indolizinoLl,2-b]quinolin -9(llH)-one;
'1 .

SUBSTlTUTE SHEET
.. . .... . .
` . .,:-` `
.`..... - ` ~ , - . ` . . .. -W092/07856 ~ },~ PCT/US91/08028 --(+)-7-(threo-1,2-dihydroxypropyl)-8-methylindolizino[1, 2-b ] quinolin-9(llH)-one;
~)-7-[(hydroxy)methoxymethyl]-8-methylindolizino[1, 2-b] qu inolin-9(llH)-onei 7-(hyd_oxymethyl)-8-methylindolizlno[1,2-b]quinolin-9(11~) -one;
2-hydro~y-8-methvl-7-(1-oxo~ro?yl)indolizino[1,2-b]quinoli n-9(llH)-onei 1-(àimet;~ylam~ me_hyl-2-hyàro~y-8-methyl-7-(1-oxopropyl) indolizino[l,2-b]quinolin-9(llHj-one;
2-cyano-8-me~hyl-7-(l-oxo?ropyljindolizino[l~2-b]quinolin 9(11~)-one;
1-methoxy-8-methyl-7-~1-oxopropyl)indolizino[1,2-b]quinoli n-9(llH)-one;
2-aminomethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]qui nolin-9(llH)-one;
2-methoxy-8-methyl-7-(l-oxopropyl)indolizino[1,2-b]quinoli n-9~llH)-one;
12-hydroxymethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]
quinolin-9(llH)-one;
7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-~`~ methylindolizino[1,2-b] quinolin-9(llH)-one;
~5 7-acetyl-8-methylindoliz no[1,2-b]quinolin-9(llH~-one;
. 12-cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(llH~-one;
` 40 12-aminomelhyl-8-me~hyl- -(l-o::~p-opyl~indolizino[1,2-b~quinolin-9(llH~-one;
(+~-12-cyano-7-(1-hydroxypropy:)-3-methylindolizino[1,2-b]
quinolin-9~llh)-one;
'' SUBSrlT~I~ S~EET

, ~ . . .. : . , .~ W 0 ~2/07856 ~ ~ ~J ~ PC~r/US91/08028 (+)-2-cyano-7-~1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9~llH)-one;
2-acetyl-8-methyl-7-~1-oxopropyl)indolizino[1,2-b]
S quinolin-9~llH)-one;
12-propyl-8-methyl-7-~1-oxopropyl)indolizino[1,2-b] ~uinolin-9~llH)-one;
~+)-1-methoxy-7-~1-hydroxypropyl)-~-methylindoli~ino[1,2-b] quinolin-9~llH)-one; and 3-methoxy-8-methyl-7-(1-cx^ -c~ l~--dc' zi^.c'1,~-: b] quinolin-9(11~)-one.

Some compounds used in the method rOr treating vir21 infections according to the present invention are known.
The publications listed herein discussing the 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 synthetic methods for preparing the inventive compounds are outline~ in the following reaction . flow charts.
In general, the inventive compounds are prepared by opening the E ring of camptothecin or a camptothecin derivative which may have the desired R7 - Rl1 substituent to obtain an ~-methyl-7-(1-oxo?ropyl)indolizino[1,2-b]quinolin-9(11R)-one. Alternatively, the E ring may be opened and then the R7 - Rll substituents introduced. In ~; yet another alternative method, an existing R7 - Rll grouo is modified to obtain the desi-ed compound. Once the E
ring is opened, the resulting X and Y groups may be further modified as needed to ..,a~e the subject comcounds.
. Starting materials are cc-~erciallv available or can be made by published methods. ~amptothecin, 10-:, ..
SUE~STITUTE SHEET

- . . . ...... .. - . . ..
.

W092/07856 2 U ~ 9 PCT/US91/08028 hydroxycamptothecin and 9-hydroxy-camptothecin are natural products. Camptothecin and 10-hydroxycamptothecin are available from sources in the People's Republic of China.
A 9-hydroxy camptothecin compound which can be used as starting ma~erial ror making some of the inventive compounds is described in Published Japanese Patent Applica~iGn No. 59-51,289. The synthesis of 9-nitrocamptothecin is described by Wall, et al. J. Med.
Chem.. 'g~5, 29, 2353. ~ tot~l synthesis or camptothecin lC is desc~i`oed by Wail, et ai., u. l`~ed. Chem. 19~0, 23, 5i~.. The 1930 ~iall, er a'. sy.. hesis can be used as a means ~o introduce sne or more R7 - Rl1 substituents into the compounds of Formula I. This involves modifying the Wall synthesis at the appropriate step in a manner which puts in place the desired subs~ituent, then continuing with the described synthesis.
Graphically, the ring-opening reaction is illustrated by Scheme 1 wherein the Q symbol indicates a substituent that may be hydrogen.

SUBSTI~VTE S~E~T

.. ..... . . .. .

,~W092/07856 ~f~ P~/US91/08028 ~h~m~L

Q ~ 2 Compounds of formula 1 are convertec to -omo~nds o' formula 2 by heating the com?ounds in a hign Doiilng, preferably unreactive, solven- s~sc~ as ~
; dimethylformamide or triglyme (~rlethylene glycol di~eth~;l ether).
As shown in Scheme 2 tre keto group of sompounds o~
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 converted to a ketal group such as a l,3-dioxolane q! (compounds 7, which are useful intermediates for further transformations). The hydroxyl group of compounds 3 can also be acylated to produce esters (8) and carbamates (9 wherein R indicates an alkyl group while R' and R"
indicate either alkyl groups or hydrogen atoms.
.
Sc~.eme 2 :~ a Q ~ Q 2 ' Q ~ a~

,~ 25 X= halo ;~, , s .

:
S~ SmUTE SHE~T

`: .

W O ~2/078S6 ~ i~ 3 J 2 ~ 9 PC~r/US91/080Z8 -a o o Q
2 Q ~5 ~ ~

Q Q
a~r~4_ ~O~
s Q Q
3 3_Q~

OCOR' Q Q
3 _Q~

` OCONR'R"

As illust~ated in Scheme 3, dehydration of alcohols 3 gives alkenes 10 which can be hydroxylated to diols 11.
; Oxidative cleavage of the diols generates the 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 and 13 give the primary alcohols 14.

..

suasrrru~ St~EE~

W092/078~6 ~ J 2 ~ 9 PCT/US~1/08028 Scheme 3 Q O O O

Q Q Q Q
Q ~ O Q ~ O
Q ~ N ~ Q ~ ~ ~

~0 Q Q
13 - Q ~

Also derived from camptothecins are the a-hydroxy ~. acids 15 which are formed by hydrogenolytic cleavage of : the lactone ring as shown in Scheme 4.
. , Scheme 4 ~ Q Q
~ Q ~
.~ 15 /.
OH
.~
:~ Some ring substituents may be labile to the ` 20 conditions used in the prefer-ed method of making `~ compounds 2 as given in Scheme 1. To make com?ounds which are unstable under those cond-.ions, the sequence set ou~
ln Scheme 5 can prôvide access to certain of those s~sm~ s~
" ' ' ' ' ' . ' W092/07856 ~ a ~ 1 9 PCT/US91/08028 ~.

compounds or provide intermediates for making other compounds.

Sche~

Q Q a Q Q Q

Q ~ - ~ Q ~ ' Q Q Q Q
t8 -More specifically, the keto group of compounds 16 is first protected as a ketal (17), and then the pyridine ring is reduced to give compounds 18, for example with sodium cyanoborohydride in an acidic solvent such as , 15 acetic acid. Finally, oxidation of compounds 18, for example by iodobenzene diacetate, gives the 2-hydroxy ketals 19 which along with the k_'o compounds 20 de- ved from the ketals by acid hydrolysis can be used to make compounds with other substituents as illustrated in Scheme 6.

~cheme ~

Q Q
. 20 ~ ~ N ~
21 ~ O

SUBS~lTUTE S~.E~l WO 92/07856 ~ ~ r, ~) 2 1 9 PCI/US91/08028 Q Q
R'COO~ ~

2 2 ~;).o Q Q
2 0 -ROC(O)O~

R~' Q Q
R'R"NC(O)O~

2 4 ~o Q Q Q Q Q Q
CF,SO,~_N~ _NC~

262 2~_ H2NCH2~

28 29 o ., ~: Q Q Q Q
R'R"N(O)C~ R'R"N(O)C~_ ::;
SUBSTITUT S~E~

. . .
- ` , ;' ' ': ~ ' WO 92/07856 ~ 9 PCl'/US91/08028 --Q Q Q Q
RO(O)C~ RO(O)C~

Q Q Q Q
HOCH2 ~ O HGCH2 J~. O
3 2 ~Q~~ ~ Q~

3 R~ '\<'O ~ R' Q Q Q Q
OIYC~ G OHC~ o 34 Q~'~) 37J~o ~, RO Q Q Q Q

~ CH3CO~

Q Q Q Q
32 2 ~ HzN~_ Q Q Q Q
RNH ~ RNH~_ SUE3STlTUT~ S~E~I

W O 92/07856 2 ~ 3 ~ 2 ~ 9 PC~r/US91/08028 Q Q Q Q
F(SO2NH ~ RSO2NH~

Q Q Q Q
R'CONH~_ R'CONH~$

The compounds in Scheme 6 are prepared either b~l 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 al, Chem. Lett. 1981, 69 gives compounds 26 which are hydrolyzed to compounds 27. Catalytic hydrogenation of the cyano group of compounds 26 gives aminomethyl ketals 28 which upon hydrolysis gives the ketones 29.
Alternatively, starting with the triflates (25), a carbonyl group can be introduced onto the ring, for example by the procedure of Cacchi, S, et al, Tetrahed~on 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 can be acylated to give carboxylates, carbonates and carbamates by methods similar to those used for preparing compounds 22, 23, and 24. Aldehydes (compounds 36) can be made by oxidizing SU~SmUTE SHEET

W092/07856 ~ Q ~ a ~1~ PCT/US91/08028 the alcohols 34 using a mild oxidant which gives the aldehyde in preference to the acid (for example, MnO2).
Deprotection gives the keto aldehydes 37 Similarly, the triflates are converted to vinyl ethers 38 following the method Or Ca~- , r~1., e a`. (J.
Org. Chem. 1990, 55, 3654), and then compounds 38 are hydrolyzed to diketones 39. Selective htd-olysis of t_he enol ether function in compounds 38 produces the 2-keto compounds that can be reduced tO seco..a~ry alcohols --o~
whlch the ketal groups can be removed -r.d the al-ohol function acylated to glve C=bG:; i ` at^ â ~ C - _~v..- _ _â
carbamates as described for co~pcu..ds 20 al~ 3r, Introduclion of an amino grGup a~ Lhe ~-posi ior. is accomplished by hydrolyzing esters 32, converting tne resulting aci.ds to acid halides (acid chlorides), treating the acid halides with sodium azide and heating those products followed by treatment with water to form the amines (40) which upon deblocking gives compounds 41.
These amines can be alkylated (42), sulfonylated (44), or ; 20 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 method of Scheme 1 can be made by using the activating effect of the 2-hydroxy grou? in compounds 19; the hydroxy group may be retained in the product or removed. These preparations are illustrated in Scheme 7.

Scheme 7 X Q X Q
HO~ HO~

'' 48 R,kO~ R' ; X = halo . I

,~

~BSTlT~3 T ~ SY,~

: .
.

. W092/07856 ~ G n J 219 PCT/US91/080~8 ~ CN Q CN Q

4 8 ~ ) HO~
(X=1) 50 ~k~ 51 ~ o CNQ CNQ CNQ
0~ Q~ Qb~;

R'R"N Q R'R"N Q
Hl~ HO~_ Halogenation of compounds 19 is accomplished by standard means to produce 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 gives compounds 51, or - alternatively, the hydroxy function can be removed from 50 by converting the compounds to the corresponding triflates 52 and then reducing them to compounds 53 by the method of Cacchi, S. et al., Tetrahedron Lett. 1986, 20 27, 5541. Hydrolysis of ketals 53 gives ketones 54.
The conversion of compounds 19 to compounds 55 is accomplished using tetramethyldiaminomethane and an acid.
:: The dioxolane protecting group can then be hydrolyzed to ~ obtain the keto compounds 56.
; 25 Methods for making compounds with different groups at the 7-position are illustrated ir. Scheme 8.

SUBSTITUTE SHEET

, - , ': ~ : ' W O 92/07856 PC~r/US91/08028 `
~3~2~

; Scheme 8 ` Q a Q Q Q Q
~' Q~s Q~ Q~

5 7 OH 5 3 OS02Cr3 5 9 Q Q
5 8 ~ Q~
~ CN

aQ QQ QQ

5 8 --Q~OR ~O ~O

Q Q
63 ~N~
~OH

Q Q Q Q
58 --~ ~ Q:b~

~` NR'R" NR'R"

., ~ SU3STITUTE SH~
., ~, , .

~ W092/07856 2 0 ~ PCT/US91/0802X

: 58 Q ~ Q ~ O

Q Q
58 ~ Q ~ O

R'R~N

Q Q Q Q Q a 68 ~ O Q~CH20H

Q Q Q Q
58 - Q ~ ~ Q ~ O

73 S R o The hydroxy compounds 57 are made as described by Sugasawa, T., et al., Chem. Pharm. Bull. 1974, 22, 771.
The triflates t5~) are prepared in the usual manner.
Reduction to compounds 59 is carried out by the same method used for compounds 52~ Cyanation of the triflates to give compounds 60 uses the method employed to prepare compounds 26. Alkoxyvinylation of the triflates to give compounds 61 is carried out as in the preparation of compounds 38; acid hydrolysis of the vinyl ethers gives the ke~ones 62 which upon reac~ion with diazomethane by the method of Kametani, T., et al. ~Heterocycles 1975, 3, 167) give methyl derivatives 63 which are reduced by hyd-ides to the alcohols 64. Coupling of the triflates : with 3-dialkylaminopropyne by he method of Echavarren, A.

SUBST~TU~E Sl !~ET
. . , :

. ;. ., .
.. . . .

W092/07856 ~ Y~ ~l 9 PCT/US91/08028 ~.

M. and Stille, J. K. (J. Am. Chem. Soc. 1988, 110, 1557) 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. (Tetrahed~on Lett, 1986, 27, 1171) gives compounds 67 which are catalytically hydrogenated to ethyl compounds o3.
Carbonylation of the triflates in the presence of an amine or an alcohol by the procedure used to make compounds 30 and 32 leads to amides 69 and esters 70, respectively.
As described for compounds S2, compounds 70 are methylated with diazomethane to give de-lvz_ives 71 w:-ch then are reduced to alcohols 72 by hvdrides.
Displacement of the triflate function `-om compo-_nd_ _3 by thiols gives sulfides 73 which are oxidized to sulfoxides 74.
Compounds with substituents in the 12-position are prepared as illustrated in Scheme 9.

Scheme 9 Q ~ O ~ O

Q Q R

Q ~ -SUE3STITUTE SHE~ET

. W O 92~07856 ~ PC~r/US91/0802X

Q a Q Cl Q~N,.~ ~ a~N~ _ ,, a~N~, 78 ~;k~ 79 ~~ ~¢

Q OAr Q OAr Ql~ Ql[~_ R' O~ R' Q NHCH2Ar Q NHCH2Ar 80 ~ Q)~ Ql~

Q I Q CN Q CN
80 ~ Q~ Q~O

15 86 ~ Q~--SUE~STITUTE SHEEI

`:
.

6 ;~ a 2 1 9 PCI/US91/08028 CH2NR'R" CH2NR'R"

85--' Q~ Q~

9 R~ko~ R' Q ~ NR'R" Q ~ NR'R"
90 ~ Q~ Q~

R~ o ~ R' Q ~ NR'R" Q ~ NR'R"
9 0--' Q~ Q~;~

94 R~ko~ R' . ~
~ 10 Q OH Q OR Q OR
85---QQ~ Q~ ' Q~
9 6 k) R~ o~ R

~j :: 15 Q~ Q~_~ Q~

`~ R' o~ 100 R' O~ 101 o SUBSrmJTE SHEET

. .
.. .
.~.

