WO1993020818A1 - SUBSTITUTED INDOLIZINO[1,2-b]QUINOLINONES - Google Patents

Abstract

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

Description

SUBSTITUTED INDOLIZINO[1,2-b]QUINOLINONES

This application is a continuation-in-part of U.S. Serial No. 07/870,649, filed on April 17, 1992, which is a continuation-in-part of U.S. Serial No.

07/783,063, filed on October 25, 1991, which is a continuation-in-part of U.S.

Serial No. 07/606,216, filed on October 31, 1990.

Scope 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-b]quinolinyl derivatives which have antiviral activity and

pharmaceutical compositions thereof.

Background

Certain 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolinones are known to have cytotoxic and antiviral activity. Camptothecin is an example of such compounds. It is a water-insoluble, cytotoxic alkaloid produced by Camptotheca acuminata trees indigenous to China and Nothapodytes foetida trees indigenous to India.

Camptothecin and its close congeners are 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, 49, 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 a 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-b]quϊnoIinones that lack the a-hydroxylactone 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[1,2-b]quinolinones lacking the a-hydroxylactone moiety do have antiviral activity but not the undesirable cytotoxicity of camptothecin. Thus, such substituted indolizino[1,2-b]quinoIinones are useful for treating viral infections.

SUMMARY 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, -CN, lower alkyl or -(CH₂)_nCH₂V where n=0-3; R⁹ is -H, -OR, -NRR¹, -CN, -(CH₂)_nCH₂V where n=0-3;

R¹⁰ is -H, -OR, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -O-(CH₂)_1-5CH₂NRR¹, -OC(O)NRR¹, 1,4'-bipiperidine-1'-carboxy, -(CH₂)_nCH₂V where n=0-3;

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

R¹¹ is -H or -O R; R¹² is -H or lower alkyl;

R¹³ is lower alkyl;

R and R¹ are independently selected from the group consisting of -H, -C_1-6 alkyl, and, when R and R¹ are substituted on nitrogen, R and R¹ can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;

R¹⁴ is -CR¹²R¹⁶R¹⁷;

-(CH₂)_nCH₂R¹⁷ (where n=1-3);

;

;

(where n=0 or 1, and CH₂R¹⁷ can be substituted on the phenyl at the 2, 3, or 4 position); -O(CH₂)_nCH₂R¹⁷ (where n = 1-3);

-NRR¹;

-NH(CH₂)_nCH₂R¹⁷ (where n = 1-3); R¹⁵ is OH, OR¹⁸ or CH₂NH₂; R¹⁶ is H or the side chain of any naturally occuring a-amino acid;

R¹⁷ is NRR¹,

where X is any pharmaceutically acceptable anion; R¹⁸ is lower alkyl;

X is -CH(OH)CH(OH)CH₃, -CHR₃R⁴ _or

.

Y is -CH₃ or -CH₂OR²; R² is -H, -C(O)H, -COR¹⁴- or -P(O)(OH)R¹⁵;

R³ is -OH, -OCOR¹⁴, or -OP(O)(OH)R¹⁵;

R⁴ is -H, lower alkyl, or -OR; and

R⁶ is -H or lower alkyl. provided that: a) if one of R⁷, R⁹ , R¹⁰ or R¹¹ is other than -H, only one of the others may be other than -H;

b) only one of R⁷, R⁹, R¹⁰ or R¹¹ may be -NRR¹; c) when X is -CHR³R⁴ and R⁴ is -OR, R³ is -OH; d) when Y is -CH₂OR², X is R .

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 -C(O)H, -CH₂OH, -C(O)CH₂CH₃, or -CH(OH)CH₂CH₃; and

b) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH₂OC(O)H, then X is not -C(O)CH₂CH₃.

Another aspect of the present invention relates to pharmaceutical compositions comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention relates to processes for making a compound of 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" and "C_1-6 alkyl" refer 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 is present in the compound. 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, sulfuric 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, particularly mammals, most particularly humans, caused by a broad variety of DNA replicating animal viruses. The present method is particularly useful in treating viral infections caused by herpes simplex virus, particularly herpes simplex virus type 1 (HSV1) and herpes simplex virus type 2 (HSV2), varicella zoster virus (VZV), or cytomegalovirus (CMV) 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 IM1

X is -CH(OH)CH(OH)CH₃, -CHR³R⁴ , or

; and Y is -CH₃ or -CH₂OR², Formula IM1 corresponding to Formula I wherein R⁷, R⁹, R¹⁰, and R¹¹ are each - H and X and Y are as described herein. A more preferred method uses compounds of Formula IM1 where X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or

OP(O)(OH)R¹⁵ and Y is -CH3, where X is

where R⁶ 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 R¹¹ are each H, R¹⁰ is as defined hereinabove for Formula I except that R¹⁰ is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM2 where R₁₀ is -OR, -CN, COR¹², or -(CH₂)_nCH₂V; or X is -CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl and Y is

-CH₃, or X is

where R⁶ is -H or lower alkyl and Y is -CH₃ or CH₂OR²

Yet another prefenred 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 R¹⁰ are as defined hereinabove for Formula I except that R⁹ and R¹⁰ are each not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM3 wherein R⁹ is -(CH₂)_nCH₂V, R¹⁰ is -OR, X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or

CH₂OR²

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

Formula IM4 corresponding to Formula I wherein R⁹, R¹⁰ 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, or -(CH₂)_nCH₂V; X is CHR³R⁴ where R³ is -

OH, OCOR¹⁴ or OP(O)(OH)R¹5 and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR².

Yet another preferred method of use according to the present invention uses compounds of Formula IM5

Formula IM5 corresponding to Formula I wherein R⁷, R¹⁰ and R^{1 1} are -H, R⁹ is as defined hereinabove for Formula 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,

OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR²

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 R¹⁰ are each H, R¹¹ is -OR, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM6 where R¹¹ is OR, X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR².

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

-C(O)H, -CH₂OH, -CH(OH)CH(OH)CH₃, -C(O)CH₂CH₃, or

-CH(OH)CH₂CH₃; and

b) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH₂OC(O)H, then X is not -C(O)CH₂CH₃. Preferred compounds of the present invention include those of Formula INI

Formula IN1 corresponding to Formula I wherein R⁷, R⁹, R¹⁰ and R¹¹ are each -H,

X is

where R⁶ is -H or lower alkyl, and Y is CH₃ or CH₂OR² (provided

R⁶ is not -CH₂CH₃ when Y is -CH₃) or X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl (provided that R⁴ is not -CH₂CH₃ when R³ is OH), and Y is -CH₃.

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

Formula IN2 corresponding to Formula I wherein R⁷, R⁹ and R¹¹ are each -H, R¹⁰ is as described hereinabove for Formula I except that R¹⁰ is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN2 include those where R¹⁰ is -OR, -CN, -COR¹², or -(CH₂)_nCH₂V, and X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR².

Another preferred group of compounds of the present invention is represented by Formula IN3

Formula IN3 corresponding to Formula I wherein R⁷ and R¹¹ are each -H, R⁹ and R¹⁰ are as described hereinabove for Formula I except that R⁹ and R¹⁰ 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, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR².

Still another preferred group of inventive compounds is represented by

Formula IN4

Formula IN4 corresponding to Formula I wherein R⁹, R¹⁰ 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 L More preferred compounds of Formula IN4 include those compounds where R⁷ is lower alkyl, -CN, or -(CH₂)_nCH₂V; X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃. Another preferred group of compounds according to the present invention is represented by Formula IN5

Formula IN5 corresponding to Formula I wherein R⁷, R¹⁰ 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,

OCOR¹⁴ or OP(O)(OH)R¹⁵ and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR².

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 -OR, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN6 are compounds where R¹¹ is -OR, X is CHR³R⁴ where R³ is -OH, OCOR¹⁴ or OP(O)(OH)R¹5 and R⁴ is -H or lower alkyl, or X is

where R⁶ is -H or lower alkyl, and Y is -CH₃ or CH₂OR². The following compounds are particularly preferred:

7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one; 7-[1-[(3-amino-1-oxopropyI)oxy]propyl]-8-methylindolizino

[1,2-b]quϊnolin-9(11H)-one;

8-methyl-7-[1-[(2-pyrrolidinylcarbonyl)oxy]propyl]indolizino

[1,2-b]quinolin-9(11H)-one;

7-[1-[[2-amino-3-(1H-imidazol-4-yl)-1-oxopropyI]oxy]propyl]-8-methylϊndoIizino[1,2-b]quinoIin-9(11H)-one;

7-[1-[(2-amino-3-methyl-1-oxobutyl)oxyJpropyl]-8-methylindolizino

[1,2-b]quinolin-9(11H)-one;

7-[1-[(2-amino-2-methyI-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinoIin-9(11H)-one; 7-[1-[(ammoacetyl)oxy]propyl]-2-cyano-8-methylindolizino-[1,2-b]qulnolin-9(11H)-one;

8-methyI-7-[1-[[(2-pyrrolidinylcarbonyl)aminoacetyl]oxy]-propyl]indolizino[1,2-b]quinoIin-9(11H)-one;

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

7-[1-[[(1,4'-bipiperidin-1 '-yl)acetyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one;

8-methyl-7-[1-[(4-morpholinylacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one; 8-methyl-7-[1-[[(4-methylpiperazin-1-yl)acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(1 lH)-one;

7-[1-[[(1-imidazolyl)acetyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one;

8-methyl-7-[1-[(pyridinioacetyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one iodide; 7-[1-[[4-[(dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one;

8-Methyl-7-[1-[[4-(pyridiniomethyl)benzoyl]oxy]propyl]indolizino[1,2-b]quinolin- 9(11H)-one trifluoroacetate;

8-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one;

7-[1-[[(aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino

[1,2-b]quinolin-9(11H)-one;

12-[[(aminoacetyl)oxy]methyl]-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one; 8-methyl-12-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino

[1,2-b]quinolin-9(11H)-one;

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

Some compounds used in the method for treating viral infections according to the present invention are known. The publications listed herein discussing the 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 lactone 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-b]quinolin-9(11H)-one. Alternatively, the lactone 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 lactone ring is opened, the resulting X and Y groups may be further modified as needed to make the subject compounds.

