WO1992007856A1 - 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

SUBSTITUTED INDOLIZINO[1,2-2.]QUINOLINONES This application is a continuation-in-part of U.S. Serial No. 07/606,216, filed on October 31, 1990. .-cope of the Invention

This invention relates to methods of treating viral infections, antiviral compounds, and pharmaceutical compositions thereof. More specifically, this invention relates to a method of treating viral infections, certain indolizino [1,2-Jb]-quinolinyl derivatives which have antiviral activity and pharmaceutical compositions thereof. Background

Certain lH-pyrano [3' , 4 ' : 6, 7] indolizino [l,2-J ]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 Camptotheca acuminata trees indigenous to China and Nothapodytes foetida 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. Med. Chem . 1988, 32, 715; Cancer Res . 1989, 49, 1465; Cancer Res . 1989, 45, 4358) .

A number of investigators have shown that camptothecin possesses antiviral activity. However, although camptothecin has demonstrated antiviral activity in in vitro tissue culture systems, camptothecin and its close analogs that have an E-ring hydroxylactone moiety cannot be considered as useful in vivo antiviral agents because they undesirably inhibit mammalian topoisomerase I, as well as host cell DNA replication, and are cytotoxic to mammalian cells. Furthermore, camptothecin is 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-J_>]quinolinones that lack the E-ring a-hydroxy lactone moiety of camptothecin have been shown to be non-cytotoxic to mammalian cells and to lack antitumor activity (Ann . Rev. Pharmcol . Toxicol . 1977, 17, 117; J. Med. Chem. 1989, 32, 715) . This is because these compounds do not contain the essential structural features required to inhibit eukaryotic topoisomerase I. However, recently we have found that certain substituted indolizino [l,2-i>]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.

S .7MMΑRY OF THE INVENTION 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

wherein:

R⁷ is -H, -Nθ2, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH2Ar, -C≡CCI^NRR¹, -CH=CHCH2NRR¹, -(CH2)_nCH2V where n=0-3 and V is -OH, -OCi-βalkyl, -OCOR¹², -OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R⁹ is -H, -OR, -N02, -NRR¹, -CN, halo, -(CH2)_nCH2 where n=0-3 and V is -OH, -OCi-βalkyl, -OCOR¹², -OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R¹⁰ is -H, -OR, -N02, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -OC(0)R¹², -OC(0)OR¹², -OC(0)CH2CH2COOR¹³, -0-(CH2) I-5CH2NRR¹, -OC(0)NRR¹, 1, 4 '-bipiperidine-1 '- carboxy, -(CH2)nCH2V where n=0-3 and V is -OH, -OCi-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 ,

° 0> CH or - -CC (CH2CH3 ) (OH) COOH; Y is -H, -CH3 , -CH2OR² ;

R² is -H, -C(0)H, -C(0)Ci-5alkyl, -C(0) Ci-4alkylCOOH or -C(0)Cι-4alkylNRR¹; R³ is -OH, halo, or -NH2;

R⁴ is -H, lower alkyl, or -OR;

R⁵ is =0, =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, R¹^ 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 =0; e) when R⁵ is =CHR, R⁶ is -H;

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

g) when Y is -CH2OR², X is R⁶, R⁵ is =0, 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, R¹⁰, and R¹¹ are all -H and Y is -CH3, then X is not -H, -C(0)H, -CH2OH, -CH(0H)CH(0H)CH3, -C(0)CH2CH3, or -CH(OH)CH2CH3; b) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH2θC(0)H, then X is not -C(0)CH2CH3; c) when R⁷, R⁹, R¹⁰, R¹¹, and Y are all -H, then X is not -CH2OH, -C(0)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 excipient. In yet another aspect, the present invention relates to processes for making a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used throughout this patent application.

"Aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase "lower alkyl" refers to an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear 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 "1, 4 '-bipiperidine-1'-carboxy" is used to identify the following radical:

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 effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound, in a suitable solvent, is reacted with an excess of an organic or inorganic acid in the case of acid addition salts of a base moiety; or an excess of organic or inorganic base in the case where the parent contains an acid group. Representative acids are hydrochloric acid, hydrobromic acid, suifuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid and methanesulfonic acid. Cationic salts are readily prepared from alkali metals such as sodium, potassium, calcium, magnesium, zinc, copper or the like as well as ammonia. Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, and the like. The 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.

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 chiral center, the present invention includes the racemic mixture, the pure enantiomers, and any enantiomerically enriched mixture 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 hereinabove, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier or excipient.

The present method is useful for treating viral infections in animals and plants caused by a broad variety of viruses. The present method is particularly useful in treating viral infections caused by herpes simplex virus, particularly herpes simplex virus type 1 (HSVl) and herpes simplex virus type 2 (HSV2) , or cytomegalovirus when the infected host is a mammal, particularly when the infected host is human.

A preferred method of treating viral infections according to the present invention uses compounds of Formula IMl

where X is -CN, -SOR, -CH(OH)CH(OH) CH3, -CHR³R⁴, R⁶ or

and Y is -CH3 or -CH2OR², Formula IMl corresponding to Formula I wherein R⁷, R⁹, R¹^, and R ¹ are each -H and X and Y are as described herein. A more preferred method uses compounds of Formula IMl where X is

- ^R5

CHR³R⁴ where R³ is -OH and Y is -CH3, where X is R⁶ where R^ is =0 and R^ is -H or lower alkyl and Y is -CH3 or -CH2OR², or where X is -CH(OH) CH(OH)CH3 and Y is -CH3. Another preferred method for treating viral infections according to the present invention uses compounds of Formula IM2

Formula IM2 corresponding to Formula I wherein R⁷, R⁹, and R ¹ are each H, R¹^ is as defined hereinabove for Formula I except that R¹^ is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM2 where R¹^ is -OR, -CN, COR¹², or -(CH2)_nCH2V, X is -CHR³R⁴ where R³ is -OH and R⁴ is -H or

lower alkyl, or

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

Formula IM3 corresponding to Formula I wherein R⁷ and R¹¹ are each

-H, R⁹ and R¹^ are as defined hereinabove for Fomula I except that R⁹ and R¹⁽^ 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)n H2V, R¹⁰ is -OR, X is CHR³R⁴ where R³ is -OH and R⁴ is -H or

lower alkyl, or

is -H or lower alkyl, and Y is -CH3.

Another preferred method of use according to the present invention uses compounds of Formula IM4

Formula IM4 corresponding to Formula I wherein R⁹, R¹⁽^ and R¹¹ are each -H, R⁷ is as defined hereinabove except that R⁷ is not -H, and X and Y are as defined hereinabove in Formula I . A more preferred method uses compounds of Formula IM4 where R⁷ is lower alkyl, -CN, -(CH2)_n H2V or -NHCH2Ar, X is CHR³R⁴ where R³ is -OH and R⁴ is -H or

lower alkyl, or

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 is represented by Formula IM5

Formula IM5 corresponding to Formula I wherein R⁷, R¹^ and R¹¹ 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

and R⁴ is -H or lower alkyl, or R⁶ where R^ is =0 and R is -H or lower alkyl, and Y is -CH3.

Still another preferred method of use according to the present invention uses compounds is represented by Formula IM6

Formula IM6 corresponding to Formula I wherein R⁷, R⁹ and R^O are each H, R¹¹ is -CN or -OR, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM6 where R¹¹ is -OCH3, X is CHR³R⁴ where R³ is -OH and R⁴ is -H or lower alkyl, or

R⁶ where R^ is =0 and R^ is -H or lower alkyl, and Y is -CH3.

Yet another preferred method of use according to the present inventions uses compounds of Formula IM7

Formula IM7 corresponding to Formula I wherein R⁷, R⁹, R¹^ and R¹¹ are -H, X is -CN, -CH2CH3 or -CH=CH2_r 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 I hereinabove except that: a) when R⁷, R⁹, R¹⁰, and R¹¹ are all -H and Y is -CH3, then X is not -H, -C(0)H, -CH2OH,

-CH(OH)CH(OH)CH3, -C(0)CH2CH3, or -CH(OH)CH2CH3; b) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH20C(0)H, then X is not -C(0)CH2CH3; c) when R⁷, R⁹, R¹⁰, R¹¹, and Y are all -H, then X is not -CH2OH, -C(0)H, -CH2Br, -OH, or -H; and d) when R⁷ is -OCH3, then X and Y are not -H.

Prefered compounds of the present invention include those of Formula INI

Formula INI corresponding to Formula I wherein R⁷, R⁹, R¹^

and R¹¹ are -H, X is -CN, -SOR,

where R⁵ is =0 and R^ is -H or lower alkyl, or CHR³R⁴ where R³ is -OH and R⁴ is -H or lower alkyl (provided that R⁴ is not -CH2CH3) , and Y is -CH3.

Compounds of Formula IN2 are also preferred according to the present invention

Formula IN2 corresponding to Formula I wherein R⁷, R⁹ and R¹¹ are each -H, R¹^ is as described hereinabove for Formula I except that R¹^ is not -H, and X and Y are as defined hereinabove for Formula I . More preferred compounds of Formula IN2 include those where R¹^ 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 =0 and R6 is -H or lower alkyl, and Y is -CH3

Another preferred group of compounds of the present invention are the compounds of Formula IN3

Formula IN3 corresponding to Formula I wherein R⁷ and R¹¹ are each -H, R⁹ and R¹^ are as described hereinabove for Formula I except that R⁹ and R¹^ are not -H, and X and Y are as defined hereinabove for Formula I . More preferred compounds of Formula IN3 include those where R⁹ is -(CH2)_nCH2V, R¹⁰ is -OR, X is CHR³R⁴ where R³ is -OH and - ^R5

R⁴ is -H or lower alkyl, or R⁶ where R^ 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

Formula IN4 corresponding to Formula I wherein R⁹, R¹^ and R¹¹ are each -H, R⁷ is as described hereinabove for Formula I except that R⁷ is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN4 include those compounds where R⁷ is lower alkyl, -CN, -(CH2)nCH2V or -NHCH2Ar, X is CHR³R⁴

where R³ is -OH and R⁴ is -H or lower alkyl, or

where R^ is =0 and R^ 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, R¹^ and R¹¹ are each -H, R⁹ is as described hereinabove for Formula I except that R⁹ is not -H, and X and Y are as defined hereinabove for Formula I . More preferred compounds of Formula IN5 include those compounds where R⁹ is -OR, X is CHR³R⁴ where R³ is -OH and R⁴ is -H or lower -< alkyl, or R⁶ where R⁵ is =0 and R^ is -H or lower alkyl, and Y is -CH3.

Yet a further group of preferred compounds is represented by Formula IN6

Formula IN6 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 for Formula I. More preferred compounds of Formula IN6 are compounds where R¹¹ is -OCH3, X is CHR³R⁴ where R³ is -OH and R⁴ is -H or lower alkyl,

or R⁶ where R^ is =0 and R^ 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, R¹^ and R¹¹ are each -H, X is -CN, -CH2CH3, -CH=CH2, and Y is

-H.