W092/07856 2 B 3 ~ 2 1 9 PCT/US91/08028 Q ~^NH2 Q ~rNH2 100 - ~ Q ~ N ~ Q ~ ~
102 ~ ~ 103 ~ O

99 --D ~N ~_ ,. ~N ~
1~4 ~ ~ 10~ ~ O

-i2~~yàroxymethyi compounds 75 are prepared by the method o- r.~iv2ska, T. et al. (Heterocycles 1981, 16, 171') using ferrous sulfate, hvdrogen peroxide and methanol with sulfuric acid. These alcohols are acylated as described for compounds 20 and 35 to produce carboxylates, carbonates and carbamates. Similarly, 12-alkyl compounds 77 are prepared by the method of Miyasaka, T. et al. (US patent 4,399,282). Oxidation of compounds 78, for example, with hydrogen peroxide in acetic acid, gives the N-oxides 79 which upon heating with tosyl chloride in N,N-dimethylformamide gives the 12-chloro com?ounds 80 that car. be converted to many o~her compounds. Heating of the chloro compounds with arylols, such as phenol, gives the 12-aryloxy compounds 81 which upon deprotection give the ketones 82; if, however, an aminomethylarene is included in the reaction, the products are compounds 83 which upon hydrolysis give keto compounds 84. The chloro substituent of compounds 80 can be replaced with an iodo group (85) by heating with ~5 potassium iodide in acetic ac d containing some acetic anhydride~ The ioào deriva_i~es are easily used in various coupl1ng reactions similar to those carried out with triflates 25 and 58. Cvanation gives compounds 86 wh-ch a~a deblocked to ket~s.aa 87 or are reduced to ~, SVBSrlTUTE SHEET

~ , . : , ~ ` ., `

.` ~ .
.;- . ; `

W092/07856 ~ PCT/US91/0802X

aminomethyl compounds 88 which give ketones 89 upon hydrolysis. Likewise, propynylamines 90 can be produced and then deprotected to compounds 91 or catalyticall~
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 gives the 12-hydroxy compounds 96 which can be alkylated using either base and alkyl halides or diazoalkanes to give 12-alkoxv compounds 97 which upon deprotection afford lC ketones 98. The 12-hydroxymethyl compounds 76 can be protected and then activated for displacement reactions by conversion to a sulfonate (99), for example, a mesyla_e.
Cyznide displacement on cori.pounds 99 gives the ke_als 1~0 which. upon hycrolysis give 12-cyanomethyl ketones 101.
1~ The cyano ketals can also be reduced 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 compounds 76 could likewise be applied to hydroxymethyl compounds 34 to produce derivatives ; corresponding to compounds 99 through 105.

; 25 The compounds of the present invention exhibit antiviral activity and are generally useful in treating a wide variety virus infections in both plants and animals.
These compounds are particularly useful in treating DNA
replicating animal virus infections, more particularly those caused by herpes sim~le~ virus (HSV). More specifically, these compounds are useful in treating infections caused by the following human pathogens:
Herpes Simplex virus types 1 and 2;
Cytomegalovirus;

SUBSrlTUTE SHEEI

." , W092/07856 ~ a 219 PCT/US9l/08028 Varicella Zoster virus;
Epstein Barr virus; and Papilloma virus (multiple types).
Infections caused by the following animal pathogens may also be treated with the present compounds:
Equlne Herpes virus;
Porcine Herpes virus; and lCMcrel~.'s disease virus.

~ c ~
The -ssay used t o tes~ the compounds of the presen i nvQ~ n. or -s.~lvi-_l ac--viry was ta.cen from ~he lilera~ure ana was modified in well-~nown ways to adapt it to curren.ly available technology. A generalized description of the assay follows.
Assay_ELQced~L~
Well plates were seeded with the appropriate cells at a concentration of lxlOs cells per well suspended in 0.5 mL of Earle's Minimum Essential Medium (EMEM) containing 10% fetal bovine serum (FBS) and antibiotic and antimycotic solution. After cells were 80-90~ confluent (24 hours), old medium was removed and washed with Hank's buffered saline solution (HBSS). Cells were then infected for 1 hour at 37C with 100-200 plaque forming units per well Oc a herpes simplex virus suspended in 250 ~L HBSS.
Following adsorption, the following were added:
A) 250 ~L/well 2 x EMEM containing Human IgG
(ca 0.1 ~g/mL; Sigma No. G-6763);
B) 250 ~L/well EMEM containing 10% FBS and 35antibiotic/antimycc-ic solution;
C) 250 ~L/well HBSS containing appropriately diluted compound.

. , . ,, . .. ~ ~ ~,. . . . ..

W092/07856 2 ~ ~ 3 2 1 ~ PCT/ us9 1/08028 --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) an~
then rinsed with water and air dried and plaques counted.
Compound effectiveness was evaluated in terms of percent plaque reduction as compared to untreated, infected controls.
This procedure can be used to test compound e''lcacy against many viruses, besides herpes simplex by simply modi~ying the cell type used in the first s~ep to mztch the virus being tested and following the procedu-e 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 ~idney cells.
`; Other assays which are useful for determining the : antiviral activity of the 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 commercially.
Pharmaceutical ComDosit;ons and ~ethod of Treatment The present invention provides a broad variety of compositions prepared from compounds of the persent invention. Such compositions have utility 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 carrier which is acceptable for the intended end use together with at least one inventive compound. For 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 insertion in the rumen. For . .

SUBSTITUTE SHEET

... W O 92/07856 2 ~ ~ 2 1 9 PC~r/US91/08028 ~ ~J V

agricultural use, the compound can be mlxed with a fertilizer, other microbiocides such as fungicides, or insecticides and the like. The present compounds may also be formulated in powders or sprays for application to plant sur~aces.
The pharmaceutical compositions of this invention com?rise one or more compounds of the present invention in admi~;ture with an inert pharmaceutically acceptable carrie- or diluent. Compositions may contain an effective amo_n- of the invenlive co~.~ound in one unit, such as in a sin~;e ~iil, capsule, or pre-measl-rei intravenous dose or pre-riiied syringe for injection, or, as is ~requently the case, ~ne composition may be prepared in indlvidual 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 a discrete amount of drug and the user applies an effective amount of the cream one or more times until the disease is in remission or has been effectively treated.
Concentrates for later dilution by the end user may also be prepared, for instance for IV formulations and multi-dose injectable formulations.
Carriers or diluents contemplated for use in these compositions are generally known in the pharmaceutical formulary arts. Reference to useful materials can be found in well known compilations such as Rem~n~ton's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18042, USA.
. 30 The nature of the composition and the pha-maceutically acceptable ca-rie- or diluent will, of course, depend upon the in~ended route of administration, for example, by intravenous and intramuscular injection, parenterally, topically, o-al`y, or by inhalation.
., ~ SU~SllTUTE SH~ET

. . . . .. ... . . . . .
- . . .
, ~ . . . . ~ .
. .
.

W O 92/07856 2~ 21 9 PC~r/US91/08028 -~.

For parenteral administration the pharmaceutlcal composition may be in the form of a sterile ln~ectable 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, llniment, lotion, paste, spray or drops suitable fGr administration to the skin, eye, ear, nose or genitalia.
For oral administration the pharmaceutical 0 composition may be in the form of a table~, capsule, powder, pellet, atroche, lozenge, syrup, liquid, o-emulsion.
The pharmaceuticaliy acceptaDle carrier employed ma~-be either a solid or liquid. ~xemplary of solid carriers are lactose, kaolin, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, mannitol, stearic acid and the like.
,j i Examples of appropriate pharmaceutically acceptable .
liquid carriers or diluents.include: for aqueous systems, water; for non-a~ueous systems, ethanol, glycerin, -~ propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water. For aerosol systems, pharmaceutically acceptable ; carriers include dichlorodifluoromethane, .I 25 chlorotrifluoroethane and compressed carbon dioxide.
;. Also, in addition to the pharmaceutical carrier o~
diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeut c action of the instant compositions.
Similarly, the carrier or diluent may include time delay materials well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, .;1 .

W092/07856 2a~2~9 PCT/VS91/08028 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 dlssolved in an aqueous solution of an organic or inorganic acid or base. If a soluble salt form is not available, the inventive compound may be dissolved in a suitable co-solvent or combinations the-eo-. rxam?les o~ such suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polye hylene glyco` 3G0, polysorbate 80, glycerin and the like in concentrations ranging rrom 0-60~ of the total vo 1~
~ will be ap?reciated that the actual preferred dosages of the compounds of the present invention used in the pharmaceutical and other compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site, host and disease being treated. These compounds are active in the concentration ranges of two commercial antiviral drugs, Cytovene (ganciclovir) and Zovirax ~acyclovir). For example, the latter is manufac_ured in 200 mg capsules with instructions ror treating herpes simplex viruses by taking one capsule every 4 hours, but not to exceed 5 capsules per day.

SU~STITV7E SHEET

, . . . . .
. . , . ' .

"

W~92/07856 , , , ~ PCT/US91/08028 -.

In the following Examples, temperature is in degrees Centigrade (C). Unless otherwise indicated, all of the starting materials were obtained from commerclal sources.
wit~ou~ further elaboration, it is believed that one skilled in ~he art can, using the preceding description, utilize the present invention to its fullest extent.
These Examples are given to illustrate the invention, not to limit its scope. Reference is made to the claims for wha- is reserved to the inventors hereunder.
~ xample 1 o~v~ethyl-7-(1-~ ropyl?~Qlizlnor~.2-~L~Ilnolin.
-9(11~)-one To a suspension of 15 (4S,3R,S)-ethyl-3,4-dihydroxy-1~-pyrano-~3',4':
: 6,7]indolizino[1,2-b]quinolin-14(4H,12H)-one (1.04 g, 3.0 mmol) (prepared by the method of T. R. Govindachari, K. R.
Ravindranath, and N. J. Viswanathan J. Chem. Soc., Perkin ; Trans., 1974, 1215) in glacial acetic acid (70 mL) was added dropwise a solution of sodium metaperiodate (1.0 g, 4.7 mmol) in H2O (20 mL). The resulting mixture was stirred at room temperature for 30 minutes, at which time ethylene glycol (1 mL) was added. Water (350 mL) was slowly added, and the mixture was cooled to 0C. The precipitate which formed was collected by filtration and recrystallized from acetone/H2O to provide yellow needles of the title compound as a hydrate mp >200C (dec). 1H
NMR (CDCl3/DMSO-d6) d 8.43 (br s, lH), 8.20 - 7.40 (m, SH), 7.23 (s, lH), 5.28 (br s, 4H), 2.95 (q obscured by HOD peak, 2H), 1.18 (t, J = 6 H-, 3H). Anal. Calcd for C20H16N204 H20: C, 65.57; H, 4.95; N, 7.65. Found: C, 65.53; H, 4.84; N, 7.33.
,~

51 I~sTlTU . _ SHEE, ~W092/07856 2 ~ 2 ~ 9 PCT/US91/08028 Exam~le 2 8-Methyl-7-(l-oxopropyl)indolizino~l 2-blquinolin-~LLL~L-o ne A sample o- 4.6 g of 4-ethyl-4-hydroxy-lH-pyrano[3',4':6,7]-indollzino[l,2-b]quinolin-3,14(4H,12~)-dione [(20 S) camptothecin] was stirred with 46 ml of N,N-dime-thylformamide. The suspension was heated at - reflu~, and the disappearance of starting material was moni~ored b~ ~PL- (C18 reverse phase column, 20-25%
ce.o~ rlle:~a e- mobile phase, perchlorate buffer at pH
a~pro~-m_tely 3.Q). The reaclion was monitored by UV
detec=io~ a~ a w2vel-~gth of 228 nm. The only responses detected under these conditions were a peak for N,N-dimethylformamide near the solvent front, a peak for the starting material and a peak for the desired product with a retention time of approximately 3.2 relative to the starting material. The reaction was heated until consumption of the starting material was complete (approximately 8 days). After cooling to ambient temperature the solid product was collected by filtration, ` and washed with methanol. After drying under vacuum to a constant weight 3.48 g (87%) of product, m.p. 233-234C
was obtained.
Examp1e 3 1-Me~ho~y-~m~thyl-7-(1-oxopropyl!indolizinQ~1,2-blquinoli n-9(llH)-~e (S~-4-Ethyl-4-hydroxy-10-methoxy-lH-pyrano-[3',4':6,7]indolizino~1,2-b]quinoline-3,14(4H,12H)-dione (T. R. Govindachari and N. Viswanathan, Indian J. Chem.
1972, 10, 453) (100 mg, 0.28 mmol) was suspended in tetraethylene glycol dimethyl ether (2 mL), heated to reflux for 3 minutes and allowed o cool to room ~emperature. The solid whic;~ o-med was suspended in SUE~Sl ITUTE SH~ET

, : .`

.~ .

W092/07856 ~ 9 PCT/US91/08028 -~

Et2O, collected by filtration and dried. The solld was purified by column chromatography on baqic alumina ~deactivated by addition of 15 wt% H2O), eluting with CH2C12. The solid obtained was further purified by radial chromatography on silica gel, eluting with 2~ MeOH in CH2Cl2 to provide the title compound as a beige solid .
H NMR (CDCl3) d 8.80 (br s, lH), 7.77 (br d, J = 8.7 Hz, lH), 7.69 (dd, J = 8.7, 7.3 Hz, lH), 7.23 (s, lH), 6.94 (br d, J = 7.4 Hz, lH), 5.27 (d, J = 1.0 Hz, 2H), 9.06 (s, 3H), 2.91 (q, J = 7.3 Hz, 2H), 2.30 ~s, 3r.), 1.24 (t, J =

7.3 Hz, 3H). Anal. Calcd for C20Hl8N2o3: C, 71.84; H, - 5.43; ~I, 8.38. Found: C, 71.51; H, 5.42; N, 8.a5.

3-Metho~.y-8-methyl-7-~l-o~opropyl)indolizin~l1.2-4lquinoli n-9(llHi-one (+)-4-Ethyl-4-hydroxy-8-methoxy-lN-pyrano[3',4':6,7]-: indolizino[1,2-b]quinoline-3,14(4~,12N)-dione ~100 mg, O.26 mmol) (prepared by the method of M. E. Wall, M. C.
Wani, S. M. Natschke, and A. W. Nicholas, J. ~ed. Chem., 1986, 29, 1553) in triethylene glycol dimethyl ether (2 mL) under an argon atmosphere was heated to reflux for 2.5 hours. After cooling to room temperature hexane was added, and the mixture was allowed to stand for 30 minutes. The solid which formed was collected by filtration, and the filtrate was concentrated under reduced pressure. The residue was treated with hexane, and the solvent was removed by decantation. The oily residue and solid material were combined and purified by `~ 30 column chromatography on basic alumina (deactivated by addition of 15 wt~ H2O), eluting with 1% MeOH in CH2Cl2.
The material which was collected was treated with MeOH (2 mL) , and upon sonication, a solid formed which was collected by filtration to provide the title compound. 1H
NM~ (CDC13) d 8.29 (s, lH), 7.&0 (d, J = 9.0 H7, lH), 7.49 SU~ST~TUTE SltE~T

.

:

W092/078S6 2 & 9 ~ 2 1 9 PCT/US91/08028 (d, J = 2.4 Hz, lH), 7.20 (m, 2H), 5.26 ~s, 2H), 4.00 ~s, 3H), 2.91 (q, J = 7.3 Hz, 2H), 2.29 (s, 3H), 1 24 ~t, J -7.3 Hz, 3H). Anal. Calcd for C20Hl8N2o3-l/4 H2O: C, 70.89; H, 5.35, N, 8.27. Found: C, 70.77; H, 5.39; N, 8.12.

