Quinolinecarboxamides as antiviral agents

The present invention provides a compound of formula I ##STR1## which is useful as antiviral agents, in particular, as agents against viruses of the herpes family.

FIELD OF THE INVENTION
 The present invention provides 4-oxo-1,4-dihydro-3-quinolinecarboxamide
 derivatives. These compounds are useful as antiviral agents, in
 particular, as agents against viruses of the herpes family.
 BACKGROUND OF THE INVENTION
 The herpesviruses comprise a large family of double stranded DNA viruses.
 They are also a source of the most common viral illnesses in man. Eight of
 the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),
 varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr
 virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and
 (HHV-8), have been shown to infect humans.
 HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals,
 respectively. They also occasionally cause infections of the eye and
 encephalitis. HCMV causes birth defects in infants and a variety of
 diseases in immunocompromised patients such as retinitis, pneumonia, and
 gastrointestinal disease. VZV is the causitive agent of chicken pox and
 shingles. EBV causes infectious mononucleosis. It can also cause lymphomas
 in immunocompromised patients and has been associated with Burkitt's
 lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the
 causitive agent of roseola and may be associated with multiple sclerosis
 and chronic fatigue syndrome. HHV-7 disease association is unclear, but it
 may be involved in some cases of roseola. HHV-8 has been associated with
 Karposi's sarcoma, body cavity based lymphomas, and multiple myeloma.
 Compounds of the present invention are distinct from other hydroxyquinoline
 antiviral agents in that the 4-substituent on the benzyl amide of the
 present invention (i.e. the chloro, bromo, cyano, or nitro substituent)
 provides significantly improved antiviral activity. Certain compounds of
 formula (I) also possess unique substituents R.sup.4 that provide improved
 antiviral activity.
 INFORMATION DISCLOSURE
 U.S. Pat. No. 5,891,878 and WO 97/04775 disclose compounds that are
 reported to be useful in the treatment of a disease state capable of being
 modulated by inhibition of production of phosphodiesterase IV or tumor
 necrosis factor. The genera of compounds disclosed in these applications
 are believed to overlap with the compounds of formula I disclosed herein.
 However, no specific compounds are prepared in these PCT applications
 having the 4-substitutedbenzamide group of the compounds of formula I
 herein.
 U.S. Pat. No. 3,960,868 discloses derivatives of 6, 7, or 8
 cycloalkyl-4-oxoquinoline-3-carboxylic acid that are reported to possess
 analgesic, anti-inflammatory, anti-microbial, and histamine liberating
 properties. The structure of these compounds differs from the structure of
 the compounds of formula I by requiring a cycloalkyl substituent at the 6,
 7, or 8 position of the quinoline ring.
 U.S. Pat. No. 4,959,363 discloses quinolonecarboxamide compounds that are
 reported to possess antiviral activity. The structure of these compounds
 differs from the structure of the compounds of formula I disclosed herein
 at the 3-position by not including a 4-substitutedbenzamide, and at the
 6-position by requiring a hydrogen or fluoro substituent.
 U.S. Pat. No. 5,175,151, discloses quinolone compounds that are reported to
 possess antihypertensive and antiviral activity. The structure of these
 compounds differs from the structure of the compounds of formula I
 disclosed herein at the 3-position by not including a
 4-substitutedbenzamide, and at the 2-position by requiring an oxygen
 linked substituent.
 U.K. Patent Application 1,191,443 discloses quinoline derivatives that are
 reported to possess antiviral activity. The structure of these compounds
 differs from the structure of the compounds of formula I disclosed herein
 by not including a 4-substitutedbenzamide at the 3-position, and by
 requiring a fused furan heterocyclic ring at the 5,6-, 6,7-, or
 7,8-position of the quinolone.
 WO 97/14682 discloses quinoline derivatives that are reported to be useful
 to treat specific hormone dependent diseases. The structure of these
 compounds differs from the structure of the compounds of formula I
 disclosed herein at the 3-position by not including a
 4-substitutedbenzamide, at the 1-position, by requiring a halogenoaralkyl,
 and at the 7-position by requiring an acylaminoaryl group.
 U.S. Pat. No. 4,786,644, discloses 1-aryl-3-quinolinecarboxamides that are
 reported to be useful to treat pain and inflammation. The structure of
 these compounds differs from the structure of the compounds of formula I
 disclosed herein at the 3-position by not including a
 4-substitutedbenzamide, and at the 1-position by requiring an optionally
 substituted phenyl substituent.
 U.S. Pat. No. 4,835,163, discloses N-alkoxyalkyl derivatives of quinolone
 carboxamides that are reported to possess anticonvulsive and psychotonic
 activity. The structure of these compounds differs from the structure of
 the compounds of formula I disclosed herein at the 3-position by not
 including a 4-substitutedbenzamide substituent.
 U.S. Pat. No. 5,096,901; U.K. Application Number 2 236 751; and T. J. Ward
 et al., Med. Chem. Res. (1993), 4, 267-272 disclose
 quinolone-3-(azabicyclo)carboxamides that are reported to possess 5-HT3
 activity and to be useful to treat neuro-psychiatric disorders. The
 structure of these compounds differs from the structure of the compounds
 of formula I disclosed herein by requiring an azabicyclo containing
 substituent at the 3-position.
 JP 02124871 discloses quinolone compounds that are reported to possess
 5-lipoxygenase activity. The structure of these compounds differs from the
 structure of the compounds of formula I disclosed herein at the 3-position
 by not including a 4-substitutedbenzamide substituent.
 EP 0 332 930A2, discloses quinolone compounds that are reported to possess
 antibacterial antiviral activity. The structure of these compounds differs
 from the structure of the compounds of formula I disclosed herein at the
 3-position by not including a 4-substitutedbenzamide, and at the
 6-position by requiring a hydrogen, halo, or nitro substituent.
 Chem. Abstracts (1969), 71, 101735q, discloses quinolone compounds that are
 reported to possess antiinflamatory activity. The structure of these
 compounds differs from the structure of the compounds of formula I
 disclosed herein at the 3-position by not including a
 4-substitutedbenzamide substituent.
 U.S. Pat. Nos. 5,051,418 and 4,908,366, disclose 8-cyano-quinolone
 compounds that are reported to possess antibacterial activity. The
 structure of these compounds differs from the structure of the compounds
 of formula I disclosed herein at the 3-position by not including a
 4-substitutedbenzamide, and at the 8-position by requiring a cyano
 substituent.
 EP 0 370 686, discloses a process for preparing quinolone carboxylic acid
 intermediates. The structure of the disclosed compounds differs from the
 structure of the compounds of formula I disclosed herein at the 3-position
 by not including a 4-substitutedbenzamide, and at the 6-position by
 requiring a fluoro substituent.
 U.S. Pat. No. 4,621,088, discloses quinolone amino acid derivatives that
 are reported to possess antiallergic activity, central nervous system
 activity and cardiovascular activity. The structure of these compounds
 differs from the structure of the compounds of formula I disclosed herein
 at the 3-position by not including a 4-substitutedbenzamide.
 U.S. Pat. No. 5,328,887 discloses an array of compounds including numerous
 quinolone compounds that are reported to be useful as fluorescent donor
 elements for use in a thermal transfer possess. The single specific
 4-quinolone compound prepared and tested in the application differs from
 the compounds of formula I disclosed herein at the 3-position by not
 including a 4-substitutedbenzamide, at the 2-position by having a phenyl
 substituent, at the 6-position by having a hydrogen, and at the 1-position
 by being unsubstituted.
 U.S. Pat. No. 4,855,291, discloses quinolone compounds that are reported to
 possess antihypertensive activity. The structure of these compounds
 differs from the structure of the compounds of formula I disclosed herein
 at the 3-position by not including a 4-substitutedbenzamide.
 U.S. Pat. No. 3,524,858, discloses quinolone compounds that are reported to
 possess anti-microbial activity. The structure of these compounds differs
 from the structure of the compounds of formula I disclosed herein at the
 3-position by not including a 4-substitutedbenzamide, and at the
 6,7-positions by requiring a methylenedioxy substituent.
 WO 98/23608 discloses quinolone compounds that are reported to possess
 integrin antagonist activity. The structure of these compounds differs
 from the structure of the compounds of formula I disclosed herein at the
 3-position by not including a 4-substitutedbenzamide.
 U.S. Pat. No. 5,026,856, discloses isoindoline compounds that are reported
 to possess antibacterial activity. The structure of these compounds
 differs from the structure of the compounds of formula I disclosed herein
 at the 3-position by not including a 4-substitutedbenzamide, and at the
 6-position by requiring a halo, hydroxy, or loweralkoxy substituent.
 U.S. Pat. No. 5,563,141, discloses an array of compounds that are reported
 to inhibit cell adhesion. Although the disclosed genus of compounds may
 include 3aminocarbonyl-4-quinolones, these compounds do not comprise a
 4-substituted-benzamide at the 3-position. All of final compounds
 specifically prepared in the patent comprise a 4-pyridyl(piperazin-1-yl)
 ring system.
 WO 9932450 discloses compounds of the following generic formula which are
 useful for the treatment of herpesvirus infections.
 ##STR2##
 Liebigs Ann. Chem. 1987, 871-879 describes the synthesis of the following
 structure through the combination of an aryl acid chloride and a
 .beta.-hydrazidoalkenyl amide.
 ##STR3##
 EP 343560 discloses antibacterial agents having the following structure.
 ##STR4##
 JP 02040379 discloses compounds useful as antibacterials having generic
 structure.
 ##STR5##
 U.S. Pat. No. 5,412,104 discloses the following generic structure as being
 useful as antiviral agents against DNA containing viruses such as herpes
 group viruses.
 ##STR6##
 SUMMARY OF THE INVENTION
 The present invention provides a compound of formula I,
 ##STR7##
 or a pharmaceutically acceptable salt thereof wherein,
 X is
 a) O, or
 b) S;
 W is
 a) R.sup.2 ;
 b) NR.sup.7 R.sup.8,
 c) OR.sup.9, or
 d) SO.sub.i R.sup.9 ;
 R.sup.1 is
 a) Cl,
 b) F,
 c) Br,
 d) CN, or
 e) NO.sub.2 ;
 R.sup.2 is
 a) (CH.sub.2 CH.sub.2 O).sub.m R.sup.10,
 b) het, wherein said het is bonded via a carbon atom,
 c) C.sub.1-7 alkyl which may be partially unsaturated and is optionally
 substituted by one or more substituents selected from a group consisting
 of NR.sup.7 R.sup.8, R.sup.11, CN, SO.sub.i R.sup.9, or OC.sub.2-4 alkyl
 which is further substituted by het, OR.sup.10, OC(.dbd.O)aryl, or
 NR.sup.7 R.sup.8, or
 d) C.sub.3-8 cycloalkyl, which may be partially unsaturated and is
 optionally substituted by R.sup.11, NR.sup.7 R.sup.8, SO.sub.i R.sup.9, or
 C.sub.1-7 alkyl optionally substituted by R.sup.11, NR.sup.7 R.sup.8, or
 SO.sub.i R.sup.9 ;
 R.sup.3 is
 a) H,
 b) halo, or
 c) C.sub.1-4 alkyl, optionally substituted by one to three halo;
 R.sup.4 is
 a) H,
 b) aryl,
 c) het,
 d) SO.sub.2 NHR.sup.12,
 e) CONHR.sup.12,
 f) NR.sup.7 R.sup.8,
 g) NHCOR.sup.12,
 h) NHSO.sub.2 R.sup.12,
 i) OC.sub.2-7 alkyl optionally substituted by --OH,
 j) SC.sub.2-7 alkyl optionally substituted by OH, or
 k) C.sub.1-8 alkyl which may be partially unsaturated and is optionally
 substituted by one or more substituents selected from a group consisting
 of N.sub.3, OR.sup.10, NR.sup.7 R.sup.8, halo, SO.sub.i R.sup.9, OR.sup.13
 or R.sup.11 ;
 R.sup.5 is
 a) H,
 b) halo,
 c) C.tbd.CR.sup.14,
 d) NR.sup.7 R.sup.8,
 e) SO.sub.2 NHR.sup.12,
 f) het, or
 g) C.sub.1-7 alkyl, optionally substituted by OH;
 R.sup.6 is
 a) H,
 b) halo,
 c) SC.sub.1-7 alkyl,
 d) C.sub.1-7 alkoxy, optionally substituted by one or more halo or OH, or
 e) C.sub.1-7 alkyl, which may be partially unsaturated and is optionally
 substituted by halo, NR.sup.10 R.sup.10, (CH.sub.2).sub.n OR.sup.13,
 R.sup.11, OC.sub.1-7 alkyl which is further substituted with het, NR.sup.7
 R.sup.8, or SO.sub.i R.sup.9 ;
 R.sup.7 and R.sup.8 are independently
 a) H,
 b) aryl,
 c) C.sub.1-7 alkyl which may be partially unsaturated and is optionally
 substituted by one or more substituents selected from a group consisting
 of NR.sup.10 OR.sup.10, CONR.sup.10 R.sup.10, R.sup.11, SO.sub.i R.sup.9,
 halo; or
 d) R.sup.7 and R.sup.8 together with the nitrogen to which they are
 attached to form a het;
 R.sup.9 is
 a) aryl,
 b) het,
 c) C.sub.3-8 cycloalkyl, or
 d) C.sub.1-7 alkyl which may be partially unsaturated and optionally
 substituted by one or more OR.sup.10, Oaryl, het, aryl, NR.sup.10
 R.sup.10, CN, SH, SO.sub.i C.sub.1-6 alkyl, SO.sub.i aryl, halo, or
 CONR.sup.10 R.sup.10 ;
 R.sup.10 is
 a) H, or
 b) C.sub.1-7 alkyl, optionally substituted by OH;
 R.sup.11 is
 a) OR.sup.10,
 b) Ohet,
 c) Oaryl,
 d) CO.sub.2 R.sup.10,
 e) het,
 f) aryl, or
 g) CN;
 R.sup.12 is
 a) H,
 b) het,
 c) aryl,
 d) C.sub.3-8 cycloalkyl, or
 e) C.sub.1-7 alkyl optionally substituted by NR.sup.7 R.sup.8, or R.sup.11
 ;
 R.sup.13 is
 a) (P.dbd.O)(OH).sub.2,
 b) (P.dbd.O)(C.sub.1-7 alkoxy).sub.2,
 c) CO(CH.sub.2).sub.n CON(CH.sub.3)(CH.sub.2).sub.n SO.sub.3.sup.- M.sup.+,
 d) an amino acid,
 e) C(.dbd.O)aryl,
 f) C(.dbd.O)C.sub.1-6 alkyl, optionally substituted by NR.sup.10 R.sup.10,
 or
 g) CO(CH.sub.2).sub.n CO.sub.2 H;
 R.sup.14 is
 a) het,
 b) (CH.sub.2).sub.n OR.sup.3, or
 c) C.sub.1-7 alkyl substituted by one or more substituents selected from a
 group consisting of R.sup.11, OC.sub.1-7 alkyl which is further
 substituted with het, NR.sup.7 R.sup.8, or SO.sub.i R.sup.9 ; aryl is a
 phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at
 least one ring is aromatic;
 het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated
 or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected
 from the group consisting of oxygen, sulfur, and nitrogen, which is
 optionally fused to a benzene ring, or any bicyclic heterocycle group;
 wherein any aryl is optionally substituted with one or more substituents
 selected from the group consisting of halo, OH, CF.sub.3, C.sub.1-6
 alkoxy, and C.sub.1-6 alkyl which maybe further substituted by one to
 three SR.sup.10, NR.sup.10 R.sup.10, OR.sup.10, or CO.sub.2 R.sup.10 ;
 wherein any het is optionally substituted with one or more substituents
 selected from the group consisting of halo, OH, CF.sub.3, C.sub.1-6
 alkoxy, oxo, oxine, and C.sub.1-6 alkyl which maybe further substituted by
 one to three SR.sup.10, NR.sup.10 R.sup.10, OR.sup.10, or CO.sub.2
 R.sup.10 ;
 i is 0, 1, or 2;
 m is 1, 2, or 3;
 n is 1, 2, 3, 4, 5, or 6; and
 M is sodium, potassium, or lithium;
 With the proviso that R.sup.1 is not Cl, Br, F, or CN; when
 X is O;
 R.sup.2 is C.sub.1-7 alkyl optionally substituted by R.sup.15 ;
 R.sup.3 is H, methyl, or halo;
 R.sup.4 is H, CONH(C.sub.1-7 alkyl), NR.sup.16 R.sup.17, or C.sub.1-7 alkyl
 optionally substituted by OR.sup.10, CN, COOH, or NR.sup.16 R.sup.17 ;
 R.sup.5 is H, halo, SO.sub.2 NHR.sup.10, NR.sup.16 R.sup.17, or C.sub.1-7
 alkyl optionally substituted by OR.sup.10 ;
 R.sup.6 is H, halo, C.sub.1-7 alkoxy, or C.sub.1-7 alkyl optionally
 substituted by halo, OR.sup.10, CO.sub.2 R.sup.10 or NR.sup.16 R.sup.17 ;
 R.sup.15 is NR.sup.16 R.sup.17, OR.sup.10, CN, or CO.sub.2 R.sup.10 ; and
 R.sup.16 and R.sup.17 are independently H or C.sub.1-7 alkyl; or NR.sup.16
 R.sup.17 together with the nitrogen to which they are attached form a 5-
 or 6-membered ring such as pyrrolidine, piperidine, morpholine, or
 piperazine.
