SUBSTITUTED INDOLIZINO[1,2-b]QUINOLINONES

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: SUBSΗTUTED INDOLIZINO[l,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[l,2-b]quinolinyl derivatives which have antiviral activity and pharmaceutical compositions thereof. Background Certain lH-pyrano[3',4':6,7]indolizino[l,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 _ndoli-άno[l,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[l,2-b]quinolinones lacking the a- hydroxylactone moiety do have antiviral activity but not the undesirable cytotoxicity of camptothecin. Thus, such substituted indolizino[l,2-b]qu_nσIinones 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: R 7 is -H, -CN, lower alkyl or -(CH2) n CH2N where n=0-3; R9 is -H, -OR, -NRR 1 , -CN, -(CH2) n CH2V where n=0-3; R!0 is -H, -OR, -NRR 1 , -CN, -COR 12 , -CH(OH)R 12 , -O-(CH2)l-5CH2NRR 1 , -OCCOJNRR 1 , l,4'-bipiperidine-l'-carboxy, -(CH2) n CH2V where n=0-3; V is -OH, -OCOR 14 OP(O)(OH)R 15 or -NRR 1 ; R π is -H or -OR; R 2 is -H or lower alkyl; R 1 ^ is lower alkyl; R and R are independently selected from the group consisting of -H, -Ci-6 alkyl, and, when R and R are substituted on nitrogen, R and R can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen; R^ is -CR^RiόRH. -(CH 2 ) n CH 2 R 17 (where n=l-3); CH— NH (where n=0 or 1, and CH2R 7 can be substituted on the phenyl at the 2, 3, or 4 position); -O(CH 2 ) n CH 2 R 17 (where n = 1-3); -NRR 1 ; -NH(CH2) n CH 2 R 17 (where n = 1-3); R 15 is OH, OR 18 or CH 2 NH2; R Ϊ 6 is H or the side chain of any naturally occuring a-amino acid; where X is any pharmaceutically acceptable anion; R 8 is lower alkyl; 6 X is -CH(OH)CH(OH)CH3, -CHR3R 4 or R . Yis -CH3 or -CH2OR 2 ; R 2 is -H, -C(O)H, -COR 14 - or -P(O)(OH)R 15 ; R 3 is -OH, -OCOR 14 , or -OP(O)(OH)R 1 5 R 4 is -H, lower alkyl, or -OR; and R6 is -H or lower alkyl. provided that: a) if one of R 7 , R , R 10 or R 11 is other than -H, only one of the others may be other than -H; b) only one of R 7 , R 9 , R 10 or R 1 1 may be -NRR 1 ; c) when X is -CHR 3 R 4 and R 4 is -OR, R 3 is -OH; d) when Y is -CH2OR 2 , X is R . This invention also provides compounds having the formula of Formula I as described hereinabove, except that: a) when R 7 , R 9 , R 10 , and R 11 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 R 7 , R 9 , R 10 and R 11 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 "Cj.g 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 "l,4'-bipiperidine-r-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. 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 (HSN1) 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 IMl Ml X is -CH(OH)CH(OH)CH3, -CHR R 4 , or and Y is -CH3 or -CH2OR 2 , Formula IMl corresponding to Formula I wherein R 7 , R 9 , R 1 ^, and R 1 are each - H and X and Y are as described herein. A more preferred method uses compounds of Formula IMl where X is CHR 3 R 4 where R 3 is -OH, OCOR 14 or OP(O)(OH)R 15 and Y is -CH3, where X is where R 6 is -H or lower alkyl and Y is -CH3 or -CH2OR 2 , 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 IM2 Formula IM2 corresponding to Formula I wherein R 7 , R 9 , and R 1 are each H, R ^ is as defined hereinabove for Formula I except that R 1 ^ is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM2 where R^° is -OR, -CN, COR 12 , or -(CH2) n CH2V; or X is -CHR 3 R 4 where R 3 is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower alkyl and Y is -CH3, or X is R where R 6 is -H or lower alkyl and Y is -CH3 or CH2OR 2 Yet another prefenred method of use according to the present invention uses compounds of Formula IM3 IM3 Formula IM3 corresponding to Formula I wherein R 7 and R 1 are each -H, R 9 and R^ are as defined hereinabove for Formula I except that R 9 and R ^ are each not -H, and X and Y are as defined hereinabove in Formula L A more preferred method uses compounds of Formula IM3 wherein R 9 is -(CH2)nCH2V, R 10 is -OR, X is CHR3R 4 where R 3 is -OH, OCOR 14 or OP(O)(OH)R 1 5 and R 4 is -H or lower alkyl, or X is is -H or lower alkyl, and Y is -CH3 or CH 2 OR 2 Another preferred method of use according to the present invention uses compounds of Formula IM4 1M4 Formula IM4 corresponding to Formula I wherein R 9 , R 1 ^ and R 11 are each -H, R 7 is as defined hereinabove except that R 7 is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM4 where R 7 is lower alkyl, -CN, or -(CH2) n CH2V; X is CHR R4 where R 3 is - O < OH, OCOR 14 or OP(O)(OH)R 1 5 and R 4 is -H or lower alkyl, or X is where R 6 is -H or lower alkyl, and Y is -CH3 or CH2OR 2 . Yet another preferred method of use according to the present invention uses compounds of Formula IM5 IM5 Formula IM5 corresponding to Formula I wherein R 7 , R 1 ^ and R 1 are -H, R 9 is as defined hereinabove for Formula I except that R 9 is not -H, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM5 where R 9 is -OR, X is CHR 3 R 4 where R is -OH, 0 OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower alkyl, or X is R where R 6 is -H or lower alkyl, and Y is -CH3 or CH 2 OR 2 Still another preferred method of use according to the present invention uses compounds is represented by Formula 1M6 IM6 Formula IM6 corresponding to Formula I wherein R 7 , R 9 and R ^ are each H, R * ■ is -OR, and X and Y are as defined hereinabove in Formula I. A more preferred method uses compounds of Formula IM6 where R 11 is OR, X is CHR3R 4 where R is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H_or lower alkyl, or X is where R 6 is -H or lower alkyl, and Y is -CH3 or CH2OR 2 . 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) hen R7, R9, RlO f and R 11 are all -H and Y is -CH3, then X _s not -C(O)H, -CH2OH, -CH(OH)CH(OH)CH3, -C(O)CH2CH3, or -CH(OH)CH2CH3; and b) when R 7 , R 9 , R 10 and R 11 are all -H and Y is -CH2θqθ)H, then X is not -C(O)CH2CH3. Preferred compounds of the present invention include those of Formula INI INI Formula INI corresponding to Formula I wherein R 7 , R 9 , R 1 ^ and R 11 are each -H, -H or lower alkyl, and Y is CH3 or CH2OR 2 (provided R 6 is not -CH 2 CH when Y is -CH3) or X is CHR 3 R 4 where R is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower alkyl (provided that R 4 is not -CH2CH3 when R 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 R 7 , R 9 and R 11 are each -H, R 1 ^ is as described hereinabove for Formula I except that R 1 ^ is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN2 include those where R 10 is -OR, -CN, -COR 12 , or -(CH2) n CH2V, and X is CHR3R 4 where R3 is -OH, OCOR 14 or OP(O)(OH)R J 5 and R 4 is -H or lower alkyl, or X is Another preferred group of compounds of the present invention is represented by Formula IN3 IN3 Formula