~xample 5 7~ v~roxviminovrovvi)-8-methylindolizino-~1 2-~l~uinoli?.-9Li~H)-one A soiu~ion Gf 8-methvl-~-(1-o~oprovyl)indolizino[1,2-b] qulnol-n-9('1H)-on~ (112 mg, 0.37 mmol) and hyd-v~ylam ne sul ate (224 m , 1.35 m~mol) in a mixture of 5 m~ aDsoiu~e EtOH and 7 m~ p;ridi..e ~as heated at 100C
for 20 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure.
The residue was suspended in H2O (8 mL), and the pH was adjusted to pH 6 with 10% NaOH (l drop). The mixture was stirred for 10 minutes and filtered. The solid which was collected was recrystallized from 95% EtOH to provide the title compound as a hydrated mixture of about equal amounts of the syn and anti isomers , mp 261-263C (dec).
H NMR (CDCl3/MeOH-d4) d 8.43 ts, lH), 8.2-7.5 (m, 4H), 7.28 and 7.18 (2s, lH), 5.23 (br s, 2H), 2.78 and 2.55 ~2q, J = 7.5 Hz, 2H), 2.24 and 2.17 ~2s, 3H), 1.13 and 1.09 (2t, J = 7.5 Hz, 3H). Anal. Calcd for C1gH17N3O2-9/10 H2O: C, 68.01; H, 5.65; N, 12 52. Found:
C, 68.09; H, 5.68; N, 12.19.

Exam~le 6 (i)-7-~1-AminQ~ropyl)-8-methvl m~Qli~ino~ q~nQli 9(11~)-one. :-.ydrochloride To a solution of 7-~1-hydroxyiminopropyl)-8-methylindolizino [1,2-b]quinolin-9(llH)-one (60 mg, 0.19 mmol) in 95~ EtOH (4 mL) at C^_ was added 10~ NaOH (4 mL), followed by nickel-aluminum a:loy (130 mg). The resulting SUBSTITIJTE SHEE~T

, ' ,.
.. . . . . . . .

wo 92/07856 ~ f, ~ PCT/US91/08028 ^

mixture was allowed to warm to room temperature. After stirring for 2 days, the mixture was concentrated under reduced pressure. Water ~15 mL) was added to the resldue, ; whlch was then extracted with CHCl3 (3x10 mL). The combined organic extracts were evaporated ln vacuo, and the resiàue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 0-10~ MeOH in C~Cl3 to give, u~on evaporation of the solvent, a pale yellow powder. Two drops of concentrated HCl were added to a sus~ension of the powder in water (1 mL), and the mixtu-e was allowed to stand overnight. The mixture was '-lte-ed ar.d the solid was washed with acetonitrile, followed b~ r.2C zo provide the green-yellow title compound~ 1H NMR (D2O/DCl, HOD at d 4.55) d 7.43 (s, lH), 15 7.17-6.66 (m, 5H), 3.81 (br s, 2H), 2 . o-l . 7 (br m, 5H), 0.85 (br t, J = 7.5 Hz, 3H).

Example 7 (+)-7-(1-Hydro~y~Lopyl)-8-methylindolizLns~-rl 2-bl~yinL~Lh,-s (llH)-one Prepared by the method of T. Kametani, H. Takeda, H.
- Nemoto, and K. Fukumoto, J. Chem. Soc. Perkin Trans I., 1975, 1825.
: .
`~ 25 Example 8 I+)~ Bromopropyl)-8-methylindolizino~1. 2-kl guinQlin-9(llH)-one A solution of ~i)-7-~1-hydroxypropyl)-8-methylindolizino tl,2-b]quinolin-9~llH)-one ~700 mg, 2.3 30 mmol) in thionyl bromide ~10 mL, 0.13 mol) was heated at 85C under an argon atmosphere. After 1.5 hours, the excess thionyl bromide was removed under reduced pressure, and the residue was dissolved in a mixture of MeOH ~1 mL) and C:~2Cl2 (20 mL). After standing overnight at 0C, the 3; solid whic~ rormed was collected by riltration, washed S~JE3ST!TU ~ ' ~H~I T

. - . , ~ ' .
, . , . W092/07856 2 C, ~ ~ 2 ~ 9 PCT/US91/08028 ~3 with CH2Cl2 and dried to give the title compound as a hydrobromide salt. This salt was dissolved in 10~ H2O in MeOH ~370 mL) and allowed to stand at room temperature overnight. The yellow-colored solution gradually became colorless, and the solvent was removed in vacuo. The residue was treated with additional 10% H2O in MeOH, and the solid which formed was collected by filtration. The filtrate was concentrated under reduced ~ressure, and the residue was treated wit:n i0~ Y.2O in MeOr.. The solid which formed was collected b~ filtra~ion. Tne solids were combined to provide the title _ompound as hyc-ate ly NM~ (CDC13) d 8.3~ (b- s, lH), 8.0-7.5 (~, 4.~), 7.49 (s, lH), 5.28 (d, J = l.1 H~, 2H), 5.13 (_, J = 7.5 Hz, lH), 2.45-2.20 (obscured m, 2H), 2.34 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H). Anal. Calcd for ClgH17BrN20 5/8 H20: C, 59.97;
H, 4.83; N, 7.36. Found: C, 59.92; H, 4.84; N, 7.40.

Example 9 8-Methyl-7-r~ ropenyllindolizinQrl~2-blquinoli ~lllf~-one To ll0 mg (0.36 mmol) of (+)-7-~1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one in a dry flask under argon atmosphere was added a solution of 680 mg (1.0 mmol) bis[a,a-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur in 5.5 mL dry CH2Cl2. Within a minute all the solid haddissolved. After 1 hour the reaction was added to a column of 25 g silica gel in CH2Cl2. After initial elution with CH2Cl2, the product was removed with 2% MeOH
in CH2Cl2. The resulting yellow residue was triturated with MeOH ~o yield pure title compound as a hyàrate, mp 283-4C ~dec). 1H NMR (CDCl3) d 8.30 (d, J = 0.6 Hz, lH), 8.19 (dd, J = 8.3, 0.6 Hz, lH), 7.89 (dd, J = 8.1, 1.2 Hz, lH), 7.79 (m, lH), 7.61 (m, lH~, 7.44 (s, lH), 6.69 (b-dd, J = 15.7, 1.1 Hz, lH), 6._6 (c , J = 15.6, 6.1 Hz, ~ ;U8SmlJTE SHg7 ., ' . `
:, . ` ~ ` : . . . .. . .
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W092/07856 ~ 1 3 PCT/US91/08028 -lH), 5.24 ~d, J = 1.0 Hz, 2H), 2.32 ~s, 3H), 2.00 ~br d, J
= 5.3 Hz, 3H). Anal. Calcd for C1gH16N20-1/8 H2O: C, 78.53; H, 5.64; N, 9.64. Found: C, 78.47; H, 5.73; N, 9.53.
. 5 Exam~Le 10 (+) -7- ( threo-l . 2-Dihydroxypropyl~-8-methylir~dolizino r 1.2-bl quinolin-~llH)-one To a sus2ension ol 55 mg t0.19 mmol) of 8-methyl-7-i 10 [l(E)-proDenvl]indolizino[1,2-b]quinolin-9(llH)-one in 2.0 mL drv pyridine were added 77 mg ~0.30 mmol) osmium tetro.Y de. 'rhe r_action immediately darkened and the solid dissolve~ ithir. 5 miniltes a ligh~-oolored solid had precipita~ed. After 1 hour hexane (~10 mL) was added to the reaction mixture to complete the precipitation of the osmate ester.which was collected by filtration.
Hydrogen sulfide was bubbled through a solution of the osmate ester in CH2C12 for _1 hour, and the resulting black osmium sulfide precipitate was removed by filtration. The filtrate yielded a light yellow solid which was triturated with MeOH to givethe title compound as a hydrate, mp 267-9C (dec). lH NMR (CDC13/MeOH-d4, referenced to CD2HOD at d3.35) d8.44 (s, lH), 8.11 (d, J =
8.5 Hz, lH), 7.93 (d, J = 8.1 Hz, lH), 7.80 (apparent dt, J = 7.2, 1.1 Hz, lH), 7.64 (m, 2H), 5.25 (s, 2H), 4.79 (d, J = 6.4 Hzt lH), 3.98 (quintet, J = 6.3 Hz, lH), 2.31 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H). Anal. Calcd for C1gHlgN203-7/8 H2O: C, 67.49; H, 5.89; N, 8.28. Found:
C, 67.58; H, 5.65; N, 8.35.
Example 11 ~+~ droxy)methoxymeth~ 8-methy~in~oliz~no~1.2-blquinQlin-9(llN)-one To a solution or 34.5 m~ (0.10 mmol) (+)-7-(threo-1,2-dihydroxypropyl)-8-methyli^.dolizino[1,2-b]quinolir.-:
SUBSTITUTE SHEE~

.

, . - .

W092/07856 ~ 2 ~ PCT/US91/03028 9(llH)-one in 5 mL glacial acetic acld was added over 3 minutes a solution of 32.5 mg (0.15 mmol) sodium periodate in l mL water. After 1 hours, 6 drops of ethylene glycol were added to destroy e~cess ~eriodate, and ~he reaction mixture was stripped to dryness in vacuo. The resulting residue was triturated with H2O and then dissolved in hot CH2Cl2 plus MeOH. After filtering, the solution was stripped, and MeOH was added ~o produce a clean solid .
Rather than the expected 7-ca_bo~.aldenyde, 1H NMR showed the product to be the title c~ ound, a hemi2cetal of the carboxaldehyde wi~h MeOH whic:- analv~ed as a hvd-ate, m~
284-6C (dec). 1-~ NM~ (C~C13/MeOU-d~! d 8.47 ~s, 1H), 8.15 (d, ~ = 8.5 Hz, 1;~ = 8.0 ..7~ 1-) r 7.Q2 (m, lH), 7.76 (s, lH), 7.68 (m, lH), 5.71 (s, lH), 5.28 15 (s, 2H), 3.64 (s, 3H), 2.33 (s, 3H). Anal. Calcd for - C18H16N203 1/2 H2O: C, 68-13; H, 5.40; N, 8.83. Found:
C, 68.27; H, 5.36; N, 8.58.

7-tHydroxy~e~yl)-8-methylindolizln~o rl 2-bl~uinolin-9l11R)-one To a solution of 34.0 mg (0.10 mmol) (+)-7-(threo-1,2-dihydroxypropyl)-8-methylindolizino~1,2-b]quinolin-9(llH)-one in 5.0 mL glacial acetic acid was added over 1.5 minutes a solution of 32.1 mg (0.15 mmmol) sodium periodate in 1 mL H2O. After 0.75 hours 6 drops of ethylene glycol were added to destroy excess periodate.
After 2 hours 32.8 mg (0.52 mmol) of sodium cyanoborohydride were added. Following another l hour, the reaction was stripped to dryness in vacuo, H2O was added and a yellow solid was collec~ed. The solid was dissolved in hot CH2Cl2 plus MeOH, and the solution was filtered and stripped to dryness. The residue was triturated with MeOH to aive _^ the title com?ound as a hydrate, mp >320C. 1~ NMR (~Cl~,'`leOH-d4) d 8.51 (b- s, SUBSTITUTE SI~E~

: : , ` , ...................... : ....... .

- : - - ~ ..

W092/078~6 ~ ~ J ~ 9 PCT/US91/08028 -lH), 8.20 ~br d, J = 9.0 Hz, lH), 8.01 ~br d, J - 8.4 Hz, lH), 7.86 (m, lH), 7.74 (s, lH), 7.69 (m, lH), 5.31 (s, 2H), 9.74 (s, 2H), 2.23 (s, 3H). Anal. Calcd for C17H1~N2O2 1/2 H2O- C, 71.07; H, 5.26; N, 9.75. Found:
C, 70.75; H, 5.12; N, 9.52.

Example 13 7-(2-E;hyl-1 3-dioxola~-2-yl)-2-hydroxv-8-indo~ n~o [ 1 ~ 2-~lquinolln-3(~1~)-one 13A. 7-(2-E ~vl-1.3-d~oxoian-2-yl)-8-methyllndolizino ~1 2-bl~uinoli~-9!~ )-one ~ -ogen chloride ~as was bubbled ir.to a susper.sion - of 15.0 g (49 mmol) &-methyl-7-(1-oxopropyl)indolizino[l,2-~]quinolin-9(llH)-one in 150 mL
ethylene glycol (exothermic) and gradual dissolution of the solid. When the solution had become saturated with : hydrogen chloride, it was warmed on a steambath for 40 minutes and then allowed to cool to room temperature.
;3 After standing overnight, the viscous solution was poured into a 1 L mixture of ice and concentrated ammonium hydroxide to produce a tan colored solid. This mixture was extracted three times with 1 L CH2Cl2 . After washing with 500 mL H2O, the CH2Cl2 solution was dried over sodium sulfate and evaporated. The residue was crystallized from 3.5 L acetonitrile to give amber brown needles of the title compound, mp 272-4C. 1H NMR (CDCl3) d 8.31 (s, lH), 8.20 (br d, J - 8.1 Hz, lH), 7.86-7.50 (m, 3H), 7.58 (s, lH), 5.25 (d, J = 1.1 Hz, 2H), 4.05 (m, 2H), 3.85 (m, 2H), 2.45 (s, 3H), 2.02 (q, J = 7.5 Hz, 2H), 1.06 (t, J =
7.4 H_. 3H). Anal. Calcd for C2lH20N2o3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.37; H, 5.65; N, 8.26.

SU~3S~ITII~E SHEET
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.. W O 92/07856 ~ 9 PC~r/US91/0802X

13B. 7-(2-Ethyl-1 3-dioxolan-2-yl)-5.5a 1l a, ~ e-~ b~lr~
8-methylindolizi~Q~1 2-blquinolin-9(llH)-one To a solution of 1.39 g (4.00 mmol) of 7-(2-ethyl-1,3-dio~olan-2-yl)-8-meth~lindoli~ r.o[',2-~uinolin-9(llH)-one in 100 mL glacial acetic acid W25 added sodium cyanoborohydride (1.60 g, 25.5 mmol) over 2 minutes. The reaction turned from orange to yellow. After 50 minutes the acetic acid was removed in vacuo. Tne -esidue was : taken up in CH2Cl2, and the solution was washed wit~. H2O
and then dried over sodium sulfate a?.d s~r ??ed. The resulting foam was triturateà with acetone tO yield the title compound as a solid mixture Or two ~somers, mp 218-; 222C. 1H ~MR NOE e:.pe-im.e~Ls sho~-e~ :~.a~ _`n ~a.~s-isomer predominated. lH NMR (CDCl3) d 7.13 - 6.97 (m, 15 2H), 6.85 - 6.58 (m, 2H), 6.47 and 6.42 (2 br s, lH), 4.82 and 4.64 (m and dd, J = 12.2, 7.1 Hz, lH), 4.40-4.05 (m, 2H), 4.03 (m, 2H), 3.78 (m, 2H), 3.57 (t, J = 11.7 Hz, lH), 3.05 (d, J = 8.6 Hz, lH), 2.85-2.42 (2m, lH), 2.29 (2s, 3H), 1.94 (q, J = 7.4 Hz, 2H), 0.94 (t, J = 7.5Hz, 20 3H). Anal. Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.51; H, 6.91; N, 8.02.