The following compounds are particularly preferred:

8-methyl-7- (1-oxopropyl) indolizino[1, 2-b]quinolin-9 (11H) -o ne;

(±)-7- (1-hydroxypropyl)-8-methylindolizino [ 1, 2-b]quinolin- 9(ll#)-one;

8-formyloxymethyl-7- (1-oxopropyl) indolizino [1, 2-b]quinolin -9(ll__)-one; (±)-7- (threo-1,2-dihydroxypropyl)-8-methylindolizino [1, 2-b ] quinolin-9 (11H) -one; (±)-7-[ (hydroxy)methoxymethyl]-8-methylindolizino[1, 2-jb]qu inolin-9 (11H)-one;

7-(hydroxymethyl)-8-methylindolizino[1, 2-b]quinolin-9 (11H)

-one;

2-hydroxy-8-methyl-7- (1-oxopropyl) indolizino[1, 2-b]quinoli n-9(ll£D-one;

1- (dimethylamino)methyl-2-hydroxy-8-methyl-7- (1-oxopropyl) indolizino [1, 2-b]quinolin-9 (11H)-one;

2-cyano-8-methyl-7-(1-oxopropyl) indolizino[1, 2-b]quinolin- 9(ll_T)-one; l-methoxy-8-methyl-7-(1-oxopropyl) indolizino[1, 2-b]quinoli n-9(HH)-one;

2-aminomethyl-8-methyl-7-(1-oxopropyl) indolizino[1, 2-b]qui nolin-9 (llH)-one;

2-methoxy-8-methyl-7- (1-oxopropyl) indolizino[1, 2-b]quinoli n-9(HH)-one;

12-hydroxymethyl-8-methyl-7-(1-oxopropyl) indolizino[1, 2-b] quinolin-9 (llH)-one;

7-(2-ethyl-l,3-dioxolan-2-yl)-2-hydroxy-8- methylindolizino [1, 2-b] quinolin-9 (11H)-one; 7-acetyl-8-methylindolizino [1, 2-b]quinolin-9 (llH)-one;

12-cyano-8-methyl-7-(1-oxopropyl) indolizino[1,2- J ]quinolin-9(11H)-one; 12-aminomethyl-8-methyl-7- (1-oxopropyl) indolizino[1,2- Jb]quinolin-9 (11H) -one;

(±) -12-cyano-7- (1-hydroxypropyl) -8-methylindolizino [1, 2-b] quinolin-9 (11H) -one; (±)-2-cyano-7- (1-hydroxypropyl)-8-methylindolizino[1,2- b]quinolin-9 (11H)-one;

2-acetyl-8-methyl-7- (1-oxopropyl) indolizino[1, 2-b] quinolin-9 (lliϊ)-one;

12-propyl-8-methyl-7- (1-oxopropyl) indolizino[1,2- jb]quinolin-9 (11H) -one; (±)-l-methoxy-7- (1-hydroxypropyl)-8-methylindolizino [1,2- i] quinolin-9 (ll__)-one; and

3-methoxy-8-methyl-7- (1-oxopropyl) indolizino[1,2- Jb]quinolin-9 (llϋf) -one.

Some compounds used in the method for treating viral 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 outlined 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 - R¹¹ substituent to obtain an 8-methyl-7- (1-oxopropyl) indolizino [1,2- i>]quinolin-9 (11H)-one. Alternatively, the E ring may be opened and then the R⁷ - R¹¹ substituents introduced. In yet another alternative method, an existing R⁷ - R¹¹ group is modified to obtain the desired compound. Once the E ring is opened, the resulting X and Y groups may be further modified as needed to make the subject compounds. Starting materials are commercially available or can be made by published methods. Camptothecin, 10- 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 material for making some of the inventive compounds is described in Published Japanese Patent Application No. 59-51,289. The synthesis of 9- nitrocamptothecin is described by Wall, et al. J. Med. Chem. 1986, 29, 2358. A total synthesis of camptothecin is described by Wall, et al. , J. Med. Chem . 1980, 23, 554. The 1980 Wall, et al. synthesis can be used as a means to introduce one or more R⁷ - R¹¹ 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 substituent, 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.

SUBST Scheme 1

Compounds of formula 1 are converted to compounds of formula 2 by heating the compounds in a high boiling, preferably unreactive, solvent such as N,N- dimethylformamide or triglyme (triethylene glycol dimethyl ether) . As shown in Scheme 2 the keto group of compounds of formula 2 can be reduced to give the corresponding hydroxy compounds 3 from which the halo compounds 4 can be derived. The keto group also can be converted to an oxime (compounds 5) which can in turn be reduced to give the primary amino compounds 6. The keto group also can be converted to a ketal group such as a 1, 3-dioxolane (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 .

Scheme 2

As illustrated 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 1 . Scheme 3

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

Scheme 4

Some ring substituents may be labile to the conditions used in the preferred method of making compounds 2 as given in Scheme 1. To make compounds which are unstable under those conditions, the sequence set out in Scheme 5 can provide access to certain of those compounds or provide intermediates for making other compounds .

Scheme 5

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 acetic acid. Finally, oxidation of compounds 18, for example by iodobenzene diacetate, gives the 2-hydroxy ketals 19 which along with the keto compounds 20 derived from the ketals by acid hydrolysis can be used to make compounds with other substituents as illustrated in Scheme 6.

Scheme 6

15

The compounds in Scheme 6 are prepared either by alkylation (compounds 21) or acylation (compounds 22, 23, and 24) of the 2-hydroxy ketones 20 or by replacement of the 2-hydroxy group in the ketals (19) via the triflates (25) . Cyanation of the triflates following the method of Kosugi, M, et 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, Tetrahedron Lett . 1986, 27, 3931. If an amine or alcohol is used, the corresponding amides (30) or esters (32) are obtained which are then hydrolyzed to the respective keto compounds 31 and 33. Reduction of the esters 32 with a hydride gives the primary alcohols 34 which upon hydrolysis produce the keto alcohols 35 which 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 the alcohols 34 using a mild oxidant which gives the aldehyde in preference to the acid (for example, Mnθ₂) . Deprotection gives the keto aldehydes 37.

Similarly, the triflates are converted to vinyl ethers 38 following the method of Cabri, W., et al. (J. Org. Chem . 1990, 55, 3654) , and then compounds 38 are hydrolyzed to diketones 39. Selective hydrolysis of the enol ether function in compounds 38 produces the 2-keto compounds that can be reduced to secondary alcohols from which the ketal groups can be removed and the alcohol function acylated to give carboxylates, carbonates and carbamates as described for compounds 20 and 35.

Introduction of an amino group at the 2-position is accomplished by hydrolyzing esters 32, converting the resulting acids 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 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 group in compounds 19; the hydroxy group may be retained in the product or removed. These preparations are illustrated in Scheme 7.

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, 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.. Methods for making compounds with different groups at the 7-position are illustrated in Scheme 8. Scheme 8

15

The hydroxy compounds 57 are made as described by Sugasawa, T., et al. , Chem . Pharm. Bull . 1974, 22, 111 . The triflates (58) 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 ketones 62 which upon reaction with diazomethane by the method of Kametani, T., et al. (Heterocycles 1975, 3, 167) give methyl derivatives 63 which are reduced by hydrides to the alcohols 64. Coupling of the triflates with 3-dialkylaminopropyne by the method of Echavarren, A. M. 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. ( Tetrahedron Lett . 1986, 27, 1171) gives compounds 67 which are catalytically hydrogenated to ethyl compounds 68. 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 62, compounds 70 are methylated with diazomethane to give derivatives 71 which then are reduced to alcohols 72 by hydrides. Displacement of the triflate function from compounds 58 by thiols gives sulfides 73 which are oxidized to sulfoxides 7 .

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

Scheme 9

12-Hydroxymethyl compounds 75 are prepared by the method of Miyaska, T. et al. (Heterocycles 1981, 16, 1713) using ferrous sulfate, hydrogen peroxide and methanol with suifuric 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 compounds 80 that can be converted to many other compounds. Heating of the chloro compounds with arylols, such as phenol, gives the 12-aryloxy compounds 81 which upon deprotection give the ketones 82; 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 potassium iodide in acetic acid containing some acetic anhydride. The iodo derivatives are easily used in various coupling reactions similar to those carried out with triflates 25 and 58. Cyanation gives compounds 86 which are deblocked to ketones 87 or are reduced to aminomethyl compounds 88 which give ketones 89 upon hydrolysis . Likewise, propynylamines 90 can be produced and then deprotected to compounds 91 or catalytically hydrogenated to compounds 92 and 94 which are hydrolyzed to keto compounds 93 and 95, respectively. Heating compounds 85 with sodium acetate in acetic acid gives the 12-hydroxy compounds 96 which can be alkylated using either base and alkyl halides or diazoalkanes to give 12- alkoxy compounds 97 which upon deprotection afford 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 mesylate. Cyanide displacement on compounds 99 gives the ketals 100 which upon hydrolysis give 12-cyanomethyl ketones 101. 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.

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 simplex 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; 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:

Equine Herpes virus; Porcine Herpes virus; and Marek's disease virus.

Assays

The assay used to test the compounds of the present invention for antiviral activity was taken from the literature and was modified in well-known ways to adapt it to currently available technology. A generalized description of the assay follows. Ass y procedure

Well plates were seeded with the appropriate cells at a concentration of 1x10^s 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 37°C with 100-200 plaque forming units per well of a herpes simplex virus suspended in 250 μL HBSS. Following adsorption, the following were added:

A) 250 μL/well 2 x EMEM containing Human IgG (ca 0.1 μg/mL; Sigma No. G-6763) ;

B) 250 μL/well EMEM containing 10% FBS and antibiotic/antimycotic solution;

C) 250 μL/well HBSS containing appropriately diluted compound. ■ After 24-48 hours (optimum time determined by examination of the plaques under microscope) , old medium was aspirated off. Each well was stained with a selected stain solution (0.5% crystal violet in MeOH:H₂0 7:3) and then rinsed with water and air dried and plaques counted. Compound effectiveness was evaluated in terms of percent plaque reduction as compared to untreated, infected controls.

This procedure can be used to test compound efficacy against many viruses, besides herpes simplex by simply modifying the cell type used in the first step to match the virus being tested and following the procedure outlined above. Other cell types which could be used in this assay include mouse mammary tumor cells, human lung fibroblasts, sheep chorioplexus cells, and green monkey kidney cells.

Other assays which are useful for determining the antiviral activity of the 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 Compositions and Method 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 agricultural use, the compound can be mixed 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 surfaces .

The pharmaceutical compositions of this invention comprise one or more compounds of the present invention in admixture with an inert pharmaceutically acceptable carrier or diluent. Compositions may contain an effective amount of the inventive compound in one unit, such as in a single pill, capsule, or pre-measured intravenous dose or pre-filled syringe for injection, or, as is frequently the case, the composition may be prepared in individual dose forms where one unit, such as a pill, contains a sub-optimal dose with the user being instructed to take two or more unit doses per treatment. When the composition is presented as a cream, it contains 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 Reminσton' s Pharmaceutical Sciences, Mack Publishing Co., Easton, PA,

18042, USA. The nature of the composition and the pharmaceutically acceptable carrier or diluent will, of course, depend upon the intended route of administration, for example, by intravenous and intramuscular injection, parenterally, topically, orally, or by inhalation. For parenteral administration the pharmaceutical composition may be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension. For topical administration the pharmaceutical composition may be in the form of a cream, ointment, liniment, lotion, paste, spray or drops suitable for administration to the skin, eye, ear, nose or genitalia. For oral administration the pharmaceutical composition may be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

The pharmaceutically acceptable carrier employed may be either a solid or liquid. Exemplary of solid carriers are lactose, kaolin, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, mannitol, stearic acid and the like.

Examples of appropriate pharmaceutically acceptable liquid carriers or diluents .include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water. For aerosol systems, pharmaceutically acceptable carriers include dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or 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 therapeutic 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, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.

To obtain a stable water soluble dose form, a pharmaceutically acceptable salt of a compound of the present invention is dissolved in an aqueous solution of an organic or inorganic acid or base. If a soluble salt form is not available, the inventive compound may be dissolved in a suitable co-solvent or combinations thereof. Examples of such suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.

It will be appreciated that the actual preferred dosages of the compounds of the present invention used in the 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 manufactured in 200 mg capsules with instructions for treating herpes simplex viruses by taking one capsule every 4 hours, but not to exceed 5 capsules per day.

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

Example 1 8-Formyloxymethyl-7-(1-oxopropvl- indolizinon.2- lquinolin

-9.llff.-one To a suspension of (4S,3R,S)-ethyl-3,4-dihydroxy-lff-pyrano-[3' ,4 ^• :

6,7] indolizino[1,2-Jb]quinolin-14 (4_ϊ,12ff)-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 arcetic 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 0°C. The precipitate which formed was collected by filtration and recrystallized from acetone/H2θ to provide yellow needles of the title compound as a hydrate mp >200°C (dec) . ¹H NMR (CDCl3/DMSO-d6) d 8.43 (br s, 1H) , 8.20 - 7.40 (m, 5H), 7.23 (s, 1H) , 5.28 (br s, 4ff) , 2.95 (q obscured by HOD peak, 2H) , 1.18 (t, J = 6 Hz, 3H) . Anal. Calcd for C20H16N2O Η2O: C, 65.57; H, 4.95; N, 7.65. Found: C, 65.53; H, 4.84; N, 7.33.

SUBSTIT Example 2 8-Methyl-7-(l-oxopropvl) indolizino.1.2-b1σuinolin-9 (llff. -o

A sample of 4.6 g of 4-ethyl-4-hydroxy-lH-pyrano [3' , 4 ' : 6,7]- indolizino [1,2-Jb]quinolin-3, 14 (4ff, 12ff)-dione [(20 S) camptothecin] was stirred with 46 ml of N,N-dimethylformamide. The suspension was heated at reflux, and the disappearance of starting material was monitored by HPLC (C18 reverse phase column, 20-25% acetonitrile:water mobile phase, perchlorate buffer at pH approximately 3.0) . The reaction was monitored by UV detection at a wavelength 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. 233-234°C was obtained.