IN3 corresponding to Formula I wherein R 7 and R 1 are each -H, R 9 and iO are as described hereinabove for Formula I except that R 9 and R ^ are not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN3 include those where R 9 is -(CH2) n CH2V, R 10 is -OR, X is CHR 3 R 4 where R 3 is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower - alkyl, or X is R where R 6 is -H or lower alkyl, and Y is -CH3 or CH2OR 2 - Still another preferred group of inventive compounds is represented by Formula IN4 IN4 Formula IN4 corresponding to Formula I wherein R 9 , R 1 ^ and R 1 are each -H, R 7 is as described hereinabove for Formula I except that R 7 is not -H, and X and Y are as defined hereinabove for Formula L More preferred compounds of Formula IN4 include those compounds where R 7 is lower alkyl, -CN, or -(CH2)nCH2V; X is CHR3R 4 where R 3 is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower alkyl, or X is is -H or lower alkyl, and Y is -CH3. Another preferred group of compounds according to the present invention is represented by Formula IN5 IN5 Formula IN5 corresponding to Formula I wherein R 7 , R!0 and R 11 are each -H, R 9 is as described hereinabove for Formula I except that R 9 is not -H, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN5 include those compounds where R 9 is -OR, X is CHR3R 4 where R3 is -OH, OCOR 14 or OP(O)(OH)R 15 and R 4 is -H or lower alkyl, or X is where R 6 is -H or lower alkyl, and Y is -CH3 or CH2OR 2 . Yet a further group of preferred compounds is represented by Formula IN6 IN6 Formula IN6 corresponding to Formula I wherein R 7 , R 9 and R 1 ^ are each -H, R 11 is -OR, and X and Y are as defined hereinabove for Formula I. More preferred compounds of Formula IN6 are compounds where R 11 is -OR, X is CHR R 4 where R3 is -OH, OCOR 14 or OP(O)(OH)R 1 5 and R 4 is -H or lower alkyl, or X is / /// < R where R 6 is -H or lower alkyl, and Y is -CH3 or CH2OR 2 . The following compounds are particularly preferred: 7-[l-[(aminoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin-9(llH)-one; 7-[l-[(3-amino-l-oxopropyI)oxy]propyl]-8-methylindolizino [l,2-b]quϊnolin-9(l IH)-one; 8-methyl-7-[l-[(2-pyrrolidinylcarbonyl)oxy]propyl]indolizino [l,2-b]quinolin-9(l lH)-one; 7-[l-[[2-amino-3-(lH-imidazol-4-yl)-l-oxopropyI]oxy]propyl]-8- methylϊndoIizino[l,2-b]quinoIin-9(HH)-one; 7-[l-[(2-amino-3-methyl-l-oxobutyl)oxyJpropyl]-8-methylindolizino [l,2-b]quinolin-9(HH)-one; 7-[l-[(2-amino-2-methyI-I-oxopropyl)oxy]propyl]-8-methylindolizino[l,2- b]quinoIin-9(l lH)-one; 7-[l-[(ammoacetyl)oxy]propyl]-2-cyano-8-methylindolizino- [l,2-b]qulnolin-9(l lH)-one; 8-methyI-7-[ 1 -[[(2-pyrrolidinylcarbonyl)aminoacetyl] oxy] - propyl]indolizino[l,2-b]quinoIin-9(llH)-one; 8-methyl-7-[l-[[(dimethylamino)acetyI]oxy]propyl]indolizino[l,2-b]quinolin- 9(llH)-one; 7-[l-[[(l,4 , -bipiperidin-r-yl)acetyl]oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(llH)-one; 8-methyl-7-[l-[(4-morpholinylacetyl)oxy]propyl]indolizino[l,2-bJquinolin-9(llH)- one; 8-methyl-7-[l-[[(4-methylpiperazin-l-yl)acetyl]oxy]propyl]indolizino[l,2- b]quinolin-9(l lH)-one; 7-[l-[[(l-imidazolyl)acetyl]oxy]propyl]-8-methylindolizino[l,2-b]quinolin-9(llH)- one; 8-methyl-7-[l-[(pyridinioacetyl)oxy]propyl]indolizino[l,2-b]quinolin-9(llH)-one iodide; 7-[l-[[4-[(dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[l,2- b]quinolin-9(l lH)-one; 8-Methyl-7-[l-[[4-(pyridiniomethyl)benzoyl]oxy]propyl]indolizino[l,2-b]quinolin- 9(1 lH)-one trifluoroacetate; 8- [[(4-morpholinoacetyl)oxy] methyl] -7- ( 1 -oxopropyl)indolizino [ 1 ,2-b] quinolin- 9(llH)-one; 7-[l-[[(aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino [l,2-b]quinolin-9(HH)-one; 12-[[(aminoacetyl)oxy]methyl]-8-methyl-7-( 1 -oxopropyl)indolizino[ 1 ,2-b]quinolin- 9(llH)-one; 8-methyl-12-[[(4-morpholinoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino [l,2-b]quinolin-9(l lH)-one; 8-methyl-7-[l-[(phosphono)oxy]propyl]inodlizino[l,2-b]quinolin-9(llH)-one; and 8-[[(dimethylaminoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2-b]quinolin- 9(llH)-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 R 7 - R 11 substituent to obtain an 8-me_hyl-7-(l-oxopropyl)indolizino[l,2-b]quinolin- 9(1 lH)-one. Alternatively, the lactone ring may be opened and then the R 7 - R 11 substituents introduced. In yet another alternative method, an existing R 7 - R 11 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, lO-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 R 7 - R 11 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 R 7 - R 1 ^ However, these methods also apply to compounds of the present invention having any other combination of R 7 - R 1 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 R 2 ^ and R 21 are groups convertible into R 14 and R 1 ^ respectively, by either deprotection or further elaboration by well-known methods. Scheme 2 As illustrated in Scheme 3, dehydration of alcohols 3 gives alkenes 10 which can be hydroxylated to diols 11. Oxidative cleavage of the diols generates 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. Scheme 3 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 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, TetrahedronLett. 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, Mnθ2). Deprotection gives the keto aldehydes 37. Similarly, the triflates are converted to vinyl ethers 38 following the method of Cabri, W., et al. (J. Org. Chem. 1990, 55, 3654), and then compounds 38 are hydrolyzed to diketones 39. Selective hydrolysis of the enol ether function in compounds 38 produces the 2-keto compounds that can be reduced to secondary alcohols from which the ketal groups can be removed and the alcohol function acylated 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 tt. 