13C. 7-_(2-Ethyl-1.3-dioxolan-2-yl~-5-hvdroxv-&-me~ylindolizinQ~1.2-blquinolin-9(11~)-one 7-~2-Ethyl-1,3-dioxolan-2-yl)-5,5a,11a,12-tetrahydro-8-methylindolizino[1,2-b]quinolin-9(llH)-one was prepared as above from 6.96 g (20.0 mmol) 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-~]quinolin-9(llH)-one, but the product was not triturated with acetone but was redissolved in 275 mL glacial acetic acid. To this solution were added 350 mL H2O ar.d then, d-opwise ove- 10 minutes, a solution of 19.3 g ~6Q mmol) iodobenzene diacetate in 225 mL warm glacial acetic acid. After 4 :~ minutes the reaction was stripped to dryness in vacuo~
The residue was e~:tracted with h_- CH2Cl p`-~s Me~H. The S""~TITUT~- S~

, ' ~. : ~ ' . :. -. . ' ; . ' . ' `

W092/07~56 ~ 9 PCT/US91/08028 -.

extract was stripped to dryness and redissolved in CH2Cl2 plus a minimum of MeOH and then added to a column of 1 5 ; kg of silica gel in CH2Cl2. After eluting wlth 4 L of CH2Cl2, 14 L of 3% MeOH in CH2Cl2 were used to elute most - 5 of the product with 5~ MeOH used as a chaser. Based on TLC (8% MeOH in CH2Cl2), fractions were combined into pools of recovered 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindoli7ino[1,2-b]quinolin-9~ )-one and product.
~oth mate izls were triturated wlth MeOH to produce yellow s~lidsi 1.73 ~ cf cl_an recovered s~arting material and 2.35 g (a3% bas~d on starting material consumed) of title -ompound 2S Z methanol solvat~, mp >300C. 1H NMR
(CDCl3/~eO~-d~) d 8 .-'7 (Sr lH) / 8.05 (d, J = 9.2 Hz, lH), 7.60 (s, lH), 7.42 (dd, J 9.2, 2.6 Hz, lH), 7.18 (d, J =
2.7 Hz, lH), 5.20 (d, J = 0.8 Hz, 2H), 4.08 (m, 2H), 3.85 . (m, 2H), 2.44 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C21H20N2O4-1/10 CH30H:
C, 68.94; H, 5.59; N, 7.62. Found: C, 68.74; H, 5.73; N, 7.36.
Ex~mpl~ 14 2-Hydroxy-8-m~thyl-7-(1-oxop~yl)indglizi~Qrl.2-blquinolin-9(11H~-one) To a suspension of 7-(2-e-hyl-1,3-dioxolanyl)-2-hydroxy-8-methylindolizino[1,2-~]quinolin-9(llH)-one (25 mg, 69 mmol) in glacial acetic acid (2.4 mL) was added 2 N
HCl (0.20 mL), and the resulting mixture was heated at 70C for 1 hour. The reaction mixture was allowed to cool to room temperature, and the solvent was removed ~n ~acuo.
; 30 The residue was triturated with H2O (2 mL) to provide a pale yellow solid which was cc`lected by filtration, ~` washed with H2O and dried to c~ve the ti~le compound as a hydrate, mp >305C. lH NMR (~`~!SO-d6) d 8.35 (s, lH), 7.90 (d, J = 9.1 Hz, lH), 7.33 (dd, J = 9.1, 2.7 H7, lH), 7.19 35 ~d, J = 2.~ H~, lH), 7.12 (s, ::i), 5.13 (s, 2H), 2.89 (q, :' :
~;U~ ~T~ S~
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W092/07856 ~ ~ ~ 9 PCT/US91/08028 ~ = 7.1 Hz, 2H), 2.01 ~s, 3H), 1.03 ~t, J ~ 7.1 Hz, 3H).
Anal. Calcd for ClgH16N2O3 H2O: C, 67.45; H, 5.36; N, 8.28. Found: C, 67.34; H, 5.28; N, 8.06.

ExamplP 15 2-Methoxy-8-methy~-7-11-Q~.Opr'~Y.~ s.dol~inoLl ~:
blquinolin-9(1lH)-~nP~
To a suspension of 2-hydroxy-8-meth~1-7-~1-oxopropyl)-indolizino[1,2-~]q~nolin-9(11~)-one (160 ms, 0.50 mmol) in dimethylformami~e (2 mT ) u~.àQ- ar. 2rso?.
atmosphere was added K2CO3 (3--5 mg, 2.5 .~moi). Arte~
stirring 20 minutes at room tem~erature, methvl iodide was added (31 mL, 0.5 m~ol), an~ _~.e ~s~ m ~ re ~as stirred at room temperature overnight. Analysis by tAin ; 15 layer chromatography indicated that the reaction was incomplete, and additional methyl iodide (16 mL, 0.25 mmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between H2O
and CH2Cl2. The aqueous phase was extracted with CH2C12 (2x), and the combined organic extracts were dried (Na2SO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 0-2~ MeOH in CH2C12. A yellow crystalline material was obtained which was recrystallized from MeOHJCH2Cl2. 1H NMR ~CDCl3) d 8.22 (s, lH), 8.07 (d, J = 9.4 Hz, lH), 7.46 (dd, J = 9.3, 2.8 Hz, lH), 7.17 (s, lH), 7.14 (d, J = 2.8 Hz, lH), 5.25 (d, J ~ 0.9 Hz, 2H), 3.98 (s, 3H), 2.90 tq, J = 7.3 Hz, 2H), 2.28 (s, 3H), 1.24 (t, J = 7.3 Hz, 3H). Anal. Calcd for C20Hl8N2o3: C, 71.89; H, 5.43; M, 8.38. Found: C, 71.72; H, 5.63; N, 8.21.

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Example 16 2-(4-Ethoxy-1 4-d.lo~:o-1-butan~l)o::y-~-meth~1-7-(1-oxopropyl)indolizino~1 2-bl~uinoli~-9(11~L~Qn~
To a mixture of 2-hydro~-8-meth~1-7-(1-oxopropyl) indolizino~l,2-b]~uinolin-9(llH)-one (160 mg, 0.5 mmol) in anhydrous D~ (12 mL) under an argon atmosphere was added sodium hydride (19 mg of 80% mineral oil dispersion, 0.55 mmol). After stirring at room temperature for 30 min, ethy' succlnyl chlorid- (78 mL, 0.55 ~o') was added. The res.l~ir.g mixtu_e WGS G1 lowed to st~- o~e-night at room tempe-ature anà then was partitioned between H2O and CH2C1~. The aaueous phase was extracted with C~2C12, and ;'~ the c~ Aed o-ga~.ic e:-r2cls wera d--e- (Na2SO~). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2% MeOH in CH2C12.
The material which was isolated was filtered through a small column of deactivated alumina, eluting with CH2C12 to afford the title compound as a pale pink solid. lH NMR
~CDC13) d 8.30 (s, lH), 8.19 (d, J = 9.2 Hz, lH), 7.69 (d, 20 J = 2.5 Hz, lH), 7.56 (dd, J = 9.2, 2.5Hz, lH), 7.25 (d, J
= 8.2 Hz, lH), 5.29 (d, J = 2.5 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2~), 2.95 (m, 4H), 2.80 tm, 2H), 1.3C (t, J = 7.1 Hz, 3H), ;.24 (t, J = 7.2 Hz, 3H). Anal. Calcd for C25H24N26: C, 66-95; H, 5.39; N, 6.25. Found: C, 25 67.07; H, 5.65; N, 6.08.

Example 17 8-~ ~ .2~ ~lnolln-9l~lP)-on-2-yl tl,4'~ eridi~e~l-1'-c~r~o~,yl~te, ~ydrochlo~ide To a stirring suspension of 3.0 g (9.4 mmol) (S)-4-~ ethyl-~,9-dihydroxy-lH-pyrano[3,,':~,7] ndoli~ino[1,2-; b]quinoline-3,14~4H, 12H)-dione in 128 mL of dry pyridine ~' under argon was added in one portion 5.00 g (18.7 mmol) ` [1,4'-bipiperdine]-1'-carbonyl ch:oride, hydrochloride.
; 35 Afte_ s.irring o~ernigh~ an addi-:ona' r^-~ion of 1.00 g ;"~
,j ~iUBSTlTlJ I _ SHEET
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r WO 92/078~6 2 ~ J 2 ~ 9 PCI/US91/080~8 (3.74 mmol) of the carbonyl chloride was added. After stirring for a second night a final portiGn of 0 75 g ~2.8 mmol) of the carbonyl chloride was added and the reaction was stirred another night. The reactlon m-:~ture was evaporated to dryness under high vacuum, and the residue was taken up in a mixture of 200 mL of CH2Cl2 anA 200 mL
of H20 adding solid sodium bicarbonate to raise the p~7. to 7. After the layers were separated, the aquecus pr.ase was extracted twice with 250 mL of CH2Cl2. .~. te~ ng ove-anhydrous sodium sulfate, the dark or~,ar. - ?:n~se was passed down a column of 200 g of basic alu~ na which nad been deactivated with 90 mL of water. Elution witn CH2C12 and evaporation o- the eluate gave 4.0 g ^- ~'den so d.
This material was chromatographed on a fiash sllica ge`
column eluting first with CH2Cl2 and then a gradient of 2-10% MeOH in CH2Cl2. Fractions containing product were combined and stripped to 3.4 g of the free base of the title compound as a pale yellow solid, mp 178-183C.
Anal. Calcd for C30H34N4O4.1/2H20: C, 68.81; H, 6.74; N, 10.70. Found: C, 69.13; H, 6.97; N, 10.75.
To a suspension of the free base (13.4 mg, 25.6 ~mol) in 2 mL water was added 15 ,UL of 2N hydrochloric acid, and the suspension was sonicated to effect dissolution.
Lyophilization gave 15.4 mg of the bright yellow title compound as a hydrate. Anal. Calcd for C30H34N4O4.HCl.3H20: C, 59.55; H, 6.83; N, 9.26. Founà:
C, 59.40; H, 6.34; N, 9.26.

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E~le 18 l-Bron~ 2~ ro:~y-~-m~h~ -7-~l-oxopropyl)in~glizino~1 2-bl~inQl1n-9(11H)-one S 18A. l-Bromo-7-(2-ethvl-1.~-dl.oxo1~.n.-2-yl)-~-h~dro.Y~-8-me~h~zino ~=~ 1 UL=QIl&
To a ~tirring sus~ension of 7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-meth~ilindolizino[1,2-b~quinolin-9(llH)-one (0.50 g, 1.37 mmol) a~.d sodium acet~_e (1.23 g, }5.0 mmol) i~ glacial acet ^ acid (10 m~) unde- a~ a-gon atmosphere was added ~ 2 (76 mL). .~te~ s ir-ing for 4 h at room temperature, additional Br~ (10 mL) W25 added, and the rea-lion mi~ w~s ~l'owed _o s__- o~;-_.ight. T:-e mixture was concentrated under reduced pressure, and the residue was partitioned between CH2C12 and H2O and filtered. The layers were separated, and the aqueous phase was extracted with CH2C12. The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 2% MeOH in CH2C12 to afford an off-white solid which was recrystallized from MeOH in CH2C12. lH
NMR ~CDC13/MeOH-d4) d 8.70 (d, J = 0~8 Hz, lH), 8.04 (dd, J = 9.2, 0.7 Hz, lH), 7.61 (s, lH), 7.53 (d, J = 9.2 Hz, lH), 5.28 (d, J = 1.1 Hz, 2H), 4.09 (m, 2H), 3.86 (m, 2H), 2.45 (s, 3H), 2.03 (q, J = 7.4 H~, 2H), 0.99 (t, J = 7.4 Hz, 3H). Anal. Calcd for C21H1gB-N204-3/4 H2O: C, 55.22;
H, 4.52; N, 6.13. Found: C, 55.05; H, 4.67; N, 6.16.

18B. 1-~romo-2-hydroxy-8-meth~l-7~
oxop ~ n-~(llH)-one A mixture of 1-bromo-7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-methyl indoli ~ ino[1,2-b~uinolin-9(llH)-one (12 mg, 27 mmol) in glacial acetic ac d (1 mL) under an argon atmosphere was treated with 2 .~ r._l ( 100 m~). The reaction mixture was hea~ed at 3C^_ fo- 3.5 h and then was U~E S~E~T
.

~ 0 92/078S6 ~ 2 ~ ~ PCT/ usg 1/08028 .

allowed to cool and was evaporated under reduced pressure.
The solid orange residue was treated with H2O (several mL), sonicated, filtered and washed with cold H2O to afford the title compound. lH NMR (CDCl3) d 8.84 (s, lH), 8.11 (d J = 9.2 Hz, lH,), 7.59 (d, J = 9.2 Hz, lH), 7.48 (s, lH), 5.35 (s, 2H), 2.97 (q, J = 7.2 Y.z, 2H), 2.29 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). Anal. Calcd for C1gH1sBrN2O3 5/8 H2O: C, 55.57; H, 3.99; N, 6.80. -cur.d:
C, 55.54; H, 4.34; N, 6.83.
Exampl~ 19 1-(Dimethylamino)methyl-2-hydroxy-8-methyl-7-(1-oxopropyl)indolizinorl~2-blquinoli~-9(l~ -one Hydrochlorlde 19A. 1-(Dimethylamino~methyl-7-~2-ethyl-1 3-dioxolan-2-vl)-2-hydroxy-8-met~ylin~QliziD~[1.2-blquinoli~-9(llH)-one A mixture of 7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-methylindolizino~1,2-b]quinolin-9(llH)-one (36.4 mg, 0.100 mmol) and tetramethyldiaminomethane (51 mg, 0.50 mmol) in 2 mL glacial acetic acid plus 2 mL CH2Cl2 was stirred for 1.25 hours and then stripped in vacuo.
Acetone was added to the residue, and crystals of the title compound formed, mp >300C. lH NMR ~CDCl3) d 8.31 25 (s, lH), 8.05 (d, J = 9.2 Hz, lH), 7.50 (s, lH), 7.38 (d, J = 9.2 Hz, lH), 5.23 (s, 2H), 4.13 (s, 2H), 4.06 (m, 2H), 3.85 (m, 2H), 2.46 (s, 6H), 2.49 (s, 3H), 2.01 (q, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). Anal. Calcd for C24H27N34: C, 68.39; H, 6.46; N, 9.97. Found: C, 68.72; H, 6.71; N, 9.67.
:, ,:, SUBSTltUTE SHEET
.

.
-, ~ ~ ` ;

W092/07856 2 C ,; 2 1 ~ PCT/US91/08028 -~

l9B. 1-(Dimethyl~mino)methyl-2-hy~oxy-8-methyL-7-(1-oxopropyl)indoLizl.no~l 2-blqu~n~L i ~-9(1~ o-~e ~ydrochlori~
A solution of 24.1 mg (0 057 mmol) 1-(dimethylamino)methyl-7-(2-ethyl-1,3-dloxolan-2-yl)-2--~ hydroxy-8-methylindoli~ino[1,2-b]quinolin-9(11H)-one in 2 mL glacial acetic acid plus 0.25 mL of 2N hydrochloric acid was heated at 70C Lsr 50 minutes an~ t;~.en stripped to dryness in vacuo. r~ater was aàded, ar.d _:~.e solu.ion was restripped. A l~ttlG watQ- was added ro c~use partial dissolution, and then a lo~ o ace_one was add-d to give the title compound as 2 fine yellow solid. îH NM~ showed the presence o' 1/ .mole eth!lene ~lyc^' w ~ ~ n W= S
confirmed by elementai analysis which also indicated 1 mole of water of hydration. iH NMR (TFA-d1) d 9.65 (br s, lH), 8.70 (br d, 2H), 8.16 (m, 2H), 5.92 (br s, 2H), 5.08 (br s, 2H), 4.09 (s, lH), 3.21 (s, 6H), 3.15 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). Anal.
Calcd for C22H24ClN3O3-1/4 C2H6O2-H2O: C, 60.40; H, 6.19;
N, 9.39. Found: C, 60.15; H, 6.19; N, 9.11.

; Exa~le 20 2-Cyano-8-methyl-7- ~l-oxo~,o~yl~ind~ ;,n~- r~ 2-bl quinol~ tllH~-one 20A. 7-(2-Ethyl-1.3-dioxolan-2-yl~-8-methvl-2-trif1~Lorom~hyl-sul~onyloxyindoLizino~1-2-~lquinolin~
9~11~ -one To a solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-a-methylindolizino[1,2-b]quinolin-9(llH)-one (109 mg, 0.30 mmol) in dimethylform~mide (20 mL) were added N-phenyltrifluoro-me~hanesulfon~mide (161 mg, 0.4~ mmol) and triethylamine (0.13 mL, 0.9 mmol). The resulting mixture was heated at 55C for 1.5 hou-s, alloweà to cool to room temperature and concentrared _-.de- reduced --e_su-e. The SUBSTITU~E SI~EET

.