E ample 3 l-Methoxy-8-methyl-7- (1-oxopropyl) indolizino , 1, 2-£>1quinoli n-9.llff. -one (S)-4-Ethyl-4-hydroxy-10-methoxy-lff-pyrano- [3 ' , 4 * : 6, 7] indolizino [ 1 , 2-b]quinoline-3, 14 (4ff, 12ff)-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 to cool to room temperature. The solid which formed was suspended in Et2θ, collected by filtration and dried. The solid was purified by column chromatography on basic alumina (deactivated by addition of 15 wt% H2O) , eluting with CH2CI2 • The solid obtained was further purified by radial chromatography on silica gel, eluting with 2% MeOH in CH2CI2 to provide the title compound as a beige solid . l-H NMR (CDCI3) d 8.80 (br s, 1H) , 7.77 (br d, J = 8.7 Hz, 1H) , 7.69 (dd, J = 8.7, 7.3 Hz, 1H) , 7.23 (s, 1H) , 6.94 (br d, J = 7.4 Hz, 1H) , 5.27 (d, J = 1.0 Hz, 2H) , 4.06 (s, 3H) , 2.91 (q, J = 7.3 Hz, 2H) , 2.30 (s, 3H) , 1.24 (t, J = 7.3 Hz, 3H) . Anal. Calcd for C20HI8N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.51; H, 5.42; N, 8.45.

Example 4 3-Methoxv-8-methyl-7- (1-oxopropyl) indolizino.1.2-2.1σuinoli n-9 (llff, -one (±)-4-Ethyl-4-hydroxy-8-methoxy-lff-pyrano[3' ,4 ^■ : 6,7]- indolizino [1,2-J ]quinoline-3,14 (4ff, 12ff)-dione (100 mg, 0.26 mmol) (prepared by the method of M. E. Wall, M. C. Wani, S. M. Natschke, and A. W. Nicholas, J. Med. Chem. , 1986, 29, 1553) in triethylene glycol dimethyl ether (2 mL) under an argon atmosphere was heated to reflux for 2.5 hours. Af er 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 column chromatography on basic alumina (deactivated by addition of 15 wt% H2O) , eluting with 1% MeOH in CH2CI2.

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. H NMR (CDCI3) d 8.29 (s, 1H) , 7.80 (d, J = 9.0 Hz, 1H) , 7.49 (d, J = 2.4 Hz, 1H), 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 C20H18N2O3•1/4 H2O: C, 70.89; H, 5.35; N, 8.27. Found: C, 70.77; H, 5.39; N, 8.12.

Example 5 7- (1-Hvdroxyiminopropvl)-8-methvlindolizino- r1,2-±>1quinolin-9.llff)-one A solution of 8-methyl-7- (1-oxopropyl) indolizino[1,2- b] quinolin-9 (llff)-one (112 mg, 0.37 mmol) and hydroxylamine sulfate (224 mg, 1.36 mmol) in a mixture of 5 mL absolute EtOH and 7 mL pyridine was heated at 100°C 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 (1 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 261-263°C (dec) . iH NMR (CDCl3/MeOH-d4) d 8.43 (s, 1H) , 8.2-7.5 (m, 4ff) ,

7.28 and 7.18 (2s, 1H) , 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

Cl9Hi7N3θ2-9/10 H2O: C, 68.01; H, 5.65; N, 12.52. Found: C, 68.09; H, 5.68; N, 12.19.

Example 6 (±)-7- (1-Aminopropyl)-8-methylindolizino .1, 2-b]quinolin-

9 (llff)-one, Hydrochloride To a solution of 7- (1-hydroxyiminopropyl)-8- methylindolizino [1, 2-b]quinolin-9 (llff)-one (60 mg, 0.19 mmol) in 95% EtOH (4 mL) at 0°C was added 10% NaOH (4 mL) , followed by nickel-aluminum alloy (130 mg) . The resulting 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 residue, which was then extracted with CHCI3 (3x10 mL) . The combined organic extracts were evaporated in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 0-10% MeOH in CHCI3 to give, upon evaporation of the solvent, a pale yellow powder. Two drops of concentrated HC1 were added to a suspension of the powder in water (1 mL) , and the mixture was allowed to stand overnight. The mixture was filtered and the solid was washed with acetonitrile, followed by Et2θ to provide the green-yellow title compound. ¹H NMR (D2O/DCI, HOD at d 4.55) d 7.43 (s 1H) , 7.17-6.66 (m, 5H) , 3.81 (br s, 2H) , 2.0-1.7 (br m, 5H) , 0.85 (br t, J= 7.5 Hz, 3H) .

Example 7 (±- -7- (1-Hvdroxvpropyl. -8-methvlindolizino- r1.2-b1σuinolin-9 (llff)-one

Prepared by the method of T. Kametani, H. Takeda, H. Nemoto, and K. Fukumoto, J. Chem. . Soc. Perkin Trans I. , 1975, 1825.

Example 8

(+)-7- (1-Bromopropγl)-8-meth lindolizino .1.2-b1quinolin-

9 (llff)-one A solution of (±)-7- (1-hydroxypropyl)-8- methylindolizino [1, 2-b]quinolin-9 (llff)-one (700 mg, 2.3 mmol) in thionyl bromide (10 mL, 0.13 mol) was heated at 85°C 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 CH2CI2 (20 mL) . After standing overnight at 0°C, the solid which formed was collected by filtration, washed with CH2CI2 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 pressure, and the residue was treated with 10% H2O in MeOH. The solid which formed was collected by filtration. The solids were combined to provide the title compound as a hydrate -^H NMR (CDCI3) d 8.34 (br s, 1H) , 8.0-7.5 (m, 4ff) , 7.49 (s, 1H) , 5.28 (d, J = 1.1 Hz, 2H) , 5.13 (t, J = 7.5 Hz, 1H) , 2.45-2.20 (obscured m, 2H) , 2.34 (s, 3H) , 1.06 (t, J = 7.2 Hz, 3H) . Anal. Calcd for Ci9Hi7BrN2θ-5/8 H2O: C, 59.97;

H, 4.83; N, 7.36. Found: C, 59.92; H, 4.84; N, 7.40.

Example 9

8-Methvl-7- .1 (E)-propenvl1indolizino 11.2- 1 uinolin- 9 (llff)-one

To 110 mg (0.36 mmol) of (±)-7- (1-hydroxypropyl) -8- methylindolizino [1,2-b]quinolin-9 (llff)-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 CH2CI2 • Within a minute all the solid had dissolved. After 1 hour the reaction was added to a column of 25 g silica gel in CH2CI2. After initial elution with CH2CI2, the product was removed with 2% MeOH in CH2CI2 • The resulting yellow residue was triturated with MeOH to yield pure title compound as a hydrate, mp 283-4°C (dec) . !H NMR (CDCI3) d 8.30 (d, J = 0.6 Hz, 1H) ,

8.19 (dd, J = 8.3, 0.6 Hz, 1H) , 7.89 (dd, J = 8.1, 1.2 Hz, 1H) , 7.79 (m, 1H) , 7.61 ( , 1H) , 7.44 (s, 1H) , 6.69 (br dd, J = 15.7, 1.1 Hz, 1H) , 6.56 (dq, J = 15.6, 6.1 Hz, IH) , 5.24 (d, J = 1.0 Hz, 2H) , 2.32 (s, 3H) , 2.00 (br d, J = 5.3 Hz, 3H) . Anal. Calcd for CigHiδ^O-1/8 H2O: C, 78.53; H, 5.64; N, 9.64. Found: C, 78.47; H, 5.73; N, 9.53.

Example 10

(+)-7-( threo-1.2-Dihvdroxypropvl)-8-methvlindolizino.1.2- bλ σuinolin-9 (llff)-one To a suspension of 55 mg (0.19 mmol) of 8-methyl-7- [1 (E)-propenyl] indolizino[1, 2-b]quinolin-9 (llff) -one in 2.0 mL dry pyridine were added 77 mg (0.30 mmol) osmium tetroxide. The reaction immediately darkened and the solid dissolved. Within 5 minutes a light-colored solid had precipitated. 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 CH2CI2 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 267-9°C (dec) . !H NMR (CDCl3/MeOH-d4, referenced to CD2HOD at d3.35) d8.44 (s, IH) , 8.11 (d, J = 8.5 Hz, IH) , 7.93 (d, J^" = 8.1 Hz, IH) , 7.80 (apparent dt, J = 7.2, 1.1 Hz, IH) , 7.64 (m, 2H) , 5.25 (s, 2H) , 4.79 (d, J = 6.4 Hz, IH) , 3.98 (quintet, J = 6.3 Hz, IH) , 2.31 (s, 3H) , 1.19 (d, J = 6.4 Hz, 3H) . Anal. Calcd for CιgHi8N2θ3-7/8 H2O: C, 67.49; H, 5.89; N, 8.28. Found:

C, 67.58; H, 5.65; N, 8.35.

Example 11 (±)-7- r (Hydroxy)methoxymethyll-8-methylindolizinoTl.2- blquinolin-9 (llff)-one To a solution of 34.5 mg (0.10 mmol) (±)-7- (threo- 1,2-dihydroxypropyl)-8-methylindolizino [1,2-b]quinolin- 9 (llff)-one in 5 mL glacial acetic acid was added over 3 minutes a solution of 32.5 mg (0.15 mmol) sodium periodate in 1 mL water. After 1 hours, 6 drops of ethylene glycol were added to destroy excess periodate, and the reaction mixture was stripped to dryness in vacuo. The resulting residue was triturated with H2O and then dissolved in hot CH2CI2 plus MeOH. After filtering, the solution was stripped, and MeOH was added to produce a clean solid . Rather than the expected 7-carboxaldehyde, -^-H NMR showed the product to be the title compound, a hemiacetal of the carboxaldehyde with MeOH which analyzed as a hydrate, mp 284-6°C (dec) . ^-H NMR (CDCl3/MeOH-d4) d 8.47 (s, IH) , 8.15 (d, J = 8.5 Hz, IH) , 7.97 (d, J - 8.0 Hz, IH) , 7.82 (m, IH) , 7.76 (s, IH) , 7.68 (m, IH) , 5.71 (s, IH) , 5.28 (s, 2H) , 3.64 (s, 3H) , 2.33 (s, 3H) . Anal. Calcd for

Ci8Hi6N2θ3-l/2 H2O: C, 68.13; H, 5.40; N, 8.83. Found:

C, 68.27; H, 5.36; N, 8.58.

Example 12 7- (Hydroxymethyl)-8-methylindolizino fl_f2-b1quinolin-

9 (llff)-one To a solution of 34.0 mg (0.10 mmol) (±)-7- ( threo- 1,2-dihydroxypropyl)-8-methylindolizino [1,2-b]quinolin- 9 (llff)-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 1 hour, the reaction was stripped to dryness in vacuo, H2O was added and a yellow solid was collected. The solid was dissolved in hot CH2CI2 plus MeOH, and the solution was filtered and stripped to dryness. The residue was triturated with MeOH to give of the title compound as a hydrate, p >320°C. ^λE NMR (CDCl3/MeOH-d4) d 8.51 (br s, IH) , 8.20 (br d, J^" - 9.0 Hz, IH) , 8.01 (br d, J = 8.4 Hz, IH) , 7.86 (m, IH) , 7.74 (s, IH) , 7.69 (m, IH) , 5.31 (s, 2H) , 4.74 (s, 2H) , 2.23 (s, 3H) . Anal. Calcd for Ci7Hi4N2θ2-l/2 H2O: C, 71.07; H, 5.26; N, 9.75. Found: C, 70.75; H, 5.12; N, 9.52.