 In another aspect, the present invention also provides:
 a pharmaceutical composition comprising a compound of formula I, or a
 pharmaceutically acceptable salt thereof, and a pharmaceutically
 acceptable carrier,
 a method of treating or preventing a herpesviral infection, comprising
 administering to a mammal in need of such treatment, a compound of formula
 (I) or a pharmaceutically acceptable salt thereof,
 a compound of formula (I) or a pharmaceutically acceptable salt thereof for
 use in medical treatment or prevention of a herpesviral infection,
 the use of a compound of formula (I) or a pharmaceutically acceptable salt
 thereof to prepare a medicament for treating or preventing a herpesviral
 infection in a mammal, and
 a method for inhibiting a viral DNA polymerase, comprising contacting (in
 vitro or in vivo) the polymerase with an effective inhibitory amount of a
 compound of formula I, or a pharmaceutically acceptable salt thereof.
 The invention also provides novel intermediates and processes disclosed
 herein that are useful for preparing compounds of formula I.
 DETAILED DESCRIPTION OF THE INVENTION
 The following definitions are used, unless otherwise described. Halo
 denotes fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both
 straight and branched groups; but reference to an individual radical such
 as "propyl" embraces only the straight chain radical, a branched chain
 isomer such as "isopropyl" being specifically referred to. When alkyl can
 be partially unsaturated, the alkyl chain may comprise one or more (e.g.
 1, 2, 3, or 4) double or triple bonds in the chain.
 Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic
 radical wherein at least one ring is aromatic. Aryl is optionally
 substituted with one or more substituents selected from the group
 consisting of halo, OH, CF.sub.3, C.sub.1-6 alkoxy, and C.sub.1-6 alkyl
 which maybe further substituted by one to three SR.sup.10, NR.sup.10
 R.sup.10, OR.sup.10, or CO.sub.2 R.sup.10 ;
 Het denotes a four- (4), five- (5), six- (6), or seven- (7) membered
 saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms
 selected from the group consisting of oxygen, sulfur, and nitrogen, which
 is optionally fused to a benzene ring, or any bicyclic heterocycle group.
 Het is optionally substituted with one or more substituents selected from
 the group consisting of halo, OH, CF.sub.3, C.sub.1-6 alkoxy, oxo, oxine,
 and C.sub.1-6 alkyl which maybe further substituted by one to three
 SR.sup.10, NR.sup.10 R.sup.10, OR.sup.10, or CO.sub.2 R.sup.10 ;
 "Amino acid," includes a residue of natural amino acid (e.g. Ala, Arg, Asn,
 Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, leu, Lys, Met, Phe, Pro, Ser,
 Thr, Trp, Tyr, and Val) in D or L form, as well as unnatural amino acids
 (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline,
 gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid,
 statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,
 ornithine, citruline, -methyl-alanine, para-benzoylphenylalanine,
 phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). An
 amino acid can conveniently be linked to the remainder of a compound of
 formula I through the carboxy terminus, the amino terminus, or through any
 other convenient point of attachment, such as, for example, through the
 sulfur of cysteine. In particular, an amino acid can conveniently be
 linked to the remainder of a compound of formula I through the carboxy
 terminus.
 Mammal denotes human and animals.
 It will be appreciated by those skilled in the art that compounds of the
 invention having a chiral center may exist in and be isolated in optically
 active and racemic forms. Some compounds may exhibit polymorphism. It is
 to be understood that the present invention encompasses any racemic,
 optically-active, polymorphic, tautomeric, or stereoisomeric form, or
 mixture thereof, of a compound of the invention, which possesses the
 useful properties described herein, it being well known in the art how to
 prepare optically active forms (for example, by resolution of the racemic
 form by recrystallization techniques, by synthesis from optically-active
 starting materials, by chiral synthesis, or by chromatographic separation
 using a chiral stationary phase) and how to determine antiviral activity
 using the standard tests described herein, or using other similar tests
 which are well known in the art.
 The carbon atom content of various hydrocarbon-containing moieties is
 indicated by a prefix designating the minimum and maximum number of carbon
 atoms in the moiety, i.e., the prefix C.sub.i-j indicates a moiety of the
 integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example,
 C.sub.1-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive.
 The compounds of the present invention are generally named according to the
 IU or CAS nomenclature system. Abbreviations which are well known to
 one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me"
 for methyl, "Et" for ethyl, "h" for hour or hours and "rt" for room
 temperature).
 Specific and preferred values listed below for radicals, substituents, and
 ranges, are for illustration only; they do not exclude other defined
 values or other values within defined ranges for the radicals and
 substituents
 Specifically, alkyl can be methyl, ethyl, propyl, isopropyl, butyl,
 iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, etc.; C.sub.3-8
 scycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
 cycloheptyl, or cyclooctyl; alkoxy can be methoxy, ethoxy, propoxy,
 isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy,
 1-methylhexyloxy, or heptyloxy; het can be azetidinyl,
 3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino, morpholino,
 thiomorpholino, or heteroaryl; and heteroaryl can be furyl, imidazolyl,
 triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,
 pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),
 thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its
 N-oxide) or quinolyl (or its N-oxide).
 A specific value for R.sup.1 is Cl.
 A specific value for R.sup.1 is F.
 A specific value for R.sup.1 is CN, or NO.sub.2.
 A specific value for R.sup.2 is (CH.sub.2 CH.sub.2 O).sub.m H, or (CH.sub.2
 CH.sub.2).sub.m C.sub.1-4 alkyl, wherein m is 2, or 3.
 A specific value for R.sup.2 is C.sub.3-8 cycloalkyl optionally substituted
 by R.sup.11, NR.sup.7 R.sup.8, SO.sub.i R.sup.9, or C.sub.1-7 alkyl
 optionally substituted by R.sup.11, NR.sup.7 R.sup.8, or SO.sub.i R.sup.9
 ; wherein R.sup.7, R.sup.8, R.sup.9, R.sup.11 and i are the same as
 defined above.
 A specific value for R.sup.2 is cyclopropyl.
 A specific value for R.sup.2 is het wherein said het is bonded via a carbon
 atom and is the same as defined above.
 A specific value for R.sup.2 is tetrahydro-2H-pyranyl, piperdinyl,
 1-methyl-piperidinyl, or 1,1 -dioxo-tetrahydro-2H-thiopyran.
 A specific value for R.sup.2 is C.sub.2-7 alkyl which is partially
 unsaturated and optionally substituted by NR.sup.7 R.sup.8, R.sup.11,
 SO.sub.i R.sup.9, or OC.sub.2-4 alkyl which is further substituted by het,
 OR.sup.10, or OC(.dbd.O)aryl; wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10
 are the same as defined above.
 A specific value for R.sup.2 is (Z or E)-CH.dbd.CHR.sup.10, or
 --C--C.tbd.CR.sup.10 ; wherein said R.sup.10 is H, or C.sub.1-7 alkyl
 optionally substituted by OH.
 A specific value for R.sup.2 is C.sub.1-7 alkyl substituted by NR.sup.7
 R.sup.8, R.sup.11, SO.sub.i R.sup.9, or OC.sub.2-4 alkyl which is further
 substituted by het, OR.sup.10, or OC(.dbd.O)aryl wherein R.sup.7, R.sup.8,
 R.sup.9, R.sup.10 and R.sup.11 are the same as defined above.
 A specific value for R.sup.2 is C.sub.1-7 alkyl substituted by OC.sub.2-4
 alkyl which is further substituted by het, OH, OC.sub.1-4 alkyl, or
 OC(.dbd.O)aryl.
 A specific value for R.sup.2 is C.sub.1-7 alkyl substituted by SO.sub.i
 R.sup.9 wherein R.sup.9 and i are the same as defined above.
 A specific value for R.sup.2 is C.sub.1-7 alkyl substituted by SO.sub.i
 R.sup.9 ; wherein R.sup.9 is C.sub.1-4 alkyl, optionally substituted by
 OH, or R.sup.9 is phenyl, optionally substituted by Cl; wherein i is 0, 1,
 or 2.
 A specific value for R.sup.2 is methyl.
 A specific value for W is NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are
 the same as defined above.
 A specific value for W is NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8
 together with the nitrogen to which they are attached to form a het
 wherein said het is the same as defined above.
 A specific value for W is morpholine, piperidine, pyrrolidine, piperazine,
 or 4-methyl-piperazine.
 A specific value for W is NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 are
 independently H or C.sub.1-4 alkyl optionally substituted by OH.
 A specific value for W is morpholine.
 A specific value for W is OR.sup.9, or SO.sub.i R.sup.9 wherein R.sup.9 is
 C.sub.1-6 alkyl which may be partially unsaturated and optionally
 substituted by OR.sup.10, Oaryl, het, aryl, NR.sup.10 R.sup.10, CN,
 CONR.sup.10 R.sup.10, or halo; wherein R.sup.10 is H or C.sub.1-4 alkyl.
 A specific value for R.sup.3 is H.
 A specific value for is CF.sub.3, or halo.
 A specific value for R.sup.4 is aryl or het.
 A specific value for R.sup.4 is SO.sub.2 NHR.sup.12, CONHR.sup.12,
 NHCOR.sup.12, or NHSO.sub.2 R.sup.12, wherein R.sup.12 is the same as
 defined above.
 A specific value for R.sup.4 is C.sub.2-8 alkyl which is partially
 unsaturated and optionally substituted by OR.sup.10, NR.sup.7 R.sup.8,
 halo, SO.sub.i R.sup.9, OR.sup.13 or R.sup.11, wherein R.sup.7, R.sup.8,
 R.sup.9, R.sup.10, R.sup.11 and R.sup.13 are the same as defined above.
 A specific value for R.sup.4 is (Z or E)-CH.dbd.CHC.sub.1-4 alkyl,
 optionally substituted by OH.
 A specific value for R.sup.4 is .tbd.C--CC.sub.1-4 alkyl, optionally
 substituted by OH or OR.sup.13, wherein R.sup.13 is (P.dbd.O)(OH).sub.2,
 (P.dbd.O)(C.sub.1-7 alkoxy).sub.2, or CO(CH.sub.2).sub.6
 CON(CH.sub.3)(CH.sub.2).sub.n SO.sub.3.sup.- M.sup.+.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by OR.sup.13
 wherein R.sup.13 is (P.dbd.O)(OH).sub.2, (P.dbd.O)(C.sub.1-7
 alkoxy).sub.2, or CO(CH.sub.2).sub.n CON(CH.sub.3)(CH.sub.2).sub.6
 SO.sub.3.sup.- M.sup.+.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by SO.sub.i
 R.sup.9, wherein R.sup.9 is the same as defined above.
 A specific value for R.sup.4 is NR.sup.7 R.sup.8, wherein R.sup.7 and
 R.sup.8 are the same as defined above.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by NR.sup.7
 R.sup.8, wherein R.sup.7 and R.sup.8 are the same as defined above.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by NR.sup.7
 R.sup.8, wherein R.sup.7 and R.sup.8 together with the nitrogen to which
 they are attached to form a het, wherein het is the same as defined above.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by NR.sup.7
 R.sup.8, wherein R.sup.7 and R 8 are independently C.sub.1-6 alkyl,
 optionally substituted by one or more substituents selected from a group
 consisting of OH, aryl, or CN wherein aryl is the same as defined above.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by N.sub.3.
 A specific value for R.sup.4 is C.sub.1-8 alkyl substituted by bet wherein
 bet is the same as defined above.
 A specific value for R.sup.4 is 4morpholine methyl.
 A specific value for R.sup.4 is C.sub.1-7 alkyl substituted by R.sup.11,
 wherein R.sup.11 is the same as defined above.
 A specific value for R.sup.5 is H or C.sub.1-7 alkyl optionally substituted
 by one or more OH.
 A specific value for R.sup.6 is OC.sub.1-7 alkyl optionally substituted by
 one or more OH.