Starting materials are commercially available or can be made by published methods. Camptothecin, 10-hydroxycamptothecin and 9-hydroxycamptothecin are natural products. Camptothecin and 10-hydroxycamptothecin are available from sources in the People's Republic of China. A 9-hydroxycamptothecin compound which can be used as starting material for making some of the inventive compounds is described in Published Japanese Patent Application No.59-51,289. The syntheses of 9- and 12-nitrocamptothecins are described by Wall, et al. (J. Med. Chem. 1986, 29, 2358). A total synthesis of camptothecin is described by Wall, et al., J. Med. Chem. 1980, 23, 554. The 1980 Wall, et al. synthesis can be used as a means to 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.

The ring-opening reaction is illustrated by Scheme 1. For the sake of convenience, all reaction schemes shown herein are illustrated with compounds which are substituted with -Η at R⁷ - R^{1 1.} However, these methods also apply to compounds of the present invention having any other combination of R⁷ - R¹¹ substituents as defined herein above, including compounds in which one or more substituents may require protection during chemical reactions and deprotection thereafter, as is well-known to those of ordinary skill in the art. 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, carbonates, and carbamates (8) or phosphorylated to produce phosphates and phosphonates (9) wherein R²^ and R²¹ are groups convertible into R¹⁴ and R¹⁰ respectively, by either deprotection or further elaboration by well-known methods.

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 aldehydes 12 which may be covalentiy solvated by water or an alcoholic solvent to produce compounds of formula 13. Hydride reduction of compounds of formula 12 and 13 give the primary alcohols 14.

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

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 carbonyl 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 (con't)

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 or phosphorylated to give phosphates or phosphonates by methods similar to those used for preparing such derivatives from compounds 3. Aldehydes (compounds 36) can be made by oxidizing the alcohols 34 using a mild oxidant which gives the aldehyde in preference to the acid (for example, MnO₂). Deprotection gives the keto aldehydes 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 or phosphorylated as described for compounds 3.

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. 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

Scheme 8 (con't)

The hydroxy compounds 57 are made as described by Sugasawa, T., et al.,

Chem. Pharm. Bull. 1974, 22, 771. 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 Utt. 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 74. Compounds with substituents in the 12-position are prepared as illustrated in Scheme 9.

Scheme 9

12-Hydroxymethyl compounds 76 are prepared by the method of Miyaska, T. et al. (Heterocycles 1981, 16, 1713) using ferrous sulfate, hydrogen peroxide and methanol with sulfuric acid. These alcohols are acylated or phosphorylated as described for compounds 3 to produce carboxylates, carbonates and carbamates, or phosphates and phosphonates. Similarly, 12-alkyl compounds 77 are prepared by the method of Miyasaka, T. et al. (U.S. Pat. No. 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 aminornethyl 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-hydroxy methyl 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.

As shown in Scheme 10, compounds 107, the open ring form of compounds 106, which are described in co-pending U.S. Ser. No. 07/839,823, are acylated or phosphorylated as described for compounds 3 to give compounds 108 and 109, respectively.

The compounds of the present invention exhibit antiviral activity and are generally useful in treating DNA replicating animal virus infections, particularly those caused by viruses in the herpes family. 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).

Lifections caused by the following animal pathogens may also be treated with the present compounds: Equine Herpes virus;

Porcine Herpes virus;

Marek's disease virus;

Feline Rhinotracheitis virus; and

Bovine Herpes 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.

Assay Procedure

Well plates were seeded with the appropriate cells at a concentration of 1×10⁵ 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 mL HBSS. Following adsorption, the following were added:

A) 250 mL/well 2 × EMEM containing Human IgG

(ca 0.1 mg/mL; Sigma No. G-6763);

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

C) 250 mL/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:H₂O 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 present 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 Remington'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 adniinistration 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.

Li 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

(±)-1-Methoxy-7-(1-hydroxypropyl)-8-methyIindolizino[1,2-b]quinolin-9(11H)-one

A solution of 1-methoxy-8-methyl-7-(I-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one (5.0 mg, 15 pmol) in a mixture of MeOΗ (0.2 mL), CΗ₂CI₂ (0.6 mL) and TΗF (0.2 mL) was treated with a single portion of sodium

borohydride (4.0 mg, 110 μmol). After stirring at room temperature for 1.5 h, the reaction mixture was concentrated under reduced pressure. The residue was treated with 10% aqueous NΗ4CI (350 pL) and allowed to stand at 4°C overnight. The solid which formed was collected by filtration, washed sparingly with H₂O and dried to afford the title compound. ¹H NMR (CDCl₃/MeOH-d₄) d 8.77 (s, 1H), 7.69 (m, 2H), 7.59 (s, 1H), 6.92 (dd, J = 6.8, 1.7 Hz, 1H), 5.23 (br s, 2H), 4.89 (m, 1H), 4.05 (s, 3H), 2.24 (s,3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Example 2

(±)-2-Cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one The title compound was prepared according to the procedure in Example 1 except using 2-cyano-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one. ¹Η NMR (CDCl₃/MeOH-d₄) d 8.29 (s, 1H), 8.32 (d, J=1.7 Hz, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.92 (dd, J= 8.8, 1.8 Hz, 1H), 7.67 (s, 1H), 5.30 (br s, 2H), 4.91 (m, 1H), 2.26 (s, 3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for

C₂₀H₁₇N₃O₂·H₂O: C, 68.75; H, 5.48; N, 12.03, Found: C, 68.97; H, 5.26; N, 11.72.

Example 3

(±)-7-[1-[(Aminoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one

Ηydrotrifluoroacetate

3A. (±)-8-Methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]aminolacetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one

To a suspension of N-[(1,1-dimethylethoxy)carbonyl]glycine (1.15 g, 6.6 mmol) in CΗ₂CI₂ (50 mL) under an argon atmosphere was added 1,3-dicyclohexylcarbodiimide (1.35 g, 6.5 mmol). After stirring at room temperature for 0.5 h, (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (1.0 g, 3.3 mmol) was added followed by a few mg of 4-mmethylaminopyridine. The resulting mixture was allowed to stir at room temperature overnight and then was filtered. The filtrate was washed successively with 2.5% aqueous NaΗCO₃ (100 mL), 0.1 NHCl (100 mL) and H₂O (100 mL), dried over sodium sulfate and concentrated in vacua. The solid residue was purified by column chromatography on silica gel eluting with a solvent gradient of 0-2% MeOH/CH₂Cl₂ to provide the title compound. ¹H NMR (CDCI₃) d 8.34 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.91, (d, J= 8.3 Hz, 1H), 7.81, (m, 1H), 7.63, (m 1H), 7.32 (s, 1H), 5.96 (apparent br t, J = 7.0 Hz, 1H), 5.25 (s, 2H), 5.03 (br s, 1H), 4.15-3.94 (m, 2H), 2.36 (s, 3H), 2.04-1.84 (m, 2H), 1.44 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H). Anal. Calcd for

C₂₆H₂₉N₃O₅·1/8 H₂O: C, 67.04; H, 6.33; N, 9.02. Found: C, 66.95; H, 6.54; N, 8.83. 3B. (±) -7-[1-[(Aminoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinoIin-9(11H)-one Ηydrotrifluoroacetate To a stirring suspension of (±)-8-methyl-7-[1- dimemylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one (1.15 g, 2.5 mmol) in 1,3-dimethoxybenzene (12 mL) under an argon atmosphere was added trifluoroacetic acid (13 mL). After stirring for 1.5 h at room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in Η₂O, extracted with Et₂O, filtered and lyophilized to afford the title compound as a pale yellow solid. ¹H NMR (DMSO-d₆) d 8.68 (s, 1H), 8.24 (m, 1H), 8.13 (m, 1H), 7.86 (apparent br t, 1H), 7.70 (apparent br t, 1H), 7.19 (s, 1H), 5.91 (apparent br t, 1H), 5.26 (s, 2H), 4.02 (br s, 2H), 2.25 (s, 3H), 2.06- 81 (m, 2H), 0.96 (t, J= 7.2 Hz, 3H). Anal. Calcd for C₂₁H₂₁N₃O₃· CF₃CO₂H·9/4 H₂O: C, 53.33; H, 5.16; N, 8.11. Found: C, 53.09; H, 4.91; N, 7.74. Example 4

(±)-7-[1-[(3-Amino-1-oxopropyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin- 9(11H)-one Ηydroacetate

4A. (±)-8-Methyl-7-[1-[[3-[[(1,1-dimethvIethoxy)carbonyl]amino]-1-oxopropynoxylpropynindolizino[1,2-b]quinolin-9(1IH)-one