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 Scheme 9 .con'tl Scheme 9 (con't) 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. Scheme 10 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 1x10^ 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 mlJwell 2 x 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:H2θ 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 th& 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 (±Vl-Methoxy-7-(l-hydroxypropylV8-methyIindolizinori.2-b1quinolin-9rilH)-one A solution of l-methoxy-8-methyl-7-(I-oxopropyl)_ndolizino[l,2- b]quinolin-9(UH)-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. l K NMR (CDC_3/MeOH-d4) d 8.77 (s, IH), 7.69 (m, 2H), 7.59 (s, IH), 6.92 (dd, J = 6.8, 1.7 Hz, IH), 5.23 (br s, 2H), 4.89 (m, IH), 4.05 (s, 3H), 2.24 (s,3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Example 2 (±)-2-Cvano-7-(l-hydroxypropy -8-methylindolizinorL2-blquinolin-9(l lH -one The title compound was prepared according to the procedure in Example 1 except using 2-cyano-8-methyl-7-(l-oxopropyl)indolizino[l,2-b]quinolin-9(l 1H)- one. J Η NMR (CDCl3 MeOH-d ) d 8.29 (s, IH), 8.32 (d, J=1.7 Hz, IH), 8.20 (d, J = 8.9 Hz, IH), 7.92 (dd, J= 8.8, 1.8 Hz, IH), 7.67 (s, IH), 5.30 (br s, 2H), 4.91 (m, IH), 2.26 (s, 3H), 1.79 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for C2θHi7N 3 O 2 -H2θ: C, 68.75; H, 5.48; N, 12.03, Found: C, 68.97; H, 5.26; N, 11.72. Example 3 (±V7-π -r(Aminoacetyl)oxy1propyn-8-methylindolizinor 1.2-blquinolin-9( 1 lHVone Ηvdrotrifluoroacetate 3A. (±V8-Methyl-7-ri-. πT(l .1-dimethylethoxy arbonvnaminol- acetvnoxvlpropvl1indolizinoπ.2-b1quinolin-9(l lH)-one To a suspension of N-[(l,l-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-(l-hydroxypropyl)-8-methylindolizino[l,2-b]quinolin-9(l lH)-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 NaΗCθ3 (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. J H NMR (CDCI3) d 8.34 (s, IH), 8.21 (d, J = 8.8 Hz, IH), 7.91, (d, J= 8.3 Hz, IH), 7.81, (m, IH), 7.63, (m IH), 7.32 (s, IH), 5.96 (apparent br t, J = 7.0 Hz, IH), 5.25 (s, 2H), 5.03 (br s, IH), 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. (±V7-ri-r(AminoacetyDoxy1propyl1-8-methylindolizinori.2-b1quinoIin- 9(1 IHVone Ηydrotrifluoroacetate To a stirring suspension of (±)-8-methyl-7-[l- dimemylethoxy)carrx)nyl]arrήno]acetvl]oxy]propyl]indolizino[l,2-b]quinolin- 9(1 lH)-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 Et2θ, filtered and lyophilized to afford the title compound as a pale yellow solid. 41 NMR (DMSO-d6) d 8.68 (s, IH), 8.24 (m, IH), 8.13 (m, IH), 7.86 (apparent br t, IH), 7.70 (apparent br t, IH), 7.19 (s, IH), 5.91 (apparent br t, IH), 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 C2lH2lN3θ3- 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 (±V7-ri-r(3-Amino-l-oxopropy oxy1propyl1-8-methylindolizinori.2-b1quinolin- 9(1 IHVone Ηvdroacetate 4A. f±V8-Methyl-7-ri-rr3-rrfl.l-dimemvIethoxy^C-irbonyllamino1-l- oxopropynoxylpropynindolizinori .2-b1quino.in-9( 1 IHVone A mixture containing (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2- biquinolin-9(UH)-one (61.2 mg, 0.20 mmol), 4-dimethylaminopyridine (7.4 mg, 0.06 mmol), 4-nitrophenyl 3-[[(l,l-dimethylethoxy)carbonyl]amino]propionate (248 mg, 0.80 mmol) and dry triethylamine (222 mL, 1.60 mmol) in 1,2- dicMoroethane (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-[[(l,l- 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 Et2θ and dried in vacuo to afford the title compound, mp 155-8°C. ^E. NMR (CDCI3) d 8.35 (s, IH), 8.22 (d, J = 8.6 Hz, IH), 7.91 (d, J = 7.2 Hz, IH), 7.81 (m, IH), 7.63 (m, IH), 7.32 (s, IH), 5.90 (dd, / = 7.7, 6.1 Hz, IH), 5.26 (s, 2H), 5.02 (br s, IH), 3.44 (m, 2H), 2.66 (q, /= 5.8 Hz, 2H), 2.02-1.80 (m, 2H), 1.38 (s, 9H), 0.98 (t, / = 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. (±V7-ri-r(3-Amino-l-oxopropvnoxvlpropvll-8- methvlindolizinoπ.2-b1quinolin-9(l IHVone Ηvdroacetate The title compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[l-[[3-[[(l,l-dimethylethoxy)carbonyl]a__iino]-l- oxopropyl]oxy]propyl]indoli_ no[l,2-b]quinolin-9(llH)-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, NMR (CDCl3/MeOH-d4) d 8.42 (s, IH), 8.20 (d, J = 8.4 Hz, IH), 7.96 (d, J = 8.3 Hz, IH), 7.84 (m, IH), 7.67 (m, IH), 7.43 (s, IH), 5.92 (dd, J = 7.7, 6.0 Hz, IH), 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, / = 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-[l-r(-2-pyrrolidinylcarbonyl " .oxy1propynindolizinori.2-b1quinolin- 9(1 IHVone Ηydrotrifluoroacetate and Separation of Isomers 5A. (R.SV 8-Methyl-7-r 1 - \(S) 1-. (1. l-dimethyle.hoxytearbonyll-2- pyrτolidinylcarbonylloxylpropyl1indolizinori.2-b1quinolin-9(l IHVone The title compound was prepared according to the procedure in Example 3A except using N-[(l,l-dimethylethoxy)carbonyl]-L-proline, N,N'- cUisopropylcarboώirnide and (±)-7-(l-hydroxypropyl)-8- methylindolizino[ 1 ,2-b]quinolin-9( 1 lH)-one. 5B. fR.SV8-Methyl-7-ri-r((SV2-pyrrolidinylcarbonvnoxy1propynindolizino .1.2-b1quinolin-9(l IHVone Ηvdrotrifluoroacetate To a mixture containing (R,SV8-methyl-7-[l-[[(S)l-[(l,l- dimethylethoxy)carbonyl]-2-pyrrolidinylcarbonyl]oxy]propyl]indolizino [l,2-b]quinolin-9(HH)-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. ^R NMR (D2O) d 7.68 and 7.64 (2 s, IH), 7.45 and 7.36 (two d, IH), 7.33-6.95 (m, 3H), 6.94 and 6.91 (two s, IH), 5.93 (m, IH), 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, IH), 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. (SV8-Methyl-7-ri-rrrS)-2-pynOlidinylcarbonvnoxy1propyllindolizino π .2-b1quinolin-9(l IHVone Ηydrotrifluoroacetate The diastereomeric mixture of (R,S)-8-methyl-7-[l-[((S)-2- pyrrolidinylcarbonyl)oxy]propyl]indolizino[l,2-b]quinolm-9(l lH)-one was purified by preparative chromatography (JY column packed with 2 kg 15-20 mm Vydac Cl8 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. iHNMR (D2O) d 7.99 (s, IH), 7.75 (d, J= 8.5 Hz, IH), 7.57 (m, IH), 7.51 (d, J= 8.2 Hz, IH), 7.33 (m, IH), 7.20 (s, IH), 6.09 (dd, J = 7.9, 5.6 Hz, IH), 4.9-4.7 (m obscured by HOD peak), 4.52 (d, /= 18.9 Hz, IH), 4.40 (d, J = 18.8 Hz, IH), 3.53 (t, J = 7.3 Hz, 2H), 2.75 (m, IH), 2.45-2.08 (m, 5H), 2.30 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H). Anal. Calcd for O24H25N3O3-2 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-V8-Methyl-7-ri-r((S ' )-2-pyιτoIidinylcarbonyl ' )oxylpropyniπdoIizino π .2-b1quinolin-9f 1 IHVone 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. Ϊ -ΗN R (D2O) d 8.00 (s, 1Η), 7.68 (d, J= 8.5 Ηz, 1Η), 7.56-7.49 (m, 2Η), 7.32 (m, IH), 7.19 (s, IH), 6.09 (dd, J = 8.0, 5.2 Hz, IH), 4.93-4.67 9m obscured by HOD peak), 4.49 (d, J = 18.9 Hz, IH), 4.40 (d, J = 19.0 Hz, IH), 3.66-3.57 (m, 2H), 2.78 (m, IH), 2.47 (m, IH), 2.29 (m, 2H), 2.24 (s, 3H), 2.15 (m, 2H), 1.17 (t, 3H). Anal. Calcd for C24H25N3O3-7 CF3CO2H- H2O: C, 35.83; H, 3.17; N, 3.30. Found: C, 35.86; H, 3.24; N, 3.64. 5E. (R.SV8-Methyl-7-n-rrfRVl-r(l.l-dimethylethoxyicarbonyll-2- pvrrolidinvlcarbonylloxylpropyl1indoIizinori.2-blquinolin-9rilH>-one To a mixture of N-[(l,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-I(l,l-dimethylethoxy)carbonyl]-D-proline anhydride. This was added to a suspension of (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2-b]quinolin-9(l 1H)- 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.SV8-Methyl-7-ri-r((RV2-pyrrolidinylcarbonyl)oxy1propynindolizino n.2-blquinolin-9(llH>-one Hvdrotrifluoroacetate The title compound was prepared according to the procedure in Example 5B except using (R,S)-8-methyl-7-[l-[[(R)-l-[(l,l-dimethylethoxy)carbonyl]-2- pyrrolidinylcarbonyl]oxy]propyl]indolizino[ 1 ,2-b]quinolin-9( 1 lH)-one. ^H 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. fRV8-Methyl-7-ri-rffRV2-pyrrolidinylcarbonvnoxy1propynindolizino ri.2-b1quinolin-9f 1 IHVone Ηvdrotrifluoroacetate The title compound was obtained by separation of the diastereomers of (R,S)-8-methyl-7-[l-[((R)-2- pyrrolidinylcarbonyl)oxy]propyl]indolizino[l,2-b]quinolin-9(l IHVone according to the procedure in Example 5C. Anal. Calcd for C24Η25N3O3-3 CF3CO2HΗ2O: C, 47.19; H, 3.96; N, 5.50. Found: C, 47.24; H, 4.30; N, 5.83. 