 A specific value for R.sup.6 is halo.
 A specific value for R.sup.6 is C.tbd.CC.sub.1-7 alkyl substituted by one
 or more OH, or C.sub.2-7 alkoxy substituted by one or more OH.
 A specific value for R.sup.6 is H or C.sub.1-7 alkyl, optionally
 substituted by halo, NR.sup.10 R.sup.10, OH, CO.sub.2 R.sup.10, or het;
 wherein R.sup.10 and het are the same as defined above.
 A specific value for M is sodium, potassium, or lithium.
 A specific value is where X is S; W, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
 R.sup.5, R.sup.6 are the same as defined above.
 A specific value is where X is O; R.sup.1, R.sup.3, R.sup.4, R.sup.5,
 R.sup.6 are the same as defined above, W is NR.sup.7 R.sup.8, OR.sup.9,
 SO.sub.i R.sup.9 or R.sup.2 ; wherein R.sup.2 is:
 a) (CH.sub.2 CH.sub.2 O).sub.n R.sup.10,
 b) het, wherein said het is bonded via a carbon atom,
 c) C.sub.1-7 alkyl which is partially unsaturated and optionally
 substituted by OH,
 d) C.sub.3-8 cycloalkyl, or
 e) C.sub.1-7 alkyl which is optionally substituted by one or more
 substituents selected from a group consisting of Ohet, Oaryl, SO.sub.i
 R.sup.9, or OC.sub.2-4 alkyl which is further substituted by het,
 OR.sup.10, or OC(.dbd.O)aryl; wherein R.sup.7, R.sup.8, R.sup.9, R.sup.10
 and n are the same as defined above.
 A specific value is where X is O or S; R.sup.1 is Cl; R.sup.3 is H; R.sup.5
 is H; R.sup.6 is H or F; R.sup.4 is 4-morpholinylmethyl; and R.sup.2 is:
 a) C.sub.1-4 alkyl substituted by SO.sub.i R.sup.9, or C.sub.1-4 alkoxy
 which is further substituted by OH, het, OC.sub.1-4 alkyl, or
 OC(.dbd.O)pheyl,
 b) (CH.sub.2 CH.sub.2 O).sub.2 C.sub.1-4 alkyl,
 c) C.sub.1-6 alkyl which is partially unsaturated and optionally
 substituted by OH,
 d) cyclopropyl, tetrahydro-2H-pyranyl, piperdinyl, mopholinyl,
 1-methyl-piperidinyl, or 1,1-dioxo-tetrahydro-2H-thiopyran; wherein
 R.sup.9 is phenyl optionally substituted by Cl, or R.sup.9 is C.sub.1-6
 alkyl optionally substituted by OH.
 A specific value is where X is O or S; R.sup.1 is Cl; R.sup.3 is H; R.sup.5
 is H; R.sup.6 is H or F; R.sup.4 is C.sub.1-6 alkyl which is partially
 unsaturated and optionally substituted by OH or OR.sup.13 ; or R.sup.4 is
 C.sub.1-4 alkyl substituted with OR.sup.13 ; W is NR.sup.10 R.sup.10,
 cyclopropyl, (CH.sub.2 CH.sub.2 O).sub.2 OR.sup.10, or C.sub.1-6 alkyl
 which may be partially unsaturated and is optionally substituted by OH,
 mopholinyl, NR.sup.10 R.sup.10 ; C(.dbd.O)OC.sub.1-4 alkyl, wherein
 R.sup.10 is H or C.sub.1-4 alkyl; R.sup.13 is (P.dbd.O)(C.sub.1-7
 alkoxy).sub.2, CO(CH.sub.2).sub.n CON(CH.sub.3)(CH.sub.2).sub.n
 SO.sub.3.sup.- M.sup.+, or (P.dbd.O)(OH).sub.2.
 A specific value is where X is O or S; R.sup.1 is Cl; R.sup.3 is H; R.sup.5
 is H; R.sup.6 is C.tbd.CC.sub.1-4 alkyl optionally substituted by OH;
 R.sup.4 is H or C.sub.1-4 alkyl which may be partially unsaturated and
 optionally substituted by OH, and W is C.sub.1-4 alkyl optionally
 substituted by OH.
 When alkyl is partially unsaturated , it can be vinyl, allyl, 1-propenyl,
 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl,
 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,
 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl;
 Examples of the present invention are
 (1)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-isopropyl-4-oxo-1,4-dihydro-
 3-quinolinecarboxamide;
 (2)
 1-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamid;
 (3)
 1-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-8-methoxy4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide;
 (4)
 N-(4-chlorobenzyl)-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-1-methyl-4-oxo-
 1,4-dihydro-3-quinolinecarboxamide;
 (5)
 N-(4-chlorobenzyl)-8-[2-hydroxy-1-(hydroxymethyl)ethoxy]-6-(3-hydroxypropy
 l)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (6)
 N-(4-chlorobenzyl)-8-fluoro-6-(hydroxymethyl)-4-oxo-1-[3-(tetrahydro-2H-py
 ran-2-yloxy)propyl]-1,4-dihydro-3-quinolinecarboxamide;
 (7)
 N-(4-chlorobenzyl)-6-[3-hydroxy-1-propenyl]-1-[2-(4-morpholinyl)ethyl]-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide;
 (8)
 N-(4-chlorobenzyl)-8-fluoro-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-di
 hydro-3-quinolinecarboxamide;
 (9)
 N-(4-chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy-1-propenyl]-1-methyl-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide;
 (10)
 N-(4-chlorobenzyl)-1-[2-(diethylamino)ethyl]-8-fluoro-6-(3-hydroxy-1-propy
 nyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (11)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-propyl-1,4-dihydro-3-q
 uinolinecarboxamide;
 (12)
 N-(4-chlorobenzyl)-1-[2-(diethylamino)ethyl]-6-(3-hydroxy-1-propynyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (13)
 N-(4-chlorobenzyl)-1-[2-(dimethylamino)ethyl]-6-(3-hydroxy-1-propynyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxarmide hydrochloride;
 (14)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-[2-(1-piperidinyl)ethy
 l]-1,4-dihydro-3-quinolinecarboxamide;
 (15)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-[3-(1-piperidinyl)prop
 yl]-1,4-dihydro-3-quinolinecarboxamide;
 (16)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(1-methyl-2-pyrrolidinyl)
 ethyl]4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (17)
 N-(4-chlorobenzyl)-1-[2-(diisopropylamino)ethyl]-6-(3-hydroxy-1-propynyl)-
 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (18)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-[2-(1-pyrrolidinyl)eth
 yl]-1,4-dihydro-3-quinolinecarboxamide;
 (19)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(4-morpholinyl)ethyl]-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide;
 (20)
 N-(4-chlorobenzyl)-1-[3-(dimethylamino)propyll-6-(3-hydroxy-1-propynyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (21)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-vinyl-1,4-dihydro-3-qu
 inolinecarboxamide;
 (22)
 N-(4-chlorobenzyl)-6-[(E)-3-hydroxy-1-propenyl]-1-methyl-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide;
 (23)
 N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-propenyl]-1-methyl-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide;
 (24)
 N-(4-chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]-1-methyl-4-oxo-1,4-dihyd
 ro-3-quinolinecarboxamide;
 (25)
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide;
 (26)
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide;
 (27)
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide;
 (28) tert-butyl
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H
 )-quinolinyl]acetate;
 (29)
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H
 )-quinolinyl]acetic acid;
 (30)
 N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-d
 ihydro-3-quinolinecarboxamide;
 (31)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide;
 (32)
 di(tert-butyl)3-(3-{[(4chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dih
 ydro-6-quinolinyl)propyl phosphate;
 (33)
 3-(3-{[(4-chlorobenzyl)aminocarbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinoli
 nyl)propyl dihydrogen phosphate;
 (34) di(tert-butyl)3-(3-{(4chlorobenzyl)amino]carbonyll
 -1-cyclopropyl-4-oxo-1,4-dihydro-6-quinolinyl)propyl phosphate;
 (35) sodium
 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-cyclopropy-4-oxo-1,4-dihyd
 ro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate;
 (36) sodium
 2-[(8-([3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-
 6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino)-1-ethanesulfonat
 e;
 (37) sodium
 2-[(8-{[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-
 6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesulfonat
 e;
 (38) sodium
 2-[(8-{13-(3-[{(4-chlorobenzyl)amino]carbonyl}-1-cyclopropyl-4-oxo-1,4-dih
 ydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesul
 fonate;
 (39)
 1-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihyd
 ro-3-quinolinecarboxamide;
 (40) sodium
 2-[{8-[3-(1-(tert-butyl)-3-{[(4-chlorobenzyl)amino]-carbonyl}4-oxo-1,4-dih
 ydro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate;
 (41) sodium
 2-[(8-{[3-(1-(tert-butyl)-3-{[(4-chlorobenzyl)amino]-carbonyl}-4-oxo-1,4-d
 ihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanes
 ulfonate;
 (42)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(2-methoxyethoxy)-ethyl]-
 4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (43)
 N-(4-cyanobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide;
 (44)
 6-{[bis(2-hydroxyethyl)amino]methyl}-N-(4-chlorobenzyl)-1-methyl-4-oxo-1,4
 -dihydro-3-quinolinecarboxamide;
 (45)
 N-(4-chlorobenzyl)-6-{[(2-hydroxyethyl)(methyl)amino]methyl}-1-methyl-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (46)
 N-(4-chlorobenzyl)-1-methyl-6-(1,4-oxazepan-4-ylmethyl)-4-oxo-1,4-dihydro-
 3-quinolinecarboxamide;
 (47)
 N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(1,4-thiazepan-4-ylmethyl)-1,4-dihydro
 3-quinolinecarboxamide;
 (48)
 N-(4-chlorobenzyl)-1-methyl-6-(2-oxa-5-azabicyclo[2.2.
 1]hept-5-ylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (49)
 N-(4-chlorobenzyl)-6-(2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl)-1-methyl-4
 -oxo-1,4-dihydro-3-quinolinecarboxamide;
 (50)
 6-((benzyl(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-1-methyl-4-oxo-
 1,4-dihydro-3-quinolinecarboxamide;
 (51)
 6-(azidomethyl)-N-(4-chlorobenzyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinec
 arboxamide;
 (52)
 N-(4-chlorobenzyl)-6-[(4,4-difluoro-1-piperidinyl)methyl]-1-methyl-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide;
 (53)
 N-(4-chlorobenzyl)-6-{[4-fluoro-3,6-dihydro-1(2H)-pyridinyl]methyl}-1-meth
 yl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (54)
 N-(4-chlorobenzyl)-1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinoline-carboxam
 ide;
 (55)
 N-(4-chlorobenzyl)-1-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy-1-propynyl)-4
 -oxo-1,4-dihydro-3-quinolinecarboxamide;
 (56)
 N-(4-chlorobenzyl)-1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6-(4-morpholinyl
 methyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (57)
 N-(4-chlorobenzyl)-1-[2-(2-hydroxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (58)
 N-(4-chlorobenzyl)-1-[2-(2-ethoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide;
 (59)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(2-propynyl)-1,4-dihydr
 o-3-quinolinecarboxamide;
 (60)
 N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (61)
 N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (62)
 N-(4-chlorobenzyl)-1-(4-hydroxy-2-butynyl)-6-(4-morpholinylmethyl)-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide;
 (63)
 N-(4chlorobenzyl)-6-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-1-met
 hyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (64)
 1-{2-[bis(2-hydroxyetbyl)amino]ethyl}-N-(4-chlorobenzyl)-6-(4-morpholinylm
 ethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (65)
 N-(4-chlorobenzyl)-1-[3-(methylsulfinyl)propyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (66)
 N-(4-chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfanyl]propyl}-6-(4-morpholiny
 lmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (67)
 N-(4-chlorobenzyl)-1-[3-(methylsulfonyl)propyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (68)
 N-(4-chlorobenzyl)-1-[2-(ethylsulfinyl)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (69)
 N-(4-chlorobenzyl)-1-[2-(ethylsulfonyl)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (70)
 N-(4-chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfinyl]propyl}-6-(4-morpholiny
 lmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (71)
 N-(4-chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfonyl]propyl}-6-(4-morpholiny
 lmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (72)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[2-(phenylsulfanyl)ethy
 l]-1,4-dihydro-3-quinolinecarboxamide;
 (73)
 N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (74)
 N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)-amino]
 methyl}-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (75)
 N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-d
 ihydro-3-quinolinecarboxamide;
 (76)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)-methy
 l]-1,4-dihydro-3-quinolinecarboxamide;
 (77)
 N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)ethyl](meth
 yl)amino]methyl}-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (78)
 N-(4-chlorobenzyl)-6-[(3,3-dihydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide;
 (79)
 N-(4-chlorobenzyl)-1-[(methylsulfinyl)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (80)
 N-(4-chlorobenzyl)-1-[(methylsulfonyl)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (81)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfinyl)-methy
 l]-1,4-dihydro-3-quinolinecarboxamide;
 (82)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfonyl)-methy
 l]-1,4-dihydro-3-quinolinecarboxamide;
 (83)
 N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-
 1,4-dihydro-3-quinolinecarboxamide;
 (84)
 N-(4-chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide;
 (85)
 N-(4-chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo-1-piperidi
 nyl)methyl]-1,4-dihydro-3-quinolinecarboxamide;
 (86)
 N-(4-chlorobenzyl)-6-{[(cyanomethyl)(methyl)amino]methyl}-1-[2-(2-methoxye
 thoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (87)
 N-(4-chlorobenzyl)-6-{[(3R)-3-hydroxypyrrolidinyl]methyl}-1-[2-(2-methoxye
 thoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (88)
 N-(4-chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-6-[(methylsulfanyl)methyl]
 -4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (89)
 N-(4-chlorobenzyl)-6-{[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl](methyl)-
 amino]methyl}-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-dihydro-3-quinoline-car
 boxamide;
 (90)
 N-(4-chlorobenzyl)-6-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-1-[2
 -(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (91)
 N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]-
 methyl}-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxami
 de;
 (92)
 1-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-(4-morpholinyl-meth
 yl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (93)
 1-{2-[2-(tert-butoxy)ethoxy]ethyl-N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-h
 ydroxyphenyl)ethyl](methyl)amino]methyl-4-oxo-1,4-dihydro-3-quinoline-carbo
 xamide;
 (94)
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-q
 uinolinecarbothioamide;
 (95)
 N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-qu
 inolinecarbothioamide;
 (96)
 N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide;
 (97)
 N-(4-chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide;
 (98)
 N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-d
 ihydro-3-quinolinecarboxamide;
 (99)
 N-(4-chlorobenzyl)-6-{[3-(hydroxyimino)-1-azetidinyl]methyl}-1-methyl-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (100)
 N-(4-chlorobenzyl)-1-{2-[2-(4-morpholinyl)ethoxy]ethyl}-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (101)
 N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfanyl]methyl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (102)
 N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfinyl]methyl)-6-(4-morpholinylme
 thyl)-4oxo-1,4-dihydro-3-quinolinecarboxainide;
 (103)
 N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfonyl]methyl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (104)
 N-(4-hlorobenzyl)-1-[(4-chlorophenoxy)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (105)
 N-(4-chlorobenzyl)-1-[(2-methoxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide;
 (106)
 2-{[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(4-morpholinylmethyl)-4-oxo-1(4H
 )-quinolinyl]methoxy}ethyl benzoate;
 (107)
 N-(4-chlorobenzyl)-1-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide;
 (108)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran-4-y
 l-1,4-dihydro-3-quinolinecarboxamide;
 (109)
 N-(4-chlorobenzyl)-1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (110)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dih
 ydro-3-quinolinecarboxamide;
 (111)
 N-(4-chlorobenzyl)-1-(1,1-dioxohexahydrothiopyran-4-yl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (112)
 N-(4-chlorobenzyl)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide;
 (113)
 N-(4-chlorobenzyl)-1-(4-methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide;
 (114)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(1-piperidinyl)-1,4-dih
 ydro-3-quinolinecarboxamide;
 (115)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(1-pyrrolidinyl)-1,4-di
 hydro-3-quinolinecarboxamide;
 (116)
 N-(4-chlorobenzyl)-1-(2R)-2-(methoxymethyl)pyrrolidinyl]-6-(4-morpholinylm
 ethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (117)
 N-(4-chlorobenzyl)-1-(dimethylamino)-6-(4-morpholinylmethyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide;
 (118)
 1-amino-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide;
 (119)
 1-amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-quinoli
 necarboxamide;
 (120)
 N-(4-chlorobenzyl)-1-(dimethylamino)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-di
 hydro-3-quinolinecarboxamide;
 (121)
 N-(4-chlorobenzyl)-1-(dimethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxam
 ide;
 (122)
 1-(Aalyloxy)-N-(4-chlorobenzyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (123)
 N-(4-chlorobenzyl)-1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (124)
 N-(4-bromobenzyl)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihy
 dro-3-quinolinecarboxamide;
 (125)
 N-(4-fluorobenzyl)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide;
 (125)
 N-(4-chlorobenzyl)-1-{[2-(4-morpholinyl)ethoxy]methyl}-6-(4-morpholinylmet
 hyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (126)
 N-(4-chlorobenzyl)-1-{[2-(dimethylamino)ethoxy]methyl}-6-(4-morpholinylmet
 hyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide;
 (127)
 N-(4-chlorobenzyl)-1-{[2-(4-methyl-1-piperazinyl)ethoxy]methyl}-6-(4-morph
 olinylmethyl)-4-oxo-1,4dihydro-3-quinolinecarboxamide;
 (128)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-{[2-(1-piperidinyl)etho
 xy]methyl}-1,4-dihydro-3-quinolinecarboxamide;
 (129)
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-{[2-(1-pyrrolidinyl)eth
 oxy]methyl}-1,4-dihydro-3-quinolinecarboxamide; or a pharmaceutically
 acceptable salt thereof.