.~ W092/07856 ~ 9 PCT/US~1/08028 residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 0-2% MeOH in CH2Cl2 to provide the title compound as a yellow solid, mp 250-1C. lH NMR (CDCl3) d 8.38 (s, lH), 8.30 (d, J = 9 9 Hz, lH), 7.84 ~d, J = 2.7 Hz, lH), 7.68 ~dd, J = 9.3, 2.7 Hz, lH), 7.60 ~s, lH), 5.30 ~d, J = 1.0 Hz, 2H), 4.08 (m, 2H), 3.85 ~m, 2H), 2.48 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). Anal. Calcd for C22H1gF3N2O6S-1/2 H2O: C, 52.28; H, 3.99; N, 5.54.
Found: C, 52.51; H, 3.86; N, 5.50.

20B. 2-Cyano-7-(2-ethyl-1.3-dioxol~n-2-yl)-~-methy-lindol 7inorl,2-~lq~inoli~-~lllH)-Qne A mixture containing tetrakis(triphenylphosphine)palladium (322 mg, 0.28 mmol) and tri-n-butyltin cyanide (242 mg, 0.77 mmol) in anhydrous 1,2-dichloroethane (3 mL) under an argon atmosphere was heated at reflux for 2 hours, and then a solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methyl-2-trifluoromethylsulfonyl-oxyindolizino[1,2-b]quinolin-9(11H)-one (119 mg, 0.24 mmol) in anhydrous 1,2-dichloroethane (2.5 mL) was added. The reaction mixture was maintained at reflux for an additional 1.3 hours and : then allowed to cool to room temperature. The yellow crystals which formed upon cooling were collected by filtration and dried in vacuo to produce the title compound, mp >320C. 1H NMR (CDCl3) d 8.47 (s, lH), 8.36 (d, J = 1.7 Hz, lH), 8.30 (d, J = 8.8 Hz, lH), 7.95 (dd, J
: = 8.8, 1.8 Hz, lH), 7.70 (s, lH), 5.31 (d, J = 0.8 Hz, 2H), 9.10 (m, 2H), 3.86 (m, 2H), 2.47 ~s, 3H), 2.02 ~q, J
= 7.4 Hz, 2H), 0.99 (t, J = 7.9 Hz). Anal. Calcd for ; C22H19N303 0-03 C2H4cl2: C, 70-39; H, 5.12; N, 11.16.
Found: C, 70.09; H, 5.09; N, 11.01.
:, ., SUBSTITUTE SHEE-r W092/07856 ~ Z'7~ J 2 ~ 9 PCT/US9l/08028 ,~

20C. 2-Cyano-8-methyl-7~ oxo~ro~yl~sll~l~LL.2 bl~uinoli~ 9(11H)-one To a suspension of 2-cyano-7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one (18.9 mg, 0.05 mmol) in acetic acid (20 mL) was added 2 N HCl (0.25 mL, 0.5 mmol). The resulting mixture was heated at 70C
for 2.3 hours and then allowed to cool. Sodium acetate (41 mg, 0.5 mmol) and H2O were added, and .he mi::ture was concentrated under reduced pressure. Met~ lene chiori~e containing a few drops of MeOH was added ~o the residue, and the solid which formeà was remove~i Dy il_ra~ion. The filtrate was concentrated under reduced pressure.
Methanol W2S added to the residue and af_e- sonlcat-o-., the solid which formed was collected by fil.ration and dried in vacuo to provide the title compound, mp 307-9C.
H NMR (CDCl3) d 8.43 (s, lH), 8.32 (d, J = 1.7 Hz, lH), 8.28 (d, J = 8.8 Hz, lH), 7.95 (dd, J = 8.8, 1.9 Hz, lH), 7.29 (s, lH), 5.34 (d, J = 1.0 Hz, 2H), 2.92 (q, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H). Anal.
20 Calcd for C20HlsN3o2 1/4 H2O: C, 71.95; H, 4.68; N, 12.59. Found: C, 72.07; H, 4.69; N, 12.50.

E~ampl~ 2l 2-A~inQm~h~l=~-methyl-7-(l-oxo~ropyl~in~Qli2i~-rl.2-kl~uinol1n-9(llH)-one Hyd~ochl~o~i~e To a mixture of 2-cyano-7-(2-ethyl-1,3-dioxolan-2-.
yl)-8-methylindolizino[1,2-b]quinolin-9~ )-one ~8, 0.13 mmol) in acetic acid ~15 mL) was added Raney nickel (prepared by washing 50~ aqueous slurry successively with H2O, absolute ethanol and acetic acid and partially drying ` to produce a powder, 79 mg). The resulting mixture was hydrogenated at 80 psi H2 ~or 25 hours. ~nalysis by thin layer chromatography indicated that the reaction was incomplete, so additional Raney nickel (79 mg of sample prepared as above) was added, and the re~c~ion mlxture was SU9STITuTE StlEE~T

W092~07856 2 ,fi 9~ ~ 9 PCT/US9l/08028 hydrogenated at 75 psi H2 for 24 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was treated with H2O containing small amounts of MeOH and acetic acid and filtered. The filtrate was purified by reversed phase chromatography (Whatman 40 ~M ODS-3 support), eluting with a solvent gradient of 0-15% MeOH in H2O to provide 2-aminomethyl-7-~2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one, hydroacetate as a pale yellow solid. To this material was added acetic acid (2 mL) and 2 N ~Cl (0.30 mL, 0.6 mmol), and the resulting mixture was heated at 70C under an argon atmosphere. After heating for 3 hours, the reaction mixture was concentr~ted under reduced pressure. Absolute ethanol was added to the residue, and after sonication, the solid which formed was collected by filtration and dried in vacuo to provide the title compound. 1H NMR (TFA-dl/CDCl3) d 9.39 (m, lH), 8.62 (m, 2H), 8.46 (m, lH), 8.20 (m, lH), 5.85 (s, 2H), 4.82 (s, 2H), 3.13 (m, 2H), 2.50 (s, 3H), 1.38 (m, 3H).
20 Anal. C~lcd for C20H20ClN302-1/4 C2H602-1~2 H20: C, 62.43; H, 5.75; N, 10.66. Found: C, 62.16; H, 5.53; N, 10.32.

~mPle 22 ; 25 2-Acetyl-8-met~yl-7-(1-oxo~ro~yl)indolizinorl,~-b1 qui~oli3=~ -one To a suspension of 7-~2-ethyl-1,3-dioxolan-2-yl)-8-methyl-2-trifluoromethylsulfonyloxyindolizino r 1,2-b]quinolin-9~llH)-one (40 mg, 0.08 mmol) in anhydrous DMF
(0.4 mL) under an argon atmosphere were added successively triethylamine ~31 mL, 0.22 mmol), n-butyl vinyl ether (71 mL, 0.55 mmol), 1,3-bis~diphenylphosphino)propane (1.4 mg, 3.4 mmol) and palladium acetate (0.6 mg, 2.7 mmol). The resulting mixture was heated a- 80C for 2.5 h and then allowed to cool and stand at room temperature ove~night.

8U~Sl`lTUTE SHEET

wo 92/07856 2 ~ ~J v ? ~ ~, PCT/US91/08028, 7, . ~ . , Addition of EtOAc and Et2O caused pale yellow needlec to form which were collected by filtration, washed with Et2O
and dried; mp 215-20C ~dec). To this material was added glacial acetic acid (0.3 mL) and 3 N HCl (1 drop). The resulting mixture was allowed to stir at room temperature for 3 d and then was partitioned between CH2C12 and H2O.
The organic extract was washed with H2O (2x) and drieà
(Na2SO4). The solvent was removed in vacuo. H~LC
analysis of the residue indicated that th~ reac_ion was incomplete. The residue was treated witn ~0:1 acetic acid/3 N HCl (0.3 mL), and the mixture was h~at~d a_ 7CG-for 1 h and then allowed to cool. The mixture was partitioned between CH2C12 and H2O. The cr~anic e:~trac was washed with H2O (2x) and dried (Na2SO4). The solven.t was removed in vacuo, and the solid residue was recrystallized from 1,2-dichloroethane to afford the title compound as a yellow crystalline solid, mp 255-7C. lH
NMR (CDC13) d 8.45 (br d, 2H), 8.26 (m, 2H), 7.25 (s, lH), 5.30 (s, 2H), 2.90 (q, 2H), 2.76 (s, 2H), 2.27 (s, 2H), 1.24 (t, 3H). Anal. Calcd for C21H1gN2O3: C, 72.82; H, ~}
5.24; N, 8.09. Found: C, 72.86; H, 5.53; N, 7.52.

; Exam~le 23 12-Hydroxym~thyl-a-methyl-7-(1-oxopropyl)indolizi~o-25[1,2-klq~inQlin-9(11~-one To a solution of 8-methyl-7-(1-oxopropyl)indolizino[1,2-b] quinolin-9(llH)-one (91 mg, 0.3 mmol) in MeOH ~1 mL) and 50% H2SO4 ~2 mL) under an argon atmosphere at 0C was added simultaneously over a 50 minutes period a mixture of iron (II) sulfate heptahydrate ~834 mg, 3.0 mmol) in H2O ~2 mL) and 30% H22 (0.35 mL, 3.0 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 24 hours. Analysis by thin layer chromatography indicated that the reaction was incomplete and additional 30% H22 (0.35 mL, 3.0 mmol) was SUBSTITUTE SHEET

. ...

W O 92/07856 ~ 2 ~ ~ PC~r/US91/08028 added over a 95 minutes period. After stirring an additional 19 hours at room temperature, the reaction mixture was poured into ice H2O ~50 mL). Sodlum bicarbonate ~3.51 g, 42 mmol) was slowly added, and the mixture was filtered. The filtrate was extracted with CH2Cl2, and the solid which formed was removed by filtration. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 5~ MeOH in CH2Cl2 to provide the title 10 com~ound , mp 247C (dec). lH NMR (CDCl3/MeOH-d4) d 8.17 (dd, J = 8.4, 0.8 Hz, lH), 8.04 (br d, J = 8.2 Hz, lH), 7.80 (m, lH), 7.65 (m, lH), 7.35 (s, lH), 5.50 (s, 2H), 5.40 (_~ 2H), 2.9~ (q, J = 7.3 Hz, 2H), 2.28 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H). Anal. Calcd for C20H18N203 1/3H20:
15 C, 70.57; H, 5.53; N, 8.23. Found: C, 70.27; H, 5.44; N, 8.22.

Exa~æle 24 8-Methyl-7-(1-oxoD~Q~yl~-12-Dhenoxyindoliz~no r1, 2-bl~uinolin-9fll~)-one ., :., 24A. 7-(2-Eth~L-1,3-dio~gl~n-2-yl)-8-methylindolizino~1.2-bl quinolin-9(llH)-one. 5-oxide ~ 7-(2-Ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-: 25 b] quinolin-9(llH)-one (5.00 g, 14.4 mmol) was dissolved in glacial acetic acid ~75 mL) by heating at 65C. To the resulting solution was added 30~ aqueous H22 ~50 mL), and the mixture was heated at 65C for 5 h and then allowed to cool~ The solid which formed was collected by filtration, washed with H2O and dried. Additional material was obtained by evaporation of the filtrate and recrystallization of the solid residue with MeOH/CH2Cl2 to afford the title compound, mp 270-1C ~dec.) lH NMR
(C~Cl3) d 8.79 (d, J = 8.8 Hz, lH), 8.32 (s, lH), 7.97 (d, J = 8.1 Hz, lH), 7.93 (s, lH), 7.86 (ddd, J = 8.4, 7.1, ~;UBSTITUTE SHEET

~ 2 ~ ;J~1 9 W092/07856 PCT/US91/08028 ~^

1.3 Hz, lH), 7.74 (ddd, J - 8.1, 7.0, 1.1 Hz, lH), 5.29 (d, J = 1.0 Hz, 2H), 4.08 (m, 2H), 3.85 (m, 2H), 2.46 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).
Anal. Calcd for C21H20N2O4-1/4 H20: C, 68.37; H, 5.60; M, 7.59. Found: C, 68.68; H, 5.61; N, 7.50.

24B,_12-Ch~o~ 2-ethyl-1L~dioxQl~-2-vl)-8-methyl~dOli~1.2-kls~li~L~llH)-Qn~
To a suspension of 7-(2-ethyl-1,3-dloxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one, 5-oxide (1.92 g, 5.3 mmol) in anhydrous DMF (40 mL) were added p-toluenesulfonyl chloride (5.03 g, 56.4 mmol) and pvridine (2.1 mL). The resulting mixture was heated a~ 115C ^~-15 min and then allowed to cool to room temperature and crystallize overnight. Methanol was added to the reaction mixture, and the crystals were collected by filtration, washed with MeOH and dried in vacuo, mp 261-3C.
Additional material was obtained by evaporation of the filtrate, addition of MeOH to the residue, and filtration.
lH NMR (CDCl3) d 8.30 (dd, lH, J = 1.1, 8.5 Hz), 8.22 (dd, lH, J = 0.6, 8.4 Hz), 7.86 (ddd, lH, J = 8.5, 7.0, 1.5 ` Hz), 7.72 (ddd, lH, J = 1.2, 7.0, 8.2 Hz), 7.56 (s, lH), 5.28 (s, 2H), 4.05 (m, 2H), 3.87 (m, 2H), 2.47 (s, 3H), 2.02 (q, 2H, J = 7.4 Hz), 0.98 (t, 3H, J = 7.4 Hz). CIMS
25 (NH3, m/e, rel. int.) 385 ~34), 383 (100) [~M+H)+]. Anal.
: Calcd for C21HlgClN2O3: C, 65.88; H, 5.00; N, 7.32.
Found: C, 65.67; H, 4.97; N, 7.37.

24C. 7-(? Ft~y~ ~3~d~oxolaR-2-vl)-8-m~
phe~Q~yindolizi~o~1.2-blquinolin-9(llH)-one A mixture containing 12-chlo-o-7-(2-ethvl-1,3-dioxolan-2-yl)-8-methylindolizino~1,2-b]quinolin-9(llH)-one ~19.2 mg, 0.05 mmol), phenol ~94 mg, 1.0 mmol) potassium carbonate (6.9 mg, 0.05 mmol) was heated at 175C for 1.5 h and then allowed ~o cool. The mi~ture was SU8ST~TIJTE SHEET

W O 92/07856 ~ ~ 9 ~ ~ 1 9 PC~rtUS91/08028 dissolved in CH2Cl2 and purified by radial chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH
in CH2Cl2 to afford the title compound as a crystalline solid, mp 290-1C. lH NMR ~CDCl3) d 8.35 (dd J = 8.4, 0.9 Hz, lH,), 8.22 (dd, J = 8.2, 0.7 Hz, lH), 7.83 (ddd, J =
8.5, 7.0, 1.5 Hz, lH), 7.63 (ddd, J = 8.2, 7.0, 1.2 Hz, lH), 7.54 (s~ lH), 7.43 (m, 2H), 7.28 (m, lH), 7.14 (m, : 2H), 4.57 (s, 2H), 4.04 (m, 2H), 3.82 (m, 2H), 2.38 (s, 3H), 2.00 (q, J = 7.4 Hz, 2H), 0.94 (t, J= 7.4 Hz, 3H).
lGAnai. Calcc ror C27H24N2O4-1/4 H2O: C, 72.88; H, 5.55; N, 6.3G. Found: C, 72.90; H, 5.66i N, 6.14.