5H. (SV8-Methyl-7-ri-r(rRV2-pyrrolidinylcarbonyl ' )oxy1propynindolizino [1.2-blquinolin-9(l IHVone Ηydrotrifluσroacetate The tide compound was obtained by separation of the diastereomers of (R,S)-8-methyl-7-[l-[((R)-2-pyrrolidinylcarbonyl)oxy]propyl]indolizino [l,2-b]quinolin-9(HH)-one according to the procedure in Example 5C. Anal. Calcd for C24Η25N3O3-8/3 CF3CO2HΗ2O: C, 48.56; H, 4.12; N, 5.79. Found: C, 48.61; H, 4.53; N, 6.10. Example 6 (Tl.SV7-ri-rrrSV2-Ar-iino-3-(lH-imidazol-4-ylVl-oxopropyl1oxy1propyl1-8- methylindolizinoπ.2-b1quinolin-9(l IHVone Ηydrotrifluoroacetate 6A. (R.SV8-Methyl-7-ri-rr(SV2-rr(l.l-dimethyIethoxy)carbonyllaminoT-3-(lH- imidazol-4-ylVl-oxopropynoxy1propynindolizinoπ.2-b1quinolin-9(llH)-one The title compound was prepared according to the procedure in Example 3 A except using N,l-bis[(l,l-dimethylethoxy)carbonyl]-L-histidine, N,N'- chisopropylcarbodiimide and (±)-7-(l-hydroxypropyl)-8- methyl doH__ino[l,2-bJquinolin-9(llH)-one. 6B. (R.SV7-ri-rr(SV2-Amino-3-(lH-imidazol-4-ylVl-oxopropynoxylpropyn-8- methylindolizinori.2-b1quinolin-9(l IHVone Ηydrotrifluoroacetate The tide compound was prepared according to the procedure in Example 5B except using (R,S)-8-methyl-7-[l-[[(S)-2-[[(l,l-dimethylethoxy)carbonyl]amino]-3- (lH-imidazol-4-yl)-l-oxopropyl]oxy]propyl]indolizino[l,2-b]quinolin-9(llH)-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. l K NMR (D2O) d 8.64 and 8.35 (two s, IH), 8.22 (d, IH), 7.90 (d, IH), 7.70 (m, 2H), 7.45 (m, 2H), 7.20 (s, IH), 6.04 (m, IH), 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-ri-r(2-Amino-3-methyl-l-oxobutyl)oxylpropyn-8- methylindolizinori.2-b1quinolin-9ri lH>-one Ηydrotrifluoroacetate 7A. (±VS-Methyl^-ri-rr∑-rrd.l-dimethylethoxy arbonyllaminol-S-methyl-l- oxobutvnoxylpropynindolizinori .2-b1quinolin-9(l lH)-one The tide compound was prepared according to the procedure in Example 3 A except using N-[(l,l-dimethylethoxy)carbonyl]-L-valine and (±)-7-(l- hydroxypropyl)-8-methylindolizino[ 1 ,2-b]quinolin-9( 1 IHVone. NMR (CDCI3) d 8.34 (s, 1Η), 8.22 (m, 1Η), 7.91 (d, / = 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, IH), 4.36 (two d, / = 4.5 Hz, IH), 2.36 (s, 3H), 2.4-2.2 (m, IH), 2.1-1.8 (m, 2H), 1.44 and 1.38 (two s, 9H), 1.00 (overlapping t and d, 9H). (±V7-ri-r(2-Amino-3-methyl-l-oxobutvnoxylpropyn-8- methylindolizinon.2-blquinolin-9(l IHVone Ηydrotrifluoroacetate The tide compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[l-[[2-[[(l,l-dimethylethoxy)carbonyl]amino]-3- methyl-l-oxobutyl]oxy]propyl]indolizino[l,2-b]quinolin-9(l IHVone. ^Trl NMR (CDCI3, MeOΗ-d4) d 8.39 and 8.35 (two s, IH), 8.20-8.13 (m, IH), 7.94-7.81 (m, 2H), 7.66 (apparent br t, IH), 7.41 (two s, IH), 6.05 (m, IH), 5.25 (s, 2H), 3.98 (two d, J= 4.4 Hz, IH), 2.55-2.36 ^ (m, IH), 2.33 (s, 3H), 2.14-1.90 (m, 2H), 1.15- 1.01 (m, 9H). Anal. Calcd for C24H27N3θ3-CF3Cθ2H-7/4 H2O: C, 56.67; H, 5.76; N, 7.63. Found: C, 56.65; H, 5.62; N, 7.29. Example 8 (±V7-ri-r(2-Amino-2-methyl-l-oxopropyl ' )oxylpropyn-8-methylindolizinori.2- b1quinolin-9(l IHVone Ηvdrotrifluoroacetate 8A. (±V8-Methyl-7-r l-rr2-rrf 1.1 -dimethylethoxykarbonvHaminol-2-methyl- 1 - oxopropylloxylpropynindolizinor 1.2-b1quinolin-9( 11 HVone To a mixture containing 2-methyl-2-[N-[(l,l- dimethylethoxy)carbonyl]amino]propionic acid (406 mg, 2.0 mmol) and dicyclohexylcarbodiimide (432 mg, 2.0 mmol) in CΗ2CI2 (3 mL) under an argon atmosphere were added (±)-7-(l-hydroxypropyl)-8-methylindolizino [l,2-b]quinolin-9(llH)-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 CΗ2G2, 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/CH2C_2 afforded the tide compound as an off- white solid. l H NMR (CDCI3) d 8.33 (s, IH), 8.20 (d, J = 8.9 Hz, IH), 7.90 (d, / = 8.3 Hz, IH), 7.80 (m, IH), 7.62 (m, IH), 7.33 (s, IH), 5.92 (dd, J = 7.5, 6.3 Hz, IH), 5.25 (s, 2H), 5.10 (br s, IH), 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, / = 7.4 Hz, 3H). 8B. f±V7-ri-rf2-Amino-2-methvI-l-oxopropyDoxy1propyn-8- methylindolizinoπ .2-b1quinolin-9(l IHVone Ηvdrotrifluoroacetate The tide compound was prepared according to the procedure in Example 3B except using (±)-8-methyl-7-[l-[[2-[[(l,l-dimethyIethoxy)carbonyl]amino]-2- methyl-l-oxopropyl]oxy]propyl]mdoUz_no[l,2-b]quinolin-9(llH)-one. 4l NMR (DMSO-d6) d 8.67 (s, 1Η), 8.11 (m, 2Η), 7.84 (m, IH), 7.70 (m, IH), 7.21 (s, IH), 5.85 (dd, /= 7.9, 5.8 Hz, IH), 5.25 (s, 2H), 2.24 (s, 3H), 2.1-1.83 (m, 2H), 1.52 (s, 3H) T 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 f±V7-ri-rfAminoacetvDoxvTpropvn-2-cvano-8-methvlindolizinori.2-b1quinolin- 9(1 IHVone Ηydrotrifluoroacetate 9A. (±V2-Cvano-8-methvI-7-ri-rrrrπ.l- dimethylethoxy.carbonyπamino1acetylloxy1propyl1indolizinori.2-b1quinolin- 9(πHVQne ' The tide compound was prepared according to the procedure in Example 3 A except using (±)-2-cyano-7-(l-hydroxypropyl)-8-methylindohzino[l,2-b]quinolin- 9(llH)-one. 9B. r±V7-ri-r(Aminoacety oxy1propyn-2-cyano-8- methylindolizinori .2-frlquinoIin-9(l IHVone The tide compound was prepared according to the procedure in Example 3B except using (±)-2-cyano-8-methyl-7-[l-[[[[(l,l- dimethylethoxy)carbonyljamino] acetyl]oxy]propyl]indolizino[ 1 ,2-b]quinolin- 9(llH)-one. NMR (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 C22H20 4O3-3/2 CF3CO2HH2O: C, 52.00; H, 4.10; N, 9.70. Found: C, 52.04; H, 4.32; N, 9.73. Example 10 (±V7-ri-r(Aminoacetyl)oxylpropyl1-12-cyano-8-methyIindolizinori.2-blquinolin- 9(1 IHVone Ηydrotrifluoroacetate 1QA, ^-^-Cyaηp-^-methyl-y-fl-rrrrdα- dimethylethoxy arbonvnaminolacetylloxylpropyllindolizinoπ^-blquinolin- 9(1 IHVone The tide compound was prepared according to the procedure in Example 3 A except using (±)-12-cyano-7-(l-hydroxypropyl)-8-methylindolizino[l,2-b]quinolin- 9(1 IHVone. J Η NMR (CDCI3) d 8.31 (d J = 8.5 Hz, IH), 8.27 (d, J = 8.3 Hz, IH), 7.95 (m, IH), 7.84 (m, IH), 7.32 (s, IH), 5.95 (apparent br t, J = 7.0 Hz, IH), 5.43 (s, 2H), 5.0 (br s, IH), 4.03 (m, 2H), 2.38 (s, 3H), 0.99 (t, J= 7.4 Hz, 3H). 