A mixture containing (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2-dich loroethane (5 mL) under an argon atmosphere was heated at reflux for 5 d. Thin layer chromatographic analysis at this time indicated that the reaction was incomplete, so the mixture was transferred to a pressure bottle and heated at 90- 95°C for 1 d. Afterwards, additional 4-nitrophenyl 3-[[(1,1-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) were added, and heating was continued for 13 d. The mixture was then purified by flash chromatography eluting with a solvent gradient of 0-3% MeOΗ/CΗ₂Cl₂. The material that was isolated was recrystallized from Et₂O and dried in vacuo to afford the title compound, mp 155-8°C. ¹H NMR (CDCI₃) d 8.35 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.81 (m, 1H), 7.63 (m, 1H), 7.32 (s, 1H), 5.90 (dd, J = 7.7, 6.1 Hz, 1H), 5.26 (s, 2H), 5.02 (br s, 1H), 3.44 (m, 2H), 2.66 (q, J= 5.8 Hz, 2H), 2.02-1.80 (m, 2H), 1.38 (s, 9H), 0.98 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₇H₃₁N₃O₅· 1/5 H₂O: C, 67.40; H, 6.58; N, 8.73. Found: C, 67.78; H, 6.48; N, 8.35. 4B. (±)-7-[1-[(3-Amino-1-oxopropyl]oxvlpropyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one Ηydroacetate

The title compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[1-[[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one with the product being purified by reversed phase chromatography on Partisil 40 ODS-3 eluting with a gradient of 0-100% MeOΗ in Η₂O containing 1% acetic acid, ¹Η NMR

(CDCl₃/MeOH-d4) d 8.42 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.84 (m, 1H), 7.67 (m, 1H), 7.43 (s, 1H), 5.92 (dd, J = 7.7, 6.0 Hz, 1H), 5.28 (s, 2H), 3.02 (br s, 2H), 2.69 (apparent br t, J = 5.9 Hz, 2H), 2.36 (s, 3H), 2.02 (s, 3H), 2.02-1.82 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). CIMS (NH3, m/e, rel. int.) 378 (100) [(M+H)+]. Anal. Calcd for C₂₂H₂₃N₃O₃·C₂H₄O₂· 13/4 H₂O: C, 58.11; H, 6.81; N, 8.47. Found: C, 58.22; H, 6.13; N, 8.10.

Example 5

8-Methyl-7-[1-[(-2-pyrrolidinylcarbonyl)oxy]propynindolizino[1,2-b]quinolin- 9(11H)-one Ηydrotrifluoroacetate and Separation of Isomers

5A. (R,S)- 8-Methyl-7-[1-[[(S)1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one

The title compound was prepared according to the procedure in Example 3A except using N-[(1,1-dimethylethoxy)carbonyl]-L-proline, N,N'- diisopropylcarbodiimide and (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. 5B. (R,S )-8-Methyl-7-[1-[((S)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino [ 1 ,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

To a mixture containing (R,S)-8-methyl-7-[1-[[(S)1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]oxy]propyl]indolizino

[1,2-b]quinolin-9(11H)-one (1.66 g, 3.3 mmol) in CΗ₂CI₂ (50 mL) was added trifluoroacetic acid (10 mL). The resulting mixture was allowed to stir at room temperature for 1.5 h and then was concentrated under reduced pressure. The residue was dissolved in H₂O (150 mL) and lyophilized to afford the title compound as a mixture of diastereomers. ¹H NMR (D₂O) d 7.68 and 7.64 (2 s, 1H), 7.45 and 7.36 (two d, 1H), 7.33-6.95 (m, 3H), 6.94 and 6.91 (two s, 1H), 5.93 (m, 1H), 4.9-4.6 (m obscured by HOD peak), 4.2-3.9 (m, 2H), 3.52 and 3.43 (overlapping m and t, 2H), 2.73-2.55 (m, 1H), 2.45-1.95 (m, 5H), 2.12 and 2.06 (two s, 3H), 1.08 (m, 3H). Anal. Calcd for C₂₄H₂₅N₃O₃·11/4 CF₃CO2H: C, 49.41; H, 3.90; N, 5.86. Found: C, 49.84; H, 4.16; N, 6.00. 5C. (S)-8-Methyl-7-[1-[((S)-2-pyrrolidinylcarbonyl)oxy]propyllindolizino

[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The diastereomeric mixture of (R,S)-8-methyl-7-[1-[((S)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino[1,2-b]quinolm-9(11H)-one was purified by preparative chromatography (JY column packed with 2 kg 15-20 mm Vydac C₁₈ RP silica), eluting with 0.1/25/75 TFA/CΗ₃CN/Η₂O. The title compound was the first to elute and was obtained after solvent removal under reduced pressure and lyophilization. ¹HNMR (D₂O) d 7.99 (s, 1H), 7.75 (d, J= 8.5 Hz, 1H), 7.57 (m, 1H), 7.51 (d, J= 8.2 Hz, 1H), 7.33 (m, 1H), 7.20 (s, 1H), 6.09 (dd, J = 7.9, 5.6 Hz, 1H), 4.9-4.7 (m obscured by HOD peak), 4.52 (d, J= 18.9 Hz, 1H), 4.40 (d, J = 18.8 Hz, 1H), 3.53 (t, J = 7.3 Hz, 2H), 2.75 (m, 1H), 2.45-2.08 (m, 5H), 2.30 (s,

3H), 1.19 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₄H₂₅N₃O₃·2 CF₃CO₂H·1/4 H₂O: C, 52.88; H, 4.36; N, 6.61. Found: C, 52.76; H, 4.50; N, 6.64.

5D. (R-)-8-Methyl-7-[1-[((S)-2-pyrroIidinylcarbonyl)oxylpropyl]indoIizino

[1 ,2-b]quinolin-9( 11H)-one Ηydrotrifluoroacetate

The remaining fractions from the separation process in Example 5C were combined and concentrated under reduced pressure. The title compound was obtained after an additional preparative chromatographic separation using the conditions in Example 5C. ¹ΗNMR (D₂O) d 8.00 (s, 1Η), 7.68 (d, J= 8.5 Ηz, 1Η), 7.56-7.49 (m, 2Η), 7.32 (m, 1H), 7.19 (s, 1H), 6.09 (dd, J = 8.0, 5.2 Hz, 1H), 4.93-4.67 9m obscured by HOD peak), 4.49 (d, J = 18.9 Hz, 1H), 4.40 (d, J = 19.0 Hz, 1H), 3.66-3.57 (m, 2H), 2.78 (m, 1H), 2.47 (m, 1H), 2.29 (m, 2H), 2.24 (s, 3H), 2.15 (m, 2H), 1.17 (t, 3H). Anal. Calcd for C₂₄H₂₅N₃O₃·7 CF₃CO₂H·4 H₂O: C, 35.83; H, 3.17; N, 3.30. Found: C, 35.86; H, 3.24; N, 3.64. 5E. (R,S)-8-Methyl-7-[1-[[(R) 1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]oxy]propyl]indoIizino[1,2-b]quinolin-9(11H)-one

To a mixture of N-[(1,l-dimethylethoxy)carbonyl]-D-proline (6.74 g, 31.3 mmol) in CΗ₂CI₂ (47 mL) under an argon atmosphere was added

dicyclohexylcarbodiimide (3.22 g, 15.6 mmol). After stirring at room temperature for 2 h, the mixture was filtered and concentrated under reduced pressure to afford N-[(1,1-dimethylethoxy)carbonyl]-D-proline anhydride. This was added to a suspension of (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (1.50 g, 4.9 mmol) and 4-dimethylaminopyridine (609 mg, 5.0 mmol) in CΗ₂CI₂ (450 mL), and the mixture was allowed to stir at room temperature under an argon atmosphere overnight. The reaction mixture was washed with H₂O (2x), dried over potassium carbonate and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a solvent gradient of 0-2% MeOH/CHCl₃ to afford the title compound.

5F. (R,S)-8-Methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino[ 1,2-b]quinolin-9(11H)-one Hydrotrifluoroacetate

The title compound was prepared according to the procedure in Example 5B except using (R,S)-8-methyl-7-[1-[[(R)-1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. ¹H NMR was essentially identical to that of the compound of Example 5B. Anal. Calcd for C₂₄Η₂₅N₃O₃·2 CF₃CO₂Η: C, 53.25; H, 4.31; N, 6.65. Found: C, 53.07; H, 4.68; N, 7.02. 5G. (R)-8-Methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propynindolizino

[1,2-b]quinolin-9( 11H)-one Ηydrotrifluoroacetate

The title compound was obtained by separation of the diastereomers of

(R,S)-8-methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one according to the procedure in Example 5C. Anal. Calcd for C₂₄Η₂₅N₃O₃·3 CF₃CO₂H.H₂O:

C, 47.19; H, 3.96; N, 5.50. Found: C, 47.24; H, 4.30; N, 5.83.

5H. (S)-8-Methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propynindolizino

[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate The title compound was obtained by separation of the diastereomers of (R,S)-8-methyl-7-[1-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino

[1,2-b]quinolin-9(11H)-one according to the procedure in Example 5C. Anal. Calcd for C₂₄Η₂₅N₃O₃·8/3 CF₃CO₂H·H₂O: C, 48.56; H, 4.12; N, 5.79. Found: C, 48.61; H, 4.53; N, 6.10.

Example 6

( R,S)-7-[1-[[(S)-2-Amino-3-(1H-imidazol-4-yl)-1-oxopropyl]oxy]propyl]-8- methylindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

6A. (R,S)-8-Methyl-7-[1-[[(S)-2-[[(1,1-dimethyIethoxy)carbonyl]amino]-3-(1H-imidazol-4-yl)-1-oxopropynoxy1propynindolizinoπ.2-b1quinolin-9(llH)-one

The title compound was prepared according to the procedure in Example 3 A except using N,1-bis[(1,1-dimethylethoxy)carbonyl]-L-histidine, N,N'-diisopropylcarbodiimide and (±)-7-(1-hydroxypropyl)-8- methylmdolizino[1,2-b]quinolin-9(11H)-one.