Example 13 7-(?.-F. hvl-1.3-dioxo_an-2-vl)-2-hvdroxv-8- met.hylindolizinori.2-b1 σuinolin-9 (llff) -one

13A. 7-(2-Ethγl-1.3-dioxolan-2-vl)-8-methvlindolizino r 1.2-bl σuinol. n-9 (llff) -one

Hydrogen chloride gas was bubbled into a suspension of 15.0 g (49 mmol) 8-methyl-7- (1- oxopropyl) indolizino[1,2-b]quinolin-9 (llff)-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. 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 CH2CI2 . After washing with 500 mL H2O, the CH2CI2 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 272-4°C. !H NMR (CDCI3) d 8.31 (s, IH) , 8.20 (br d, J = 8.1 Hz, IH) , 7.86-7.50 (m, 3H) , 7.58 (s, IH), 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 Hz. 3H) . Anal. Calcd for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C, 72.37; H, 5.65; N, 8.26. 13B. 7- (2-Ethyl-l.3-dioxolan-2-vl)-5.5a.11a.12-tetrahydro- 8-methvlindolizinofl.2-blσuinolin-9 (llff)-one

To a solution of 1.39 g (4.00 mmol) of 7- (2-ethyl- 1,3-dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin- 9 (llff)-one in 100 mL glacial acetic acid was 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. The residue was taken up in CH2CI2, and the solution was washed with H2O and then dried over sodium sulfate and stripped. The resulting foam was triturated with acetone to yield the title compound as a solid mixture of two isomers, mp 218- 222°C. ¹H NMR NOE experiments showed that the tranε- isomer predominated. !R NMR (CDCI3) d 7.13 - 6.97 (m, 2H) , 6.85 - 6.58 (m, 2H) , 6.47 and 6.42 (2 br s, IH) , 4.82 and 4.64 (m and dd, J^" = 12.2, 7.1 Hz, IH) , 4.40-4.05 (m, 2H) , 4.03 ( , 2H) , 3.78 (m, 2H) , 3.57 (t, J = 11.7 Hz, IH) , 3.05 (d, J = 8.6 Hz, IH) , 2.85-2.42 (2m, IH) , 2.29 (2s, 3H) , 1.94 (q, J = 7.4 Hz, 2H) , 0.94 (t, J = 7.5Hz, 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-Ethvl-l.3-dioxolan-2-yl)-2-hγdroxγ-8- methvlindolizino r1.2-blσuinolin-9 (llff)-one 7- (2-Ethyl-l,3-dioxolan-2-yl)-5,5a, 11a, 12-tetrahydro- 8-methylindolizino[1,2-b]quinolin-9(llff)-one was prepared as above from 6.96 g (20.0 mmol) 7- (2-ethyl-l, 3-dioxolan- 2-yl)-8-methylindolizino[l,2-b]quinolin-9 (llff) -one, but the product was not triturated with acetone but was redissolved in 275 mL glacial acetic acid. To this solution were added 350 L H2O and then, dropwise over 10 minutes, a solution of 19.3 g (60 mmol) iodobenzene diacetate in 225 mL warm glacial acetic acid. After 45 minutes the reaction was stripped to dryness in vacuo. The residue was extracted with hot CH2CI2 plus MeOH. The extract was stripped to dryness and redissolved in CH2CI2 plus a minimum of MeOH and then added to a column of 1.5 kg of silica gel in CH2CI2• Af er eluting with 4 L of CH2CI2, 14 L of 3% MeOH in CH2CI2 were used to elute most of the product with 5% MeOH used as a chaser. Based on TLC (8% MeOH in CH2CI2), fractions were combined into pools of recovered 7- (2-ethyl-l,3-dioxolan-2-yl)-8- methylindolizino [1,2-b]quinolin-9 (llff)-one and product. Both materials were triturated with MeOH to produce yellow solids; 1.73 g of clean recovered starting material and 2.35 g (43% based on starting material consumed) of title compound as a methanol solvate, mp >300°C. ¹H NMR (CDCl3/MeOH-d4) d 8.17 (s, IH) , 8.05 (d, J = 9.2 Hz, IH) , 7.60 (s, IH) , 7.42 (dd, J 9.2, 2.6 Hz, IH) , 7.18 (d, J = 2.7 Hz, IH) , 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 CH3OH: C, 68.94; H, 5.59; N, 7.62. Found: C, 68.74; H, 5.73; N, 7.36.

Example 14

2-Hydroxv-8-methvl-7-(l-oxopropvl) indolizinori.2- blqυiϊ -lin-9(llff)-one)

To a suspension of 7- (2-ethyl-l,3-dioxolanyl)-2- hydroxy-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (25 mg, 69 mmol) in glacial acetic acid (2.4 mL) was added 2 N HC1 (0.20 mL) , and the resulting mixture was heated at 70°C for 1 hour. The reaction mixture was allowed to cool to room temperature, and the solvent was removed in vacuo . The residue was triturated with H2O (2 mL) to provide a pale yellow solid which was collected by filtration, washed with H2O and dried to give the title compound as a hydrate, mp >305°C. ^ NMR (DMSO-d6) < 8.35 (s, IH) , 7.90 (d, J^" = 9.1 Hz, IH) , 7.33 (dd, J = 9.1, 2.7 Hz, IH) , 7.19 (d, J = 2.6 Hz, IH) , 7.12 (s, IH) , 5.13 (s, 2H) , 2.89 (q, J = 7.1 Hz, 2H) , 2.01 (s, 3H) , 1.03 (t, J = 7.1 Hz, 3H) . Anal. Calcd for C19H16N2O3Η2O: C, 67.45; H, 5.36; N, 8.28. Found: C, 67.34; H, 5.28; N, 8.06.

Example 15

2-Methoxy-8-methyl-7-(l-oxopropyl) indolizino.1.2- blquinolin-9 (llff)-one

To a suspension of 2-hydroxy-8-methyl-7- (1- oxopropyl) -indolizino[1,2-b]quinolin-9 (llff)-one (160 mg, 0.50 mmol) in dimethylformamide (2 mL) under an argon atmosphere was added K2CO3 (345 mg, 2.5 mmol) . After stirring 20 minutes at room temperature, methyl iodide was added (31 mL, 0.5 mmol), and the resulting mixture was stirred at room temperature overnight. Analysis by thin 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 CH2CI2. The aqueous phase was extracted with CH2CI2 (2x) , and the combined organic extracts were dried (Na2S04) . 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 CH2CI2. A yellow crystalline material was obtained which was recrystallized from MeOH/CH2Cl2- ¹H NMR (CDCI3) d 8.22 (s, IH) , 8.07 (d, J = 9.4 Hz, IH) , 7.46 (dd, J = 9.3, 2.8 Hz, IH) , 7.17 (s, IH) , 7.14 (d, J = 2.8 Hz, IH) , 5.25 (d, J = 0.9 Hz, 2H) , 3.98 (s, 3H) , 2.90 (q, J = 7.3 Hz, 2H) , 2.28 (s, 3H) , 1.24 (t, J = 7.3 Hz, 3H) . Anal. Calcd for C20HI8N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C,

71.72; H, 5.63; N, 8.21. Example 16

2- (4-Ethoxγ-l.4-dioxo-l-butanγl)oxv-8-methvl-7- (1- oxopropyl) indolizino .1.2-blquinolin-9 (llff)-one To a mixture of 2-hydroxy-8-methyl-7-(1-oxopropyl) indolizino [1,2-b]quinolin-9 (llff)-one (160 mg, 0.5 mmol) in anhydrous DMF (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, ethyl succinyl chloride (78 mL, 0.55 mmol) was added. The resulting mixture was allowed to stir overnight at room temperature and then was partitioned between H2O and CH2CI2. The aqueous phase was extracted with CH2CI2, and the combined organic extracts were dried (Na2S04) . The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 2% MeOH in CH2CI2■ The material which was isolated was filtered through a small column of deactivated alumina, eluting with CH2CI2 to afford the title compound as a pale pink solid. ^H NMR (CDCI3) d 8.30 (s, IH) , 8.19 (d, J = 9.2 Hz, IH) , 7.69 (d, J = 2.5 Hz, IH) , 7.56 (dd, J^" = 9.2, 2.5Hz, IH) , 7.25 (d, J = 8.2 Hz, IH) , 5.29 (d, J = 2.5 Hz, 2H) , 4.21 (q, J = 7.2 Hz, 2H) , 2.95 (m, 4H) , 2.80 (m, 2H) , 1.30 (t, J = 7.1 Hz, 3H) , 1.24 (t, J = 7.2 Hz, 3H) . Anal. Calcd for C25H24 2O6: C, 66.95; H, 5.39; N, 6.25. Found: C, 67.07; H, 5.65; N, 6.08.

Example 17 8-Methyl-7- (1-oxopropyl) indolizinoTl.2-blquinolin-9 (llff)- on-2-vl ri.4'-bipiperidine1-l'-carboxvlate. Hydrochloride To a stirring suspension of 3.0 g (9.4 mmol) (S)-4- ethyl-4, 9-dihydroxy-lff-pyrano[3,4 ' : 6,7]indolizino[1,2- b]quinoline-3, 14 (4ff, 12ff)-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 chloride, hydrochloride. After stirring overnight an additional portion of 1.00 g (3.74 mmol) of the carbonyl chloride was added. After stirring for a second night a final portion of 0.75 g (2.8 mmol) of the carbonyl chloride was added and the reaction was stirred another night. The reaction mixture was evaporated to dryness under high vacuum, and the residue was taken up in a mixture of 200 mL of CH2CI2 and 200 mL of H2O adding solid sodium bicarbonate to raise the pH to 7. After the layers were separated, the aqueous phase was extracted twice with 250 mL of CH2CI2 ■ After drying over anhydrous sodium sulfate, the dark organic phase was passed down a column of 200 g of basic alumina which had been deactivated with 40 mL of water. Elution with CH2CI2 and evaporation of the eluate gave 4.0 g of golden solid.

This material was chromatographed on a flash silica gel column eluting first with CH2CI2 and then a gradient of 2-

10% MeOH in CH2CI2. 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 178-183°C.

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 μmol) in 2 mL water was added 15 μL 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.3H2O: C, 59.55; H, 6.83; N, 9.26. Found:

C, 59.40; H, 6.34; N, 9.26.

Example 18 l-Bromo-2-hγdroxv-8-methγl-7-(l- oxopropγ-1) indolizinori.2-blσuinolin-9 (llff)-one

IRA. l-Bromo-7-(2-ethyl-1.3-dioxolan-2-yl)-2-hvdroxγ-8- ethvlindoli inori.2-blσuinolin-9 (llff)-one

To a stirring suspension of 7- (2-ethyl-l,3-dioxolan- 2-yl)-2-hydroxy-8-methylindolizino[1,2-b]quinolin-9 (llff)- one (0.50 g, 1.37 mmol) and sodium acetate (1.23 g, 15.0 mmol) in glacial acetic acid (10 mL) under an argon atmosphere was added Br2 (76 mL) . After stirring for 4 h at room temperature, additional Br2 (10 mL) was added, and the reaction mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between CH2CI2 and H2O and filtered. The layers were separated, and the aqueous phase was extracted with CH2CI2. The combined organic extracts were dried (Na2Sθ4) and evaporated in vacuo . The residue was purified by flash chromatography on silica gel eluting with 2% MeOH in CH2CI2 to afford an off-white solid which was recrystallized from MeOH in CH2CI2. -^-H NMR (CDCl3/MeOH-d4) d 8.70 (d, J = 0.8 Hz, IH) , 8.04 (dd, J = 9.2, 0.7 Hz, IH) , 7.61 (s, IH) , 7.53 (d, J = 9.2 Hz, IH) , 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 Hz, 2H) , 0.99 (t, J = 7.4

Hz, 3H) . Anal. Calcd for C2lHχ9BrN2θ4-3/4 H2O: C, 55.22; H, 4.52; N, 6.13. Found: C, 55.05; H, 4.67; N, 6.16.

18B. l-Bromo-2-hγdroxy-8-methγl-7- (1- oxopropyl) indolizino .1.2-blquinolin-9 (llff)-one

A mixture of l-bromo-7- (2-ethyl-l,3-dioxolan-2-yl) -2- hydroxy-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (12 mg, 27 mmol) in glacial acetic acid (1 mL) under an argon atmosphere was treated with 2 N HC1 (100 mL) . The reaction mixture was heated at 80°C for 3.5 h and then was 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. !__ NMR (CDCI3) d 8.84 (s, IH) , 8.11 (d J = 9.2 Hz, IH,), 7.59 (d, J = 9.2 Hz, IH) , 7.48 (s, IH), 5.35 (s, 2H), 2.97 (q, J = 7.2 Hz, 2H) , 2.29 (s, 3H) , 1.26 (t, <J = 7.2 Hz, 3H) . Anal. Calcd for Ci9Hχ5Br 2θ3-5/8 H2O: C, 55.57; H, 3.99; N, 6.80. Found: C, 55.54; H, 4.34; N, 6.83.

Example 19 1- (Dimethvlamino)methvl-2-hvdroxγ-8-methγl-7- (1- oxopropyl) indolizino ri,2-blσuinolin-9 (llff) -one.