10B. (±V7-ri-r(AminoacetvDoxylpropyπ-12-cvano-8- methylindolizinof 1.2-b1quinolin-9(l IHVone Ηydrotrifluoroacetate The tide compound was prepared according to the procedure in Example 3B except using (±)-12-cyano-8-methyl-7-[l-[[[[(l,l- dimemylemoxy)carbonyl]amino]acetyl]oxy]propyl]indolizino[l,2-b]quinolin- 9(1 IHVone. ~R NMR (CDCl3/MeOΗ-d4) d 8.28 (d, J = 8.5 Hz, IH), 8.22 (d, J = 8.4 Hz, IH), 7.95 (m, IH), 7.82 (m, IH), 7.36 (s, IH), 6.00 (apparent t, J= 6.6 Hz, IH), 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.SV8-Memyl-7-ri-rr(SVf2-p\τrolidinylcarbonv aminoacetylloxy1- propyllindolizinori .2-b1quinolin-9f 1 IHVone Ηydrotrifluoroacetate 1 T A. .SVS-Me hvl^-ri-rrrrfSΗ-rfl.l-dimethvlethoxv^carhonvll^- py-Tθliά^nylcarbonyl1aτrιinolacetyl1oxy1propyl1indoli-tinori.2-b1-quinoIin-9(llH^ one The tide compound was prepared according to the procedure in Example 5E except using (±)-7-[l-[(aminoacetyl)oxy]propyl]-8-methylindolizino [I,2-b]quinolin-9(llH)-one. 11B. fR.SV8-Methyl-7-π-rr(SVf2- pyrrolidinvIC-_rbonyDaπιinoacetyl1oxylpropyl1indoli- nori.2-b1quinolin-9(llH)-one Ηvdrotrifluoroacetate The tide compound was prepared according to the procedure in Example 5B except usmg fJl,S)-8-meu yl-7-[l-[[[[(S)l-[(l,l-dimethylethoxy)carbonyl]-2- pyιτoUdinylcarrx)nyl]ar-ino]acetyl]oxy]propyl]-ndolizino[l,2-b]-quino_-n-9(llH)- one. Anal. Calcd for C26Η28 4O4-3/2 CF3CO2H-H2O: C, 53.62; H, 4.89; N, 8.63. Found: C, 53.64; H, 5.29; N, 8.50. Example 12 f±V8-Methyl-7-ri-rr(dimethylamϊno ' .ace-vI1oxy1propyHindolizinori.2-b1quinolin- 9(1 IHVone Ηvdrochloride 12A. r±^^-fl-^Chloroacetv oxylpropyn-S-methylindolizinόri^-blquinolin- 9mHVone To a suspension of (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2- b]quinolin-9(llH)-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 die 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 vacua to afford the tide compound, NMR (CDCI3) d 8.35 (s, IH), 8.24 (d, IH), 7.93 (d, IH), 7.85 (m, IH), 7.65 (m, IH), 7.33 (s, IH), 5.99 (dd, IH), 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 C21H19CIN2O34/2 H2O: C, 64.37; H, 5.14; N, 7.15. Found: C, 64.29; H, 4.86; N, 6.82. 12B. (±)-7-ri-r(Iodoacetyl ' .oxylpropyn-8-methylindolizinori.2-blquinolin- 9(1 IHVone To a mixture of (±)-7-[l-[(chloroacetyl)oxy]propyl]-8-methylindolizino[l,2- b]quinolin-9(UH)-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 CΗ2CI2 and H2O. The organic extract was washed with H2O (3x), dried over sodium sulfate and concentrated under reduced pressure to afford the tide compound. l H NMR (CDCI3) d 8.35 (s, IH), 8.22 (d, J = 8.2 Hz, IH), 7.92 (d, / = 8.0 Hz, IH), 7.81 (m, IH), 7.66 (m, IH), 7.38 (s, IH), 5.91 (dd, J = 7.9, 6.0 Hz, IH), 5.26 (two s, 2H), 3.84 (d, J = 10.1 Hz, IH), 3.75 (d, J= 10.1 Hz, IH), 2.36 (s, 3H), 2.10-1.83 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). Anal. Calcd for C2lHi9ΪN2θ3-l/2 H2O: C, 52.19; H, 4.17; N, 5.80. Found: C, 52.16; H, 4.05; N, 5.39. 12C. (±V8-Methyl-7-ri-rr(dimethylamino acetvnoxy1proρvnindolizinori.2- b1quinolin-9(l IHVone Ηvdrochloride A stream of dimethylamine was introduced into a solution containing (±)-7- [l-[(iodoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin-9(l lH)-one (50 mg, 0.11 mmol). in anhydrous CΗ2CI2 (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. l U NMR (DMSO-d6) d 8.68 (s, IH), 8.15 and 8.12 (two overlapping d, 2H), 7.86 (m, IH), 7.71 (m, IH), 7.17 (s, IH), 5.96 (apparent br t, IH), 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, / = 7.3 Hz, 3H). CIMS (NH3, m/e, rel. int.) 392 (100) [(M+H)+]. Anal. Calcd for C23H25 3O3-2HCH3/8H2O: C, 55.96; H, 6.18; N, 8.51. Found: C, 56.27; H, 6.03; N, 8.04. Example 13 (±)-7-ri-rr(1.4'-Bipiperidin- -y acetynoxy1propylT-8-methylindolizinori.2- blquinolin-9(l IHVone Ηydroiodide To a suspension of (±)-7-[l-[(iodoacetyl)oxy]propyl]-8- methylindolizino[l,2-b]quinoIin-9(llH)-one (50 mg, 0.11 mmol) in CΗ2CI2 (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 tide compound was obtained after lyophilization. tøNMR (CDCI3) d 8.35 (s, IH), 8.21 (d, J = 8.4 Hz, IH), 7.92 (d, J = 8.3 Hz, IH), 7.83 (m, IH), 7.63 (m, IH), 7.34 (s, IH), 5.94 (apparent t, IH), 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 (±V8-Methyl-7-ri-rr4-morpholinylacetyl)oxy1propynindolizinori.2-b1quinolin- 9(1 IHVone Ηydrochloride The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[l-[(iodoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(llH)-one and morpholine. J ΗNMR (CDC_3/MeOH-d4) d 8.51 (s, IH), 8.26 (d, J= 8.5 Hz, IH), 7.99 (d, J= 8.3 Hz, IH), 7.88 (m, IH), 7.70 (m, IH), 7.53 (s, IH), 5.98 (dd, /= 7.4, 5.9 Hz, IH), 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 C25H27N3O4-2HC1-H2O: C, 57.25; H, 5.96; N, 8.01. Found: C, 57.37; H, 6.28; N, 7.65. Example 15 (±V8-Methyl-7-ri-rr(4-methylpiperazin-l-yl'.acetynoxylpropyl]indolizinori.2- b1quinolin-9(HH>-one Ηydrochloride The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[ l-[(iodoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(llH)-one and N-methylpiperazine. NMR (DMSO-d6) d 8.67 (s, 1Η), 8.15 (m, 2Η), 7.87 (m, IH), 7.72 (m, IH), 7.11 (s, IH), 5.84 (m, IH), 5.25 (s, 2H), 3.5- 2.6 (m, 13H), 2.23 (s, 3H), 2.04-1.82 (m, 2H), 0.95 (t, / = 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 (±^^-ri-rrd-ImidazolyDacetynoxylpropyn-S-methylindolizinon^-blquinolin- 9(1 IHVone Ηvdrochloride The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[l-[(iodoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(llH)-one and imidazole. J Η NMR (CDCl3/MeOH-d4) d 9.17 (s, IH), 8.60 (s, IH), 8.34 (d, IH), 8.04 (d, IH), 7.95 (m, IH), 7.75 (m, IH), 7.61 (s, IH), 7.51 (br s, IH), 7.41 (br s, IH), 5.95 (m, IH), 5.65 (d, IH), 5.42 (d, IH), 5.33 (s, 2H), 2.36 (s, 3H), 2.1-1.9 (m, 2H), 1.07 (t, 3H). Anal. Calcd for C24H22N4O3-2 HCM 1/4 H2O: C, 53.68; H, 5.35; N, 10.43. Found: C, 53.52; H, 5.58; N, 10.29. Example 17 r±V8-Methvl-7-n-rfpvridinioacetvnoxvlpropyllindolizinori.2-b1quinolin-9(llH)- pne iodide The tide compound was prepared according to the procedure in Example 13 except using (±)-7-[l-[(iodoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(1 lH)-one and pyridine. 1H NMR (CDCl3/MeOΗ-d4) d 9.09 (d, J = 5.5 Hz, 2H), 8.65 (t, J = 7.9 Hz, IH), 8.51 (s, IH), 8.17 ( , 3H), 7.99 (d, J = 8.1 Hz, IH), 7.89 (m, IH), 7.70 (m, IH), 7.50 (s, IH), 6.05 (d, /= 17.2 Hz, IH), 6.02 (m, 1H).5.87 (d, J= 17.2 Hz, IH), 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 (±V7-ri-rr4-r(Dimethylamino ' )methyllbenzoyl1oxy1propyl1-8-methylindolizinori.2- b1quinolin-9f 1 IHVone Ηydrochloride 18A. r±V7-ri-rr4-rChloromethvDbenzovnoxy1propyn-8-methylindolizinori.2- frlqmnolin-9π IHVone The tide compound was prepared according to the procedure in Example 3A except using (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2-_/]quinolin-9(l 1H one and 4-(chloromethyl)benzoic acid. l R NMR (CDCI3) d 8.33 (s, 1Η), 8.16 (m, 3Η), 7.91 (br d, /= 7.3 Hz, IH), 7.78 (m, IH), 7.61 (m, IH), 7.51 (d, J = 8.3 Hz, 2H), 7.40 (s, IH), 6.11 (dd, J= 8.1, 6.1 Hz, IH), 5.26 (s, 2H), 4.63 (s, 2H), 2.45 (s, 3H), 2.21-1.93 (m, 2H), 1.08 (t, / = 7.3 Hz, 3H). Anal. Calcd for C27H23C1N2O3-1/2 H2O: C, 69.30; H, 5.17; N, 5.99. Found: C, 69.39; H, 5.16; N, 6.02. 