6B. (R,S)-7-[1-[[[S)-2-Amino-3-(1H-imidazol-4-yl)-1-oxopropyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The title compound was prepared according to the procedure in Example 5B except using (R,S)-8-methyl-7-[1-[[(S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-(1H-imidazol-4-yl)-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one and was purified by preparative MPLC eluting first with 0.1% TFA/Η₂O followed by a solvent gradient of 20-50% MeOH in H₂O containing 0.1% TFA. ¹H NMR (D2O) d 8.64 and 8.35 (two s, 1H), 8.22 (d, 1H), 7.90 (d, 1H), 7.70 (m, 2H), 7.45 (m, 2H), 7.20 (s, 1H), 6.04 (m, 1H), 4.9-4.6 (m obscured by HOD peak), 3.68-3.47 (m, 2H), 2.23 and 2.19 (two s, 3H), 2.15-1.96 (m, 2H), 1.04 and 0.96 (two t, 3H). Anal. Calcdfor C₂₅H₂₅N₅O₃·2.8 CF₃CO₂H: C, 48.18; H, 3.67; N, 9.18. Found: C, 48.29; H, 3.93; N, 9.15. Example 7

(±)-7-[1-[(2-Amino-3-methyl-1-oxobutyl)oxylpropyl]-8- methylindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate 7A. (±)-8-Methyl-7-[1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutyl]oxylpropynindolizino[1,2-b]quinolin-9(11H)-one

The tide compound was prepared according to the procedure in Example 3 A except using N-[(1,1-dimethylethoxy)carbonyl]-L-valine and (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one. ¹H NMR (CDCI₃) d 8.34 (s, 1Η), 8.22 (m, 1Η), 7.91 (d, J = 8.2 Ηz, 1Η), 7.80 (m, 1Η), 7.62 (m, 1Η), 7.34 (two s, 1Η), 5.94 (m, 1Η), 5.26 (s, 2Η), 5.04 (two br d, J = 9.3 Hz, 1H), 4.36 (two d, J = 4.5 Hz, 1H), 2.36 (s, 3H), 2.4-2.2 (m, 1H), 2.1-1.8 (m, 2H), 1.44 and 1.38 (two s, 9H), 1.00 (overlapping t and d, 9H). 7B, (±)-7-[1-[(2-Amino-3-methyl-1-oxobutyl]oxylpropyn-8-methylindolizino[1 ,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The tide compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutyl]oxy]propyl]indolizino[1,2-b]quinolin-9(1IH)-one. ¹ H NMR (CDCI₃, MeOΗ-d₄) d 8.39 and 8.35 (two s, 1H), 8.20-8.13 (m, 1H), 7.94-7.81 (m, 2H), 7.66 (apparent br t, 1H), 7.41 (two s, 1H), 6.05 (m, 1H), 5.25 (s, 2H), 3.98 (two d, J= 4.4 Hz, 1H), 2.55-2.36 (m, 1H), 2.33 (s, 3H), 2.14-1.90 (m, 2H), 1.15-1.01 (m, 9H). Anal. Calcd for C₂₄H₂₇N₃O₃·CF₃CO₂H·7/4 H₂O: C, 56.67; H, 5.76; N, 7.63. Found: C, 56.65; H, 5.62; N, 7.29.

Example 8

(±)-7-[1-[(2-Amino-2-methyl-1-oxopropyl)oxylpropyn-8-methylindolizino[1,2- b]quinolin-9(11H)-one Ηydrotrifluoroacetate 8A, (±)-8-Methyl-7-[1-[[2-[[(1,1-dimethylethoxy)carbonyl]aminol-2-methyl-1-oxopropyl]oxy]propynindolizino[1,2-b]quinolin-9(11H)-one

To a mixture containing 2-methyl-2-[N-[(1,1-dimethylethoxy)carbonyl]amino]propionic acid (406 mg, 2.0 mmol) and dicyclohexylcarbodiimide (432 mg, 2.0 mmol) in CH₂CI₂ (3 mL) under an argon atmosphere were added (±)-7-(1-hydroxypropyl)-8-methylindolizino [1,2-b]quinolin-9(11H)-one (153 mg, 0.5 mmol) and 4-dmethyla-ninopyridine (25 mg). The resulting mixture was allowed to stir at room temperature for 4 d and then was poured into CH₂CI₂, washed successively with 5% aqueous NaHCO₃, 0.5 N HCI and H₂O, and dried over sodium sulfate. Removal of the solvent in vacuo and purification of the residue by column chromatography (silica gel) eluting with a solvent gradient of 1.5-5% MeOH/CH₂CI₂ afforded the tide compound as an offwhite solid. ¹H NMR (CDCI₃) d 8.33 (s, 1H), 8.20 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.80 (m, 1H), 7.62 (m, 1H), 7.33 (s, 1H), 5.92 (dd, J = 7.5, 6.3 Hz, 1H), 5.25 (s, 2H), 5.10 (br s, 1H), 2.38 (s, 3H), 2.08-1.82 (m, 2H), 1.56 (s, 3H), 1.55 (s, 3H), 1.41 (s, 9H), 0.99 (t, J = 7.4 Hz, 3H).

8B. (±)-7-[1-[(2-Amino-2-methyl-1-oxopropyl)oxy]propyn-8-methylindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The title compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[1-[[2-[[(1,1-dimethyIethoxy)carbonyl]amino]-2-methyl-1-oxopropyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. ¹H NMR (DMSO-d₆) d 8.67 (s, 1Η), 8.11 (m, 2Η), 7.84 (m, 1H), 7.70 (m, 1H), 7.21 (s, 1H), 5.85 (dd, J= 7.9, 5.8 Hz, 1H), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s, 3H), 1.49 (s, 3H), 0.97 (t, J=7.3 Hz, 3H). Anal. Calcd for

C₂₃H₂₅N₃O₃·CF₃CO₂H·2 H₂O: C, 55.45; H, 5.58; N, 7.76. Found: C, 55.85; H, 5.19; N, 7.83.

Example 9

(±)-7-[1-[(Aminoacetyl)oxy]propy l]-22cyano-8-methylindolizino[1,2-b]quinolin- 9(11H)-one Ηydrotrifluoroacetate

9A, (±)-2-Cyano-8-methvI-7-[1-[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxy]propyl]indolizinori.2-b]quinolin- 9( 11H)-one

The title compound was prepared according to the procedure in Example 3 A except using (±)-2-cyano-7-(1-hydroxypropyl)-8-methylindohzino[1,2-b]quinolin-9(11H)-one.

9B. (±)-7-[1-[(Aminoacetyl)oxy]propyl]-2-cyano-8-methylindolizinori.2-b]quinoIin-9(11H)-one The tide compound was prepared according to the procedure in Example 3B except using (±)-2-cyano-8-methyl-7-[1-[[[[(1,1-dimethylethoxy)carbonyljamino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. ¹ HNMR (DMSO-d₆) d 8.81 (d, J= 1.5 Ηz, 1Η), 8.77 (s, 1Η), 8.27 (d, J= 8.9 Ηz, 1Η), 8.13 (dd, J = 8.9, 1.8 Ηz, 1Η), 7.24 (s, 1Η), 5.91 (apparent br t, J = 6.7 Ηz, 1Η), 5.29 (s, 2Η), 3.98 (br s, 2H), 2.26 (s, 3H), 2.05-1.81 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₂H₂₀N₄O₃·3/2 CF₃CO₂H·H₂O: C, 52.00; H, 4.10; N, 9.70. Found: C, 52.04; H, 4.32; N, 9.73. Example 10

(±)-7-[1-[(Aminoacetyl)oxylpropyl]-12-cyano-8-methyIindolizino[1,2-b]quinolin- 9(11H)-one Ηydrotrifluoroacetate

10A, (±) -12-Cyano-8-methyl-7-[1-[[[[(1 ,1-dimethylethoxy)carbonyl]aminolacetylloxylpropyllindolizino[1 ,2-b]quinolin- 9(11H)-one

The title compound was prepared according to the procedure in Example 3 A except using (±)-12-cyano-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin¬

9(11H)-one. ¹Η NMR (CDCI₃) d 8.31 (d J = 8.5 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.95 (m, 1H), 7.84 (m, 1H), 7.32 (s, 1H), 5.95 (apparent br t, J = 7.0 Hz, 1H), 5.43

(s, 2H), 5.0 (br s, 1H), 4.03 (m, 2H), 2.38 (s, 3H), 0.99 (t, J= 7.4 Hz, 3H).

10B. (±)-7-[1-[(Aminoacetyl)oxylpropyl]-12-cyano-8-methylindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The title compound was prepared according to the procedure in Example 3B except using (±)-12-cyano-8-methyl-7-[1-[[[[(1,1-dimemylemoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one. ¹Η NMR (CDCl₃/MeOΗ-d4) d 8.28 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.95 (m, 1H), 7.82 (m, 1H), 7.36 (s, 1H), 6.00 (apparent t, J= 6.6 Hz, 1H), 5.41 (s, 2H), 3.92 (br s, 2H), 2.33 (s, 3H), 2.08-1.82 (m, 2H), 1.00 (t, J= 7.2 Hz, 3H). Anal. Calcd for C₂₂H₂₀N₄O₃·3/2 CF₃CO₂H 5/2 H₂O: C, 49.67; H, 4.42; N, 9.27. Found: C, 49.41; H, 4.23; N, 9.29. Example 11

(R.S)-8-Methyl-7-[1-[[(S)-(2-pyrrolidinylcarbonyl)aminoacetyl]oxy]- propyllindolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate 11A. (R.S)-8-Methyl-7-[1-[[(S)-(2 -dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]a mino]acetyl]oxy]propyl]indoli zino[1,2-b]-quinoIin-9(11H)-one

The title compound was prepared according to the procedure in Example 5E except using (±)-7-[1-[(aminoacetyl)oxy]propyl]-8-methylindolizino

[I,2-b]quinolin-9(11H)-one.