Hydrochloride

19A. l-(Dimethylamino)methvl-7-(2-ethvl-1.3-dioxolan-2- yl, -2-hvdroxγ-8-methγlindolizinori.2-blσuinolin-9(llff)-one A mixture of 7- (2-ethyl-l,3-dioxolan-2-yl)-2-hydroxy- 8-methylindolizino[1,2-b]quinolin-9 (llff)-one (36.4 mg, 0.100 mmol) and tetramethyldiaminomethane (51 mg, 0.50 mmol) in 2 mL glacial acetic acid plus 2 mL CH2CI2 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 >300°C. ^H NMR (CDCI3) d 8.31

(s, IH), 8.05 (d, J = 9.2 Hz, IH) , 7.50^"<s, IH) , 7.38 (d, J = 9.2 Hz, IH) , 5.23 (s, 2H) , 4.13 (s, 2H) , 4.06 (m, 2H) , 3.85 (m, 2H) , 2.46 (s, 6H) , 2.44 (s, 3H) , 2.01 (q, J = 7.4 Hz, 2H) , 0.97 (t, J = 7.4 Hz, 3H) . Anal. Calcd for C24H27N3O4: C, 68.39; H, 6.46; N, 9.97. Found: C, 68.72; H, 6.71; N, 9.67. 19B. 1-(Dimethγlamino)methvl-2-hvdroxv-8-methvl-7- (1- oxopropvl) indolizino , 1.2-blσuinolin-9 (llff)-one. Hydrochloride

A solution of 24.1 mg (0.057 mmol) 1- (dimethylamino)methyl-7- (2-ethyl-l,3-dioxolan-2-yl)-2- hydroxy-8-methylindolizino[l,2-b]quinolin-9 (llff)-one in 2 mL glacial acetic acid plus 0.25 mL of 2N hydrochloric acid was heated at 70°C for 50 minutes and then stripped to dryness in vacuo. Water was added, and the solution was restripped. A little water was added to cause partial dissolution, and then a lot of acetone was added to give -the title compound as a fine yellow solid. --H NMR showed the presence of 1/4 mole ethylene glycol which was confirmed by elemental analysis which also indicated 1 mole of water of hydration. !H NMR (TFA-dχ) d 9.65 - (br s, IH) , 8.70 (br d, 2H) , 8.16 ( , 2H) , 5.92 (br s, 2H) , 5.08 (br s, 2H) , 4.09 (s, IH) , 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 C22H24CI 3O3 •1/4 C2H6O2Η2O: C, 60.40; H, 6.19; N, 9.39. Found: C, 60.15; H, 6.19; N, 9.11.

Example 20 2-Cyano-8-methyl-7- (1-oxopropyl) indolizino- .1,2- blσuinolin-9 (llff)-one

20A. 7-(2-Ethyl-1.3-dioxolan-2-γl)-8-methyl-2- trifluoromethvl-sulfonvloxvindolizinofl.2-blquinolin-

9 (llff)-one

To a solution of 7- (2-ethyl-l,3-dioxolan-2-yl)-2- hydroxy-8-methylindolizino[1,2-b]quinolin-9 (llff) -one (109 mg, 0.30 mmol) in dimethylformamide (20 mL) were added N- phenyltrifluoro-methanesulfonimide (161 mg, 0.45 mmol) and triethylamine (0.13 mL, 0.9 mmol) . The resulting mixture was heated at 55°C for 1.5 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a solvent gradient of 0-2% MeOH in CH2CI2 to provide the title compound as a yellow solid, mp 250-l°C. iH NMR (CDCI3) d 8.38 (s, IH) , 8.30 (d, J = 9.4 Hz, IH) , 7.84 (d, J = 2.7 Hz, IH) , 7.68 (dd, cT = 9.3, 2.7 Hz, IH), 7.60 (s, IH) , 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 C22H19F3N206S-1/2 H2O: C, 52.28; H, 3.99; N, 5.54. Found: C, 52.51; H, 3.86; N, 5.50.

20B. 2-Cvano-7- (2-ethyl-l.3-dioxolan-2-vl)-8-methγ- lindolizinofl.2-blqninolin-9 (llff)-one A mixture containing tetrakis (triphenylphosphine)palladium (322 mg, 0.28 mmol) and tri-__-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-l,3-dioxolan-2-yl)-8-methyl-2- trifluoromethylsulfonyl-oxyindolizino[1,2-b]quinolin- 9 (llff)-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 >320°C. ¹H NMR (CDCI3) d 8.47 (s, IH) , 8.36

(d, J = 1.7 Hz, IH) , 8.30 (d, J = 8.8 Hz, IH) , 7.95 (dd, J = 8.8, 1.8 Hz, IH) , 7.70 (s, IH) , 5.31 (d, J = 0.8 Hz, 2H) , 4.10 (m, 2H) , 3.86 (m, 2H) , 2.47 (s, 3H) , 2.02 (q, J = 7.4 Hz, 2H) , 0.99 (t, J^" = 7.4 Hz) . Anal. Calcd for C22H19N3O3-0.03 C2H4CI2 : C, 70.39; H, 5.12; N, 11.16. Found: C, 70.09; H, 5.09; N, 11.01. 20C. 2-Cvano-8-methvl-7-(l-oxopropvl) indolizinoT1.2- blquinolin-9 (llff)-one

To a suspension of 2-cyano-7- (2-ethyl-l,3-dioxolan-2- yl)-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (18.9 mg, 0.05 mmol) in acetic acid (20 mL) was added 2 N HC1 (0.25 mL, 0.5 mmol) . The resulting mixture was heated at 70°C for 2.3 hours and then allowed to cool. Sodium acetate (41 mg, 0.5 mmol) and H2O were added, and the mixture was concentrated under reduced pressure. Methylene chloride containing a few drops of MeOH was added to the residue, and the solid which formed was removed by filtration. The filtrate was concentrated under reduced pressure. Methanol 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, mp 307-9°C. ¹H NMR (CDCI3) d 8.43 (s, IH) , 8.32 (d, J = 1.7 Hz, IH) ,

8.28 (d, J^" = 8.8 Hz, IH) , 7.95 (dd, J^" = 8.8, 1.9 Hz, IH) ,

7.29 (s, IH) , 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. Calcd for C20H15 3O2•1/4 H2O: C, 71.95; H, 4.68; N, 12.59. Found: C, 72.07; H, 4.69; N, 12.50.

Example 21 2-Aminomethγl-8-methyl-7- (1-oxopropyl) indolizino- ri.2-blσuinolin-9 (llff)-one Hydrochloride

To a mixture of 2-cyano-7- (2-ethyl-l,3-dioxolan-2- yl)-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (48, 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 for 25 hours. Analysis 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 reaction mixture was 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 μM ODS-3 support) , eluting with a solvent gradient of 0-15% MeOH in H2O to provide 2-aminomethyl-7- (2-ethyl-l,3-dioxolan-2-yl) -8-methylindolizino[1,2- b]quinolin-9 (llff) -one, hydroacetate as a pale yellow solid. To this material was added acetic acid (2 mL) and 2 N HCl (0.30 mL, 0.6 mmol), and the resulting mixture was heated at 70°C under an argon atmosphere. After heating for 3 hours, the reaction mixture was concentrated 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-dι/CDCl3) d 9.39 (m, IH) , 8.62 (m, 2H), 8.46 (m, IH) , 8.20 (m, IH) , 5.85 (s, 2H) , 4.82 (s, 2H) , 3.13 (m, 2H) , 2.50 (s, 3H) , 1.38 (m, 3H) . Anal. Calcd for C20H20 IN3O2 •1/4 C2H6θ2'l/2 H2O: C,

62.43; H, 5.75; N, 10.66. Found: C, 62.16; H, 5.53; N, 10.32.

Example 22 2-Acetγl-8-methyl-7- (1-oxopropyl) indolizinoQ.2- blquinolin-9 (llff)-one To a suspension of 7- (2-ethyl-l,3-dioxolan-2-yl)-8- methyl-2-trifluoromethylsulfonyloxyindolizino[1,2- b]quinolin-9 (llff) -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 at 80°C for 2.5 h and then allowed to cool and stand at room temperature overnight. Addition of EtOAc and Et2θ caused pale yellow needles to form which were collected by filtration, washed with Et2θ and dried; mp 215-20°C (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 CH2CI2 and H2O. The organic extract was washed with H2O (2x) and dried ( a2S04) . The solvent was removed in vacuo . HPLC analysis of the residue indicated that the reaction was incomplete. The residue was treated with 10:1 acetic acid/3 N HCl (0.3 mL) , and the mixture was heated at 70°C for 1 h and then allowed to cool. The mixture was partitioned between CH2CI2 and H2O. The organic extract was washed with H2O (2x) and dried (Na2S0 ) . The solvent 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 255-7°C. ¹H NMR (CDCI3) d 8.45 (br d, 2H) , 8.26 (m, 2H) , 7.25 (s, IH) ,

5.30 (s, 2H) , 2.90 (q, 2H) , 2.76 (s, 2H) , 2.27 (s, 2H) , 1.24 (t, 3H) . Anal. Calcd for C21H18 2O3: C, 72.82; H, 5.24; N, 8.09. Found: C, 72.86; H, 5.53; N, 7.52.

Example 23 12-Hvdroxvmethyl-8-methyl-7-(1-oxopropyl) indolizino- r1.2-blquinolin-9 (llff)-one

To a solution of 8-methyl-7-(1- oxopropyl) indolizino [1,2-b] quinolin-9 (llff)-one (91 mg, 0.3 mmol) in MeOH (1 mL) and 50% H2SO4 (2 mL) under an argon atmosphere at 0°C 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% H2O2 (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% H2O2 (0.35 mL, 3.0 mmol) was added over a 45 minutes period. After stirring an additional 19 hours at room temperature, the reaction mixture was poured into ice H2O (50 mL) . Sodium bicarbonate (3.51 g, 42 mmol) was slowly added, and the mixture was filtered. The filtrate was extracted with CH2CI2- 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 CH2CI2 to provide the title compound , mp 247°C (dec) . ¹H NMR (CDCl3/MeOH-d4) d 8.17 (dd, J - 8.4, 0.8 Hz, IH) , 8.04 (br d, J = 8.2 Hz, IH) , 7.80 (m, IH) , 7.65 (m, IH) , 7.35 (s, IH) , 5.50 (s, 2H) , 5.40 (s, 2H) , 2.94 (q, J = 7.3 Hz, 2H) , 2.28 (s, 3H) , 1.26 (t, J = 7.3 Hz, 3H) . Anal. Calcd for C20H18N2O3 -1/3H20: C, 70.57; H, 5.53; N, 8.23. Found: C, 70.27; H, 5.44; N, 8.22.

Example 24

8-Methyl-7- (1-oxopropyl) -12-phenoxyindolizinor1.2- blquinoli).-- (llff)-one

24A. 7- (2-Ethyl-l.3-dioxolan-2-γl)-8-methylindolizino.1.2- Jb. quinolin-9 (llff)-one. 5-oxide

7- (2-Ethyl-l, 3-dioxolan-2-yl) -8-methylindolizino [1,2- b] quinolin-9 (llff)-one (5.00 g, 14.4 mmol) was dissolved in glacial acetic acid (75 mL) by heating at 65°C. To the resulting solution was added 30% aqueous H2O2 (50 mL) , and the mixture was heated at 65°C 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-l°C (dec.) ^-H NMR (CDCI3) d 8.79 (d, J = 8.8 Hz, IH) , 8.32 (s, IH) , 7.97 (d, J = 8.1 Hz, IH), 7.93 (s, IH) , 7.86 (ddd, J = 8.4, 7.1, 1.3 Hz, IH) , 7.74 (ddd, J = 8.1, 7.0, 1.1 Hz, IH) , 5.29 (d, J^" = 1.0 Hz, 2H) , 4.08 (m, 2H) , 3.85 (m, 2H) , 2.46 (s, 3H) , 2.02 (q, .7= 7.4 Hz, 2H) , 0.98 (t, J = 1.4 Hz, 3H) . Anal. Calcd for C21H20N2O4 •1/4 H2O: C, 68.37; H, 5.60; N, 7.59. Found: C, 68.68; H, 5.61; N, 7.50.