 The following Charts A-AA describe the preparation of the compounds of the
 present invention. All of the starting materials are prepared by
 procedures described in these charts or by procedures analogous thereto,
 which would be well known to one of ordinary skill in organic chemistry.
 All of the final compounds of the present invention are prepared by
 procedures described in these charts or by procedures analogous thereto,
 which would be well known to one of ordinary skill in organic chemistry.
 All of the variables used in the charts are as defined below or as in the
 claims.
 Chart A
 The ethyl ester of Formula A-1, which is ethyl
 4-hydroxy-6-iodo-3-quinolinecarboxylate, is prepared by heating
 4-iodoaniline with diethyl ethoxymethylene malonate, first at about
 150.degree. C., then in refluxing diphenyl ether. Aminolysis of compound
 A-1 with 4-substituted-benzylamine at about 160.degree. C. provides amide
 A-2. Palladium and copper mediated coupling of A-2 with propargyl alcohol
 leads to compound A-3. Alkylation of the pyridone nitrogen is accomplished
 with potassium carbonate and an optionally substituted alkyl halide,
 affording the compound of Formula A-4. Alternatively, compound A-3 is
 partially hydrogenated to the alkenyl derivative, compound A-5 (E or Z).
 Similarly, 4-quinolone structures of Formula A-4 are partially
 hydrogenated to afford alkenyl derivatives of Formula A-6 (E or Z).
 Alkylation of compound A-5 with optionally substituted alkyl halides and
 potassium carbonate also provides compounds of Formula A-6.
 ##STR8##
 Chart B
 The compound of Formula B-1, which is 2-fluoro-5-iodobenzoic acid, is
 prepared by carbonation of the anion of 4-fluoroiodobenzene, which is
 prepared by deprotonation of 4-fluoroiodobenzene with LDA. Reaction of
 acid B-1 with carbonyldiimidazole, followed by treatment of the resulting
 acyl imidazolide with ethyl trimethylsilyl malonate and subsequent
 decarboxylation, affords .beta.-ketoester B-2. The ketoester is converted
 to quinolinones B-3 by sequential treatment with triethyl orthoformate, an
 amine, and potassium tert-butoxide. Aminolysis of the ester is
 accomplished with 4-chlorobenzylamine, giving compounds of Formula B-4.
 Coupling of propargyl alcohol is effected using palladium and copper
 catalysis, leading to compounds of Formula B-5. Hydrogenation of the
 triple bond using hydrogen gas and platinum catalyst provides
 hydroxypropyl derivatives B-6.
 ##STR9##
 Chart C
 Palladium catalyzed carbonylation of the
 6-iodo-4-hydroxyquinoline-3-carboxamide A-2 affords the corresponding
 ester C-1 which is then reduced with LAH to afford the alcohol C-2.
 Alkylation of the pyridone nitrogen with an alkyl bromide, iodide, or
 tosylate (X=I, Br, Ts, R.sup.2 is the same as defined above) in the
 presence of an alkali metal carbonate provides compounds of the general
 structure C-3. Treatment of compound C-3 with methanesulfonyl chloride
 followed by displacement with an amine, HNR.sup.7 R.sup.8 wherein R.sup.7
 and R.sup.8 are the same as defined above, affords compounds of the
 structure described by Formula C4.
 ##STR10##
 Chart D
 Compounds of Formula D-1 are phosphitylated with di-tert-butyl diethyl
 phosphoramidite to give an intermediate phosphite, which is oxidized in
 situ with m-chioroperbenzoic acid to provide di-tert-butyl phosphates of
 Formula D-2. Treatment of the phosphates with trifluoroacetic acid cleaves
 the tert-butyl groups, providing phosphoric acids of Formula D-3.
 ##STR11##
 Chart E
 Alcohols of Formula D-1 are coupled with suleptanic acid triethylammonium
 salt, which is triethylammonium
 2-[(7-carboxyheptanoyl)(methyl)amino]-1-ethanesulfonate, using
 diisopropylcarbodiimide and 4-dimethylaminopyridine, to provide the
 corresponding esters. Exchange of the triethylammonium salt with sodium
 ion affords sodium salts E-1.
 ##STR12##
 Chart F
 4-Iodoaniline (F-0) is reductively alkylated with
 [(1-ethoxycyclopropyl)oxy]trimethylsilane and sodium cyanoborohydride to
 give the N-cyclopropyl aniline (F-1). Treatment with diethyl
 ethoxymethylenemalonate in pyridine affords the enamine (F-2) which is
 cyclized with polyphosphoric acid to the quinoline (F-3). Treatment with
 p-chlorobenzylamine at elevated temperature converts the ester to the
 amide (F-4). Palladium catalyzed coupling of the iodide with propargyl
 alcohol affords F-5. Reaction with platinum and hydrogen gas affords the
 saturated propyl alcohol (F-6).
 ##STR13##
 Chart G
 4-Nitrobenzyl bromide is treated with morpholine and potassium carbonate in
 acetone to give 4-(4-Nitrobenzyl)morpholine (G-1). The nitro group is
 reduced with platinum and hydrogen gas to afford the aniline (G-2) which
 is then treated with [(1-ethoxycyclopropyl)-oxy]trimethylsilane and sodium
 cyanoborohydride to give the N-cyclopropyl aniline (G-3). Reaction with
 diethyl ethoxymethylenemalonate in pyridine affords the enamine (G-4)
 which is cyclized with polyphosphoric acid to the quinoline (G-5).
 Treatment with p-chlorobenzylamine at elevated temperature converts the
 ester to the amide (G-6).
 ##STR14##
 Chart H
 Alkylation of
 N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide with
 potassium carbonate and tert-butylbromoacetate affords H-1. Palladium
 catalyzed coupling of the iodide with propargyl alcohol affords H-2.
 Reaction with platinum and hydrogen gas affords the saturated propyl
 alcohol (H-3). Treatment with trifluoroactic acid affords the free acid
 (H4). Alternatively, H-2 is treated with trifluoroacetic acid to give H-5.
 ##STR15##
 Chart I
 1-Fluoro-4-nitrobenzene (I-1) is converted to
 2-(4-nitroanilino-N-ethyl)-1-ethanol (I-2) by heating with the
 N-ethylethanolamine in ethanol. Compound I-2 is converted to the
 corresponding acetate (I-3) by treatment with acetyl chloride. The nitro
 group is reduced to the free amine with palladium on carbon and hydrogen
 gas. The resulting aniline is treated with diethyl ethoxymethylenemalonate
 to give compound I-4. The resulting enamine is cyclized by heating in
 diphenyl ether to give the quinoline (I-5). Compound I-5 is N-alkylated at
 the pyridone nitrogen by treatment with iodoalkyl and potassium carbonate
 to afford compound I-6. Aminolysis of the diester with 4-chlorobenzylamine
 affords (I-7).
 ##STR16##
 Chart J
 2-Fluoro-6-iodoaniline is condensed with diethyl ethoxymethylenemalonate
 and then heated in diphenyl ether to afford the 4-hydroxyquinoline ethyl
 ester (J-1). Aminolysis of compound J-1 with 4-chlorobenzylamine affords
 the corresponding amide (J-2). Compound J-2 is heated in the presence of
 an alkoxide to afford compound J-3. Palladium catalyzed coupling of the
 resulting quinoline with propargyl alcohol affords alkyne J-4. The
 pyridone nitrogen of J4 is then N-alkylated with an alkyl halide and
 potassium carbonate to afford 4-quinolones of Formula J-5. Hydrogenation
 of compound J-5 affords the hydroxypropyl derivate of Formula J-6.
 ##STR17##
 Chart K
 Palladium catalyzed carbonylation of the
 6-iodo-8-fluoro-4-hydroxyquinoline-3-carboxamide J-2 affords the
 corresponding ester K-1 which is then reduced with LAH to afford the
 alcohol K-2. Alkylation of the pyridone nitrogen with an alkyl halide and
 potassium carbonate affords compounds of Formula K-3.
 ##STR18##
 Chart L
 Palladium catalyzed coupling of the
 6-iodo-8-fluoro-4-hydroxyquinoline-3-carboxamide J-2 with propargyl
 alcohol affords alkyne L-1. The pyridone nitrogen of L-1 is then
 N-alkylated with an alkyl halide and potassium carbonate to afford
 4-quinolones of Formula L-2. Subsequent semi-hydrogenation of compound L-2
 affords hydroxyalkenyl derivatives of Formula L-3.
 ##STR19##
 Chart M
 Treatment of compound C-2 with methanesulfonyl chloride followed by
 reaction with morpholine affords compound M-1. Alkylation of the pyridone
 nitrogen with an alkyl bromide, iodide, or tosylate (X=I, Br, Ts, R is
 alkyl) in the presence of an alkali metal carbonate or alternatively with
 the corresponding alkyl alcohol under Mitsunobu conditions affords
 compounds of Formula M-2.
 ##STR20##
 Chart N
 Treatment of compound C-3 with methanesulfonyl chloride affords the
 benzylic chloride N-1. Treatment of compound N-1 with a corresponding
 primary or secondary amine affords compounds of Formula C-4 or the
 chloride atom may be displaced by other nucleophiles (e.g. azide).
 ##STR21##
 Chart O
 Treatment of compound M-1 with a thiol-containing alkyl halides in the
 presence of an inorganic base or alternatively with the corresponding
 thiol-containing alkyl alcohols under Mitsunobu conditions affords
 compounds of Formula O-1 (wherein R.sup.9 is the same as defined above).
 Oxidation of the sulfides of Formula O-1 with m-chloroperoxybenzoic acid
 in the presence of p-toluenesulfonic acid affords compounds of Formula
 O-2.
 ##STR22##
 Chart P
 Compound A-2 may be reacted with an alkyl bromide, iodide, or tosylate
 (X=Br, I, Ts, R is alkyl) in the presence of an alkali metal carbonate to
 afford compounds of the formula P-1. The resulting oiodo-4-quinolones are
 coupled with trialkyl alkenyl stannanes (e.g. tributyl vinyl stannane)
 catalyzed by PdCl.sub.2 (PPh.sub.3).sub.2 to afford compounds such as
 those described by formula P-2
 ##STR23##
 Chart Q
 Alkyl chloride N-1 is treated with the sodium salt of an alkyl thiol to
 afford sulfides of the general formula Q-1 (wherein R.sup.2 and R.sup.9 is
 the same as defined above).
 ##STR24##
 Chart R
 Compounds with the 3-thioamide substitution are prepared from compound A-2
 (see Chart A) by reaction with PCl.sub.5 to provide the chloroimidate R-1.
 Subsequent treatment of chloroimidate R-1 with H.sub.2 S provides the
 thioamide R-2 which is alkylated under Mitsunobu conditions to provide
 R-3. Compound R-3 may then be transformed to the desired analogs employing
 chemistry analogous to the carboxamide derivatives depicted in Charts A-E,
 N, P, or Q.
 ##STR25##
 Chart S
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (Chart A-2,
 R=Cl) is treated with phosphorus pentachloride to form the
 quinolinecarboximidoyl chloride S-1. This is then treated with hydrogen
 sulfide to form the thioamide S-2. Alkylation under Mitsonobu conditions
 gives S-3 (wherein R is alkyl) which is coupled to propargyl alcohol using
 palladium catalysis to afford S-4.