11B. (R,S)-8-Methyl-7- [1-[[(S)-(2-pyrrolidinyIcarbonyl)am inoacetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The title compound was prepared according to the procedure in Example 5B except using (R ,S)-8-methyl-7-[1-[[[[(S)1-[(1,1-dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]amino]acetyl]oxy]propyl]indolizino[1,2-b]-quinolin-9(11H)-one. Anal. Calcd for C₂₆Η₂₈N₄O₄·3/2 CF₃CO₂H·H₂O: C, 53.62; H, 4.89; N, 8.63. Found: C, 53.64; H, 5.29; N, 8.50.

Example 12

(±)-8-Methyl-7-[1-[[(dimethylamϊno )acetvl]oxy]propyl]indolizinori.2-b]quinolin- 9(11H)-one Ηydrochloride 12A. (±)-7-[1-[ (Chloroacetyl)oxylpropyl]-8-methylindolizino[[1,2-b]quinolin-9( 11H)-one

To a suspension of (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (306 mg, 1.0 mmol) in freshly distilled CΗCI₃ (45 mL) were added chloroacetic anhydride (205 mg, 1.2 mmol), pyridine (80 mL, 1.0 mmol) and 4-dimemylaminopyridine (12.2 mg, 0.1 mmol). The resulting mixture, which became homogeneous after 20 min, was allowed to stir at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH₂CI₂, washed successively with H₂O (2x), 0.1 N NaOH and H₂O and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound, ¹Η NMR (CDCI₃) d 8.35 (s, 1H), 8.24 (d, 1H), 7.93 (d, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.33 (s, 1H), 5.99 (dd, 1H), 5.28 (s, 2H), 4.19 (s, 2H), 2.40 (s, 3H), 2.12-1.95 (m, 2H), 1.00 (t, 3H). Anal. Calcd for C₂₁H₁₉CIN₂O₃·1/2 H₂O: C, 64.37; H, 5.14; N, 7.15. Found: C, 64.29; H, 4.86; N, 6.82. 12B. (±)-7-[1-[(Iodoacetyl)oxylpropyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one

To a mixture of (±)-7-[1-[(chloroacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (100 mg, 0.26 mmol) in acetone (10 mL) was added sodium iodide (150 mg, 1.0 mmol), and the resulting solution was heated at reflux for 1 h. Upon cooling, a solid precipitate appeared. The solvent was removed in vacuo, and the residue was partitioned between CH₂CI₂ and H₂O. The organic extract was washed with H₂O (3x), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. ¹H NMR (CDCI₃) d 8.35 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.81 (m, 1H), 7.66 (m, 1H), 7.38 (s, 1H), 5.91 (dd, J = 7.9, 6.0 Hz, 1H), 5.26 (two s, 2H), 3.84 (d, J = 10.1 Hz, 1H), 3.75 (d, J= 10.1 Hz, 1H), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₁H₁₉IN₂O₃·1/2 H₂O: C, 52.19; H, 4.17; N, 5.80. Found: C, 52.16; H, 4.05; N, 5.39. 12C. (±)-8-Methyl-7-[1-[[(dimethylamino)acetyl]oxy]proρyl]indolizino[1,2-b]quinolin-9(11H)-one Ηvdrochloride

A stream of dimethylamine was introduced into a solution containing (±)-7- [1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (50 mg, 0.11 mmol). in anhydrous CH₂CI₂ (15 mL). The resulting solution was allowed to stir for 2 h and then was concentrated under reduced pressure. The residue was partitioned between CH₂CI₂ and H₂O, and the organic layer was washed several times with H₂O and dried over sodium sulfate. Into this solution was bubbled a stream of HCI gas, and the resulting cloudy mixture was stirred for 15 min and then was concentrated in vacuo. The residue was dissolved in H₂O and lyophilized to afford the title compound as an orange solid. ¹Η NMR (DMSO-d₆) d 8.68 (s, 1H), 8.15 and 8.12 (two overlapping d, 2H), 7.86 (m, 1H), 7.71 (m, 1H), 7.17 (s, 1H), 5.96 (apparent br t, 1H), 5.26 (s, 2H), 4.41 (s, 2H), 2.84 (br s, 6H), 2.26 (s, 3H), 2.20-1.86 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). CIMS (NH3, m/e, rel. int.) 392 (100) [(M+H)⁺]. Anal. Calcd for C₂₃H₂₅N₃O₃·2HCl·13/8H₂O: C, 55.96; H, 6.18; N, 8.51. Found: C, 56.27; H, 6.03; N, 8.04. Example 13

(±)-7-[1-[[(1,4'-Bipiperidin- 1'-yl)acetynoxy]propyl]-8-methylindolizino[1,2- b]quinolin-9(11H)-one Ηydroiodide

To a suspension of (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinoIin-9(11H)-one (50 mg, 0.11 mmol) in CH₂CI₂ (4 mL) was added 4-piperidinopiperidine (17.6 mg, 0.11 mmol). After stirring at room temperature for 3.5 h, thin layer chromatographic analysis indicated that the reaction was incomplete,. Additional 4-piperidinopiperidine (2.7 mg, 0.016 mmol) was added, and stirring was continued for 2 d. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography eluting with a solvent gradient of 0-100% MeOH in H₂O containing 1% HOAc. The title compound was obtained after lyophilization. tøNMR (CDCI₃) d 8.35 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.83 (m, 1H), 7.63 (m, 1H), 7.34 (s, 1H), 5.94 (apparent t, 1H), 5.26 (s, 2H), 3.32 (s, 2H), 3.00 (brm, 2H), 2.37 (s, 3H), 2.6-1.4 (m, 13H), 0.98 (t, 7=7.4 Hz, 3H). Anal. Calcd for C₃₁H₃₈N₄O₃·1/4 HI·3/8 H₂O: C, 67.28; H, 7.10; N, 10.12. Found: C, 67.67; H, 6.79; N, 9.69. Example 14

(±)-8-Methyl-7-[1-[(4-morpholinylacetyl)oxy]propynindolizino[1,2-b]quinolin- 9(11H)-one Ηydrochloride

The title compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and morpholine. ¹ΗNMR (CDCl₃/MeOH-d₄) d 8.51 (s, 1H), 8.26 (d, J= 8.5 Hz, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.88 (m, 1H), 7.70 (m, 1H), 7.53 (s, 1H), 5.98 (dd, J = 7.4, 5.9 Hz, 1H), 5.30 (s, 2H), 4.29 (s, 2H), 4.02 (br s, 4H), 3.45 (br s partially obscured by HOD peak), 2.33 (s, 3H), 2.10-1.87 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₅H₂₇N₃O₄·2HCl·H₂O: C, 57.25; H, 5.96; N, 8.01. Found: C, 57.37; H, 6.28; N, 7.65. Example 15

(±)-8-Methyl-7-[1-[[(4-methylpiperazin-1-yl)acetyl]oxylpropyl]indolizino[1,2- b]quinolin-9( 11H)-one Ηydrochloride The title compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and N-methylpiperazine. ¹Η NMR (DMSO-d₆) d 8.67 (s, 1Η), 8.15 (m, 2Η), 7.87 (m, 1H), 7.72 (m, 1H), 7.11 (s, 1H), 5.84 (m, 1H), 5.25 (s, 2H), 3.52.6 (m, 13H), 2.23 (s, 3H), 2.04-1.82 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H). Anal. Calcd for C₂₆H₃₀N₄O₃·2 HCl-9/2 H₂O: C, 52.00; H, 6.88; N, 9.33. Found: C, 52.12; H, 9.11; N, 9.30.

Example 16

(±)-7-[1-[[(1-Imidazolyl)acetynoxylpropyl]-8-methylindolizino[1,2-b]quinolin- 9(11H)-one Ηydrochloride

The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and imidazole. ¹Η NMR (CDCl₃/MeOH-d₄) d 9.17 (s, 1H), 8.60 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7.95 (m, 1H), 7.75 (m, 1H), 7.61 (s, 1H), 7.51 (br s, 1H), 7.41 (br s, 1H), 5.95 (m, 1H), 5.65 (d, 1H), 5.42 (d, 1H), 5.33 (s, 2H), 2.36 (s, 3H), 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C₂₄H₂₂N₄O₃·2 HCl·11/4 H₂O: C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29. Example 17

(±)-8-Methvl-7-n-[(pyridinioacetyl]oxy]propyl]indolizino[1,2-b]quinolin-9(11H)- one iodide

The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[1-[(iodoacetyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one and pyridine. ¹H NMR (CDCl₃/MeOΗ-d₄) d 9.09 (d, J = 5.5 Hz, 2H), 8.65 (t, J = 7.9 Hz, 1H), 8.51 (s, 1H), 8.17 (m, 3H), 7.99 (d, J = 8.1 Hz, 1H), 7.89 (m, 1H), 7.70 (m, 1H), 7.50 (s, 1H), 6.05 (d, J= 17.2 Hz, 1H), 6.02 (m, 1H).5.87 (d, J= 17.2 Hz, 1H), 5.30 (s, 2H), 2.31 (s, 3H), 2.18-1.94 (m, 2H), 1.09 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₆H₂₄IN₃O₃·1/4H₂O: C, 55.97; H, 4.43; N, 7.53. Found: C, 55.72; H, 4.30; N, 7.26.