24B. 12-Chloro-7- (2-ethyl-l. -dioxolan-2-vl)-8- methylindolizino .1.2-blquinolin-9 (llff)-one

To a suspension of 7- (2-ethyl-l,3-dioxolan-2-yl)-8- methylindolizino [1,2-b]quinolin-9 (llff)-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 pyridine (2.1 mL) . The resulting mixture was heated at 115°C for 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 261-3°C. Additional material was obtained by evaporation of the filtrate, addition of MeOH to the residue, and filtration. ^-H NMR (CDCI3) d 8.30 (dd, IH, .7 = 1.1, 8.5 Hz), 8.22 (dd, IH, J = 0.6, 8.4 Hz), 7.86 (ddd, IH, .7 = 8.5, 7.0, 1.5 Hz), 7.72 (ddd, IH, J = 1.2, 7.0, 8.2 Hz), 7.56 (s, IH) , 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 (NH3, m/e, rel. int.) 385 (34), 383 (100) [ (M+H) ⁺] . Anal. Calcd for C21H19CIN2O3 : C, 65.88; H, 5.00; N, 7.32. Found: C, 65.67; H, 4.97; N, 7.37.

24C. 7-(2-Ethyl-1.3-dioxolan-2-yl)-8-methyl-l_- phenoxyindolizino .1,2-blquinolin-9 (llff)-one

A mixture containing 12-chloro-7- (2-ethyl-l,3- dioxolan-2-yl)-8-methylindolizino[1,2-b]quinolin-9 (llff)- one (19.2 mg, 0.05 mmol), phenol (94 mg, 1.0 mmol) potassium carbonate (6.9 mg, 0.05 mmol) was heated at 175°C for 1.5 h and then allowed to cool. The mixture was dissolved in CH2CI2 and purified by radial chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH in CH2CI2 to afford the title compound as a crystalline solid, mp 290-l°C. ^XE NMR (CDCI3) d 8.35 (dd J = 8.4, 0.9 Hz, IH, ), 8.22 (dd, J = 8.2, 0.7 Hz, IH) , 7.83 (ddd, J = 8.5, 7.0, 1.5 Hz, IH) , 7.63 (ddd, J = 8.2, 7.0, 1.2 Hz, IH) , 7.54 (s, IH), 7.43 (m, 2H) , 7.28 (m, IH) , 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, = 7.4 Hz, 3H) . Anal. Calcd for C27H2 N2O •1/4 H2O: C, 72.88; H, 5.55; N, 6.30. Found: C, 72.90; H, 5.66; N, 6.14.

24D. 8-Methyl-7-(l-oxopropγl)-12-phenoxvindolizino,1.2-b1 σuinolin-9 (llff)-one To a solution of 7- (2-ethyl-l,3-dioxolan-2-yl)-8- methyl-12-phenoxyindolizino [1,2-b]quinolin-9 (llff)-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 75°C 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 filtration of the mixture afforded the title compound as a pale yellow solid, mp 212-3°C. ^λH NMR (CDCI3) d 8.38

(dd, J = 8.3, 1.2 Hz, IH) , 8.19 (d, J = 8.4 Hz, IH) , 7.85 (ddd J = 8.3, 6.9, 1.4 Hz, IH, ) , 7.65 (ddd, J = 8.1, 7.0, 1.1 Hz, IH) , 7.45 (m, 2H) , 7.30 (m, IH) , 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 C25H20N2O3 -3/4 H2O: C, 73.25; H, 5.29; N, 6.83. Found: C, 73.09; H, 5.35; N, 6.48. Example 25 12- r (3.4-Dimethoxyphenyl)methvllamino-8-methvl-7- (1-oxopropvl) indolizino.1.2-blσuinolin-9 (llff)-one

25A. 12- r (3.4-Dimethoxvphenyl)methvllamino-7-(2-ethyl-l.3- dioxolan-2-yl)-8-methylindolizino Fl.2-blσuinolin-9 (llff)- one (SB 201043)

A mixture containing 12-chloro-7- (2-ethyl-l,3-dioxolan-2- yl)-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (38 mg, 0.1 mmol), phenol (66 mg, 0.7 mmol), 3,4- dimethoxybenzylamine (105 mL, 0.7 mmol) and a crystal of potassium iodide was heated at 175°C for 1.5 h and then was allowed to cool to room temperature and stand overnight. The reaction mixture was dissolved in CH2CI2 containing a small amount of MeOH and purified by radial chromatography on silica gel eluting with a solvent gradient of 0-5% MeOH in CH2CI2. The material which was isolated was further purified by recrystallization from MeOH in CH2CI2 to afford the title compound , mp 232-7°C. ÷-H NMR (CDCI3) d 8.09 (dd, J = 8.4, 0.9 Hz, IH) , 7.87 (d, J = 8.2 Hz, IH) , 7.69 (ddd, J^" = 8.0, 7.1, 0.9 Hz, IH) , 7.47 (m, 2H) , 6.86 (m, 3H) , 5.68 (apparent br t J = 5.7 Hz, IH, ), 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 C30H31N3O5-3/2 H2O: C, 66.65; H, 6.34; N, 7.77. Found: C, 66.58; H, 6.40; N, 7.46.

25B. 12- r (3.4-Dimethoxyphenyl)methyllamino-8-methyl-7-(l- oxopropyl) indolizinoTl,2-blquinolin-9 (llff)-one

To a solution of 12-[(3, 4- dimethoxyphenyl)methyl]amino-7- (2-ethyl-l,3-dioxolan-2- yl)-8-methylindolizino[1,2-b]quinolin-9(llff)-one (24 mg, 45 mmol) in glacial acetic acid (2 mL) was added 2 N HCl (0.3 mL) . The resulting mixture was stirred at room temperature for 2 h and then was heated at 70°C 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 CH2CI2. The material that was isolated was sonicated with a mixture of MeOH and H2O. The solid which formed was collected by filtration and dried under reduced pressure to afford the title compound, mp 240-2°C. ^XH NMR (CDCI3) d 8.08 (d, J = 8.5 Hz, IH) , 7.82 (d, J = 8.1 Hz, IH) , 7.71 (ddd, J = 8.2, 7.2, 1.0 Hz, IH) , 7.50 (ddd J = 8.3, 7.0, 1.3 Hz, IH, ) , 7.19 (br s, IH) , 6.90 (m, 3H) , 5.57 (br, IH) , 5.42 (s, 2H) , 4.87 (d, J = 5.5 Hz, 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 C28H27N3O -3/4 CH3OH: C, 69.96;

H, 6.13; N, 8.51. Found: C, 70.22; H, 6.43; N, 8.08.

Example 2 12-Cvano-8-methvl-7-(1-oxopropγl) indolizino.1.2- blquinolin-9 (llff)-one

26A. 7-(2-Ethyl-1.3-dioxolan-2-vl)-12-iodo-8- methylindolizino .1,2-blquinolin-9 (llff)-one A mixture containing 12-chloro-7- (2-ethyl-l,3- dioxolan-2-yl)-8-methylindolizino [1,2-b]quinolin-9 (llff)- one (38.3 mg, 0.1 mmol), potassium iodide (166 mg, 1.0 mmol), acetic anhydride (0.3 mL) and glacial acetic acid (3 mL) was heated at 120°C for 45 min. After cooling, the mixture was concentrated under reduced pressure. The residue was covered with H2O, sonicated and filtered. The solid was washed thoroughly with H2O. The solid residue was treated with MeOH/CH2Cl2. and filtered. This material was further purified by repeated trituration with MeOH/CH2Cl2 to afford the title compound, mp>320°C. !R NMR (CDCI3) d 8.17 (d, J^" = 8.4 Hz, IH) , 8.12 (d, J = 8.5 Hz, IH) , 7.86 (m, IH) , 7.72 (m, IH) , 7.61 (s, IH) , 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 = .4 Hz, 3H) . Anal. Calcd for C21H19IN2O3: C, 53.18; H, 4.04; N, 5.91. Found: C, 52.94; H, 4.19; N, 5.86.

26B. 12-Cyano-7-(2-ethvl-1.3-dioxolan-2-yl)-8- methvlindolizino .1.2-blσuinolin-9 (llff)-one 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 added to a solution of 7- (2-ethyl-l,3-dioxolan-2-yl)-12- iodo-8-methylindolizino[1,2-b]quinolin-9 (llff)-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 257-8°C. ÷-H NMR (CDCI3) d 8.28 (2 overlapping dd, 2H) ,

7.93 (ddd, J^" = 8.6, 7.0, 1.6 Hz, IH) , 7.82 (ddd, J = 8.3, 7.0, 1.3 Hz, IH) , 7.59 (s, IH) , 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 C22H19N3O3: C, 70.76; H, 5.13; N, 11.25. Found: C, 71.13; H, 5.37; N, 10.79. 26C. 12-Cγano-8-methγl-7- (1-oxopropvl) indolizinori.2- blquinolin-9 (llff) -one

To a solution of 12-cyano-7- (2-ethyl-l, 3-dioxolan-2- yl)-8-methylindolizino [1,2-b]quinolin-9 (llff)-one (20 mg, 54 mmol) in glacial acetic acid (2 mL) was added 2 N HCl (0.3 mL) . The resulting mixture was heated at 75°C for 30 min and then after cooling was concentrated under reduced pressure. Methanol was added to the solid residue which was then collected and dried to afford the title compound, mp 270-5°C. ¹H NMR (CDCI3) d 8.29 (2 overlapping d, 2H) , 7.96 (ddd, J = 8.5, 7.0, 1.5 Hz, IH) , 7.86 (ddd, J = 8.3, 7.0, 1.3 Hz, IH) , 7.26 (s, IH) , 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 C20^H15^N3θ2 * H2O: C, 71.95; H, 4.68; N, 12.59. Found: C, 72.27; H, 4.74; N, 12.22.

Example 2

(±)-12-Cγano-7- (l-hvdroxvpropvl)-8-methylindolizinor1. -bl quinolin-9 (llff)-one

12-Cyano-8-methyl-7- (1-oxopropyl) indolizino[1,2- b]quinolin-9 (llff) -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 NH4CI and allowed to stand at 0°C overnight. The solid which formed was collected by filtration, washed sparingly with H2O and dried to afford the title compound. 1H NMR (CDCI3) d 8.11 (d, J = 8.3 Hz, IH) , 7.82 (m, 2H) ,

7.56 (m, 2H) , 5.43 (d J = 20.1 Hz, IH, ) , 5.26 (d, J = 20.1 Hz, IH) , 4.91 (dd, J = 7.6, 5.4 Hz, IH, 2.21 (s, 3H) , 1.90-1.50 (m obscured by HOD peak, 4H) , 1.03 (t, J^" = 7.4 Hz, 3H) . Anal. Calcd for C2θHl7 3θ2'l 1/8 H2O: C, 68.31; H, 5.52; N, 11.95. Found: C, 68.62; H, 5.12; N, 11.21. Example 28

2-Aminomethyl-8-methyl-7- (l-oxopropvl) indolizinori.2- blquinolin-9 (llff)-one

28A. 12-Aminoτn_thvl-7-(2-ethvl-l.3-dioxolan-2-vl)-8- methvlindolizino fl.2-blσuinolin-9 (llff)-one

To a solution of 12-cyano-7- (2-ethyl-l,3-dioxolan-2- yl)-8-methylindolizino[l,2-b]quinolin-9 (llff)-one (47 mg, 0.13 mmol) in glacial acetic acid (10 mL) was added Raney nickel (109 mg) which had been freshly washed with acetic acid and dried. The resulting mixture was shaken on a Parr hydrogenator at 80 psi H2 for 49 h, after which the catalyst 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 235-45°C (dec) . ^ NMR (CDCI3, MeOH-d4) d 8.23 (m, 2H) , 7.82 (m, IH) , 7.71 (m, 2H) , 7.37 (s, IH) , 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 = 7.4 Hz, 3H) . Anal. Calcd for C22H23N3O3•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.

28B. 12-Aminomethyl-8-methyl-7- (1- oxopropyl) indolizino \1.2-bl σuinolin-9 (llff)-one A solution containing 12-aminomethyl-7- (2-ethyl-l,3- dioxolan-2-yl)-8-methylindolizino [1,2-b]quinolin-9 (llff)- one (18 mg, 44 mmol) and 2 N HCl (0.3 mL) in glacial acetic acid (2.75 mL) was heated at 75°C for 2 h and after cooling, was concentrated under reduced pressure. Methanol was added to the solid residue which was then sonicated, filtered and dried to afford the title compound as the hydrochloride salt, mp 285-95°C (dec) . ^-H NMR (TFA-di) d 8.70 (m, 2H) , 8.40 (m, IH) , 8.25 (m, 2H) , 6.05

(br s, 2H) , 5.36 (br s, 2H) , 3.20 (q, J = 7.1 Hz, 2H) , 2.46 (s, 3H) , 1.39 (t, J^" = 6.8 Hz, 3H) . Anal. Calcd for C20Hl9^N3θ2'HCl-l/4 H20-1/6 C2H6O2: C, 63.48; H, 5.63; N, 10.92. Found: C, 63.59; H, 5.73; N, 10.92.