 ##STR26##
 Chart T
 Palladium catalyzed carbomethylation of
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (S-2)
 provides the quinoline 6-methyl ester T-1. Reduction to the alcohol
 followed by mesylation and displacement with morpholine provides the
 6-morpholinylmethyl quinoline T-3. Methylation under Mitsonobu conditions
 gives
 N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-qu
 inolinecarbothioamide (T-4).
 ##STR27##
 Chart U
 2-Iodoaniline is treated with diethyl ethoxyethylenemalonate at 130.degree.
 C. The resulting enamine is then dissolved in Ph.sub.2 O and heated to
 250.degree. C. to give the ethyl quinolinecarboxylate U-1. Condensation
 with neat 4-chlorobenzylamine at 180.degree. C. gives the
 4-chlorobenzylamide U-2 which is methylated with iodomethane to provide
 N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4
 dihydro-3-quinolinecarboxamide (U-3). Palladium catalyzed coupling to
 acetylenes or alkenes provides compounds of the general formula U-4.
 ##STR28##
 Chart V
 4-Nitrobenzylbromide is treated with triphenylphosphine to form the
 phosphonium salt V-1. Deprotonation to form the Wittig reagent and
 condensation with tetrahydropyran-4-one gives the nitrobenzylidene V-2.
 Hydrogenation to the saturated amine and condensation with diethyl
 ethoxymethylenemalonate followed by thermal cyclization of the resulting
 enamine gives the quinolinecarboxylic ester V-3. The resulting ester is
 condensed with 4-chlorobenzylamine and methylated to afford V-5.
 ##STR29##
 Chart W
 Aniline of Formula G-2 is reductively alkylated with a substituted
 cyclohexanone (W-1;Z=O, NMe, NBoc) to give the N-alkylated aniline
 (W-2;Z=O, NMe, NBoc). Reaction with diethyl ethoxymethylenemalonate
 affords the enamine (W-3; Z=O, NMe, NBoc) which is cyclized with
 polyphosphoric acid to the quinoline (W-4; Z=O, NMe, NH). Treatment with
 4-chlorobenzylamine at elevated temperature converts the ester to the
 amide (W-5; Z=O, NMe, NH). Likewise, Aniline of Formula G-2 is reductively
 alkylated with tetrahydrothiopyran-4-one (W-1; Z=S) to give the
 N-alkylated aniline (W-2; Z=S). Reaction with diethyl
 ethoxymethylenemalonate affords the enamine (W-3; Z=S). Oxidation with
 m-chloroperoxybenzoic acid affords the sulfone (W-2; Z=SO.sub.2) which is
 reacted with diethyl ethoxymethylenemalonate to afford the enamine (W-3;
 Z=SO.sub.2) then cyclized with polyphosphoric acid to the quinoline (W-4;
 Z=SO.sub.2). Treatment with 4-chlorobenzylamine at elevated temperature
 converts the ester to the amide (W-5; Z=SO.sub.2)
 ##STR30##
 Chart X
 Reductive amination of 3-bromo-4-fluorobenzaldehyde with morpholine and
 sodium triacetoxyborohydride affords aryl bromide X-1. Halogen-lithium
 exchange followed by acetylation with a N-methoxy-N-methylacetamide gives
 methyl ketone X-2. The resulting ketone is then converted .beta.-keto
 ester X-3 with diethyl carbonate under basic conditions. Refluxing
 .beta.-keto ester X-3 in triethylorthoformate and acetic anhydride
 produces an intermediate enol ether which is then reacted with a selected
 hydrazide. The resulting enamine X-4 is then cyclized by heating with
 sodium hydride in THF to afford the corresponding quinolone-3-ester X-5.
 Direct thermolysis of the ester with 4-substituted-benzylamine (X=Cl, Br,
 F, or CN, R.sup.7 and R.sup.8 are the same as defined above) at
 190.degree. C. affords amides of the general formula X-6.
 ##STR31##
 Chart Y
 Butyl acetate silyl ketene acetal is reacted with
 2-chloro-5-iodobenzoylchloride to afford .beta.-ketoester Y-1. Refluxing
 Y-1 in triethylorthoformate and acetic anhydride produces an intermediate
 enol ether which is then reacted with a selected hydrazide. The resulting
 enamine Y-2 (wherein R.sup.7 and R.sup.8 are the same as defined above) is
 then cyclized by heating with sodium hydride to afford the corresponding
 quinolone-3-ester Y-3. Direct thermolysis of the ester with
 4-chlorobenzylamine affords amides of the general formula Y-4. Palladium
 catalyzed coupling of Y-4 with propargyl alcohol affords compounds of
 general formula Y-5. Subsequent catalytic hydrogenation of the alkyne
 provides hydroxypropyl derivatives of the general formula Y-6.
 ##STR32##
 Chart Z
 Alternatively where the N1-substituent is amino,
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (A-2) is
 treated with O-(mesitylsulfonyl)hydroxylamine to afford 1-amino-quinolone
 Z-1. Compound Z-1 may then be transformed in a similar fashion to that
 described for general intermediate Y-4 above.
 ##STR33##
 Chart AA
 Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (AA-1) is refluxed in
 triethylorthoformate and acetic anhydride to afford an intermediate enol
 ether which is then reacted with a selected N-alkoxyarnine. The resulting
 enamine AA-2 is then cyclized by heating with sodium hydride to afford the
 corresponding quinolone-3-ester AA-3. Direct thermolysis of the ester with
 4-chlorobenzylamine affords amides of the general formula AA-4.
 ##STR34##
 In cases where compounds are sufficiently basic or acidic to form stable
 nontoxic acid or base salts, administration of the compounds as salts may
 be appropriate. Examples of pharmaceutically acceptable salts are organic
 acid addition salts formed with acids which form a physiological
 acceptable anion, for example, tosylate, methanesulfonate, acetate,
 citrate, malonate, tartarate, succinate, benzoate, ascorbate,
 etoglutarate, and glycerophosphate. Suitable inorganic salts may also be
 formed, including hydrochloride, sulfate, nitrate, bicarbonate, and
 carbonate salts.
 Pharmaceutically acceptable salts may be obtained using standard procedures
 well known in the art, for example by reacting a sufficiently basic
 compound such as an amine with a suitable acid affording a physiologically
 acceptable anion. Alkali metal (for example, sodium, potassium or lithium)
 or alkaline earth metal (for example calcium) salts of carboxylic acids
 can also be made.
 Compounds of the present invention can conveniently be administered in a
 pharmaceutical composition containing the compound in combination with a
 suitable excipient, the composition being useful in combating viral
 infections. Pharmaceutical compositions containing a compound appropriate
 for antiviral use are prepared by methods and contain excipients which are
 well known in the art. A generally recognized compendium of such methods
 and ingredients is Remington's Pharmaceutical Sciences by E. W. Martin
 (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of the
 present invention can be administered parenterally (for example, by
 intravenous, intraperitoneal or intramuscular injection), topically,
 orally, or rectally, depending on whether the preparation is used to treat
 internal or external viral infections.
 For oral therapeutic administration, the active compound may be combined
 with one or more excipients and used in the form of ingestible tablets,
 buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
 and the like. Such compositions and preparations should contain at least
 0.1% of active compound. The percentage of the compositions and
 preparations may, of course, be varied and may conveniently be between
 about 2 to about 60% of the weight of a given unit dosage form. The amount
 of active compound in such therapeutically useful compositions is such
 that an effective dosage level will be obtained.
 The tablets, troches, pills, capsules, and the like may also contain the
 following: binders such as gum tragacanth, acacia, corn starch or gelatin;
 excipients such as dicalcium phosphate; a disintegrating agent such as
 corn starch, potato starch, alginic acid and the like; a lubricant such as
 magnesium stearate; and a sweetening agent such as sucrose, fructose,
 lactose or aspartame or a flavoring agent such as peppermint, oil of
 wintergreen, or cherry flavoring may be added. When the unit dosage form
 is a capsule, it may contain, in addition to materials of the above type,
 a liquid carrier, such as a vegetable oil or a polyethylene glycol.
 Various other materials may be present as coatings or to otherwise modify
 the physical form of the solid unit dosage form. For instance, tablets,
 pills, or capsules may be coated with gelatin, wax, shellac or sugar and
 the like. A syrup or elixir may contain the active compound, sucrose or
 fructose as a sweetening agent, methyl and propylparabens as
 preservatives, a dye and flavoring such as cherry or orange flavor. Of
 course, any material used in preparing any unit dosage form should be
 pharmaceutically acceptable and substantially non-toxic in the amounts
 employed. In addition, the active compound may be incorporated into
 sustained-release preparations and devices.
 The compounds or compositions can also be administered intravenously or
 intraperitoneally by infusion or injection. Solutions of the active
 compound or its salts can be prepared in water, optionally mixed with a
 nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid
 polyethylene glycols, triacetin, and mixtures thereof and in oils. Under
 ordinary conditions of storage and use, these preparations contain a
 preservative to prevent the growth of microorganisms.
 Pharmaceutical dosage forms suitable for injection or infusion can include
 sterile aqueous solutions or dispersions or sterile powders comprising the
 active ingredient which are adapted for the extemporaneous preparation of
 sterile injectable or infusible solutions or dispersions, optionally
 encapsulated in liposomes. In all cases, the ultimate dosage form should
 be sterile, fluid and stable under the conditions of manufacture and
 storage. The liquid carrier or vehicle can be a solvent or liquid
 dispersion medium comprising, for example, water, ethanol, a polyol (for
 example, glycerol, propylene glycol, liquid polyethylene glycols, and the
 like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures
 thereof. The proper fluidity can be maintained, for example, by the
 formation of liposomes, by the maintenance of the required particle size
 in the case of dispersions or by the use of surfactants. The prevention of
 the action of microorganisms can be brought about by various antibacterial
 and antifungal agents, for example, parabens, chlorobutanol, phenol,
 sorbic acid, thimerosal, and the like. In many cases, it will be
 preferable to include isotonic agents, for example, sugars, buffers or
 sodium chloride. Prolonged absorption of the injectable compositions can
 be brought about by the use in the compositions of agents delaying
 absorption, for example, aluminum monostearate and gelatin.
 Sterile injectable solutions can be prepared by incorporating the active
 compound in the required amount in the appropriate solvent with various of
 the other ingredients enumerated above, as required, followed by filter
 sterilization. In the case of sterile powders for the preparation of
 sterile injectable solutions, the preferred methods of preparation are
 vacuum drying and the freeze drying techniques, which yield a powder of
 the active ingredient plus any additional desired ingredient present in
 the previously sterile-filtered solutions.
 For topical administration, the present compounds may be applied in pure
 form, i.e., when they are liquids. However, it will generally be desirable
 to administer them to the skin as compositions or formulations, in
 combination with a dermatologically acceptable carrier, which may be a
 solid or a liquid.
 Useful solid carriers include finely divided solids such as talc, clay,
 microcrystalline cellulose, silica, alumina and the like. Useful liquid
 carriers include water, alcohols or glycols or water-alcohol/glycol
 blends, in which the present compounds can be dissolved or dispersed at
 effective levels, optionally with the aid of non-toxic surfactants.
 Adjuvants such as fragrances and additional antimicrobial agents can be
 added to optimize the properties for a given use. The resultant liquid
 compositions can be applied from absorbent pads, used to impregnate
 bandages and other dressings, or sprayed onto the affected area using
 pump-type or aerosol sprayers. Thickeners such as synthetic polymers,
 fatty acids, fatty acid salts and esters, fatty alcohols, modified
 celluloses or modified mineral materials can also be employed with liquid
 carriers to form spreadable pastes, gels, ointments, soaps, and the like,
 for application directly to the skin of the user.
 Examples of useful dermatological compositions which can be used to deliver
 the compounds of formula I to the skin are known to the art; for example,
 see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No.
 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat.
 No. 4,820,508).
 Useful dosages of the compounds of formula I can be determined by comparing
 their in vitro activity, and in vivo activity in animal models. Methods
 for the extrapolation of effective dosages in mice, and other animals, to
 humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
 The compound is conveniently administered in unit dosage form; for example,
 containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50
 to 500 mg of active ingredient per unit dosage form. The desired dose may
 conveniently be presented in a single dose or as divided doses
 administered at appropriate intervals, for example, as two, three, four or
 more sub-doses per day. The sub-dose itself may be further divided, e.g.,
 into a number of discrete loosely spaced administrations; such as multiple
 inhalations from an insufflator or by application of a plurality of drops
 into the eye.
 For internal infections, the compositions can be administered orally or
 parenterally at dose levels, calculated as the free base, of about 0.1 to
 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be
 used in man in a unit dosage form, administered one to four times daily in
 the amount of 1 to 1000 mg per unit dose.
 For parenteral administration or for administration as drops, as for eye
 infections, the compounds are presented in aqueous solution in a
 concentration of from about 0.1 to about 10%, more preferably about 0.1 to
 about 7%. The solution may contain other ingredients, such as emulsifiers,
 antioxidants or buffers.
 Generally, the concentration of the compound(s) of formula I in a liquid
 composition, such as a lotion, will be from about 0.1-25 wt-%, preferably
 from about 0.5-10 wt-%. The concentration in a semi-solid or solid
 composition such as a gel or a powder will be about 0.1-5 wt-%, preferably
 about 0.5-2.5 wt-%.
 The exact regimen for administration of the compounds and compositions
 disclosed herein will necessarily be dependent upon the needs of the
 individual subject being treated, the type of treatment and, of course,
 the judgment of the attending practitioner.
 The antiviral activity of a compound of the invention can be determined
 using pharmacological models which are well known to the art, or using
 Test A described below.
 The compounds of formula (I) and pharmaceutically acceptable salts thereof
 are useful as antiviral agents. Thus, they are useful to combat viral
 infections in animals, including man. The compounds are generally active
 against herpes viruses, and are particularly useful against the varicella
 zoster virus, the Epstein-Barr virus, the herpes simplex virus, the human
 herpes virus type 8 (HHV-8) and the cytomegalovirus (CMV).
 While many of the compounds of the present invention have shown activity
 against the CMV polymerase, these compounds may be active against the
 cytomegalovirus by this or other mechanisms of action. Thus, the
 description below of these compounds' activity against the CMV polymerase
 is not meant to limit the present invention to a specific mechanism of
 action.
 Test A
 The HCMV polymerase assay is performed using a scintillation proximity
 assay (SPA) as described in several references, such as N. D. Cook, et
 al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K.
 Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No.