Example 18

(±)-7-[1-[[4-[(Dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[1,2- b]quinolin-9(11H)-one Ηydrochloride

18A. (±)-7-[1-[[4-(Chloromethyl)benzoyl]oxy]propyl]-8-methylindolizino[1,2- b]quinolin-9(11H)-one

The tide compound was prepared according to the procedure in Example 3A except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and 4-(chloromethyl)benzoic acid. ¹H NMR (CDCI₃) d 8.33 (s, 1Η), 8.16 (m, 3Η), 7.91 (br d, J= 7.3 Hz, 1H), 7.78 (m, 1H), 7.61 (m, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.40 (s, 1H), 6.11 (dd, J= 8.1, 6.1 Hz, 1H), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H), 2.21-1.93 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H). Anal. Calcd for

C₂₇H₂₃ClN₂O₃·1/2 H₂O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16; N, 6.02.

18B. (±)-7-[ 1-[[4-[(Dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[1.2-b]quinolin-9(11H)-one Ηydrochloride

A suspension containing (±)-7-[1-[[4-(chloromethyl)benzoyl]oxy]propyl]-8-methylindolizino[1,2-b]quinoIin-9(11H)-one (35 mg, 0.08 mmol) and sodium iodide (57 mg, 0.38 mmol) in dry acetone (50 mL) was heated at reflux for 1 h and then allowed to cool and stir at room temperature overnight. Into this mixture

dimethylamine was bubbled for several min, and the mixture was allowed to stir at room temperature for 1 h. The rriixture was concentrated under reduced pressure, and the residue was partitioned between H₂O and CH₂CI₂. The organic layer was washed with H₂O and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography eluting with a solvent gradient of 0-5% MeOH/CH₂Cl₂. The isolated material was treated with 3 mL H₂O and 0.3 mL 0.1 N HCI and lyophilized to afford the title compound as a beige solid. ¹H NMR (CDCl₃/MeOH-d₄) d 8.44 (s, 1H), 8.26 (d, J= 8.3 Hz, 2H), 8.17 (d, J = 8.6 Hz, 1H), 7.96 (d, J= 8.4Hz, 1H), 7.82 (m, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.66 (m, 1H), 7.55 (s, 1H), 6.14 (dd, J= 7.9, 5.8 Hz, 1H), 5.28 (s, 2H), 4.31 (s, 2H), 2.80 (s, 6 H), 2.44 (s, 3H), 2.20-1.95 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₉H₂₉N₃O₃·3/2 HCl· 7/2 H₂O: C, 59.51; H, 6.46; N, 7.18. Found: C, 59.91; H, 6.85; N, 6.85.

Example 19

(±)-8-Methyl-7-[1-[[4-(pyridiniomethyl)benzoynoxy]propynindolizino[ 1,2- b]quinolin-9(11H)-one trifluoroacetate

To a suspension of (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and (77 mg, 0.25 mmol) in pyridine (8 mL) under an argon atmosphere was added 4-(chloromethyl)benzoic acid (250 mg, 1.3 mmol). The resulting mixture was allowed to stir at room temperature for 2.5 d and then was concentrated under reduced pressure. The residue was partitioned between H₂O and CH₂CI₂, and the phases were separated. The aqueous phase was adjusted to pH 7.5 by the addition of 5% aqueous NaHCO₃ and re-extracted with CH₂CI₂. The aqueous layer was concentrated under reduced pressure, and the residue was applied to a RPl8 column and eluted with a solvent gradient of H₂O to MeOH. The material that was isolated was chromatographed two additional times on a RPI8 column, eluting with a solvent gradient of 0.1% TFA/H₂O to 0.1% TFA/MeOH to afford, after lyophilization, the title compound, ¹Η NMR (CDCl3/MeOH-d4) d 9.07 (d, J = 5.7 Hz, 2H), 8.46 (m, 1H), 8.39 (s, 1H), 8.23 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.6 Hz, 1H), 8.05 (m, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.81 (m, 1H), 7.65 (m, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.49 (s, 1H), 6.13 (dd, J = 7.8, 5.9 Hz, 1H), 6.00 (s, 2H), 5.27 (s, 2H), 2.42 (s, 3H), 2.2-2.0 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₃₄H₂₈F₃N₃O₅·5/2 CF₃CO₂H·5/2 H₂O: C, 49.53; H, 3.78; N, 4.44. Found: C, 49.53; H, 3.31; N, 4.27.

Example 20

(±)-7-[1-[[(Chloromethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2- b]quinolin-9(11H)-one Triethylamine Salt

To a suspension of (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (92 mg, 0.3 mmol) in CH₂CI₂ (5 mL) under an argon atmosphere was added E-3N (42 mL, 0.3 mmol) followed by

chloromethylphosphonic dichloride (31 mL, 0.3 mmol). The resulting mixture was allowed to stir at room temperature for 2.5 d, and then E.3N (42 mL) and MeOH (200 mL) were added and stirring was continued overnight. The mixture was concentrated under reduced pressure, and the residue was partitioned between H₂O and CH₂Cl₂. The organic layer was washed with H₂O (2x), and the combined aqueous extracts were lyophilized. The material that was obtained was applied to a RP₁₈ column, eluted with a solvent gradient of H₂O to MeOH and lyophilized to afford the title compound. ¹Η NMR (CDCI₃) d 8.27 (br s, 1H), 8.13 (m, 1H), 7.9-7.5 (m, 4H), 5.60 (m, 1H), 5.19 (br s, 2H), 3.49 (br d, J= 10.2 Hz, 2H), 3.05 (m, ~3H), 2.0-1.8 (m, 2H), 1.28 (t, 7=7.3 Hz, ~5-6H)1.00 (t, J= 7.2 Hz, 3H). Anal. Calcd for C₂₀H₂₀ClN₂O4P·1/2 C₆H₁₅N·7/4 H₂O: C, 55.15; H, 6.24; N, 6.99. Found: C, 54.94; H, 5.81; N, 6.92.

Example 21

(±)-7-[1-[(2-Cyanoethoxy)hydroxyphosphinyl)oxylpropyl]-8-methylindolizino[1,2- b]quinolin-9(11H)-one Sodium Salt

(±)-7-(1-Ηydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one (153 mg, 0.50 mmol).2-cyanoethyl phosphate (derived from 322 mg, 1.0 mmol of the barium salt by the procedure of Moffatt, J.G., J. Am. Chem. Soc. 1963, 85, 1118), and N,N'-dicyclohexyIcarbodiimde (462 mg, 2.24 mmol) in dry pyridine (4.0 mL) were heated at 45°C for 24 h with exclusion of moisture. Water and MeOΗ were added to the reaction, and the solvents were all stripped off in vacuo.

Additional H₂O and MeOH were added along with NaOAc (1.02 g), an insoluble solid was removed by filtration, and the solvents were stripped off again. The residue was applied as an aqueous solution to a reversed phase column of Partisil 40 ODS-3 and eluted with a gradient of 0- 100% MeOH/H2θ to give the tide compound. iHNMR (MeOH-d4) d 8.58 (s, 1H), 8.19 (d, J= 8.1 Hz, 1H), 8.05 (dd, J = 8.1, 1.0 Hz, 1H), 7.86 (m, 1H), 7.71 (s, 1H), 7.68 (m, 1H), 5.54 (m, 1H), 5.29 (s, 2H), 3.98 (m, 2H), 2.65 (t, J = 6.1 Hz, 2H), 2.36 (s, 3H), 2.07-1.88 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₂₂H₂₁N₃NaO₅P· 15/4 H₂O: C, 49.96; H, 5.43; N, 7.94. Found: C, 49.95; H, 5.22; N, 7.63. Example 22

(±)-8-Methyl-7-[1-[(phosphono)oxy]propynindolizinori.2-b]quinolin-9(11H)-one

Trimethylamine Salt To (±)-7-[1-[(2-cyanoethoxy)hydroxyphosphinyl)oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one sodium salt (89.4 mg, 0.19 mmol) in MeOΗ (1.0 mL) was added 1N NaOΗ (1.65 mL), and the reaction mixture was stirred under argon for 7 h at room temperature. The reaction was acidified with IN ΗCl (1.75 mL), stripped and redissolved in H₂O. This solution was applied of a reversed phase column of Partisil 40 ODS-3 and eluted with a gradient of 0-100% MeOH/H₂O. After some of the tide compound eluted as a sodium salt, another fraction came off as mostly the free acid. The acid fraction was dissolved in MeOH, and (CH₃)₃N in MeOH was added to raise the pH to approximately 10. The MeOH was stripped off, H₂O was added and the solution was lyophilized to give the title compound as a partial sodium salt, ¹H NMR (MeOH-d₄/D₂O) d 8.58 (s, 1H), 8.16 (d, J= 8.5 Hz, 1H), 8.04 (d, J= 8.3 Hz, 1H), 7.85 (m, 1H), 7.74 (s, 1H), 7.68 (m, 1H), 5.50 (br dd, 1H), 5.26 (s, 2H), 2.92 (s, -6.5H), 2.33 (s, 3H), 1.95 (m, 2H), 1.08 (t, J = 7.4 Hz, 3H). Anal. Calcd for C₁₉H₁₈N₂O₅P·3/4 C₃H₁₀N·1/4 Na·9/2 H₂O: C, 49.35; H, 6.72; N, 7.45. Found: C, 49.41; H, 6.43; N, 7.02.

Exaτnple 23

(±)- 7-[1-[[(Aminomethyl)hydroxyphosphinyl]oxylpropyl]-8-methylindolizino[1 ,2- b]quinolin-9(11H)-one 23A, (±)-7-[1-[[[[[(9- Fluorenylmethoxy)carbonyl]amino]methyl]hydroxvphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one

The title compound was prepared according to the procedure in Example 21 except using (±)-7-(1-hydroxypropyl)-8-methylindolizino[1,2-b]quinolin-9(11H)-one and [[[(9-fluorenylmethoxy)carbonyl]amino]methyl]phosphonic acid. Anal. Calcd for C₃₅Η₃₂N₃O₆P·9/8 H₂O: C, 65.49; H, 5.38; N, 6.55. Found: C, 65.83; H, 5.28; N, 6.14.