Example 29 12-r3-(Dimethylamino)propyl1-8-methyl-7-(l- oxopropyl) indolizino .1.2-blσuinolin-9 (llff) -one

29A. 12- .3- .Dimethvlamino. -1-propvn-l-vl1-7- (2-ethyl-l.3- dioxolan-2-yl) -8-methvlindolizino fl.2-blquinolin-9 (llff) - one

To a solution of 7- (2-ethyl-l,3-dioxolan-2-yl)-12- iodo-8-methylindolizino [1,2-b]quinolin-9 (llff)-one (89 mg, 0.19 mmol) in DMF (1 mL) were added l-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 90-5°C for 3 h and then allowed to cool. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with a solvent gradient of 0-5% MeOH in CH2CI2. The title compound was obtained as a yellow crystalline solid, mp 161.5-2.5°C. !H NMR (CDCI3) d 8.34 (dd, J = 8.4, 1.2 Hz,

IH) , 8.21 (dd, J = 8.2, 0.6 Hz, IH) , 7.81 (ddd, J = 8.4, 6.9, 1.5 Hz, IH) , 7.67 (ddd, J = 8.0, 6.9, 1.1 Hz, IH) , 7.57 (s, IH) , 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 Hz, 3H) . Anal. Calcd for C26H27N303-1/4 H2O: C, 71.98; H, 6.39; N, 9.68. Found:

C, 72.12; H, 6.27; N, 9.50. 29 . 12-,3- (Dimethylamino) ropvll-7-(2-ethvl-l.3-dioxolan- 2-vl)-8-methylindolizinofl.2-blσuinolin-9 (llff)-one

A solution of 12-[3-(dimethylamino)-1-propyn-l-yl]-7- (2-ethyl-l,3-dioxolan-2-yl)-8-methylindolizino[l,2- b]quinolin-9 (llff)-one (43.2 mg, 0.10 mmol) in absolute EtOH containing Ptθ2 (3.6 mg) was stirred under an H2 atmosphere overnight. The mixture was then concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel eluting with a solvent gradient of 3-10% MeOH in CH2CI2. The material obtained was further purified by treatment with EtOAc containing some trifluoroacetic acid to give the title compound as the hydrotrifluoroacetate salt. ¹H NMR (CDCI3, MeOH-d4) d

8.22 (d, J^" = 8.4 Hz, IH) , 8.16 (d, J = 8.3 Hz, IH) , 7.81 (ddd, J = 8.2, 6.9, 1.3 Hz, IH) , 7.68 (m, IH) , 7.66 (s, IH) , 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-C2HF3θ2 -5/2 H2O: C, 56.75; H, 6.29; N, 7.09. Found: C, 56.66; H, 6.20; N, 7.05.

29C. 7-(2-Ethyl-1.3-dioxolan-2-yl)-8-methyl-12- propvlindolizinoFl.2-blσuinolin-9 (11H)-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(HH)-one ^XR NMR (CDCI3) d 8.22 (br d, J = 8.7 Hz, IH) , 8.10 (br d, J^" = 8.5 Hz, IH) , 7.77 (m, IH) , 7.62 (m, IH) , 7.57 (s, IH) , 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 Hz, 3H) , 0.98 (t, J = 7.4 Hz, 3H) .

SUBSTITUTESHEET 29D. 12-r3- (Dimethylamino) ropvl1-8-methvl-7- (1-oxopropγl) indolizino r1.2-blσuinolin-9 (llff)-one

A solution of 12-[3- (dimethylamino)propyl _*]-7- (2- ethyl-1,3-dioxolan-2-yl)-8-methylindolizino[1,2- b]quinolin-9(llff) -one (19.5 mg, 45 mmol) and ^*_ N HCl (0.3 mL) in glacial acetic acid (1.5 mL) was heated at 70-5°C for 2 h. The mixture was then allowed to cool and concentrated under reduced pressure, dissolved in water and lyophilized to give the title compound as the dihydrochloride salt. Anal. Calcd for C24H27N3θ2'2 HCl• 9/4 H2θ: C, 57.31; H, 6.71; N, 8.35; Cl, 14.10. Found: C, 57.63; H, 6.28; N, 7.82; Cl, 14.00.

Example 30 8-Methyl-7-(l-oxoproPvl)-12-propvlindolizinori.2- blσuinolin-9 (llff)-one

A solution of 7- (2-ethyl-l, 3-dioxolan-2-yl)-8-methy1- 12-propylindolizino[1,2-b]quinolin-9 (llff)-one (9.7 mg, 25 mmol) and 2 N HCl (0.3 L) in glacial acetic acid (1.5 mL) was heated at 70-5°C 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- 80°C. ^λE NMR (CDCI3) d 8.20 (dd, J = 8.5, 1.1 Hz, IH) , 8.12 (dd, J = 8.5, 1.2 Hz, IH) , 7.79 (ddd, J = 8.3, 6.9, 1.4 Hz, IH), 7.66 (ddd, J = 8.1, 6.8, 1.3 Hz, IH) , 7.24 (s, IH) , 5.27 (s, 2H) , 3.17 (m, 2H) , 2.91 (q, J = 7.3 Hz, 2H) , 2.30 (s, 3H) , 1.84 (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. Example 31 _-Ethvl-9.11-dihvdro-a-hvdroxv-8-methvl-9- oxoindolizinori.2-bl σuinoline-7-acetic acid A mixture of camptothecin (150 mg, 0.43 mmol), triethylamine (1 mL) , and 10% palladium on carbon (36 mg) in DMF (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 redissolved in a mixture of DMF (10 mL) , H2O (10 mL) and acetic acid (2 mL) and chromatographed on a preparative

Dynamax Cχ8 reversed column using a 57.5/42.5/0.15 mixture of MeOH, H2O and acetic acid as the mobile phase to give the title compound. ¹H NMR (d6~DMSO) d 8.64 (s, IH) , 8.16 (d, IH) , 8.10 (d, IH), 7.84 (dd, IH) , 7.68 (dd, IH) , 7.47 (s, IH) , 5.24 (s, 2H) , 2.13 (s, 3H) , 2.05 ( , 2H) , 0.82 (s, 3H) . CIMS (NH3, m/e, rel. int.) 351 (100) [ (M+H) +] .

Example 32

Indolizinori.2-blσuinolin-9 (llff)-one

32A. 7-Trifluoromethanesulfonvloxvindolizino1^"1.2- blσuinolin-9 (llff)-one

To a solution containing 7-hydroxy-indolizino[1,2- b]quinolin-9 (llff)-one (25 mg, 0.10 mmol) in dimethylformamide (5 mL) were added triethylamine (42 mL, 0.30 mmol) and N-phenyltrifluoro-methanesulfonimide (54 mg, 0.15 mmol) . The resulting mixture was heated at 50°C for 2 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in 1:1 EtOAc/Et2θ, filtered and the solid was washed with Et2θ to afford pale yellow crystals of the title compound, mp 266-268°C (dec) . Anal. Calcd for C16H9F3N2O4S: C, 50.27; H, 2.37; N, 7.33. Found: C,

50.40; H, 2.42; N, 7.22. 32B. Indolizino r1.2-blσuinolin-9 (llff)-one

To a solution of 7- trifluoromethanesulfonyloxyindolizino[1,2-b] quinolin- 9 (llff)-one (38 mg, 0.10 mmol) in dimethylformamide (5 L) 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 resulting solution was heated at 65°C for 2 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 5% MeOH in CHCI3. The dark solid that was isolated was dissolved in CHCI3 (2 mL) and extracted with 6 N HCl (3 x 2 mL) . The combined aqueous extracts were neutralized with concentrated NH4OH. The precipitate which formed was collected by filtration, dried and recrystallized from MeOH/CHCl3 to afford the title compound (7 mg, 30%) . ^-H NMR (CDCl3/MeOH-d4) d 8.36 (s, IH) , 8.10 (d, IH) , 7.86 (br d, IH) , 7.79-7.52 (m, 3H) , 7.33 (dd, IH) , 6.66 (d, IH) , 5.17 (s, 2H) .

Example 33 7-Cvanoindolizino r1.2-blσuinolin-9 (llff)-one A mixture containing tri-n-butyltin cyanide (565 mg, 1.79 mmol) and tetrakis (triphenylphosphine)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 time, was allowed to cool, and 7-trifluoro- methanesulfonyloxyindolizino[1,2-b]quinolin-9 (llff)-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 filtration, washed successively with 1,2-dichloroethane and Et2θ and dried to provide the title compound as a yellow powder. ¹H NMR (CDCl3/MeOH-d4) d 8.49 (br s, IH) , 8.21 (br d, J = 9 Hz, IH) , 8.07-7.59 (m, 3H) , 7.46 (br s, IH) , 7.00 (br s, IH) , 5.30 (s, 2H) . FAB+ MS (m/e, rel. int.) 260 [(M+H)⁺, 17], 155 (64), 119 (100), 85 (80) . IR (KBr) 3500 - 3400, 3080, 2240, 1680 - 1660, 1630 - 1605 cm^-1. Anal. Calcd for C16H9N3O: C,

74.12; H, 3.50; N, 16.21. Found: C, 73.82; H, 3.49; N, 16.13.

Example 34

7-Ethenvlindolizino, 1.2-blσuinolin-9 (llff)-one To a suspension of 7-trifluoromethanesulfonyl- oxyindolizino[l,2-b]quinolin-9 (llff)-one (120 mg, 0.31 mmol) in dimethylformamide (8 mL) under an argon atmosphere were added dichloro[l, 1'- bis (diphenylphosphino) ferrocene]palladium (II) (9.2 mg, 12.6 mmol) lithium chloride (41.2 mmol, 0.97 mmol), tetravinyltin (77.2 mL, 0.43 mmol), 4A sieves (30 mg) and 2, 6-di-t-butyl-4-methylphenol (catalytic amount) . The resulting mixture was heated to 70°C 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 between H2O and 10% MeOH in CHCI3. The aqueous phase was extracted with 10%MeOH in CHCI3 (2x) , and the combined organic extracts were concentrated in vacuo . The residue was purified by flash chromatography on silica gel, eluting with 2% MeOH in CHC13, to afford a tan powder which was triturated with Et2θ (3x) . Recrystallization from hot MeOH (0.5 mL) afforded the title compound as a crystalline solid rather than the expected 7- (1-oxopropyl) compound. -^H NMR (CDCI3) d 8.38 (s, IH) , 8.23 (d, J = 8.4 Hz, IH) , 7.94 (d, J^" = 8.2 Hz, IH) , 7.82 (m, IH) , 7.65 (m, IH) , 7.47 (s, IH) , 6.71 (dd, J = 17.6, 10.7 Hz, IH) , 6.62 (s, IH) , 6.11 (d, J^" = 17.5 Hz, IH) , 5.60 (d, J = 10.8 Hz, IH) , 5.24 (s, 2H) . CIMS (NH3) m/e 261 (M+H)⁺. IR (KBr) 3450-3400, 3050, 1675, 1620, 1600 cm^-1. Anal. Calcd for C17H12N2O: C, 78.45; H, 4.65; N, 10.76. Found: C, 78.26; H, 4.89; N, 10.55.

Example 35

7-Ethvlindolizinor1.2-blσuinolin-9 (llff)-one To a solution of 7-ethenylindolizino[1,2-b]quinolin- 9 (llff)-one (10.2 mg, 0.04 mmol) in MeOH (2.5 mL) was added 5% palladium on activated carbon (1.2 mg) . The resulting mixture was stirred under a hydrogen atmosphere overnight. Analysis by thin layer chromatography indicated that the reaction was incomplete, so additional 5% palladium 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. ¹H NMR (CDCI3) d 8.36 (s, IH) , 8.25 (d, J = 9 Hz, IH) , 8.0-7.5 (m, 3H) , 7.22 (br s, IH) , 6.56 (s, IH) , 5.23 (s, 2H) , 2.67 (q, J = 1 Hz, 2H) , 1.30 (t, .7 = 7 Hz, 3H) . CIMS (CH4) (m/e, rel. int.) 263 [(M+H)+, 42], 262 (M⁺,

100), 247 (30) . IR (KBr) 3480-3420, 2970, 1670, 1600 cm^{" 1} .