1 B. r±V7-π -rr4-r(Dimethylamino')methvnbenzovnoxy1propyl1-8- methylindolizinoπ .2-b1quinolin-9(l IHVone Ηydrochloride A suspension containing (±)-7-[l-[[4-(chloromethyl)benzoyl]oxy]propyl]-8- methylindolizino[l,2-b]quinoIin-9(llH)-one (35 mg, 0.08 mmol) and sodium iodide (57 mg, 0.38 mmol) in dry acetone (50 mL) was heated at reflux for 1 h and then allowed to cool and stir at room temperature overnight. Into this mixture dimethylamine was bubbled for several min, and die mixture was allowed to stir at room temperature for 1 h. The rriixture was concentrated under reduced pressure, and the residue was partitioned between Η2O 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 tide compound as a beige solid. 1H NMR (CDCl3/MeOH-d4) d 8.44 (s, IH), 8.26 (d, /= 8.3 Hz, 2H), 8.17 (d, J = 8.6 Hz, lH), 7.96 (d, J= 8.4Hz, lH), 7.82 (m, lH), 7.74 (d, J= 8.4 Hz, 2H), 7.66 (m, IH), 7.55 (s, IH), 6.14 (dd, J= 7.9, 5.8 Hz, IH), 5.28 (s, 2H), 4.31 (s, 2H), 2.80 (s, 6Ti), 2.44 (s, 3H), 2.20-1.95 (m, 2H), 1.11 (t, J = 7.4 Hz, 3H). Anal. Calcd for O29H29N3O3-3/2 HC17/2 H2O: C, 59.51; H, 6.46; N, 7.18. Found: C, 59.91; H, 6.85; N, 6.85. Example 19 (±V8-Methyl-7-ri-rr4-(pyridiniomethyl)benzoynoxy1propynindolizinoπ.2- blquinolin-9(l IHVone trifluoroacetate To a suspension of (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2- b]quinolin-9(HH)-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 Η2O 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 tide compound, NMR (CDCl3/MeOH-d4) d 9.07 (d, / = 5.7 Hz, 2H), 8.46 (m, IH), 8.39 (s, IH), 8.23 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.6 Hz, IH), 8.05 (m, 2H), 7.93 (d, / = 8.5 Hz, IH), 7.81 (m, IH), 7.65 (m, IH), 7.59 (d, J = 8.2 Hz, 2H), 7.49 (s, IH), 6.13 (dd, J = 7.8, 5.9 Hz, IH), 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 (±V7-ri-rr(Chloromethyl ' )hydroxyphosphinyl]oxy1propyn-8-methylindolizinori.2- blquinolin-9(l IHVone Triethylamine Salt To a suspension of (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2- b]quinolin-9(llH)-one (92 mg, 0.3 mmol) in CΗ2CI2 (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 RPI8 column, eluted with a solvent gradient of H2O to MeOH and lyophilized to afford the tide compound. NMR (CDCI3) d 8.27 (br s, IH), 8.13 (m, IH), 7.9- 7.5 (m, 4H), 5.60 (m, IH), 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 C20H20C1N2O4P- 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 f±V7-ri-rf2-Cyanoethoxy')hydroxyphosphiny oxylpropyl1-8-methylindolizinori.2- b1quinolin-9(l IHVone Sodium Salt (±)-7-(l-Ηydroxypropyl)-8-methylindolizino[l,2-b]quinolin-9(llH)-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 Η2O 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, IH), 8.19 (d, J= 8.1 Hz, IH), 8.05 (dd, J = 8.1, 1.0 Hz, IH), 7.86 (m, IH), 7.71 (s, IH), 7.68 (m, IH), 5.54 (m, IH), 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, / = 7.4 Hz, 3H). Anal. Calcd for C22H2lN3Naθ5P- 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-ri-r(phosphono ' .oxylpropynindolizinori.2-b1quinolin-9(llH)-one Trimethylaming Salt To (±)-7-[l-[(2-cyanoethoxy)hydroxyphosphinyl)oxy]propyl]-8- methylindolizino[l,2-b]quinolin-9(llH)-one sodium salt (89.4 mg, 0.19 mmol) in MeOΗ (1.0 mL) was added IN NaOΗ (1.65 mL), and the reaction mixture was stirred under argon for 7 h at room temperature. The reaction was acidified with IN ΗC1 (1.75 mL), stripped and redissolved in Η2O. This solution was applied of a reversed phase column of Partisil 40 ODS-3 and eluted with a gradient of 0-100% MeOH/H2θ. 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, NMR (MeOH-d4/D2θ) d 8.58 (s, IH), 8.16 (d, J= 8.5 Hz, IH), 8.04 (d, J= 8.3 Hz, IH), 7.85 (m, IH), 7.74 (s, IH), 7.68 (m, IH), 5.50 (br dd, IH), 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 Ci9HiδN2θ5P-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 (±^^-ri-rKAminomethy hydroxyphosphinylloxylpropyll-S-methylindolizinori^- b1quinolin-9(l IHVone 23A, (±)-7-π-rrrrr(9- Fluorenvlmethoxv)carbonvnaminolmethvnhvdroxvphosphinvnoxv1propvll-8- methylindolizinori.2-b1quinolin-9(l IHVone The tide compound was prepared according to the procedure in Example 21 except using (±)-7-(l-hydroxypropyl)-8-methylindolizino[l,2-b]quinolin-9(l 1HV one and [[[(9-fluorenylmethoxy)carbonyl]amino]methyl]phosphonic acid. Anal. Calcd for C35Η32N3θ<sP-9/8 H2O: C, 65.49; H, 5.38; N, 6.55. Found: C, 65.83; H, 5.28; N, 6.14. 23B. (±V7-ri-rr(Aminomethyl')hydroxyphosphinylloxy1propyll-8- methylindolizinoπ ,2-blquinolin-9(l IHVone A mixture of Et2NH (10 mL) and (±)-7-[l-[[[[[(9- fluorenylmemoxy)carbonyl]amino]methyl]hydroxyphosphinyl]oxy]propyl]-8- methylindolizino[l,2-b]quinolin-9(llH)-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 Η2O 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 tide compound as a partial Et2NH salt l R NMR (CDCl3/MeOH-d4) d 8.49 (s, IH), 8.12 (d, /= 8.7 Hz, IH), 8.00 (d, 7= 8.3 Hz, IH), 7.84 (m, IH), 7.69 (overlapping s and m, 2H), 5.59 (dd, 7 = 14.9, 6.5 Hz, IH), 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, 7 = 7.4 Hz, 3H). Anal. Calcd for C20H22N3θ4P-l/4 C4HnN-5 H2θ: C, 49.68; H, 6.90; N, 8.97. Found: C, 50.08; H, 6.49; N, 8.46. Example 24 12-rr(Aminoacety oxy1methyll-8-methyl-7-(l-oxopropy indolizinori.2-- b1quinolin-9(l IHVone Ηydrofluoroacetate 24A. S-Methyl-^-rrrrrfl.l-dimethylethoxy arbonyllaminolacetylloxylmethyll- 7-(l-oxopropy indoIizinoπ.2-b1quinolin-9(llH)-one The tide compound was prepared according to the procedure in Example 5E except using 12-0ιydroxymethyl)-8-methyl-:7-(l-oxopropyl)indolizino[l,2- b]quinolin-9(llH)-one and N-[(l,l-dimethyIethoxy)carbonyl]glycine. 