 4,568,649 (1986); which are incorporated by reference herein. Reactions
 are performed in 96-well plates. The assay is conducted in 100 .mu.l
 volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl.sub.2, 0.36
 mg/ml BSA, and 90 nM .sup.3 H-dTTP. Assays are run with and without CHAPS,
 (3-[(3-Cholamidopropyl)dimethylammonio]-1-propane-sulfonate) at a final
 concentration of 2 mM. HCMV polymerase is diluted in enzyme dilution
 buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100
 .mu.g/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is
 expressed in recombinant baculovirus-infected SF-9 cells and purified
 according to literature procedures, is added at 10% (or 10 .mu.l) of the
 final reaction volume, i.e., 100 .mu.l. Compounds are diluted in 50% DMSO
 and 10 .mu.l are added to each well. Control wells contain an equivalent
 concentration of DMSO. Unless noted otherwise, reactions are initiated via
 the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to
 reaction mixtures containing the enzyme, substrate, and compounds of
 interest. Plates are incubated in a 25 C. or 37 C. H.sub.2 O bath and
 terminated via the addition of 40 .mu.l/reaction of 0.5 M EDTA (pH 8) per
 well. Reactions are terminated within the time-frame during which
 substrate incorporation is linear and varied depending upon the enzyme and
 conditions used, i.e., 30 min. for HCMV polymerase. Ten .mu.l of
 streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added following
 termination of the reaction. Plates are incubated 10 min. at 37 C., then
 equilibrated to room temperature, and counted on a Packard Topcount.
 Linear regressions are performed and IC.sub.50 's are calculated using
 computer software.
 A modified version of the above HCMV polymerase assay is performed as
 described above, but with the following changes: Compounds are diluted in
 100% DMSO until final dilution into assay buffer. In the previous assay,
 compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to
 the polymerase buffer. Also, a different lot of CMV polymerase is used,
 which appears to be more active resulting in a more rapid polymerase
 reaction. Results of the testing of representative compounds of formula I
 in this assay are shown in Table 1 below.
 TABLE 1
 Biological Data
 polymerase IC.sub.50 (.mu.M)
 Example HCMV HSV VZV
 1 1.7 nd nd
 2 1.6 nd nd
 3 2.3 nd nd
 4 0.6 1.0 1.2
 5 1.6 nd nd
 6 7.2 nd nd
 7 1.0 1.1 0.77
 8 1.0 nd nd
 9 &lt;0.78 nd nd
 10 1.7 nd nd
 11 1.5 nd nd
 12 2 3.0 1.9
 13 2.9 nd nd
 14 1.3 1.2 1.1
 15 4.1 nd nd
 16 2.8 nd nd
 17 0.8 2.0 1.1
 18 2.7 nd nd
 19 1.8 nd nd
 20 3.8 nd nd
 21 1.4 nd nd
 22 0.81 nd nd
 23 0.62 nd nd
 24 23.6 nd nd
 25 1.6 1.6 1.5
 26 0.53 0.78 0.49
 27 0.61 nd nd
 28 1.8 nd nd
 29 1.0 nd nd
 30 0.95 nd nd
 31 1.1 1.3 1.0
 32 27.2 nd nd
 33 3.7 nd nd
 34 &gt;20 nd nd
 36 &gt;20 nd nd
 37 &gt;20 nd nd
 39 2.2 nd nd
 42 1.2 nd nd
 43 9.4 nd nd
 44 9.3 nd nd
 45 11.9 nd nd
 46 5.5 nd nd
 47 7.2 nd nd
 48 13.6 nd nd
 49 2.2 nd nd
 50 11.5 nd nd
 51 1.3 nd nd
 52 9.6 nd nd
 53 11.7 nd nd
 54 3.3 nd nd
 55 2.3 2.4 1.4
 56 3.0 nd nd
 57 1.2 nd nd
 58 1.4 nd nd
 59 1.9 nd nd
 60 1.1 nd nd
 61 1.1 0.9 0.5
 62 1.3 1.1 0.61
 63 1.3 nd nd
 64 0.95 nd nd
 65 0.9 1.0 0.63
 66 1.1 nd nd
 67 0.7 nd nd
 68 0.93 nd nd
 69 0.9 nd nd
 70 0.87 nd nd
 71 0.8 nd nd
 72 3.0 nd nd
 73 1.1 nd nd
 74 0.89 2.8 1.6
 75 3.3 4.4 4.0
 76 0.18 &lt;0.31 &lt;0.31
 77 1.3 4.1 2.1
 78 0.27 nd nd
 79 1.1 nd nd
 80 1.1 nd nd
 81 0.35 nd nd
 82 0.53 nd nd
 83 0.6 nd nd
 84 1.2 nd nd
 85 6.0 nd nd
 86 2.5 nd nd
 87 4.0 nd nd
 88 5.9 nd nd
 89 6.7 nd nd
 90 4.4 nd nd
 91 2.1 nd nd
 93 6.2 nd nd
 94 0.77 nd nd
 95 0.3 nd nd
 96 1.0 nd nd
 97 1.5 nd nd
 98 0.31 nd nd
 99 8.0 nd nd
 100 2.9 nd nd
 101 0.3 nd nd
 102 0.59 nd nd
 103 0.83 nd nd
 104 1.6 nd nd
 105 1.3 nd nd
 106 3.1 nd nd
 107 0.84 nd nd
 108 0.82 nd nd
 109 0.48 nd nd
 110 0.67 nd nd
 111 0.73 nd nd
 112 0.42 nd nd
 113 0.64 nd nd
 114 0.88 nd nd
 115 0.62 nd nd
 116 14.0 nd nd
 117 1.5 nd nd
 118 1.1 nd nd
 119 0.5 nd nd
 120 2.5 nd nd
 121 3.9 nd nd
 122 2.8 nd nd
 123 8.2 nd nd
 124 1.2 nd nd
 125 1.1 nd nd

DESCRIPTION OF PREFERRED EMBODIMENTS
 Preparation 1
 N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide
 ##STR35##
 A mixture of 11.85 g of 2-fluoro-4-iodoaniline and 10.81 g of
 diethylethoxymethylene malonate is heated to 130.degree. C. in a flask
 equipped with a Dean-Stark trap to collect formed ethanol. The mixture is
 then cooled to 75.degree. C. and diluted with hexanes. The resulting solid
 is collected and dried. The solid is then dissolved in 60 mL diphenyl
 ether and heated to 250.degree. C. for 3 h in a flask equipped with a
 Dean-Stark trap to collect the ethanol. The solution is allowed to cool to
 room temperature and the resulting solid is collected and dried to yield
 11.73 g of ethyl 8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxylate. This
 material (0.55 g) and 3 mL of 4-chlorobenzylamine are heated at
 180.degree. C. for 1 h. The reaction is cooled and poured into 75 mL
 diethyl ether. The resulting solid is filtered and recrystallized from
 ethyl acetate/hexanes to give the title compound as an off-white solid
 (0.45 g).
 Physical characteristics are as follows:
 Mp 268-270.degree. C.; .sup.1 H NMR (DMSO) .delta.10.17, 8.59, 8.29, 8.05,
 7.37, 7.33, 4.51; IR (mull) 3180, 3078, 3059, 3004, 1647, 1607, 1551,
 1524, 1489, 1344, 1297, 1285, 1240, 1183, 805 cm.sup.-1 ; MS (ES-) 454.9
 (M-H.sup.+); HRMS (FAB) found 456.9628.
 Preparation 2
 N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide
 ##STR36##
 N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide (2.95
 g) from Preparation No. 1 and sodium hydride (60% dispersion, 520 mg) is
 suspended in DMF (60 mL) and to the mixture is added methanol (288 .mu.L).
 After being heated for 1 h at 135.degree. C., additional sodium hydride
 (200 mg) is added, and the mixture is heated for an additional 1 h. The
 reaction mixture is allowed to cool to rt and then is poured into
 saturated aqueous ammonium chloride (200 mL). The resulting precipitate is
 filtered and washed with water (20 mL), tert-butyl methyl ether (20 mL),
 and heptane (20 mL). The crude product is purified by column
 chromatography (heptane/2-propanol, 9/1; 4/1) to afford 1.68 g (56%) of
 the title compound as a white solid. Recrystallization (acetic acid,
 water) affords a hydrate (1H.sub.2 O).
 Physical characteristics are as follows:
 Mp 241-243.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.12.43, 10.28,
 8.57, 8.09, 7.61, 7.41-7.34, 4.53, 4.04; .sup.13 C NMR (CF.sub.3 CO.sub.2
 D) .delta.173.3, 167.3, 149.0, 141.4, 134.8, 133.2, 129.8, 129.2, 129.0,
 124.9, 124.5, 122.5, 106.7, 94.4, 56.4, 44.0; IR (drift) 3072, 1646, 1612,
 1594, 1558, 1530, 1492, 1306, 1298, 1255, 1202, 1082, 851, 846, 804
 cm.sup.-1 ; MS (ESI-) for m/z 467 (M-H).sup.-. Anal. Found for C.sub.18
 H.sub.14 ClIN.sub.2 O.sub.3.H.sub.2 O: C, 44.39; H, 3.46; N, 5.76; Cl,
 7.34. Water (KF): 3.67.
 Preparation 3
 N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinoline
 carboxamide
 ##STR37##
 N-((4-Chlorobenzyl)-4-hydroxy-6-iodo-8-methoxy-3-quinolinecarboxamide (469
 mg) from Preparation No. 2, copper (1) iodide (57 mg), and
 bis(triphenylphosphine)palladium (II) chloride (35 mg) are suspended in
 diethylarine (15 mL). Propargyl alcohol (70 .mu.L) is added and the
 mixture is allowed to stir at rt for 16 h. The reaction mixture is poured
 into water (50 mL) and extracted with ethyl acetate (2.times.50 mL). The
 organic layer is washed with saturated aqueous ammonium chloride
 (3.times.10 mL) and brine (10 mL). The aqueous layer is back-extracted
 with ethyl acetate (20 mL). The combined organic layers are dried
 (MgSO.sub.4) and concentrated. The crude product is purified by column
 chromatography (dichloromethane/methanol, 50/1; 33/1; 25/1; 20/1) to
 afford 289 mg (73%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 207-208.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.12.45, 10.3,
 8.58, 7.79, 7.42-7.34, 5.38, 4.53, 4.34, 4.05; .sup.13 C NMR
 (DMSO-d.sub.6) .delta.178.0, 167.1, 151.8, 145.9, 141.5, 134.2, 132.6,
 132.1, 131.2, 129.6, 122.5, 121.7, 117.0, 114.4, 93.3, 86.1, 59.5, 52.3,
 44.3; IR (drift) 3196, 3157, 3074, 2234, 1649, 1603, 1568, 1562, 1523,
 1491, 1314, 1200, 1089, 1021, 805 cm.sup.-1 ; MS (ESI-) m/z 395
 (M-H).sup.-. Anal. Found for C.sub.21 H.sub.17 ClN.sub.2 O.sub.4 : C,
 63.26; H, 4.35; N, 7.07; Cl, 8.94.
 PREATION 4
 N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide
 ##STR38##
 4-Iodoaniline (8.60 g) and diethyl ethoxymethylenemalonate (7.90 mL) are
 heated at 130.degree. C. for 1 hour. The reaction is cooled to room
 temperature and 60 mL diphenyl ether is added. The solution is heated at
 250.degree. C. for 1.5 hours with removal of ethanol by a Dean-Stark trap.
 The reaction is cooled to room temperature and the resulting solid is
 filtered, washed with hexanes, and dried to yield 11.20 g of ethyl
 4-hydroxy-6-iodoquinoline-3-carboxylate. A mixture of this ester (0.58 g)
 and 4chlorobenzylamine (4.0 mL) are heated at 180.degree. C. for 1.5
 hours. The reaction is cooled and poured into 50 mL diethyl ether. The
 resulting solid is filtered, triturated in ethyl acetate, and filtered
 again to give the desired product (0.50 g).
 Physical characteristics are as follows:
 Mp 297-299.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 12.71, 10.27,
 8.76, 8.50, 8.02, 7.50, 7.38, 7.33, 4.52; IR (mull) 3151, 3078, 3039,
 1631, 1610, 1572, 1563, 1545, 1527, 1512, 1491, 1433, 1351, 1303, 799
 cm.sup.-1 ; MS (ES) 438.9 (M+H), 460.9 (M+Na), 436.9 (M-H). Anal. Found:
 C, 46.61; H, 2.81; N, 6.34; Cl, 8.19.
 Preparation 5
 N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamid
 e
 ##STR39##
 To a mixture of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide
 from Preparation No. 4 (0.494 g) in Et.sub.2 NH (12.9 mL) is added CuI
 (10.8 mg) and (Ph.sub.3 P).sub.2 PdCl.sub.2 (39.7 mg). DMF (2 mL) is added
 to solubilize the reactants. To this solution is added propargyl alcohol
 (0.066 mL) and the reaction is stirred at room temperature for 2 days. The
 reaction mixture is concentrated to remove Et.sub.2 NH. The resulting
 residue is partitioned between CH.sub.2 Cl.sub.2 (3.times.) and H.sub.2 O.
 A brown solid precipitated from the CH.sub.2 Cl.sub.2 layer is filtered
 and collected to obtain pure product as indicated by NMR. The organic
 layers are combined, dried over Na.sub.2 SO.sub.4, and concentrateed to
 obtain a brown residue. The residue is placed under high vac to remove
 residual DMF. The residue is adsorbed onto silica and chromatographed
 eluting with 2% MeOH in CH.sub.2 C.sub.12 and 3% MeOH in CH.sub.2
 Cl.sub.2. Fractions homogenous by TLC are combined, condensed and
 recrystallized with EtOAc/hexanes to obtain a creme solid. The two crops
 yielded 325.4 mg (79%) of the desired product as a tan solid.
 Physical characteristics are as follows:
 MP 248-250 C.; .sup.1 H NMR (300 MHz, DMSO) 12.85, 10.31, 8.78, 8.22, 7.78,
 7.70, 7.38, 5.39, 4.55, 4.33; IR (drift) 3161, 3073, 3003, 2960, 2914,
 1656, 1614, 1557, 1517, 1487, 1299, 1014, 1006, 826, 805 cm.sup.-1 ; MS
 (ESI) 367.0 (M+H).sup.+, 365.1 (M-H).sup.-. Anal. Found: C, 65.23; H,
 4.24; N, 7.60.
 Preparation 6
 Methyl
 3-(((4-Chlorobenzyl)amino)carbonyl)-8-fluoro-4-hydroxy-6-quinolinecarboxyl
 ate.