23B. (±)-7-[1-[[(Aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-blquinolin-9(11H)-one A mixture of Et₂NH (10 mL) and (±)-7-[1-[[[[[(9-fluorenylmemoxy)carbonyl]amino]methyl]hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (328 mg, 0.51 mmol) was stirred at room temperature in a capped vial for 3h. The reaction mixtiire was stripped to dryness, and H₂O was added. The this partial solution was extracted with EtOAc, filtered and lyophilized to give a viscous oil which was triturated with CH₃CN to produce a golden solid. The solid was dissolved in H₂O and lyophilized to give the title compound as a partial Et₂NH salt ¹H NMR (CDCl₃/MeOH-d₄) d 8.49 (s, 1H), 8.12 (d, J= 8.7 Hz, 1H), 8.00 (d, 7= 8.3 Hz, 1H), 7.84 (m, 1H), 7.69

(overlapping s and m, 2H), 5.59 (dd, J= 14.9, 6.5 Hz, 1H), 5.27 (s, 2H), 2.98 (q, 7 = 7.2 Hz, -1.1H), 2.85 (dd, 7= 12.7, 2.6 Hz, 2H), 2.31 (s, 3H), 2.02-1.83 (m, 2H), 1.31 (t, I = 7.3 Hz, -1.8H), 1.05 (t, J= 7.4 Hz, 3H). Anal. Calcd for

C₂₀H₂₂N₃O₄P·1/4 C₄H _{1 1}N·5 H₂O: C, 49.68; H, 6.90; N, 8.97. Found: C, 50.08; H, 6.49; N, 8.46.

Example 24

12-[[(Aminoacetyl)oxy]methyl]-8-methyl-7-(1-oxopropyl)indolizinori.2- b]quinolin-9(11H)-one Ηydrofluoroacetate 24A. S-Methyl-12-[[[[[(1,1-dimethylethoxy)carbonyl]amino]acetyl]oxylmethyl]- 7-(1-oxopropyl)indoIizino[1,2-b]quinolin-9(11H)-one

The tide compound was prepared according to the procedure in Example 5E except using 12-(hydroxymethyl)-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one and N-[(1,1-dimethyIethoxy)carbonyl]glycine.

24B. 12-[[(Aminoacetyl)oxy]methyl]-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one Ηydrotrifluoroacetate

The title compound was prepared according-to the procedure in Example 5B except using 8-methyl-12-[[[[[(1,1-dimemyIemoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one. ¹HNMR (D₂O/DSS) d 7.6-7.3 (m, 4Η), 6.64 (s, 1H), 5.58

(s, 2H), 4.58 (s, 2H), 4.20 (s, 2H), 2.92 (q, 7= 7.2 Hz, 2H), 1.94 (s, 3H), 1.22 (t, 7 =

7.2 Hz, 3H). Anal. Calcd for C₂₂H₂₁N₃O₄·CF₃CO₂H·H₂O: C, 55.07; H, 4.62; N,

8,03. Found: C, 55.32; H, 4.69; N, 7.98. Example 25

8-Methyl-12-[[(4-morpholinoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2- b]quinolin-9( 11H)-oneHydrochloride

To a suspension of 12-hydroxymethyl-8-methyl-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one (523 mg, 1.56 mmol) in anhydrous CΗ₂CI₂ (58 mL) at room temperature under an argon atmosphere was added anhydrous pyridine (130 μL, 1.61 mmol) and 4-dimethylaminopyridine (19 mg, 0.16 mmol). The reaction was stirred for 10 min and then was treated with iodoacetic anhydride (554 mg, 1.57 mmol) in one portion. After 1 h the turbid orange solution was treated with morpholine (815 μL, 9.4 mmol) and stirred for 1 h. The reaction mixture was filtered to remove morpholine hydroiodide, and the filtrate was concentrated in vacuo at 15°C and purified by flash chromatography eluting with 2% MeOH in CHCI₃ to give, after removal of solvent, a yellow powder which was suspended in H₂O (10 mL) and treated with 0.1N HCI (16 mL) to give a pH of 1.7. The resulting slurry was filtered and washed with MeCN followed by Et₂O to give the title compound as yellow flakes(, mp. 148-150°C (dec). ¹H NMR (CDCI₃) d 8.22 (d, 7= 8.6 Hz, 1H), 8.11 (d, J= 8.6 Hz, 1H), 7.84 (m, 1H), 7.70 (m, 1H), 7.25 (s, 1H), 5.77 (s, 2H), 5.50 (s, 2H), 3.73 (m, 4H), 3.33 (s, 2H), 2.92 (q, 7 = 7.6 Hz, 2H), 2.58 (m, 4H), 2.31 (s, 3H), 1.26 (t, J= 7.6 Hz, 3H). Anal. Calcd for C₂₆H₂₇N₃O₅· HCl·1/2 H₂O: C, 61.60; H, 5.77; N, 8.29. Found: C, 61.62; H, 5.94; N, 8.25.

Example 26

8-[[(Dimethylaminoacetyl)oxylmethyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin- 9(11H)-one Hydrochloride

26A. 8-[[(Iodoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1 ,2-b]quinolin-9(11H)-one

To a suspension of (±)-3-ethyl-1,11-dihydro-3-hydroxy-3H,13H-furo[3',4':6,7]indolizino[1,2-b]quinolin-13-one (320 mg, 1.00 mmol) in dry CΗ₂CI₂ (20 mL) under argon was added over 4 min diisobutylaluminum hydride (1.10 mL of 1.0M in CH₂Cl₂). After 15 min iodoacetic anhydride (530 mg, 1.50 mmol) was added in one portion. After 2 h, MeOH (10 mL) was added to the reaction, and after stirring 20 min, the solvent was removed in vacuo. The residue was dissolved in CH₂CI₂ and chromatographed on silica gel eluting with a gradient of 0-5% MeOH/CH₂Cl₂ to give the title compound and some unreacted starting material. ¹HNMR (CDCI₃) d 8.42 (s, 1H), 8.24 (d, 7= 8.4 Hz, 1H), 7.96 (d, 7= 8.3 Hz, 1H), 7.85 (m, 1H), 7.69 (m, 1H), 7.29 (s, 1H), 5.33 (s, 4H), 3.70 (s, 2H), 2.99 (q, 7= 7.2 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). CIMS (NH₃, m/e, rel. int.) 489 (100) [(M+H)+]. Anal. Calcd for C₂₁H₁₇IN₂O₄.1/2 H₂O: C, 50.72; H, 3.65; N, 5.63. Found: C, 50.53; H, 3.35; N, 5.45.

26B. 8-[[(Dimethylaminoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinoιin-9(11H)-one Hydrochloride

A suspension of 8-[[(iodoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2b]quinolin-9(11H)-one (48.8 mg, 0.098 mmol) in dry CΗ₂CI₂ (5.0 mL) was covered by an atmosphere of (CH3)₂NH (balloon). Within a few min the solid had dissolved and after 5 min the reaction was stripped to dryness. The residue was dissolved in CH₂CI₂, washed first with 5% aqueous NaHCO₃ and then with H₂O, and dried over Na₂SO₄. The solvent was removed in vacuo, and the residue was suspended in H₂O (20 mL) to which was added 1N HCI (100 μL) to dissolve most of the solid. After filtration, lyophilization gave the tide compound. ¹H NMR (CDCl₃/MeOH-d₄) d 8.47 (s, 1H), 8.23 (d, J= 8.3 Hz, 1H), 7.98 (d, 7= 7.5 Hz, 1H), 7.87 (m, 1H), 7.71 (m, 1H), 7.44 (s, 1H), 5.38 (s, 2H), 5.35 (s, 2H), 3.95 (s, 2H), 3.05 (s, 6H), 3.02 (q, J= 7.1 Hz, 2H), 1.27 (t, J= 7.1 Hz, 3H). Anal. Calcd for C₂₃H₂₃N₃O₄ΗCl.7/4H₂O: C, 58.35; H, 5.86; N, 8.88. Found: C, 58.26; H, 5.51; N, 8.68.

Example 27

8-[[(4-Morpholinoacetyl)oxy]methyn-7-(1-oxopropyl)indolizino[1.2-b]quinolin- 9(11H)-one Hydrochloride

A suspension of 8-[[(iodoacetyl)oxy]methyl]-7-(1-oxopropyl)indolizino[1,2-b]quinolin-9(11H)-one (138.2 mg, 0.278 mmol) in dry CΗ₂CI₂ (18 mL) containing morpholine (75 μL, 0.86 mmol) was stirred with moisture exclusion for 1.5 h, and then H₂O was added and the layers separated. The organic layer was washed successively with H₂O, 5% aqueous NaHCO3, and finally H₂O. After drying over Na2SO4, the organic layer was stripped to dryness, and H₂O (50 mL) and 1N HCI (284 μL) were added to dissolve all the residue. Lyophilization gave the tide compound. 1H NMR (CDCl₃/MeOH-d₄) d 8.50 (s, 1H), 8.23 (d, 7= 8.6 Hz, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.88 (m, 1H), 7.72 (m, 1H), 7.47 (s, 1H), 5.37 (s, 2H), 5.35 (s, 2H), 4.08 (br s, 4H), 3.99 (s, 2H), 3.50 (br s, 4H), 3.05 (s, 6H), 3.03 (q, J =

7.1 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). Anal. Calcd for C₂₅H₂₅N₃O₅.5/4HCl-7/4 H₂O: C, 57.24; H, 5.72; N, 8.01. Found: C, 57.17; H, 5.33; N, 7.62.