24D. 8-~et~ 7-(1-o~.opro~yl)-12-phenoxyindolizlno~l 2-bl ~u l ~. o l 1 n--9 ( ~ o~e 15To a solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methyl-12-phenoxyindolizino[1,2-b]quinolin-9(llH)-one (12 mg, 27 mmol) in glacial acetic acid ~1.5 mL) was added 2 N
HCl (300 mL). The resulting mixture was heated at 75C
for 2.5 h and then was allowed to cool to room temperature. The reaction mixture was concentrated in .' vacuo, and H2O was added to the solid residue. Sonication and filtra~ion of the mixture afforded the title compound ''A~ as a pale yellow solid, mp 212-3C. lH NMR (CDC13) d 8.38 (dd, J = 8.3, 1.2 Hz, lH), 8.19 (d, J = 8.4 Hz, lH), 7.85 ' 25 (ddd J = 8.3, 6.9, 1.4 Hz, lH,), 7.65 (ddd, J = 8.1, 7.0, 1.1 Hz, lH), 7.45 (m, 2H), 7.30 (m~ lH), 7.18 (m, 3H), 4.57 (s, 2H), 2.88 (q, J - 7.3 Hz, 2H), 2.21 ~s, 3H), 1.22 (t ,J = 7.3 Hz, 3H). Anal. Calcd for C2sH20N2o3~3/4 H2O:
C, 73.25; H, 5.29; N, 6.83. Found: C, 73.09; H, 5.35; N, 30 6.48.

SUBSTITUTE SHET

W092/07856 2 ~ 2 ~ ~ PCT/US91/080~8 Exam~le 12-r(3~9-~imethoxyphenyl)methyllamino-8-~thyl-7-(1-oxo~o~yl)indolizino~1 2-~ n~]in-9(11~l-one 25A. 12- r (3.4-Dim~thoxyphenyl)methylla~;=z_ L~ ~1 3-dio~olan-2-yl)-~-m~thy1indolizino~1 2-~lquinolin-9(llH~-one (S~ 201043) A mixture containing 12-chloro-7-(2-ethyl-1,3-dioxolan-2-- 10 yl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one (38 mg, O.1 mmol), phenol (66 mg, 0.7 mmol), 3,4-dimetnoxybenzylamine (105 mL, 0.7 mmol) and a crystai of potassium iodide was heated at 175C for 1.5 h and then was allowed to cool to room temperature and stand overnight. The reaction mixture was dissolved in CH2Cl2 containing a small amount of MeOH and purified by radial ` chromatography on silica gel eluting with a solvent gradient of 0-5% MeOH in CH2Cl2. The material which was isolated was further purified by recrystallization from MeOH in CH2Cl2 to afford the title compound , mp 232-7C.
H NMR tCDCl3) d 8.09 (dd, J = 8.4, 0.9 Hz, lH), 7.87 (d, j J = 8.2 Hz, lH), 7.69 (ddd, J = 8.0, 7.1, 0.9 Hz, lH), 7.47 ~m, 2H), 6.86 (m, 3H), 5.68 (apparent br t J = 5.7 Hz, lH,), 5.34 (s, 2H), 4.82 (d, J = 5.7 Hz, 2H), 4.03 (m, 2H), 3.9-3.7 (overlapping s and m, 8H), 2.42 (s, 3H), 1.99 (q, J = 7.4 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C30H31N30s 3/2 H2O: C, 66.65; H, 6.34; N, 7 77.
Found: C, 66.58; H, 6.40; N, 7.46.

25~ 2~ r ~3~4-Dim~ m~5~ aminQ=~=m&~h~l-7 oxo~2ro~yl)in,d~1iz1norl,2-bl6~ 1in-9~ )-one To a solution of 12-[(3,4-dimethoxyphenyl)methyl]amino-7-(2-ethyl-1,3-dioxolan-2-yl~-3-methylindolizino[1,2-b]quinolin-9(11~)-one (24 mg, 45 mmol) in glacial acetic acic (2 mL) was added 2 N HCl ~u~sm~T~ SHEET
.. . .

, WO92/07856 2 "~ 9 J 219 PCl/US91/08l~28 (0 . 3 mL) . The resulting mixture was stirred at room temperature for 2 h and then was heated at 70C for 1 h.
After cooling, the mixture was concentrated under reduced pressure. The residue was dissolved in MeOH/CH2Cl2 and purified by flash chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH in CH2Cl2. The material tnat was isolated was sonicated with a mixture of MeOH and H2O. The solid which formed was collected by fil~ra_ion and dried under reduced pressure to afford the title csm~ound, mp 240-2C. I r~ N~R (C~C13) d ~. 08 (d, J =
8.5 H~, ~H), 7.82 (d, J = ~ , lH) ~ 7.71 (ddd, J = 8.2 7 .2, 1.0 rHz~ lr.) ~ 7 .5û (ddd J = 8.3~ 7 .0~ 1.3 Hz~ lH~ ) 7.19 (br s, lH), 6.9û (m, 3H), 5.57 (br, lH), 5.42 (s, 2H), 4.87 (d, J = 5.5 H~, 2H) ~ 3.88 (s~ 3H) ~ 3.87 (S~ 3H) 2.89 (q, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.22 (t, J = 7.3 Hz~ 3H) . Anal. Calcd for C2gH27N3O4-3/4 CH30H: Ct 69 . 96;
H, 6.13; N, 8.51. Found: C, 70.22; H, 6.43; N, 8.08.
,, . ,Exan~lQ~
12-Cyano-8-met~yl-7-(1-oxopropyl)indoliz~Ql1.2-blqui~Qli~-9(11H)-one 26A. 7- (2-Ethvl-1.3-dioxolan-2-yl)-12-iodo-8-methylindolizino~1,2-blquinolin-9(llH)-one A mixture containing 12-chloro-7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b~quinolin-9(llH)-one (38 .3 mg, 0.1 mmol), potassium iodide ~166 mg, 1.0 mmol), acetic anhydride (0 .3 mT ) and glacial acetic acid (3 mL) was heated at 120C Ior 45 min. After cooling, the 30 mixture was concentrated under reduced pressure. The residue was covered with H2O, sor.icated and filtered. The solid was washed thoroughly w -h H2O- The solid residue was treated with MeOH/CH2Cl2, and filtered. This material was further purified by repea e~ rituration with MeOH/CH?Cl2 to afford the ~itle compound, mp>320C. 1H

SUBSTITUTE SHE~T

W092/07856 2,aJJ~ PCT/US91/OgO28!~-NMR (CDCl3) d 8.17 (d, J = 8.4 Hz, lH), 8.12 ~d, J ~ 8.5 Hz, lH), 7.86 (m, lH), 7.72 (m, lH), 7.61 (s, lH), 5.17 (s, 2H), 4.09 (m, 2H), 3.86 ~m, 2H), 2.46 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). Anal.
Calcd for C21HlgIN2O3: C, 53.18; H, 4.04; N, 5.91.
;~ Found: C, 52.94; H, 4.19; N, 5.86.

26B 12-Cy~no-7-~2-e~hyl-l,~iQ~olan-2-yl)-8-~1 me~hvlindQlizino~ =blquinQ~L~ LLE--on~
- 10 To anhydrous 1,2-dichloroethane (4 mL) under an argon atmosphere were added tetrakis~triphenylphosphine)palladium(0) (434 mg, 0.38 mmol) and tributyltin cyanide (338 mg, 1.03 mmol). The resulting mixture was heated at reflux for 2 h and then lS added to a solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-12-iodo-8-methylindolizino[1,2-b]quinolin-9(llH)-one in 1,2-dichloroethane (1 mL). The resulting mixture was heated at reflux for 1.3 h and then allowed to cool to room temperature and stand overnight. The reaction mixture was placed directly on a silica gel flash chromatography column and eluted with a solvent gradient of 0-5%
MeOH/CH2Cl2. The title compound was isolated and further purified by radial chromatography on silica gel eluting with a solvent gradient of 10-20% acetone in hexanes; mp 257-8C. 1H NMR (CDCl3) d 8.28 (2 overlapping dd, 2H), 7.93 (ddd, J = 8.6, 7.0, 1.6 Hz, lH), 7.82 (ddd, J = 8.3, 7.0, 1.3 Hz, lH), 7.59 (s, lH), 5.43 (s, 2H), 4.09 (m, 2H), 3.86 (m, 2H), 2.47 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H), 0.98 (t J = 7.4 Hz, 2H,). Anal. Calcd for C22H1gN3O3: C, 70.76; H, 5.13; N, 11.25. Found: C, 71.13; H, 5.37; N, 10.79.

SUBS~I~UTE SHEET

.

. W092/0~836 ~ f; .i ~ 2 1 9 PCT/US91/08028 26C. 12-Cyano-8-methyl-7-(1-o~Qp~R~l)indo1izinQ~I., ?-~ blquinolin-9(~ -one : To a solution of 12-cyano-7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizi~o[1,2-b]quinolin-9(llH)-one (20 mg, 54 mmol) in glacial acetic acid (2 m~) was added 2 N HCl - (0.3 mL). The resulting mixture was heated at 75C for 30 min and ~nen after cooling was concentrated under reduced pressure. Methanol was added to the solid residue which was then collected and dried to aff~;d the ~itle compound, mp 27G-8~C. 1H N-~ (CDCl3) d &.29 (2 overlapping d, 2H), -: 7.96 (dàd~ J = 8.5, 7.0, 1.5 H-, lH), 7.86 (ddd, J = 8.3, 7.0, 1.3 Hz, lH), 7.26 (s, lH), 7.48 (s, 2H), 5.48 (s, 2H), 2.92 (q, J = 7.2 Hz, 2H), 2.32 ~s, 3H), 1.26 (t J =
7.2 Hz, 3H,). Anal. Calcd for C20H15N302 1/4 H2O: C, 71.95; H, 4.68; N, 12.59. Found: C, 72.27; H, 4.74; N, . 12.22.
.;, .
~xample 27 ~+~ 8-methy~j~u~aLizi~o r lr2-bl quinolin-9(11~)-one 12-Cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9~11R)-one (11.5 mg, 34 mmol) was placed in 1:1:1.5 MeOH/THF/CH2Cl2 (1.4 mL) and sodium borohydride (7.6 mg, 0.20 mmol) was added. After stirring at room temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was treated with 10~
aqueous NH4Cl and allowed to stand at 0C overnight. The solid which formed was collected by filtration, washed sparingly with H2O and dried to afford the title compound.
lH NMR ~CDCl3) d 8.11 (d, J = 8.3 Hz, lH), 7.82 (m, 2H), 7.56 (m, 2H), 5.43 (d J = 20.1 H_, lH,), 5.26 (d, J = 20.1 Hz, lH), 4.91 (dd, J = 7.6, 5.4 Y.z, lH, 2.21 ~s, 3H), 1.90-1.50 (m obscured by HOD peak, 4H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd ror C20Hl7N3O2~ 8 H2O: C, 68.31;
H, 5.52; N, 11.95. Found: C, 68.62; H, 5.12; N, 11.21.

SUE3STlTUTE SHE~T

.
. .- .

.

. .

W092/07856 ~ ?l ~ PCT/US91/08028 r, 2-~minomethyl-8-methyl-7-(~ Qxo~ro~yl) indQllzi~Ll.2=
blquin~olin-9~lL~L~one ; 5 28A. 12-Aminomethyl-7-(2-~thyl-1 3-dioxolan-2-yl)-8-methylindolizino~1.2-blquinQl1n-9(llH)-one To a solution of 12-cyano-7-(2-ethyl-1,3-dioxolan-2-~`~ vl)-a-methylindol -ino[1,2-b]quinolin-9~11H)-one (47 mg, ~` 10 0.13 mmol) in glacial acetic acid ~10 mL) was added Raney nicke (109 mg) which had been freshly washed with acetic acid and dried. The resulting mixture was shaken on a Par- hydrogenator at 80 psi H2 for 49 h, after which the catalvst was filtered off and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of 95:5:0.3 to 90:10:0.3 CH2Cl2/MeOH/Et3N. The material which was isolated was triturated with MeOH and dried to afford the title compound as partial hydroacetate salt, mp 235-45C ~dec). lH NMR (CDCl3, MeOH-d4) d 8.23 ~m, 2H), 7.82 (m, lH), 7.71 (m, 2H), 7.37 (s, lH), 5.39 (s, 2H), 4.46 (s, 2H), 4.10 (m, 2H), 3.87 (m, 2H), 2.45 (s, 3H), 2.03 ~q, J = 7.4 Hz, 2H), 0.99 (t, J = 7.9 Hz, 3H). Anal. Calcd for C22H23N303-1/2 H20-3/5 C2H4O2: C, 65.96; H, 6.30; N, 9.95. Found: C, 66.27; H, 6.19; N, 9.68.

28~, 12-Am~LnQmethyl-8-methyl-7-~1-oXQ~rOpyl--Lind ~ lin-9~llH)-one A solution containing 12-aminomethyl-7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9tllH)-one ~18 mg, 44 mmol) and 2 N H~l (0.3 mL) in glacial acetic acid (2.75 mL) was heated at 75C for 2 h and after cooling, was concentrated unde- reduced pressure.
Methanol was added to the solià residue which was then SU8Srl~UTE SHE~T

, . . . ~ . . ~ .................................. ... . .

- .:

.-~; W092/07856 2 u~ 'i a 219 PCT/US91/080Z8 sonicated, filtered and dried to afford the title compound as the hydrochloride salt, mp 285-95C (dec). 1H NMR
(TFA-d1) d 8.70 ~m, 2H), 8.40 (~, lH), 8.25 (m, 2H), 6.05 ; (br s, 2H), 5.36 (br s, 2H), 3.20 (q, J = 7.1 Hz, 2H), 5 2.46 (s, 3H), 1.39 (t, J = 6.8 Hz, 3H). Anal. Calcd for C2oHl9N3o2~Hcl~l/4 H2o~l/6 C2HsO2: C, 63.48; H, 5.63; ~, 10.92. Found: C, 63.59; H, 5.73; N, 10.52.
' Exam~ - ~
1012-~3-(~imethylamino`)~-o~ er:~yl-/-(1-o~.opro~yl)i ndolizlnr~ rl ~ 2-~l q~ no ~ ?.-3 ~ ) -one 29A. 12-r3-(Dimethvlamlno)-l-~-o~yn-l-vll-7-(2-ethv~ 3 dioxolan-2-~ 8-~ Qth.~l in.dol ~ 7 n(? r ' . 2-~1 q~ ~ n.o.lln-9 ( 1 1.") -one To a solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-12-iodo-8-methylindolizino[1,2-b]quinolin-9(llH)-one (89 mg, 0.19 mmol) in DMF (1 mL) were added 1-dimethylamino-2-propyne (30 mL, 0.28 mmol), triethylamine (112 mL, 0.22 mmol) and bis(triphenylphosphine)palladium dichloride (4.8 mg, 6.8 mmol). The resulting mixture was heated at 90-5C
for 3 h and then allowed to cool. The mixture was concentrated under reduced prQssure, and the residue was purified by flash chromatography on silica gel eluting with a solvent gradient of 0-5~ MeOH in CH2C12~ The title compound was obtained as a yellow crystalline solid, mp 161.5-2.5C. lH NMR (CDC13) à 8.34 ~dd, J = 8.4, 1.2 Hz, lH), 8.21 (dd, J = 8.2, 0.6 Hz, lH), 7.81 (ddd, J = 8.4, 6.9, 1.5 Hz, lH), 7.67 (ddd, J = 8.0, 6.9, 1.1 Hz, lH), 7.57 (s, lH), 5.29 (s, 2H), 4.08 (m, 2H), 3.89 (m, 2H), 3.78 (s, 2H), 2.50 (s, 6H), 2.46 ~s, 3H), 2.03 (q, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 H-, 3H). Anal. Calcd Fo_ C26H27N3O3 1/4 H2O: C, 71.98; H, 6.39; ~, 9.68. Found:
C, 72.12; H, 6.27; N, 9.50.