 ##STR40##
 A solution of
 N-[(4-chlorobenzyl]-8-fluoro-4-hydroxy-6-iodo-3-quinolinecarboxamide from
 Preparation No. 1 (1.0 g), Et.sub.3 N (0.61 mL), methanol (3.55 mL),
 Pd(OAc).sub.2 (13.7 mg), and 1,3-bis(diphenylphosphino)propane (25.2 mg)
 in DMSO (12 mL) is stirred at rt until dissolution. CO(g) is slowly
 bubbled through the reaction for 3 h and the mixture is heated at
 70.degree. C. overnight. CO(g) is bubbled through the reaction mixture
 again for 4 h. The mixture is cooled to rt and diluted with water. The
 white solid that precipitates is collected and the filtrate partitioned
 against CH.sub.2 Cl.sub.2. The aqueous layer is washed with CH.sub.2
 Cl.sub.2. The combined organic layers are dried (Na.sub.2 SO.sub.4) and
 condensed to obtain an orange residue. The residue is placed under high
 vacuum to remove residual DMSO. The previously collected solid is combined
 with the residue, dissolved in methanol, and absorbed onto silica. The
 crude product is chromatagraphed eluting with 2% methanol/CH.sub.2
 Cl.sub.2. Fractions homogeneous by TLC are combined, condensed, and
 recrystallized from EtOAc/hexanes to yield 0.418 g of the title compound
 as a white solid.
 Physical characteristics are as follows:
 MP 288-290.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta.13.17, 10.09,
 8.63, 8.58, 8.04, 7.39, 7.34, 4.54, 3.30 ppm; IR (drift) 3071, 1727, 1660,
 1634, 1611, 1576, 1557, 1527, 1496, 1311, 1288, 1234, 1191, 803, 765
 cm.sup.-1 ; HRMS (FAB) found 389.0706. Anal. Found: C, 58.64; H13.84; N,
 7.24.
 Preparation 7
 N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxam
 ide
 ##STR41##
 Methyl
 3-{[(4-chlorobenzyl)amino]carbonyl}-8-fluoro-4-hydroxy-6-quinolinecarboxyl
 ate from Preparation No. 6 (150 mg) was dissolved in distilled THF (45 mL).
 The solution was heated to 35.degree. C. to get the starting material into
 solution, then cooled to 18.degree. C. for addition of LiAlH.sub.4 (27.0
 mg). After 2 hours additional LiAlH.sub.4 (27.0 mg) was added because not
 much progress was seen in complete conversion to product. Complete
 conversion to product was achieved in 61/2 hrs. The reaction was quenched
 by adding 0.1 mL H.sub.2 O, 0.1 mL 15% NaOH, and 0.1 mL to the reaction
 mixture. The reaction mixture was filtered to get rid of the aluminum salt
 that had precipitated. The filtrate was condensed to obtain a green
 residue. The green residue was adsorbed onto silica and chromatographed
 eluting with 2% MeOH in CH.sub.2 Cl.sub.2 and 3% MeOH in CH.sub.2
 Cl.sub.2. Fractions homogenous by TLC were condensed to yield 76.8 mg
 (55%) of the desired product as a white solid.
 Physical characteristics are as follows:
 MP 263-265 C; .sup.1 H NMR (300 MHz, DMSO) .delta.12.85, 10.32, 8.62, 8.03,
 7.63, 7.41, 7.36, 5.49, 4.62, 4.55; IR (drift) 3082, 2939, 1658, 1614,
 1575, 1543, 1514, 1495, 1346, 1301, 1292, 1265, 891, 800, 679 cm.sup.-1 ;
 MS (ESI) 361.1 ((M+H).sup.+, 359.1 (M-H).sup.-. Anal. Found: C, 59.76; H,
 4.00; N, 7.85.
 Preparation 8
 Methyl 3-{[(4-chlorobenzyl)amino]carbonyl}-4-hydroxy-6-quinolinecarboxylate
 ##STR42##
 A solution of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide
 from Preparation No. 4 (30.0 g), Et.sub.3 N (19.1 mL), MeOH (110.6 mL),
 Pd(OAc).sub.2 (431 mg), and 1,3-bis (diphenylphosphino) propane (791.9 mg)
 in 375 mL anhydrous DMF is stirred at room temperature until everything
 dissolves. CO(g) is slowly bubbled through for 2 days and the reaction is
 maintained at 70.degree. C. The reaction is cooled to room temperature.
 The product is precipitated by adding 160 mL 1N HCl to the reaction
 mixture. An orange solid precipitates and is collected. The solid is
 triturated with EtOAc, filtered, and washed with CH.sub.2 Cl.sub.2 to
 afford 23.8 g (93%) of the title compound as an off-white solid.
 Physical characteristics are as follows:
 Mp 290-292.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta.12.96, 10.26,
 8.83, 8.25, 7.80, 7.39, 4.57, 3.9; IR (drift) 3222, 1724, 1646, 1619,
 1574, 1544, 1512, 1489, 1404, 1359, 1288, 1277, 1242, 1210,738 cm.sup.-1 ;
 HRMS (FAB) Found 371.0794. Anal. Found: C, 61.54; H, 3.88; N, 7.51.
 Preparation 9
 N-(4-Chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide
 ##STR43##
 In a flame-dried 1 L 3-necked roundbottom, methyl
 3-{[(4-chlorobenzyl)amino]-carbonyl}-4-hydroxy-6-quinolinecarboxylate from
 Preparation No. 8 (3.0 g) is dissolved in 700 mL distilled THF. The
 suspension is heated to 67.degree. C. to solubilize the starting material.
 The reaction is allowed to cool to room temperature and then cooled in an
 ice bath to 10.degree. C. Lithium aluminum hydride (552.2 mg) is added in
 one portion. The reaction is stirred at 25.degree. C. and monitored by
 mass spectroscopy for conversion to desired product. The reaction is
 quenched by adding 2 mL H.sub.2 O, 2 mL 15% NaOH, and 2 mL H.sub.2 O to
 the reaction mixture. The reaction mixture is filtered to remove the
 aluminum salt that had precipitated. The filtrate is condensed to obtain a
 yellow-green residue. The residue is adsorbed onto silica and
 chromatographed eluting with 2% MeOH in CH.sub.2 Cl.sub.2 (1 L), 3% MeOH
 in CH.sub.2 Cl.sub.2 (2 L), 4% MeOH in CH.sub.2 Cl.sub.2 (2 L), 5% MeOH in
 CH.sub.2 Cl.sub.2 (1 L), 6% MeOH in CH.sub.2 Cl.sub.2 (1 L), and 7% MeOH
 in CH.sub.2 Cl.sub.2 (2 L). The desired product elutes with 4-7% MeOH in
 CH.sub.2 Cl.sub.2. Fractions homogenous by TLC are condensed to yield 1.85
 g (67%) of the title compound as yellow crystals.
 Physical characteristics are as follows:
 Mp 288-289.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta.12.71, 10.48,
 8.74, 8.21, 7.71, 7.66, 7.39, 5.38, 4.63, 4.56; MS (ESI) 343.3
 ((M+H).sup.+, 341.3 (M-H).sup.-.
 Preparation 10
 N-(4-Chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide
 ##STR44##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from
 Preparation No. 9 (300 mg,), K.sub.2 CO.sub.3 (485.1 mg), and CH.sub.3 I
 (0.11 mL) in 4 mL anhydrous DMF is heated at 90.degree. C. for 3 h. The
 reaction is cooled to room temperature and diluted with H.sub.2 O to
 dissolve any salts and precipitate the product. The crude product is
 adsorbed onto silica and chromatographed eluting with 3% MeOH in CH.sub.2
 Cl.sub.2. Fractions homogenous by TLC are combined and condensed to afford
 154.2 mg (49%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 168-170.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta.10.45, 8.87,
 8.30, 7.80, 7.38, 5.42, 4.66, 4.57,4.02; MS (ESI) 357.2 (M+H).sup.+, 355.3
 (M-H).sup.-. Anal. Found: C, 63.73; H, 4.62; N, 7.70.
 Preparation 11
 N-(4-Chlorobenzyl)-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quinol
 inecarboxamide and
 Preparation 12
 N-(4-Chlorobenzyl)-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]4-oxo-3-quinoli
 necarboxamide
 ##STR45##
 A mixture of N-(4-chlorobenzyl)-4-hydroxy
 -6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5
 (5.48 g) and Pd/C (10%, 0.55 g) in 3:1 CH.sub.2 Cl.sub.2 /MeOH (150 mL)
 are placed on a Parr hydrogenator under 50 psi of H.sub.2 and shaken for 4
 h. Another 0.30 g of Pd/C was added, and the resulting mixture was shaken
 for 2 h. The reaction mixture is then filtered through Celite, 0.55 g of
 fresh catalyst is added, and the resulting mixture is shaken under H.sub.2
 for 3 h. The reaction mixture is then filtered through Celite and
 concentrated in vacuo. Trituration from CHCl.sub.3 /MeOH affords a solid
 which is purified by HPLC chromatography on a 0.46.times.25 cm Chiralcel
 OD-H column eluting with EtOH at a rate of 0.3 mL/min to give 0.383 g of
 N-(4-chlorobenzyl)-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quino
 linecarboxamide (cis title compound), and 0.492 g of
 N-(4-chlorobenzyl)-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quino
 linecarboxamide (trans title compound). Crystallization of the cis isomer
 from ethyl acetate gave 0.29 g of the title cis compound as a solid.
 Crystallization of the trans isomer from CH.sub.2 Cl.sub.2 /MeOH gave
 0.289 g of the title trans compound as a solid.
 Physical characteristics of
 N-(4-Chlorobenzyl)-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quino
 linecarboxamide (PREATION 11) are as follows:
 Mp 188-191.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.12.77,
 10.47-10.41, 8.75, 8.05, 7.71-7.65, 7.42-7.36, 6.58, 5.91, 4.98, 4.56,
 4.30 ppm; IR (drift) 3257, 3249, 3210, 3166, 3083, 3063, 3018, 2971, 2941,
 1646, 1616, 1552, 1525, 1489, 798 cm.sup.-1 ; MS (EI) m/z 368 (M+), 228,
 201, 154, 142, 140, 127, 125, 115, 89, 77; HRMS (FAB) calcd for C.sub.20
 H.sub.17 ClN.sub.2 O.sub.3 +H 369.1006, found 369.0996.
 Physical characteristics of
 N-(4-Chlorobenzyl)-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quino
 linecarboxamide (PREATION 12) are as follows:
 Mp 212-215.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.12.74,
 10.45, 8.73, 8.16, 7.92, 7.66, 7.42-7.33, 6.72, 6.54-6.47,4.92,4.56, 4.17
 ppm; IR (drift) 3078, 3059, 3053, 3026, 3010, 2971, 2928, 1651, 1615,
 1576, 1552, 1525, 1490, 1297, 802 cm.sup.-1 ; MS (EI) m/z 368 (M+), 228,
 201, 198, 142, 140, 127, 125, 89, 77, 73; HRMS (FAB) calcd for C.sub.20
 H.sub.17 ClN.sub.2 O.sub.3 +H 369.1006, found 369.0993.
 Preparation 13
 Ethyl 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 ##STR46##
 Ethyl 8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxylate (18.1 g) prepared as
 an intermediate in Preparation No. 1 is dissolved in DMF (430 mL), and
 K.sub.2 CO.sub.3 (36.1 g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol)
 are added. The reaction mixture is heated to 95.degree. C. for 6 h, then
 allowed to stir at room temperature overnight. The mixture is split into
 two parts. The first part is poured into H.sub.2 O and extracted with five
 100-mL portions of CH.sub.2 Cl.sub.2. The combined organic layers are
 washed with five 200-mL H.sub.2 O, dried over MgSO.sub.4, filtered, and
 concentrated in vacuo. The work-up is then repeated on the second portion
 of the reaction mixture to give a total of 15.8 g of the title compound.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.8.49, 8.23, 7.95-7.89, 5.73,
 4.19, 4.00, 1.26 ppm.
 PREATION 14
 N-(4-Chlorobenzyl)-8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolineca
 rboxamide
 ##STR47##
 A solution of ethyl
 8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxylate from
 Preparation No. 13 (15.8 g) in p-chlorobenzylarnine (15.4 mL) is warmed to
 190.degree. C. The mixture is then cooled to room temperature, and hexane
 is added. The resulting precipitate is collected by filtration to give the
 title compound as a solid. An analytical sample is prepared by
 recrystallization from EtOH.
 Physical characteristics are as follows:
 Mp 243.3-244.8.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6)
 .delta.10.17-10.12, 8.80, 8.43, 8.12, 7.40, 7.35, 4.55, 4.15 ppm; IR
 (drift) 3051,3039, 1657, 1603, 1575, 1552, 1491, 1468, 1359, 1314, 1251,
 1131, 880, 803, 705 cm.sup.-1 ; MS (EI) mz 486 (M.sup.+). Anal. found: C,
 45.94; H, 2.71; N, 5.94.
 Preparation 15
 N-(4-Chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinec
 arboxamide
 ##STR48##
 To a mixture of
 N-(4-chlorobenzyl)-8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxamide of
 Preparation No. 1 (0.466 g) in 15 mL diethylamine is added CuI (0.010 g)
 and (Ph.sub.3 P).sub.2 PdCl.sub.2 (0.035 g). Propargyl alcohol (0.058 mL)
 is then added and the reaction is stirred overnight at room temperature.
 The diethylamine is removed in vacuo. The residue is partitioned between
 EtOAc and water. The insoluble material is filtered off and saved. The
 organic layer is washed with brine, dried and condensed. The residue is
 combined with the insoluble material and adsorbed onto silica and
 chromatographed, eluting with 3% MeOH/CH.sub.2 Cl.sub.2. Fractions
 homogeneous by TLC are combined and condensed to yield 0.192 g of the
 desired product as a tan solid.
 Physical characteristics are as follows:
 Mp 277-279.degree. C.; .sup.1 H NMR (300 MHz, DMSO) 13.02, 10.15, 8.59,
 8.00, 7,76, 7.40, 7.33, 5.41, 4.52, 4.32; IR (mull) 3137, 3070, 3008,
 1661, 1632, 1608, 1577, 1550, 1520, 1495, 1307, 1289, 1198, 1017, 802
 cm.sup.-1 ; MS (EI) m/z 384 (M+), 386, 384, 271, 244, 217, 142, 141, 140,
 125,60; HRMS (FAB) found 385.0773.
 Preparation 16
 Ethyl
 6-[[2-(acetyloxy)ethyl](ethyl)amino]-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxylate
 ##STR49##
 To a pressure tube containing 1-fluoro-4-nitrobenzene (5.3 mL) and is added
 2-(ethylamino)-1-ethanol (10.7 g). The reaction is tightly sealed and
 heated to 135.degree. C. with stirring. After 1 hour, the reaction is
 cooled to room temperature and concentrated under reduced pressure. The
 residue is dried in vacuo. The residue is chromatographed on silica
 eluting with ethyl acetate. The product-containing fractions are
 evaporated to give 10.1 g of 2-(ethyl-4-nitroanilino)-1-ethanol as an
 orange solid.