Example 36 7-AcetylindolizinoI^"1.2-blquinolin-9 (llff) -one

36A. 7- (1-Butoxyethenyl) indolizino .1,2-blquinolin-9 (llff)- one

To a suspension of 7-trifluoromethanesulfonyloxy- indolizino [1,2-b]quinolin-9 (llff)-one (382 mg, 1.0 mmol) in anhydrous DMF (3 mL) under an argon atmosphere were added successively triethylamine (0.28 L, 2.0 mmol), n-butyl vinyl ether (0.64 mL, 5.0 mmol), 1,3- bis (diphenylphosphino)propane (12.2 mg, 29 mmol) and palladium acetate (5.6 mg, 25 mmol) . The resulting mixture was heated at 80°C for 3.5 h and then allowed to cool and stand at room temperature overnight. The mixture was poured into Et2θ (5 mL) , and the solid collected and dried to afford the title compound as light orange needles. ^-H NMR (CDCI3) d 8.10 (m, 2H) , 7.90-7.38 (m, 3H) , 7.32 (m, IH) , 6.96 (s, IH) , 5.04 (s, 2H) , 4.95 (d, IH) , 4.43 (d, IH), 3.87 (br t, 2H) , 1.91-1.33 (m, 4H) , 1.00 (br t, 3H) .

36B. 7-Acetvlindolizinoπ.2-blσuinolin-9 (llff)-one

To a solution of 7- (1-butoxyethenyl) indolizino[1,2- b]quinolin-9 (llff)-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 CH2CI2 washed with H2O and dried (Na2Sθ4) . The solvent was removed in vacuo, and the residue was recrystallized from 1,2-dichloroethane to afford the title compound as light orange needles, mp 265-85°C (dec) . ¹H NMR (CDCI3) d 8.40 (s, IH) , 8.24 (d J^" = 8.4 Hz, IH, ) , 7.90 (d, J^" = 8.2 Hz, IH) , 7.84 (m, IH) , 7.75 (d, J = 1.4 Hz, IH), 7.70 (ddd, J^" = 8.4 7.0, 1.4, Hz, IH) , 7.22 (d, J - 1.6 Hz, IH) , 5.31 (s, 2H) , 2.66 (s, 3H) . Anal. Calcd for C17H12 2O2: C, 73.90; H, 4.38; N, 10.14. Found: C, 73.49; H, 4.48; N, 9.95.

Example 37 7-Acetyl-8-methylindolizino .1,2-blquinolin-9 (llff) -one To a solution of 7-acetylindolizino[1,2-b]quinolin- 9 (llff)-one (64 mg, 0.23 mmol) in 5:1 CHCl3/MeOH (18 mL) at 0°C was added dropwise a solution of diazomethane in Et2θ (10 mL) . The resulting mixture was stirred at 0°C 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 CHCI3 (minimum volume) and treated with Et2θ. The precipitate which formed was collected and recrystallized from 1,2-dichloroethane (2.5 mL) . The pale pink solid was further purified by preparative HPLC (Zorbax column, 2.1 x 25 cm), eluting with 3% EtOH in CH2CI2 to provide an off-white powder, which was recrystallized from 1, 2-dichloroethane, mp 274-6°C (dec) . !H NMR (CDCI3) d 8.39 (s, IH) , 8.23 (d, J = 8. Hz, IH) , 7.94 (d, J = 8.0 Hz, IH) , 7.83 (m, IH) , 7.66 (m, IH) , 7.35 (s, IH) , 5.31 (d, J = 1.1 Hz, 2H) , 2.63 (s, 3H) , 2.36 (s, 3H) . Anal. Calcd for C18H14N2O2 : C, 74.47; H, 4.86; N, 9.65. Found: C, 74.78; H, 4.99; N, 9.59.

Example 38 7- T3- (Dimethylamino)-1-propyn-l-vll indolizino ri.2- blquinolin-9 (llff)-one To a mixture containing 7- trifluoromethanesulfonyloxy-indolizino[1,2-b]quinolin- 9 (llff)-one (191 mg, 0.5 mmol), triethylamine (0.3 mL, 2.2 mmol) and 90% N,iV-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 85°C for 1 h and then allowed to cool to room temperature. The solid which formed was collected by filtration, washed successively with EtOAc and Et2θ and dried. The title compound was obtained as a yellow crystalline solid. A portion of this material was recrystallized from acetonitrile; mp 201-3°C. R NMR (CDCI3) d 8.40-8.13 (m, 2H) , 8.00-7.50 (m, 3H) , 7.28 (m, IH) , 6.77 (br s, IH) , 5.30 (s, 2H) , 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.

Example 39

7- ,3- (Dimethylamino)propyll indolizinoQ.2-blσuinolin-

9 (llff)-one A mixture of 7- [3-(dimethylamino)-1-propyn-l- yl]indolizino[1,2-b]quinolin-9(llff)-one (29 mg, 0.09 mmol) and 5% palladium on barium sulfate (3 mg) in dry pyridine (2 mL) was stirred at room temperature under a hydrogen atmosphere. After 3 h, the catalyst was filtered off, and the filtrate concentrated under reduced pressure to afford a pale tan powder which was crystallized from acetonitrile and dried, mp 169-71°C. ^-H NMR (CDCI3) d 8.33-8.12 (m, 2H) , 7.96-7.50 (m, 3H) , 7.20 (br s, IH) , 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 C20H21N3OΗ2O: C, 71.19; H, 6.87; N, 12.45. Found: C, 71.50; H, 6.60; N, 12.18.

Claims

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

wherein:

R⁷ is -H, -NO2, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH₂Ar, -C≡CO^NRR¹, -CH=CHCH2NRR¹; -(CH2)_nCH2V where n = 0-3 and V is -OH, -OCi-βalkyl, -OCOR¹², -OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R⁹ is -H, -OR, -NO₂, -NRR¹, -CN, halo; -(CH₂)_nCH₂V where n = 0-3 and V is -OH, -OCι_₆alkyl, -OCOR¹², -OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R¹⁰ is -H, -OR, -NO₂, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -OC(0)R¹², -OC(0)OR¹², -OC(0)CH2CH₂COOR¹³, -0-(CH2)ι-5CH₂NRR¹, -OC(0)NRR¹, 1, 4 '-bipiperidine-1 '- carboxy; -(CH2)_nCH₂V where n = 0-3 and V is -OH, -OCi-βalkyl, -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, -Cχ_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,

-CSCCH2NRR¹, -CH2CH2CH2NRR¹, lower alkyl, R⁶ ,

or -C (CH₂CH₃) (OH) COOH;

Y is -H, -CH3, -CH₂OR² ; R² is -H, -C (0) H, -C (0) Cι-5alkyl, -C (0) Cι_ alkylCOOH or -C (0) Ci-₄alkylNRR¹;

R³ is -OH, halo, or -NH₂ ; R⁴ is -H, lower alkyl, or -OR;

R⁵ is =0, =N0H, 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 =0; e) when R⁵

f) when X

-OH, and R⁷, R⁹, and R¹¹ are -H, and Y is -CH3; and g) when Y is -CH2OR², X is R⁶ where R⁵ is =0, and R⁶ is -H or lower alkyl.

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

-CHR³R⁴, -C(CH₂CH₃)

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 (llff)-one.

5. The method of claim 3 wherein said compound is (±)-7- [ (hydroxy)methoxymethyl]-8-methylindolizino

[1,2-b]quinolin-9 (llff)-one,

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

7. The method of claim 1 wherein: X is

where R⁵ is =0 and R⁶ is -H or lower alkyl; and Y is -CH3 or

-CH₂0R².

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

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

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

11. The method of claim 1 wherein said compound is (±)-7-

(threo-1,2-dihydroxypropyl)-8-methylindolizino[1,2- b]quinolin-9(llff)-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 =0 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 (llff)-one.

15. The method of claim 13 wherein: R¹⁰ is -(CH₂)_nCH2V;

- ^RS and X is R⁶ where R⁵ is =0 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 (llff)-one.

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

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

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

20. The method of claim 13 wherein said compound is 2- acetyl-8-methyl-7- (1-oxopropyl) indolizino[1,2- b]quinolin-9 (llff)-one.

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

22. The method of claim 12 wherein said compound is 8- methyl-7- (1-oxopropyl) indolizino[1,2-b]quinolin- 9 (llff)-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, -OCι_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 R where R⁵ is =0 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 (llff)-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, -(CH )_nCH₂V or -NHCH₂Ar; X is -CHR³R⁴ where R³ is -OH

and R⁴ is -H or lower alkyl, or R where R⁵ is =0 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 (llff)-one.

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

30. The method of claim 27 wherein said compound is 12- hydroxymethy1-8-methyl-7-(1-oxopropyl) indolizino[1,2- b] quinolin-9 (llff)-one.

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

32. The method of claim 27 wherein said compound is (±)- 12-cyano-7-(1-hydroxypropyl)-8-methylindolizino [1,2- b]quinolin-9 (llff)-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 R⁶ where R⁵ is =0 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 (llff)-one.

36. The method of claim 34 wherein said compound is (±)-l- methoxy-7- (1-hydroxypropyl)-8-methylindolizino[1,2- b]quinolin-9 (llff)-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 (llff)-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

wherein: R⁷ is -H, -NO₂, -CN, lower alkoxy, lower alkyl, -OAr, -NHCH₂Ar, -C≡=CCH₂NRR¹, -CH=CHCH₂NRR¹; -(CH₂)_nCH₂V

SUBSTITUTESHEE where n = 0-3 and V is -OH, -OCi-βalkyl, -OCOR¹², -OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R⁹ is -H, -OR, -NO2, -NRR¹, -CN, halo; -(CH2)_nCH2V where n = 0-3 and V is -OH, -OCi-βalkyl, -OCOR¹²,

-OCOOR¹³, -OCONRR¹, -NRR¹, or -CN;

R¹⁰ is -H, -OR, -N0₂, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -OC(0)R¹², -OC(0)OR¹², -OC(0)CH2CH₂COOR¹³, -0-(CH₂)ι-5CH2NRR¹, -OC(0)NRR¹, 1, 4 '-bipiperidine-1 '- carboxy; -(CH2)_nCH2V where n = 0-3 and V is -OH, -OCi-βalkyl, -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, -Cι_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, R⁶ ,

or -C(CH₂CH₃) (OH)COOH;

Y is -H, -CH3, -CH₂OR²;

R² is -H, -C(0)H, -C(0)Cι-₅alkyl, -C(O)Cι_₄alkylCOOH or -C(0)Cι-₄alkylNRR¹;

R³ is -OH, halo, or -NH₂; R⁴ is -H, lower alkyl, or -OR; R5 is =0, =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 =0; e) whe

f) when H, and R⁷, R⁹, and R¹¹ are

g) when

R⁵ is =0, 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(0)H, -CH₂0H, -CH(OH)CH(OH)CH3, -C(0)CH2CH₃, or -CH(OH)CH₂CH₃; i) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH₂OC(0)H, then X is not -C(0)CH₂CH3; j) when R⁷, R⁹, R¹⁰, R¹¹' and Y are all -H, then X is not -CH₂OH, -C(0)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

R⁶ where R⁵ is =0 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 (llff)-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 R where R⁵ is =0 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[l, 2-b]quinolin-9 (llff) -one.

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

47. A compound of claim 44 wherein: R¹⁰ is -(CH₂)_nCH₂ ;

and X is R⁶, where R⁵ is =0 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 (llff)-one.

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

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

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

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

53. A compound of claim 43 wherein said compound is 8- methyl-7- (1-oxopropyl) indolizino[1,2-b]quinolin- 9 (llff)-on-2-yl[1, '-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)_nCH₂ ;

R¹⁰ is -OR; X is -CHR³R⁴ where R³ is -OH and R⁴ is -H

or lower alkyl, or X is R⁶ where R⁵ is =0 and R⁶ is -H or lower alkyl; and Y is -CH3.

56. A compound of claim 55 wherein said compound is 1- (dimethylamino)methyl-2-hydroxy-8-methyl-7- (1- oxopropyl) indolizino[1,2-b]quinolin-9 (llff)-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 R⁶ where R⁵ is =0 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 (llff)-one.

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

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

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

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

R⁶ where R⁵ is =0 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 (llff)-one.

67. A compound of claim 65 wherein said compound is (±)-l- methoxy-7- (1-hydroxyρropyl)-8-methylindolizino[1,2- b]quinolin-9 (llff)-one.

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

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

70. A compound of claim 40 wherein: R⁷, R⁹, R¹⁰, and R¹¹ 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. The method of claim 1 wherein said viral infection is caused by cytomegalovirus and the infected host is a mammal.