SUE3S~ITUTE S~IEE~
~` -. .
. :
~`
:

`~092/07~56 ~S~ i 9 PCT/US91/08028 29B. 12-~3-(Dimethylami~o~pro~ =ethyl=~3~ Ll3D~
2-yl)-8-me~hylindolizino~1 2-bl~u1LQli~-9l~L~L~Qne A solution of 12-~3-~dimethylamino)-1-propyn-1-yl]-7-(2-ethyl-lr3-dioxolan-2-yl)-8-methylindolizino[l~2-b]quinolin-9(11~)-one (43.2 mg, 0.10 mmol) in absolute EtOH containing PtO2 (3.6 mg) was stirred under an H2 atmospnere overnight. The mixlure was then concentrated - under reduced ~ressure, and the residue was purified by flas;~ ch~o~ato~ra~hy on silica gel eluting with a solvent gradienL o_ 3-10~ MeOH in CH2Cl2. The material obtained ~as rur.he- pu-i~ied by treatm~nt with EtOAc containing some ~rirluoroacelic acid to g ve the title compound as the hydrotrifluo-oacetate sal.. 1H NMR (CDCl3, MeOH-d4) d 8.22 (d, J = ~.4 H-, lH), 8.16 (d, J = 8.3 Hz, lH), 7.81 15(ddd, J = 8.2, 6.9, 1.3 Hz, lH), 7.68 (m, lH), 7.66 (s, lH), 5.26 (s, 2H), 4.07 (m, 2H), 3.88 (m, 2H), 3.24 (m, 2H), 2.65 (m, 2H), 2.46 ~s, 3H), 2.38 (s, 6H), 2.03 (overlapping m and q, 2H), 0.99 (t, J = 7.4 Hz, 3H).
Anal. Calcd for C26H31N3O3-C2HF302-5/2 H2O: C, 56.75; H, 6.29; N, 7.09. Found: C, 56.66; H, 6.20; N, 7.05.

29~. 7-~2-Ethyl-1 3-dioxolan=2-ylL-8-methyl-12-pro~ylindolizinorl.2-blquinolin-9~llH)-one Also isolated from the above chromatography was 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methyl-12-propylindolizino~1,2-b]quinolin-9(llH)-one 1H NMR (CDCl3) d 8.22 ~br d, J =
8.7 Hz, lH), 8.10 ~br d, J = 8.5 Hz, lH), 7.77 (m, lH), 7.62 (m, lH), 7.57 ~s, lH), 5.23 ~s, 2H), 4.07 ~m, 2H), 3.85 (m, 2H), 3.15 (apparent t, J = 7.8 Hz, 2H), 2.46 (s, 3H), 2.02 (q, J = 7.4 Hz, 2H, 1.83 (apparent sextet, J =
7.6 Hz, 2H), 1.08 (t, J = 7.4 :--, 3H), 0.98 (t, J = 7.4 Hz, 3H).

SlJBSTITUTE SHEFT

- :
.

`, . W092/07856 2 u ;~ J 2 1 n PCT/US9~/08028 29D. 12-~3-(Dimethylamino)propyll-8-m~th~ 7- (1-Q~R~
indolizinorl 2-blquinolin-9(llH)-one A solution of 12-[3-(dimethylamino)propyl]-7-(2-ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9(llH)-one (19.5 mg, 45 mmol) and ~ N HCl (0.3 .- mL) in glacial acetic acid (1.5 mL) was heated at 70-5C
. for 2 h. The mixture was then allowed to cool and concentrated under reduced pressure, dissolved in water and lyophilized to give the title csr?ou..d 2s the dihydrochloride salt. Anal. Calcd or C24-i27N3O2-2 HCl-9/4 H2O: C, 57.31; H, 6.7-; N, 8.3_; C~ .i0.
Found: C, 57.63; H, 6.28; N, 7.82; Cl, 14.0û.

Ex~m~le 30 8-Methyl-7-(1-oxopropyl)-12-propylindolizino~1.2-blquinolin-9(llH)-one A solution of 7-(2-ethyl-1,3-dioxolan-2-yl)-8-methyl-12-propylindolizino[1,2-~]quinolin-9(llH)-one (9.7 mg, 25 mmol) and 2 N HCl (0.3 mL) in glacial acetic acid ~1.5 mL) was heated at 70-5C for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was treated with a mixture of MeOH and H2O, and the solid which formed was collected by filtration, washed with H2O and dried to afford the title compound, mp 179-80C. lH NMR (CDCl3) d 8.20 (dd, J = 8.5, 1.1 Hz, lH), 8.12 (dd, J = 8.5, 1.2 H-, lH), 7.79 ~ddd, J = 8.3, 6.9, 1.4 Hz, lH), 7.66 (ddd, J = 8.1, 6.8, 1.3 Hz, lH), 7.24 (s, lH), 5.27 (s, 2H), 3.17 ~m, 2H), 2.91 ~q, J = 7.3 Hz, 2H), 2.30 ~s, 3H), 1.89 (apparent sextet, J = 7.6 Hz, 3H).
Anal. Calcd for C22H22N2O2-5/8 H2O: C, 73.87; H, 6.55; N, 7.83. Found: C, 73.74; H, 5.91; N, 7.55.

~:;
:":

SUBSTITUTE SHEE~
. `

W092/07856 ~, j , PCT/US91/08028,-,~, iV ~ ,i w ~

~Q~

oxoindolizino~1.2-bl ~uinoline-7-~cet~_ A mixture of camptothecin (150 mg, 0.43 mmol), triethylamine ~1 mL), and 10~ palladium on carbon (36 mg) in ~MF ~10 mL) under a hydrogen atmosphere was stirred for 24h. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was redissol-~e~ i~ a mixtu-~ o_ DMF ~10 mL), H20 ~10 mL) and ace~ic ac'd (2 mL) and chromatographed on a preparative Dynama:~ Cla -ev~rsed colu~ us-ng a 57.5/~2.5/0.15 mixture of MeOH, H2O and acetic acid as the moDlie phase to give the title compound. lH NMR (d6-~MSO) d 8.64 (s, lH), 8.16 ~d, lH), 8.10 ~d, lH), 7.84 ~dd, lH), 7.68 ~dd, lH), 7.47 15 (s, lH), 5.24 ~s, 2H), 2.13 ~s, 3H), 2.05 ~m, 2H), 0.82 (s, 3H). CIMS (NH3, m/e, rel. int.) 351 (100) ~(M+H)+].

EXamal~ 32 Indolizinorl.2--blquinolin-9(11~ -one 32A 7-Tr if ~ methan~aulf~u~ Lh~li bl~4Lnolin-9(11~-one To a solution containing 7-hydroxy-indolizino~1,2-; b]quinolin-9(llH)-one (25 mg, 0.10 mmol) in dimethylformamide (5 mL) were added triethylamine (42 mL, 0.30 mmol) and N-phenyltrifluo-o-methanesulfonimide (S4 mg, 0.15 mmol). The resulting mi~ture was heated at 50C
for 2 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in 1:1 EtOAc/Et2O, filtered and the solid was washed with Et2O to afford pal~ yellow c-ystals of the title compound, mp 266-268C (~c). Anal. Calcd for C16HgF3N2O4S: C, 50.27; H, 2.37; N, 7.33. Found: C, 50.40; H, 2.42; N, 7.22.

.,, SVBSTITUTE Stl~r . . .
, ~W092/078~6 ~ ~ 9 ~ 2 ~ 9 PCT/US91/~8028 32B. Indo~izinorl 2-bl~uinolin-9(llH)-one To a solution of 7-trifluoromethanesulfonyloxyindollzino[l,2-b] quinolin-9(llH)-one (38 mg, 0.10 mmol) ~ dimQthylfo-mamide (5 mr~
under an argon atmosphere were added palladium (II) acetate (12.5 mg, 55.7 mmol), triphenylphosphine (29 mg, 111 mmol), tri-n-butylamine (104 mL, 4.4 mmol) and 98~
formic acid (10 mL, 0.3 mmol). The resultinc solution was heated at 65C for 2 hours, al owed to cool -o room temperature and concentrated ur.der reduced ?~essur_. The residue was purified by flash chromatography on sllica gel, elutina with 5~ MeOH in C:Cl3. The da~k solid that was isolated was dissolved in CUC1J (2 mT ) 2-.~ ext aczed with 6 N HCl (3 x 2 mL). The combined aqueous extracts were neutralized with concentrated NHqO~. The precipitate which formed was collected by filtration, dried and recrystallized from MeOH/CHCl3 to afford the title compound (7 mg, 30%). lH NMR (CDCl3/MeOH-d4) d 8.36 (s, lH), 8.10 (d, lH), 7.86 (br d, lH), 7.79-7.52 (m, 3H), 7.33 (dd, lH), 6.66 (d, lH), 5.17 (s, 2H).
:
Exam~le 33 7-Cya~oin~olizinorl.2-k'quinolin-9(llH)-one A mixture containing tri-n-butyltin cyanide (565 mg, 1.79 mmol) and tetrakis(tripher.ylphosphine)palladium ~879, 0.76 mmol) in anhydrous 1,2-dichloroethane (40 mL) under an argon atmosphere was heated at reflux for 2.5 hours.
The reaction mixture, which became homogeneous during this tlme, was allowed to cool, and 7-trifluoro-methanesulfonyloxyindolizino~1,2-b]quinolin-9(llH)-one (290 mg, 0.76 mmol) was added. The resulting mixture was heated at reflux for 2 hours, allowed to cool to room temperature and stirred for 48 hours. The solid which formed was collected by filtra -on, washed successively with 1,2-dichloroethane and Et ~ and dried ~o p_ovide the -...

SUESTITUTE SltEET
.

. : .

W092/07856 ~ ' 21 9 PCT/US91/08028 .~.

title compound as a yellow powder. lH NMR ~CDCl3/MeOH-dq) d 8.49 (br s, lH), 8.21 ~br d, J = 9 Hz, lH), 8.07-7.59 (m, 3H), 7.46 ~br s, lH), 7.00 ~br s, lH), 5.30 (s, 2H).
FAB+ MS ~m/e, rel. int.) 260 [~M+H)+, 17], 155 (64), 119 (100), 85 ~80). IR ~r) 3500 - 3400, 3080, 2240, 1680 -1660, 1630 - 1605 cm~1. Anal. Calcd for C16HgN3O: C, 74.12; H, 3.50; N, 16.21. Found: C, 73.~2; H, 3.49; N, 16.13.

~ ample 3d 7-~the~vlin~ol~ ~.o~ 7 . 2-~1 q~ln^l-r.-~(l^H)-~ne To a suspension or 7-~rifiuoromet;~anesulronyl-oxyindolizino[l,2-b]qulnolin-9(llH)-one (120 mg, 0.31 mmol) in dimethylformam~de (8 mL) unàe- en argon atmosphere were added dichloro[1,1'-bis~diphenylphosphino)ferrocene]palladium ~ 9.2 mg, 12.6 mmol) lithium chloride (41.2 mmol, 0.97 mmol), tetravinyltin t77.2 mL, 0.43 mmol), 4A sieves (30 mg) and 2,6-di-t-butyl-4-methylphenol (catalytic amount). The resulting mixture was heated to 70C at 65 psi carbon monoxide. After 18 hours, the reaction mixture was allowed to cool, vented and concentrated under reduced pressure. The residue was partitioned ~etween H2O and 10 MeOH in CHCl3. The aqueous phase was extracted with 10~MeOH in CHC13 (2x), and the combined organic extracts were concentrated in vacuo. The residue was puri~ied by flash chromatography on silica gel, eluting with 2~ MeOH
in CHCl3, to afford a tan powde- which was triturated with Et2O (3x). Recrystalli7ation from hot MeOH (0.5 mL) afforded the title compound as a crystalline solid rather than the expected 7~ oxopropvl) com~ound. lH NMR
~CDCl3) d 8.38 (s, lH), 8.23 (d, ~~ = 8.4 H_, lH), 7.94 (d, J ~ 8.2 Hz, lH), 7.82 (m, lH)! 7.65 (m, lH), 7.47 (s, lH), 6.71 (dd, J = 17.6, 10.7 H~, lr.i, 6.62 (s, lH), 6.11 (d, ~ 17.5 H , lH), 5.60 (d, J = lQ.8 H7, lH), 5.24 (s, 2H).

SUBST~ SHEET

., , -5W092/07856 2 ~ ~ ~ 2 ~ 9 PCT/US9l/08028 CIMS ~NH3) m/e 261 (M+H)+. IR (KBr) 3450-3400, 3050, 1675, 1620, 1600 cm~l. Anal. Calcd for C17H12N2O: C, 78.45; H, 4.65; N, 10.76. Found: C, 78.26; H, 4.89; N, -~ 10.55.

Exam~le 35 7-~thylindolizino~1,2-blquinolin-9(llH)-one To a solution of 7-ethenylindolizino[1,2-b]quinolin-9(11H)-one (10.2 mg, 0.04 mmol) in MeOU (2.5 .T.~) W2S a._d_~-5% palladium on activated carbon ~i.2 mg). The resul.ins mixture was stirred unàer a hydrogen a~mospn-re o~-e~nig-l Analysis by thin layer chromatography indicated that the reaction was incomplete, so additional 5~ pall~dium on activated carbon (1.2 mg) was added, and the mixture was stirred under a hydrogen atmosphere for an additional 1 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to provide an off-white powder. Recrystallization from MeOH
(0.25 mL) afforded the title compound as a crystalline solid. lH NMR ~CDC13) d 8.36 (s, lH), 8.25 ~d, J = 9 Hz, lH), 8.0-7.5 ~m, 3H), 7.22 (br s, lH), 6.56 ~s, lH), 5.23 (s, 2H), 2.67 (q, J = 7 Hz, 2H), 1.30 (t, J = 7 Hz, 3H).
CIMS (CH4) (m/e, rel. int.j 263 [(M+H)+, 42], 262 ~M+, 100), 247 (30). IR (KBr) 3480-3420, 2970, 1670, 1600 cm~

`
Exam~
7-Ace~vlindolizinorl,2-b~quin~1j~-9~ )-one , ...
:
36AJ_ 7-(1-Butoxye~henyl)indolizino~1~2-bl~Ln~lin-9(11~ -, Q~ , To a suspension of 7-trifluo-omethanesul-onyloxy-indolizino[1,2-~]quinolin-9(11H)-one (382 mg, 1.0 mmol) in anhydrous DMF (3 mL) under an argon atmos~here were added successively triethylamine (0.28 mL, 2.0 mmol), n-butyl ` ~:

. . .
SU~STITUT~ SH~E~

:

W092/07856 ~U-J~ 2 1 '~ PCT/US9~/08028,-7~

vinyl ether (0.64 mL, 5.0 mmol), 1,3-bis(diphenylphosphino)propane (12.2 m~, 29 mmol~ and palladium acetate (5.6 mg, 25 mmol). The resulting mixture was heated at 80C for 3.5 h and then allowed to cool and stand at room temperature overnigA~. The mixture was poured into Et2O (5 mL), and the solid collected and dried to afford the title compound as light orange needles. 1H NMR (CDCl3) d 8.10 (m, 2H), 7.90-7.38 (m, 3H), 7.32 (m, lH), 6.~6 (a~ lHj~ 5.04 (S~ 2H; ~ 5 (d, lH), 4.43 (d, lH), 3.87 (br t, 2H), 1.91-1.33 (m, 4H), 1.00 (br t, 3H).