24B. 12-rr(AminoacetvDoxy1methyll-8-methyl-7-(l-oxopropyl)indolizinoπ.2- b]quinolin-9(l IHVone Ηydrotrifluoroacetate The tide compound was prepared according-to the procedure in Example 5B except using 8-methyl-12-[[[[[(l,l- dimemyIemoxy)carbonyl]amino]acetyl]oxy]methyl]-7-(l-oxopropyl)indolizino[l,2- b]quinolin-9(HH)-one. iΗNMR (D2O/DSS) d 7.6-7.3 (m, 4Η), 6.64 (s, IH), 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-CF3 O2H-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-rr(4-morpholinoacetyl')oxy1methyn-7-(l-oxopropyDindolizinori.2- b1quinolin-9f 1 lH>-oneHvdrochloride To a suspension of 12-hydroxymethyl-8-methyl-7-(l- 5 oxopropyl)indoU-άno[l,2-b]quinolin-9(HH)-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 0 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 5 pH of 1.7. The resulting slurry was filtered and washed with MeCN followed by Et2θ to give the tide compound as yellow flakes(, mp. 148-150°C (dec). l H NMR (CDCI3) d 8.22 (d, 7= 8.6 Hz, IH), 8.11 (d, 7 = 8.6 Hz, IH), 7.84 (m, IH), 7.70 (m, IH), 7.25 (s, IH), 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, 7 = 7.6 Hz, 3H). Anal. Calcd for 0 C26H27N3O5ΗCM/2 H2O: C, 61.60; H, 5.77; N, 8.29. Found: C, 61.62; H, ~ 5.94; N, 8.25. Example 26 8-rrπ_ ) imethylaminoacetyl ' )oxylmethyl1-7-(l-oxopropyl ' .indolizinori.2-b1quinolin- 5 9(1 IHVone Hvdrochloride 26A. 8-rr(Iodoacetyl)oxy1methvn-7-(l-oxopropyl indolizinoπ.2-b1quinolin- 9fl IHVone To a suspension of (±)-3-ethyl-l,ll-dihydro-3-hydroxy-3H,13H- 0 furo[3',4':6,7]indolizino[l,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 CH2C-2)- 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 5 in CH2CI2 and chromatographed on silica gel eluting with a gradient of 0-5% MeOH/CH2Cl2 to give the tide compound and some unreacted starting material. iHNMR (CDCI3) d 8.42 (s, IH), 8.24 (d, 7= 8.4 Hz, IH), 7.96 (d, 7= 8.3 Hz, IH), 7.85 (m, IH), 7.69 (m, IH), 7.29 (s, IH), 5.33 (s, 4H), 3.70 (s, 2H), 2.99 (q, 7= 7.2 Hz, 2H), 1.28 (t, 7= 7.2 Hz, 3H). CIMS (NH3, m/e, rel. int.) 489 (100) [(M+H)+]. Anal. Calcd for C2lHi7_ 2θ4-l/2 H2O: C, 50.72; H, 3.65; N, 5.63. Found: C, 50.53; H, 3.35; N, 5.45. 26B. 8-ir(Dimethylaminoacetyl')oxy1methyn-7-(l-oxopropy indolizinori.2- frlquinoιin-9(l IHVone Hvdrochloride A suspension of 8-[[(iodoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2- b]quinolin-9(HH)-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 rnin 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 IN HCI (100 μL) to dissolve most of the solid. After filtration, lyophilization gave the tide compound. 1 H NMR (CDCl3/MeOH-d4) d 8.47 (s, IH), 8.23 (d, 7 = 8.3 Hz, IH), 7.98 (d, 7= 7.5 Hz, IH), 7.87 (m, IH), 7.71 (m, IH), 7.44 (s, IH), 5.38 (s, 2H), 5.35 (s, 2H), 3.95 (s, 2H), 3.05 (s, 6H), 3.02 (q, 7 = 7.1 Hz, 2H), 1.27 (t, 7 = 7.1 Hz, 3H). Anal. Calcd for C23H23N3O4ΗC1-7/4H2O: C, 58.35; H, 5.86; N, 8.88. Found: C, 58.26; H, 5.51; N, 8.68. Example 27 8-rr(4-Morpholinoacetyl ' )oxy1methyn-7-(l-oxopropyl')indolizinori.2-blquinolin- 9(1 IHVone Hvdrochloride A suspension of 8-[[(iodoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2- b]quinolin-9(HH)-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 H20, 5% aqueous NaHCO3, and finally H2O. After drying over Na2SO4, the organic layer was stripped to dryness, and H2O (50 mL) and IN HCI (284 μL) were added to dissolve all the residue. Lyophilization gave the tide compound. l R NMR (CDC_3/MeOH-d4) d 8.50 (s, IH), 8.23 (d, 7= 8.6 Hz, IH), 8.00 (d, 7= 8.1 Hz, IH), 7.88 (m, IH), 7.72 (m, IH), 7.47 (s, IH), 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, 7 = 7.1 Hz, 2H), 1.28 (t, 7 = 7.2 Hz, 3H). Anal. Calcd for C25H25N3O5-5/4HC1-7/4 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: R 7 is -H, -CN, lower alkyl, or -(CH2) n CH2V where n=0-3; R9 is -H, -OR, -NRR 1 , -CN, -(CH2) n CH2V where n=0-3; R χ 0 is -H, -OR, -NRR 1 , -CN, -COR 12 , -CH(OH)R 12 , -O-(CH2)l-5CH2NRR 1 , -OC^NRR 1 , '-bipiperidme-l'-carboxy, -(CH2) n CH2V where n=0-3; V is -OH, -OCOR 14 , -NRR 1 ; R^ is -Hor -OR R 12 is -H or lower alkyl; R and R 1 are independentiy selected from the group consisting of -H, -Cl-6 alkyl, and, when R and R 1 are substituted on nitrogen, R and R 1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen; R 14 is -CR 12 R 16 R 17 , -(CH2)nCH 2 R 17 (where n=l-3); (where n=0 or 1, and CH2R 7 can be substituted on the phenyl at the 2, 3, or 4 position); -O(CH 2 ) n CH2R 17 (where n = 1-3); -NRR 1 ; -NH(CH2) n CH 2 R 17 (where n = 1-3); R 15 is OH, OR 18 , or CH 2 NH 2 ; R ^ is H or the side chain of any naturally occuring a-amino acid; , where X is any pharmaceutically acceptable anion; R 18 is lower alkyl; Y is -CH3, -CH2OR 2 ; R 2 is -H, -C(O)H, -COR 14 or -P(O)(OH)R 15 ; R 3 is -OH, -OCOR 14 , or -OP(0)(OH) 15 ; R 4 is -H, lower alkyl, or -OR; and R6 is -H or lower alkyl; provided that: a) if one of R 7 , R 9 , R 1 ^ or R 1 is otiier than -H, only one of the others may be other than -H; b) only one of R 7 , R 9 , R 10 or R 1 1 may be -NRR 1 ; c) when X is -CHR R 4 and R 4 is -OR, R 3 is -OH; and 2. The method of claim 1 wherein: R 7 , R 9 , R 10 , andR 11 are each -H; X is -CHR 3 R 4 and Y is -CH3 or -CH2θR 2 . 3. The method of claim 2 wherein: X is -CHR 3 R 4 , where R 3 is -OH; and Y is -CH3. 4. The method of claim 2 wherein: X is -CHR 3 R 4 , where R 3 is OCOR 14 ; and Yis CH3. 5. The method of Claim 4 wherein said compound is 7-[l- [(aminoacetyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin-9(llH)-one. 6. The method of Claim 4 wherein said compound is 7-[l-[(3-amino- 1- oxopropyl)oxy]propyl]-8-methylindolizino[ 1 ,2-b]quinolin-9( 1 lH)-one. 7. The method of Claim 4 wherein said compound is 8-methyl-7-[l-[(-2- pyπOlidinylcarbonyl)oxy]propyl]indolizino[ 1 ,2-b]quinolin-9( 1 lH)-one. 8. The method of Claim 4 wherein said compound is 7-f l-[(2-amino-2-methyl- l-oxopropyl)oxy]propyl]-8-methylindolizino[l,2-b]quinolin-9(HH)-one. 9. The method of Claim 4 wherein said compound is 8-methyl-7-[l-[(4- morpholinylacetyl)oxy]propyl]indolizino[l,2-b]quinolin-9(llH)-one. 10. The method of Claim 4 wherein said compound is 8-methyl-7-[l- [(pyridinioacetyl)oxy]propyl]indolizino[l,2-b]quinolin-9(llH)-one iodide. 11. The method of Claim 4 wherein said compound is 7-[l-[[4- [(dimemylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(llH)-one. 12. The method of Claim 2 wherein: X is -CΗR 3 R 4 , where R 3 is OP(O)(OH)R 15 ; and Y is CH 3 . 13. The method of Claim 12 wherein said compound is 8-methyl-7-[l- [(phosphono)oxy]propyljindolizino[l,2-b]quinolin-9(llH)-one. 14. The method of Claim 12 wherein said compound is 7-[l- [[(arninomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[l,2- b]quinolin-9(l lH)-one. 15. The method of claim 1 wherein: X is ; and Y is CΗ2OR 2 . 16. The method of claim 15 wherein said compound is 8-[[(4- morpholinoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2-b]quinolin-9(llH)- one. 17. The method of claim 1 wherein: R 7 is CH2OR 2 ; X is ; and Y is -CH3. 18. The method of claim 17 wherein said compound is 8-methyl-12-[ (4- morpholinoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2-b]quino-in-9(llH)- one hvdrochloride. 19. The method of claim 1 wherein: R 7 , R 9 , and R 11 are each -Η; provided thatR 10 is not-Η. 20. The method of claim 18 wherein: R 10 is -OR, -CN, -COR 12 , or -(CH2) n CH2N; and Xis -CHR 3 R 4 , where R 4 is -H or lower alkyl, or X is 21. The method of claim 20 wherein: R 10 is -(CH2) n CH2V; and Xis R where R 6 is CH2CH3. 