Claims

We claim:

1. A method for treating viral infections comprising administering to an infected host in need thereof an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, alone or in combination with a carrier

wherein:

R⁷ is -H, -CN, lower alkyl, or -(CH₂)_nCH₂V where n=0-3; R⁹ is -H, -OR, -NRR¹, -CN, -(CH₂)_nCH₂V where n=0-3;

R¹⁰ is -H, -OR, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -O-(CH₂)1-5CH₂NRR¹, -OC(O)NRR¹, 1,4'-bipiperidme-1'-carboxy, -(CH₂)_nCH₂V where n=0-3;

V is -OH, -OCOR¹⁴, OP(O)(OH)R ¹⁵, or -NRR¹;

R ¹¹ is -H or -OR;

R¹² is -H or lower alkyl;

R and R¹ are independentiy selected from the group consisting of -H,

-C_1-6 alkyl, and, when R and R¹ are substituted on nitrogen, R and R¹ can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;

R¹⁴ is -CR¹²R¹⁶R¹⁷, -(CH₂)_nCH₂R¹⁷ (where n=1-3);

;

;

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

-O(CH₂)_nCH₂R¹⁷ (where n = 1-3);

-NRR¹;

-NH(CH₂)_nCH₂R¹⁷ (where n = 1-3);

R¹⁵ is OH, OR¹⁸, or CH₂NH₂; R¹⁶ is H or the side chain of any naturally occuring a-amino acid;

R^{1 7} is NRR¹,

, , where X is any pharmaceutically acceptable anion; R¹⁸ is lower alkyl;

X is CHR³R⁴ or

;

Y is -CH₃, -CH₂OR²; R² is -H, -C(O)H, -COR¹⁴ or -P(O)(OH)R¹⁵;

R³ is -OH, -OCOR¹⁴, or -OP(O)(OH)R¹⁵;

R⁴ is -H, lower alkyl, or -OR; and

R⁶ is -H or lower alkyl; provided that: a) if one of R⁷, R⁹ , R¹⁰ or R¹¹ is otiier than -H, only one of the others may be other than -H; b) only one of R⁷, R⁹, R¹⁰ or R¹¹ may be -NRR¹; c) when X is -CHR³R⁴ and R⁴ is -OR, R³ is -OH; and

d) when Yis -CH₂OR², X is

.

2. The method of claim 1 wherein: R⁷, R⁹, R¹⁰, andR¹¹ are each -H; X is

-CHR³R⁴ or

; and Y is -CH₃ or -CH₂OR².

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

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

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

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

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

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

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

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

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

12. The method of Claim 2 wherein: X is -CΗR³R⁴, where R³ is

OP(O)(OH)R¹⁵; and Y is CH₃.

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

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

15. The method of claim 1 wherein: X is

; and Y is CΗ₂OR².

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

17. The method of claim 1 wherein: R⁷ is CH₂OR²; X is

; and Y is

-CH₃.

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

19. The method of claim 1 wherein: R⁷, R⁹, and R¹¹ are each -Η; provided thatR¹⁰ is not-Η.

20. The method of claim 18 wherein: R¹⁰ is -OR, -CN, -COR¹², or

-(CH₂)_nCH₂V; and Xis -CHR³R⁴, where R⁴ is -H or lower alkyl, or X is

21. The method of claim 20 wherein: R¹⁰ is -(CH₂)_nCH₂V; and X is

where R⁶ is CH₂CH₃.

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

23. The method of claim 1 wherein: R⁷ is -H; R⁹ is -OR, -ΝRR¹, -CΝ, or -(CH₂)_nCH₂V; R¹¹ is -H;

24. The method of claim 23 wherein: R⁹ is -(CH₂)_nCH₂V; R¹⁰ is -OR; X is -

CHR³R⁴ where R³ is -OH and R⁴ is -H or lower alkyl, or X is

, and Y is

-CH₃.

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

26. The method of claim 25 where R⁷ is lower alkyl, -CN, or -(CH₂)_nCH₂V; X is -CHR³R⁴ where R⁴ is -H or lower alkyl, or X is

.

27. The method of claim 26 wherein said compound is

7-[1-[(aminoacetyl)oxy]propyl]-12-cyano-8-methylindolizino[1,2-b]quinolin- 9(11H)-one.

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

29. The method of claim 28 wherein: R⁹ is -OR, X is -CΗR³R⁴ where R⁴ is -H or lower alkyl.

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

31. A compound of Formula I, or a pharmaceutically acceptable salt thereof

wherein:

R⁷ is -H, -CN, lower alkyl, -(CH₂)_nCH₂V where n=0-3; R⁹ is -H, -OR, -NRR¹, -CN, -(CH₂)_nCH₂V where n=0-3;

R¹⁰ is -H, -OR, -NRR¹, -CN, -COR¹², -CH(OH)R¹², -O-(CH₂)_1-5CH₂NRR¹, -OC(O)NRR¹, 1,4'-bipiperidine-1'-carboxy, -(CH₂)_nCH₂V where n=0-3; V is -OH, -OCOR¹⁴, -OP(O)(OH)R¹⁵, or -NRR¹;

R¹¹ is -H, or -OR; R¹² is -H or lower alkyl;

R and R¹ are independendy selected from the group consisting of -H,

-C_1-6 alkyl, and, when R and R¹ are substituted on nitrogen, R and R¹ can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen;

R¹⁴ is -CR¹²R¹⁶R¹⁷,

-(CH₂)_nCH₂R¹⁷ (where n=1-3);

;

;

(where n=0 or 1, and CH₂R¹⁷can be substituted on the phenyl at the 2, 3, or 4 position);

-O(CH₂)_nCH₂R¹⁷ (where n = 1-3);

-NRR¹;

-NH(CH₂)_nCH₂R¹⁷ (where n = 1-3); R¹⁵ is OH, OR¹⁸, or CH₂NH₂; R¹⁶ is H or the side chain of any naturally occuring a-amino acid;

R¹⁷ is NRR¹,

, where X is any pharmaceutically acceptable anion;

R¹⁸ is lower alkyl;

X is -CHR³R⁴ or

; Y is -CH₃, or -CH₂OR²;

R² is -H, -C(O)H, -COR¹⁴, or -P(O)(OH)R¹⁵;

R³ is -OH, -OCOR¹⁴, or -OP(O)(OH)R¹⁵

R⁴ is -H, lower alkyl, or -OR; and

R⁶ is -H or lower alkyl; provided that: a) if one of R⁷, R⁹ , R¹⁰ or R¹¹ is other than -H, only one of the others may be other than -H; b) only one of R⁷, R⁹, R¹⁰ or R¹¹ may be -NRR¹; c) when X is -CHR³R⁴ and R⁴ is -OR, R³ is -OH;

d) when Y is -CH₂OR², X is

; e) when R⁷, R⁹, R¹⁰, and R₁₁ are all -H and Y is -CH₃, then X is not -C(O)H, -CH₂OH, -C(O)CH₂CH₃, or -CH(OH)CH₂CH₃; f) when R⁷, R⁹, R¹⁰ and R¹¹ are all -H and Y is -CH₂OC(O)H, then X is not -C(O)CH₂CH₃; and g) when R⁷, R⁹, R¹⁰, R¹¹. and Y are all -H, then X is not -CH₂OH or

-C(O)H.

32. A compound of claim 31 wherein: R⁷, R⁹, R¹⁰, and R¹¹ are each -H; X is

-CHR³R⁴ where R⁴ is -H or lower alkyl, or X is R where R⁶ is -H or lower alkyl; and Y is -CH₃ or CH₂OR².

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

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

35. A compoundof claim 32 wherein saidcompound is 8-methyl-7-[1-[(-2-pyrrolidinyIcarbonyl)oxy]propyl]indolizino[1,2-b]quinolin-9(11H)-one.

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

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

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

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

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

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

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

43. A compound of claim 1 wherein: X is

; and Y is CΗ₂OR².

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

45. A compound of claim 1 wherein: R⁷ is CΗ₂OR²; X is

; and Y is

-CH₃.

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

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

48. A compound of claim 47 wherein: R¹⁰ is -OR, -CN, -COR¹², or

-(CΗ₂)_nCΗ₂V; X is -CHR³R⁴ where R⁴ is -H or lower alkyl, or X is

.

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

50. A compound of claim 48 wherein: R¹⁰ is -(CH₂)_nCH₂V; and Xis

, R⁶ is CH₂CH₃.

51. A compound of claim 31 wherein: R⁷ and R¹¹ are each -H; provided that R⁹ andR¹⁰ are each not -H.

52. A compound of claim 51 wherein: R⁹ is -(CH₂)_nCH₂V; R¹⁰ is -OR; X is

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

; and Y is -CH₃ or CH₂OR²

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

54. A compound of claim 53 where R⁷ is lower alkyl, -CN, or -(CH₂)_nCH₂V; X is -CHR³R⁴ where R⁴ is -H or lower alkyl, or X is

.

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

56. A compound of claim 31 wherein: R⁷, R¹⁰. andR¹¹ are each -Η; provided that R⁹ is not -Η.

57. A compound ofclaim 56 wherein: R⁹ is -OR, X is -CΗR³R⁴ where R⁴ is - H or lower alkyl.

58. A compound of claim 31 wherein: R⁷, R⁹, and R¹⁰ are each -H; provided thatR¹¹ is not-H.

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

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

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

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

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

64. The method of claim 1 wherein said viral infection is caused by

cytomegalovirus and the infected host is a mammal.

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