36B. 7--~ce~yl~nd~ 7norl~2-~la~ no7~-r-9('lH)-o~.~
To a solution of 7-(1-butoxyethenyl)indolizino[1,2-b]quinolin-9(llH)-one (213 mg, 0.64 mmol) in glacial acetic acid (10 mL) was added 3 N HCl (4 drops), and the resulting mixture was allowed to stir at room temperature for 1 h. The reaction mixture was diluted with water, and the resulting solid was filtered off. The solid was dissolved in CH2Cl2 washed with H2O and dried (Na2SO4).
The solvent was removed in vacuo, and the residue was recrystallized from 1,2-dichloroethane to afford the title compound as light oranse needles, mp 265-85C (dec). lH
NM~ (CDCl3) d 8.40 (s, lH), 8.24 (d J = 8.4 Hz, lH,), 7.90 (d, J = 8.2 Hz, lH), 7.84 (m, lH), 7.75 (d, J = 1.4 Hz, lH), 7.70 (ddd, J = 8.4 7.0, 1.4, Hz, lH), 7.22 (d, J =
1.6 Hz, lH), 5.31 (s, 2H), 2.66 (s, 3H). Anal. Calcd for C17H12N202: C, 73.90; H, 4.39; N, 10.14. Fou~d: C, 73.49; H, 4.48; N, 9.95.
Examp'~ 37 ?-~c~tyl-a-meth~lindol~zinc :.2-~l~uinc'~?.-~ !-or.e To a solution of 7-acetyl ndolizino[1,2-b]quinolin-9(11H)-one (64 mg, 0.23 m~mol) n 5:1 CHCl3/MeOH ~18 mE) at 0C was added dropwise a solu~_on of diazomethane in Et2O

SIJ8STITIJTE SHE~T

.. . .

W092/07856 ~ ~ 9 ~ ~19 PCT/US91/08028 (10 mL). The resulting mixture was stirred at 0C for 0.5 h and then allowed to slowly warm to room temperature and stir overnight. The excess diazomethane was destroyed by the addition of acetic acid, and the mixture was concentrated under reduced pressure. The solid residue was dissolved in CHCl3 (minimum volume) and treated with Et2O. The precipitate which formed was collected and recrystallized from 1,2-dichloroethane (2.5 mL). The ~al~
pink solid was further purified by preparative HPT_ 10 (Zorbax column, 2.1 x 25 cm), eiuting with 3% EtGH in CH2Cl2 to provide an off-white powder, whlch was recrys_allized from 1,2-dichloroethane, mp 274-6C (dec).
lH NMR (CDCl3) d 8.39 (s, lH), 8.23 (d, J = 8.4 H7~
7.94 (d, J = 8.0 Hz, lH), 7.83 (m, lH), 7.66 (m, lH), 7.35 15 (s, lH), 5.31 (d, J = 1.1 Hz, 2H), 2.63 ~s, 3H), 2.36 (s, 3H). Anal. Calcd for C1gH14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.78; H, 4.99; N, 9.59.

Example 38 7-~3-(Dimethylami~Q)-1-pro~yn-1-yllind~izino~1.2-bl~uinoli~lllEL=QD~
To a mixture containing 7-trifluoromethanesulfonyloxy-indolizino~1,2-b]quinolin-9(11H)-one (l91 mg, 0.5 mmol), triethylamine (0.3 mL, 2.2 25 mmol) and 90% N,N-dimethylpropargylamine (82 mL, 0.7 mmol) in anhydrous DMF (1.5 mL) under an argon atmosphere was added bis(triphenylphosphine)palladium(II) chloride ~10 mg, 14 mmol). The resulting mixture was heated at 85C
for 1 h and then allowed to cool to room temperature. The solid which formed was collected by filtration, washed successively with EtOAc and Et2~ and dried. The title compound was obtained as a yellow crystalline solid. A
portion of this material was recrystallized from acetonitrile; mp 201-3C. 1H N~ ~CDC13) d 8.40-8.13 (m, 2H), 8.00-7.50 (m, 3H), 7.28 (m, lH), 6.77 (br s, lH), :, SUBSrlTUTE SHEEl 2 ~ ~ a 2 ~ 9 PCT/US91/08028 , 5.30 ~s, ZH), 2.55 (s, 2H), 2.41 ~s, 6H). Anal. Calcd for C20H17N3O: C, 76.17; H, 5.43; N, 13.32. Found: C, 76.39; H, 5.63; N, 12.68.

Exa~le 39 7-~3-(Dimethvl~no)~ v~ Q~inor~ l~ n 9(11H)-one A mixture of 7-[3-~dimethylamino)-1-p-Goyn-1-yl]indolizino~1,2-b]quinolln-9~11H)-one (23 my~ ^.03 ~umol) and 5% palladium on barlum sulfa~e (3 mg) in dry pyridlne (2 mL) was stirred at room temperature unde- ~ hydrogen atmosphere. After 3 h, the catalyst was riitered of~, and the filtrate concentrated under reduced oressure to afford a pale tan powder which was crystalli7ed f-om acetonit-ile and dried, mp 169-71C. 1H NM~ (CDC13) d 8.33-8.12 (m, 2H), 7.96-7.50 (m, 3H), 7.20 (br s, lH), 6.57 (s, 2H), 5.21 (s, 2H), 2.80-2.50 (m, 2H), 2.50-2.29 (overlapping s and m, 8H), 2.10-1.70 (m, 2H). Anal. Calcd for C20H2lN3o-H2o: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.50; H, 6.60; N, 12.18.

8UBSTI~TE $H~T

Claims (76)

What is claimed is:

1. A method for treating viral infections comprising administration 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 vehicle (I) wherein:
R7 is -H, -NO2, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH2Ar, -C?CCH2NRR1, -CH=CHCH2NRR1; -(CH2)nCH2V
where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R9 is -H, -OR, -NO2, -NRR1, -CN, halo; -(CH2)nCH2V
where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R10 is -H, -OR, -NO2, -NRR1, -CN, -COR12, -CH(OH)R12, -OC(O)R12, -OC(O)OR12, -OC(O)CH2CH2COOR13, -O-(CH2)1-5CH2NRR1, -OC(O)NRR1, 1,4'-bipiperidine-1'-carboxy; -(CH2)nCH2V where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R11 is -H, -CN, or -OR;
R12 is -H or lower alkyl;
R13 is lower alkyl;
R and R1 are independently selected from the group consisting of -H, -C1-6 alkyl, and, when R and R' are substituted on nitrogen, R and R1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;
X is -H, -OH, -CN, -SOR, -CH(OH)CH(OH)CH3, -CHR3R4, -C?CCH2NRR1, -CH2CH2CH2NRR1, lower alkyl, , , or -C(CH2CH3)(OH)COOH;
Y is -H, -CH3, -CH2OR2;
R2 is -H, -C(O)H, -C(O)C1-5alkyl, -C(O)C1-4alkylCOOH
or -C(O)C1-4alkylNRR1;
R3 is -OH, halo, or -NH2;
R4 is -H, lower alkyl, or -OR;
R5 is =O, =NOH, or =CHR;
R6 is -H, lower alkyl, or -NRR1; and Ar is phenyl, monosubstituted phenyl, disubstituted phenyl, 3-pyridyl, monosubstituted 3-pyridyl, or disubstituted 3-pyridyl, where substitutents can be -CN or lower alkoxy;
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 -NO2 or -NRR1;
c) when X is -CHR3R4 and R4 is -OR, R3 is -OH;
d) when R6 is -NRR1, R5 is =O;
e) when R5 is =CHR, R6 is -H;

f) when X is , R10 is -OH, and R7, R9, and R11 are -H, and Y is -CH3; and g) when Y is -CH2OR2, X is where R5 is =O, and R6 is -H or lower alkyl.

2. The method of claim 1 wherein: R7, R9, R10, and R11 are each -H; X is -CN, -SOR, -CH(OH)CH(OH)CH3, -CHR3R4, -C(CH2CH3)(OH)COOH, , 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 3 wherein said compound is (?)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11N)-one.

5. The method of claim 3 wherein said compound is (?)-7-[(hydroxy)methoxymethyl]-8-methylindolizino [1,2-b]quinolin-9(11H)-one,

6. The method of claim 3 wherein said compound is 7-(hydroxymethyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

7. The method of claim 1 wherein: X is where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3 or -CH2OR2.

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

9. The method of claim 7 wherein said compound is 7-acetyl-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

10. The method of claim 7 wherein said compound is 8-formyloxymethyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

11. The method of claim 1 wherein said compound is (?)-7-(threo-1,2-dihydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

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

13. The method of claim 12 wherein: R10 is -OR, -CN, -COR12, or -(CH2)nCH2V; and X is -CHR3R4, where R3 is -OH and R4 is -H or lower alkyl, or , where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

14. The method of claim 12 wherein said compound is 7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

15. The method of claim 13 wherein: R10 is -(CH2)nCH2V;
and X is where R5 is =O and R6 is CH2CH3.

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

17. The method of claim 13 wherein said compound is 2-cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

18. The method of claim 13 wherein said compound is 2-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

19. The method of claim 13 wherein said compound is 2-hydroxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

20. The method or claim 13 wherein said compound is 2-acetyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-3(11H)-one.

21. The method of claim 13 wherein said compound is (?)-2-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

22. The method of claim 12 wherein said compound is 8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-on-2-yl[1,4'-bipiperidine]-1'-carboxylate.

23. The method of claim 1 wherein: R7 is -H; R9 is -OR, -NO2, -NRR1, -CN, halo; -(CH2)nCH2V where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN; R11 is -H; provided that R10 is not -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 where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

25. The method of claim 24 wherein said compound is 1-(dimethylamino)methyl-2-hydroxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

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

27. The method of claim 26 where R7 is lower alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar; X is -CHR3R4 where R3 is -OH

and R4 is -H or lower alkyl, or where R5 is =O
and R6 is -H or lower alkyl; and Y is -CH3.

28. The method of claim 27 wherein said compound is 12-cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

29. The method of claim 27 wherein said compound is 12-aminomethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]
quinolin-9(11H)-one.

30. The method of claim 27 wherein said compound is 12-hydroxymethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

31. The method of claim 27 wherein said compound is 12-propyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

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

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

34. The method of claim 33 wherein: R9 is -OR, X is -CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, or where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

35. The method of claim 34 wherein said compound is 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

36. The method of claim 39 wherein said compound is (?)-1-methoxy-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

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

38. The method of claim 37 wherein said compound is 3-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

39. The method of claim 1 wherein: R7, R9, R10, and R11 are each -H; X is -CN, -CH2CH3, or -CH=CH2; and Y is -H.

40. A compound of Formula I, or a pharmaceutically acceptable salt thereof (I) wherein:
R7 is -H, -NO2, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH2Ar, -C?5CCH2NRR1, -CH=CHCH2NRR1; -(CH2)nCH2V

where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R9 is -H, -OR, -NO2, -NRR1, -CN, halo; -(CH2)nCH2V
where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R10 is -H, -OR, -NO2, -NRR1, -CN, -COR12, -CH(OH)R12, -OC(O)R12, -OC(O)OR12, -OC(O)CH2CH2COOR13, -O-(CH2)1-5CH2NRR1, -OC(O)NRR1, 1,4'-bipiperidine-1'-carboxy; -(CH2)nCH2V where n = 0-3 and V is -OH, -OC1-6alkyl, -OCOR12, -OCOOR13, -OCONRR1, -NRR1, or -CN;
R11 is -H, -CN, or -OR;
R12 is -H or lower alkyl;
R13 is 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;
X is -H, -OH, -CN, -SOR, -CH(OH)CH(OH)CH3, -CHR3R4, -C?CCH2NRR1, -CH2CH2CH2NRR1, lower alkyl, , , or -C(CH2CH3)(OH)COOH;

Y is -H, -CH3, -CH2OR2;
R2 is -H, -C(O)H, -C(O)C1-5alkyl, -C(O)C1-4alkylCOOH
or -C(O)C1-4alkylNRR1;
R3 is -OH, halo, or -NH2;
R4 is -H, lower alkyl, or -OR;
R5 is =O, =NOH, or =CHR;

R6 is -H, lower alkyl, or -NRR1; and Ar is phenyl, monosubstituted phenyl, disubstituted phenyl, 3-pyridyl, monosubstituted 3-pyridyl, or disubstituted 3-pyridyl, where substitutents can be -CN or lower alkoxy;
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 -NO2 or -NRR1;
c) when X is -CHR3R4 and R4 is -OR, R3 is -OH;
d) when R6 is -NRR1, R5 is =O;
e) when R5 is =CHR, R6 is -H;

f) when X is , R10 is -OH, and R7, R9, and R11 are -H, and Y is -CH3;

g) when Y is -CH2OR2, X is , R5 is =O, and R6 is -H
or lower alkyl;
h) when R7, R9, R10, and R11 are all -H and Y is -CH3, then X is not -H, -C(O)H, -CH2OH, -CH(OH)CH(OH)CH3, -C(O)CH2CH3, or -CH(OH)CH2CH3;
i) when R7, R9, R10 and R11 are all -H and Y is -CH2OC(O)H, then X is not -C(O)CH2CH3;
j) when R7, R9, R10, R11, and Y are all -H, then X is not -CH2OH, -C(O)H, -CH2Br, -OH, or -H; and k) when R7 is -OCH3, then X and Y are not -H.

41. A compound of claim 40 wherein: R7, R9, R10, and R11 are each -H; X is -CN, -SOR, -C(CH2CH3)(OH)COOH, -CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, or where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

42. A compound of claim 41 wherein said compound is 7-acetyl-8-methylindolizino[1,2-b]quinolin-9(11H)-one,

43. A compound of claim 40 wherein: R7, R9, and R11 are each -H; provided that R10 is not -H.

44. A compound of claim 43 wherein: R10 is -OR, -CN, -COR12, or -(CH2)nCH2V; X is -CHR3R4 where R3 is -OH

and R4 is -H or lower alkyl, or X is where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

45. A compound of claim 43 wherein said compound is 7-(2-ethyl-1,3-dioxolan-2-yl)-2-hydroxy-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

46. A compound of claim 44 wherein said compound is (?)-2-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

47. A compound of claim 44 wherein: R10 is -(CH2)nCH2V;

and X is , where R5 is =O and R6 is CH2CH3.

48. A compound of claim 47 wherein said compound is 2-aminomethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

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

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

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

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

53. A compound of claim 43 wherein said compound is 8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-on-2-yl[1,4'-bipiperidine]-1'-carboxylate.

54. A compound of claim 40 wherein: R7 and R11 are each -H; provided that R9 and R10 are each not -H.

55. A compound of claim 54 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 where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

56. A compound or claim 55 wherein said compound is 1-(dimethylamino)methyl-2-hydroxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

57. A compound of claim 40 wherein: R9, R10, and R11 are each -H; provided that R7 is not -H.

58. A compound of claim 57 where R7 is lower alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar; X is -CHR3R4 where R3 is -OH

and R4 is -H or lower alkyl, or where R5 is =O
and R6 is -H or lower alkyl; and Y is -CH3.

59. A compound of claim 58 wherein said compound is 12-cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

60. A compound of claim 58 wherein said compound is 12-aminomethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

61. A compound of claim 58 wherein said compound is 12-hydroxymethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

62. A compound of claim 58 wherein said compound is 2-propyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

63. A compound of claim 58 wherein said compound is (?)-12-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

64. A compound of claim 40 wherein: R7, R10, and R11 are each -H; provided that R9 is not -H.

65. A compound of claim 64 wherein: R9 is -OR, X is -CHR3R4 where R3 is -OH and R4 is -H or lower alkyl, or where R5 is =O and R6 is -H or lower alkyl; and Y is -CH3.

66. A compound of claim 65 wherein said compound is 1-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

67. A compound of claim 65 wherein said compound is (?)-1-methoxy-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one.

68. A compound of claim 40 wherein: R7, R9, and R10 are each -H; provided that R11 is not -H.

69. A compound or claim 68 wherein said compound is 3-methoxy-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one.

70. A compound of claim 40 wherein: R7, R9, R10, and are each -H; X is -CN or -CH=CH2; and Y is -H.

71. A formulation comprising a compound of claim 40 in admixture with a carrier or excipient.

72. The formulation of claim 71 where the carrier is a pharmaceutically acceptable carrier or excipient.

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

74. The method of claim 73 wherein said virus is herpes simplex type 1 and the infected host is a mammal.

75. The method of claim 73 wherein said virus is herpes simplex type 2 and the infected host is a mammal.

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