22. The method of claim 20 wherein said compound is 7-[ 1- [(aιι_ oacetyl)o--y]propy-]-2-cyanc 8-mem^ 23. The method of claim 1 wherein: R 7 is -H; R 9 is -OR, -ΝRR 1 , -CΝ, or -(CH2)nCH2V; R^ is -H; 24. The method of claim 23 wherein: R 9 is -(CH2)nCH2V; R 10 is -OR; X is - CHR 3 R 4 where R 3 is -OH and R 4 is -H or lower alkyl, or X is and Y is -CH3. 25. The method of claim 1 wherein: R 9 , R 1 ^, and R 11 are each -H; provided that R 7 is not -H. or -(CH2)nCH2V; X 27. The method of claim 26 wherein said compound is 7-[l-[(aminoacetyl)oxy]propyl]-12-cyano-8-methylindolizino[l,2-b]quinolin- 9(llH)-one. 28. The method of claim 1 wherein: R 7 , R ^, and R are each -Η; provided that R 9 is not -Η. 29. The method of claim 28 wherein: R 9 is -OR, X is -CΗR 3 R 4 where R 4 is -H or lower alkyl. 30. The method of claim 1 wherein: R 7 , R 9 , and R 1 ^ are each -H; and provided that R is not -H. 31. A compound of Formula I, or a pharmaceutically acceptable salt thereof wherein: R 7 is -H, -CN, lower alkyl, -(CH2) n CH2V where n=0-3; R 9 is -H, -OR, -NRR 1 , -CN, -(CH2) n CH2V where n=0-3; R 10 is -H, -OR, -NRR 1 , -CN, -COR 12 , -CH(OH)R 12 , -O-(CH2)l-5CH2NRR 1 , -OC^NRR 1 , l,4'-bipiperidine-r-carboxy, -(CH2) n CH2V where n=0-3; V is -OH, -OCOR 14 , -OP(O)(OH)R 15 , or -NRR 1 ; R 11 is -H, or -OR; R 12 is -H or lower alkyl; R and R 1 are independendy selected from the group consisting of -H, -Ci-6 alkyl, and, when R and R 1 are substituted on nitrogen, R and R 1 can be taken together to form a 5-7 membered saturated heterocyclic ring containing the nitrogen; R^is -CR^R^R 17 , -(CH2) n CH2R 17 (where n=l-3); CH— NH (where n=0 or 1, and CH2R 17 can be substituted on the phenyl at the 2, 3, or 4 position); -O(CH2) n CH 2 R 17 (where n = 1-3); -NRR 1 ; -NH(CH 2 ) n CH2R 17 (where n = 1-3); R 15 is OH, OR 18 , or CH 2 NH 2 ; R ^ is H or the side chain of any naturally occuring a-amino acid; R „ 17 is NRR , 1 ,- ♦ —-- } x~ •-α . , where X is any pharmaceutically acceptable anion; R 8 is lower alkyl; Y is -CH3, or -CH2OR 2 ; R 2 is -H, -C(O)H, -COR 14 , or -P(O)(OH)R 1 5; R 3 is -OH, -OCOR 14 , or -OPCOXOHQR 1 R 4 is -Hi lower alkyl, or -OR; and R6 is -H or lower alkyl; provided that: a) if one of R 7 , R 9 , R 1 ^ or R 1 J is other than -H, only one of the others may be other than -H; b) only one of R 7 , R 9 , RlO OΓ R 1 may be -NRR 1 ; c) when X is -CHR 3 R 4 and R 4 is -OR, R 3 is -OH; e) when R 7 , R 9 , R 10 , and R 1 1 are all -H and Y is -CH3, then X is not -C(O)H, -CH2OH, -C(O)CH2CH3, or -CH(OH)CH2CH3; f) when R 7 , R 9 , R 10 and R 11 are all -H and Y is -CH2OC(O)H, then X is not -C(O)CH2CH3; and g) when R 7 , R 9 , R 10 , R 11 . and Y are all -H, then X is not -CH2OH or -C(O)H. 32. A compound of claim 31 wherein: R 7 , R 9 , R 1 ^, and R 1 ■ are each -H; X is -CHR 3 R 4 where R 4 is -H or lower alkyl, or X is R where R*> is -H or lower alkyl; and Y is -CH3 or CH 2 OR 2 . 33. A compound of claim 32 wherein said compound is 7-[l- [(a-__ noacetyl)oxy]propyl]-8-me yl_ndoU-__no[l,2-b]quinolin-9(llH)-one. 34. A compound of claim 32 wherein said compound is 7-[l-[(3-amino- 1- oxopropyl)oxy]propyl3-8-methylindolizino[l,2-b]quino-in-9(l lH)-one. 35. A compound of claim 32 wherein said compound is 8-methyl-7-[l-[(-2- pyιτoUd!_nyIc-_rrx)nyl)oxy]propyl]-ndolizino[l,2-b quinolin-9(llH)-one. 36. A compound of claim 32 wherein said compound is 7-[l-[(2-amino-2- me yl-l-oxopropyl)oxy]propyl]-8-memylindolizino[l,2-b]quinolin-9(llH)-one. 37. A compound of claim 32 wherein said compound is 8-methyl-7-[l-[[(2- py_τoKdinylcarb<)nyl)arj-_inoacetyl]oxy]propyl]indoh_dno[l,2-b]qu_nolm^ one. 38. A compound of claim 32 wherein said compound is 8-methyl-7-[l-[(4- moιpho]inylacetyl)oxy]propyl]-ndoliz_no[l,2-b]qu-nolin-9(l IHVone. 39. A compound of claim 32 wherein said compound is 8-methyl-7-[l- [(pyridinioacetyl)oxy]propyl]indolizino[l,2-b]quinolin-9(l lH)-one iodide. 40. A compound of claim 32 wherein said compound is 7-[l-[[4- [(dimethylamino)methyl]benzoyl]oxy]propyl]-8-methylindolizino[l,2-b]quinolin- 9(1 IHVone. 41. A compound of claim 32 wherein said compound is 8-methyl-7-[l- [(phosphono)oxy]propyl]indolizino[l,2-b]quinolin-9(HH)-one. 42. A compound of claim 32 wherein said compound is 7-[l- [[(aminomethyl)hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[l,2- b]quinolin-9(HH)-one. 43. A compound of claim 1 wherein: X is 44. A compound of claim 43 wherein said compound is 8-[[(4- morpholinoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2-b]quinolin-9(llH)- one. 45. A compound of claim 1 wherein: R 7 is CΗ2OR 2 ; X is and Y is -CH 3 . 46. A compound of claim 45 wherein said compound is 8-methyl-12-[[(4- morpholinoacetyl)oxy]methyl]-7-(l-oxopropyl)indolizino[l,2-b]quinolin-9(llH)- one hydrochloride. 47. A compound of claim 31 wherein: R 7 , R 9 , and R 11 are each -Η; provided that R 10 is not -Η. 48. A compound of claim 47 wherein: R 10 is -OR, -CN, -COR 12 , or -(CΗ2)nCΗ2V; X is -CHR 3 R 4 where R 4 is -H or lower alkyl, or X is 49. A compound claim 48 wherein said compound is 7-[l- [(aminoacetyl)oxy]propyl]-2-cyano-8-methylindolizino[l,2-b]quinolin-9(llH)-one. 50. A compound of claim 48 wherein: R 1 ^ is -(CH2)nCH2 ; and Xis -5 51. A compound of claim 31 wherein: R 7 and R 11 are each -H; provided that R 9 andR 10 are each not -H. 52. A compound of claim 51 wherein: R 9 is - CH2) n CH2V; R 10 is -OR; X is _ . -CHR 3 R 4 where R 4 is -H or lower alkyl, or X is R ; and Y is -CH3 or 0 CH2OR 2 53. A compound ofclaim 31 wherein: R 9 , R 1 ^, and R 11 are each -H; provided that R 7 is not -H. 5 54. A compound of claim 53 where R 7 is lower or -(CH2)nCH2V; X is -CHR 3 R 4 where R 4 is -H or lower alkyl, or X is 55. A compound of claim 54 wherein said compound 7-[l- [(armnoacetyl)oxy]propyl]-12-cy_mo-8-me ylindoU_άno[l,2-b]quinolin-9(llH)- 0 one. 56. A compound of claim 31 wherein: R 7 , R 1 ^. andR 11 are each -Η; provided that R 9 is not -Η. 5 57. A compound ofclaim 56 wherein: R 9 is -OR, X is -CΗR 3 R 4 where R 4 is - H or lower alkyl. 58. A compound of claim 31 wherein: R 7 , R 9 , and R 1 ^ are each -H; provided thatR 11 is not-H. 0 59. A formulation comprising a compound of claim 31 in admixture with a carrier or excipient. 60. The formulation of claim 59 where d e carrier is a pharmaceutically acceptable carrier or excipient. c 5 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. 10 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 15 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.

Inventors: BERGES DAVID ALAN, HERTZBERG ROBERT PHILIP, JOHNSON RANDALL KEITH, KINGSBURY WILLIAM DENNIS, BERGES, DAVID, ALAN, HERTZBERG, ROBERT, PHILIP, JOHNSON, RANDALL, KEITH, KINGSBURY, WILLIAM, DENNIS
Applicants: BERGES DAVID ALAN, HERTZBERG ROBERT PHILIP, JOHNSON RANDALL KEITH, KINGSBURY WILLIAM DENNIS, SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, C07D471, C07F9