 To a flask containing 2-(ethyl-4-nitroanilino)-1-ethanol (4.2 g) and
 4-dimethylaminopyridine (0.12 g) in pyridine (20 mL) at 0.degree. C. under
 a drying tube is added acetic anhydride (5.0 mL) dropwise. The reaction
 mixture is allowed to warm to room temperature overnight. The reaction
 mixture is diluted with ethyl acetate and partioned against saturated
 aqueous sodium carbonate. The layers are separated and the aqueous phase
 extracted with two additional portions of ethyl acetate. The combined
 organic phases are washed with brine, dried over sodium sulfate and
 concentrated under reduced pressure. The residue is azeotroped three times
 with toluene to remove residual pyridine. The residue is adsorbed onto
 silica and chromatographed on silica eluting with 50% ethyl acetate in
 heptane. The product-containing fractions are evaporated to give 4.9 g of
 2-(ethyl-4-nitroanilino)ethyl acetate as a yellow oil.
 To a Parr bottle containing 2-(ethyl4-nitroanilino)ethyl acetate (2.5 g)
 and ethyl acetate (25 mL) is added 10% palladium on carbon (0.11 g). The
 reaction mixture is shaken for 1 hour under 50 psi of hydrogen gas. The
 reaction mixture is filtered through Celite with ethyl acetate washes. The
 filtrate is concentrated under reduced pressure. The residue is treated
 with diethyl ethoxymethylenemalonate (2.4 mL) and heated to 140.degree. C.
 under a flow of argon gas. After 1 hour the reaction is cooled to room
 temperature, adsorbed onto silica gel, and chromatographed on silica
 eluting with 50% ethyl acetate in heptane. The product-containing
 fractions are evaporated to give crude diethyl
 2-({4-[[2-(acetyloxy)ethyl]-(ethyl)amino]anilino}methylene)malonate as an
 orange oil.
 To a flask containing crude diethyl
 2-({4-[[2-(acetyloxy)ethyl](ethyl)amino]-anilino}methylene)malonate (2.2
 g) is added diphenyl ether (15 mL). The reaction mixture is heated from
 room temperature to 260.degree. C. over 45 minutes under a flow of argon
 gas. After 1 hour at 260.degree. C. the hot reaction is slowly and
 carefully added to stirred diethyl ether (150 mL). The resulting
 precipitate is filtered and washed repeatedly with heptane. The residue is
 adsorbed onto silica and chromatographed on silica eluting with 3% to 10%
 methanol in dichloromethane. The product-containing fractions are
 evaporated to give 0.68 g of ethyl
 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate as a
 brown solid.
 To a flask containing ethyl
 6-[[2-(acetyloxy)ethyl](ethyl)amino]-4-hydroxy-3-quinolinecarboxylate
 (0.17 g) in DMF (5 mL) is added potassium carbonate (0.21 g) and
 iodomethane (0.05 mL). The reaction is tightly capped and heated to
 90.degree. C. After 3 hours, the reaction is cooled to room temperature,
 diluted with dichloromethane, filtered and concentrated under reduced
 pressure. The residue is adsorbed onto silica and chromatographed on
 silica eluting with 4% to 8% methanol in dichloromethane. The
 product-containing fractions are evaporated to give 0.22 g of the title
 compound as a orange solid.
 Physical characteristics are as follows:
 .sup.1 HNMR (300 MHz, CDCl.sub.3) 8.7, 7.6, 7.3, 7.1, 4.3, 4.2, 3.8, 3.6,
 3.4, 2.0, 1.4, 1.2; MS (ESI) m/z 399 (M+K.sup.+).
 Preparation 17
 N-Cyclopropyl-4-iodoaniline
 To a flask containing 4-iodoaniline (2.19 g) is added methanol (25 mL) and
 a few dozen dry molecular sieves (3A). The mixture is treated with acetic
 acid (6 mL) followed by [(1-ethoxycyclopropyl)oxy]trimethylsilane (2.5
 mL). After 1 hour, the reaction mixture is carefully treated with sodium
 cyanoborohydride (2.8 g) and heated to reflux under a nitrogen atmosphere
 overnight. The reaction mixture is cooled to room temperature, filtered,
 and concentrated under reduced pressure. The residue is diluted with ethyl
 acetate and washed with aqueous sodium hydroxide (2N). The aqueous is
 back-extracted once with ethyl acetate and the combined organic layers are
 washed with brine, dried over sodium sulfate, and concentarted under
 reduced pressure. The residue is adsorbed onto silica and chromatographed
 on silica eluting with 3% to 9% ethyl acetate in heptane. The
 product-containing fractions are combined and evaporated to afford 1.85 g
 of the title compound as a tan oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 7.5, 6.8, 2.4, 0.9, 0.7; MS (ESI) m/z
 260 (M+H.sup.+).
 Preparation 18
 Diethyl 2-[(cyclopropyl4-iodoanilino)methylene]-malonate
 To a flask containing N-yclopropyl-iodoaniline from Preparation No. 17
 (0.85 g) is added diethyl ethoxymethylenemalonate (0.9 mL) and pyridine
 (0.5 mL). The flask is tightly capped and heated to 130.degree. C.
 overnight. The reaction is cooled to room temperature and azeotroped under
 reduced with toluene (3.times.). The residue is dissolved in
 dichloromethane and washed with brine, dried and concentrated under
 reduced pressure. The residue is adsorbed onto silica gel and
 chromatographed on silica eluting with 25% to 75% ethyl acetate in
 heptane. The product-containing fractions are evaporated to give 0.78 g of
 the title compound as a tan solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 7.8, 7.7, 7.0, 4.2, 4.1, 3.1, 1.3, 0.9,
 0.7; MS (ESI) m/z 430 (M+H.sup.+).
 Preparation 19
 Ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 To a flask containing diethyl
 2-[(cyclopropyl-4-iodoanilino)methylene]malonate from Preparation No. 18
 (0.22 g) is added polyphosphoric acid (1.4 g). The reaction mixture is
 capped and heated to 120.degree. C. over 1 hour. After 2 hours at
 120.degree. C. the reaction is cooled to room temperature, treated with
 ice and partioned between dichloromethane and saturated aqueous
 bicarbonate. The basic aqueous layer is extracted with two additional
 portions of dichloromethane. The combined organic layers are washed with
 brine, dried over sodium sulfate and concentrated under reduced pressure
 to afford 0.19 g of the title compound as a tan solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 8.8, 8.6, 7.9, 7.7, 4.4, 3.4, 1.4, 1.3,
 1.1; MS (ESI) m/z 384 (M+H.sup.+).
 Preparation 20
 N-(4-Chlorobenzyl)-1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarbox
 amide
 ##STR50##
 To a flask containing ethyl
 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from
 Preparation No. 19 (0.19 g) is added p-chlorobenzylamine (1.0 mL). The
 reaction is tightly capped and heated to 180.degree. C. for 1 hour. The
 reaction is cooled to room temperature and partioned between
 dichloromethane containing methanol and dilute hydrochloric acid. The
 aqueous layer is extracted with dichloromethane and the combined organic
 layers are washed with brine, dried and concentarted under reduced
 pressure. The residue is adsorbed onto silica and chromatographed on
 silica eluting with 2% to 6% methanol in dichloromethane. The product
 containing fractions are evaporated to give 0.10 g of the title compound
 as a tan solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.2, 8.7, 8.6, 8.2, 8.0, 7.4, 4.5,
 3.7, 3.5, 1.3, 1.1; MS (ESI) m/z 479 (M+H.sup.+).
 Preparation 21
 4-(4-Nitrobenzyl)morpholine
 To a flask containing 4-nitrobenzyl bromide (21.6 g) in dry acetone (100
 mL) is added potassium carbonate (34.5 g) and morpholine (10 mL). The
 mixture is heated to reflux overnight under a drying tube. The reaction is
 partioned between ethyl acetate and water and separated. The basic aqueous
 layer is extracted with two additional portions of ethyl acetate. The
 combined organic layers are washed with brine, dried, and concentrated
 under reduced pressure to afford 21.3 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 75-79.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) 8.2, 7.6, 3.7, 3.6,
 2.4.
 Preparation 22
 4-(4-Aminobenzyl)morpholine
 To a solution of 4-(4-Nitrobenzyl)morpholine from Preparation No. 21 (0.89
 g) in ethyl acetate (10 mL) is added 5% platinuim on carbon (0.04 g). The
 reaction is shaken under 30 psi of hydrogen gas for 1 hour. The mixture is
 filtered with ethyl acetate washes. The filtrate is concentrated under
 reduced pressure to afford 0.71 g of the title compound as a yellow solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 7.1, 6.6, 3.7, 3.6, 3.4, 2.4; MS (ESI)
 m/z 193 (M+H.sup.+).
 Preparation 23
 N-Cyclopropyl-4-(4-morpholinylmethyl)aniline
 To a flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22
 (0.96 g) is added methanol (12 mL) and a few dozen dry molecular sieves
 (3A). The mixture is treated with acetic acid (3 mL) followed by
 [(1-ethoxycyclopropyl)oxyl-trimethylsilane (1.25 mL). After 15 minutes,
 the reaction mixture is carefully treated with sodium cyanoborohydride
 (1.4 g) and heated to reflux under a nitrogen atmosphere overnight. The
 reaction mixture is cooled to room temperature, filtered with methanol
 washes, and concentrated under reduced pressure. The residue is diluted
 with diethyl ether and washed with aqueous sodium hydroxide (2N). The
 aqueous is back-extracted once with diethyl ether and once with
 dichloromethane. The combined organic layers are washed with brine, dried
 over sodium sulfate, and concentarted under reduced pressure. The residue
 is adsorbed onto silica and chromatographed on silica eluting with 2% to
 8% methanol in dichloromethane. The product-containing fractions are
 combine and evaporated to afford 0.13 g of the title compound as a pink
 solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 7.1, 6.8, 3.7, 3.4, 2.4, 0.7, 0.5; MS
 (ESI) m/z 233 (M+H.sup.+).
 Preparation 24
 Diethyl 2-{[cyclopropyl-4-(4-morpholinylmethyl)anilino]methylene}malonate
 To a flask containing N-cyclopropyl-4-(4-morpholinylmethyl)aniline (0.55 g)
 from Preparation No. 23 is added diethyl ethoxymethylenemalonate (0.45 mL)
 and pyridine (0.33 mL). The flask is tightly capped and heated to
 145.degree. C. for 2 hours. The reaction is cooled to room temperature and
 azeotroped under reduced pressure with toluene (3.times.). The residue is
 dissolved in dichloromethane and washed with brine, dried and concentrated
 under reduced pressure. The residue is chromatographed on silica eluting
 with 2% to 6% methanol in dichloromethane. The product-containing
 fractions are evaporated to give 0.77 g of the title compound as an oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 7.8, 7.3, 7.1, 4.2, 4.1, 3.8, 3.1, 2.4,
 1.3, 0.8, 0.7; MS (ESI) m/z 403 (M+H.sup.+).
 Preparation 25
 Ethyl
 1-cyclopropyl-6-(4-morpholinylmethyl-4-oxo-1,4-dihydro-3-quinolinecarboxyl
 ate
 ##STR51##
 To a flask containing diethyl
 2-{[cyclopropyl-4-(4-morpholinylmethyl)anilino]methylene}malonate from
 Preparation No. 24 (0.77 g) is added polyphosphoric acid (4.4 g). The
 reaction mixture is tightly capped and heated to 120.degree. C. After 1
 hour the reaction is cooled to room temperature. The reaction mixture is
 carefully added to a vigorously stirred mixture of dichloromethane and
 saturated aqueous bicarbonate. The layers are separated and the basic
 aqueous layer is extracted with two additional portions of
 dichloromethane. The combined organic layers are washed with brine, dried
 over sodium sulfate and concentrated under reduced pressure. The residue
 is chromatographed on silica eluting with 3% to 15% methanol in
 dichloromethane to afford 0.38 g of the title compound as a yellow solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 8.6, 8.4, 7.9, 7.7, 4.4, 3.7, 3.6, 3.5,
 2.5, 1.4, 1.3, 1.1; MS (ESI) m/z 357 (M+H.sup.+).
 Preparation 26
 tert-Butyl
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-iodo-4-oxo-1(4H)-quinolinyl]aceta
 te
 ##STR52##
 To a flask containing
 N-(4-chlorobenzyl)-6-iodo-4-hydoxy-3-quinolinecarboxamide (0.22 g)
 obtained as described in Preparation No. 4 in DMF (5 mL) is added
 potassium carbonate (0.21 g) and tert-butylbromoacetate (0.11 mL). After
 stirring overnight, the reaction is diluted with dichloromethane and
 partioned against water. The organic phase is washed with brine, dried
 over sodium sulfate, concentrated under reduced pressure, and dried in
 vacuo to give 0.26 g of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 10.2, 8.9, 8.6, 8.1, 7.4, 7.3, 5.4, 4.5,
 1.4. Anal. found: C, 49.91; H, 4.09; N, 5.08.
 Example 1
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-isopropyl-4-oxo-1,4-dihydro-3
 -quinolinecarboxamide
 ##STR53##
 N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de (366 mg) from Preparation No. 5 and potassium carbonate (276 mg) are
 dissolved in DMF (5 mL). 2-Bromopropane (470 .mu.L) is added and the
 mixture is heated to 100.degree. C. for 1 h. The reaction mixture is
 allowed to cool to rt, poured into water (25 mL) and extracted with ethyl
 acetate (2.times.50 mL). The organic layer is washed with sat. aqueous
 brine (10 mL). The aqueous layer is back-extracted with ethyl acetate (20
 mL). The combined organic layers are dried (MgSO.sub.4) and concentrated.
 The crude product is purified by column chromatography (EtOAc/heptane, 1/1
 to 1/0) and recrystallization (EtOH) to afford 70 mg (17%) of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 189-191.degree. C. dec; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.28, 8.87,
 8.34, 8.08, 7.85, 7.42-7.35, 5.40, 5.18, 4.55, 4.35, 1.53; IR (drift)
 3314, 2227 (w), 1902 (w), 1648 (s), 1597, 1572, 1547, 1491 (s), 1342,
 1321, 1214, 1037, 1025, 813, 682 cm.sup.-1. Anal. Found for C.sub.23
 H.sub.21 ClN.sub.2 O.sub.3 : C, 67.53; H, 5.14; N, 6.66.
 Example 2
 1-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide
 ##STR54##
 N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de (366 mg) from Preparation No. 5 and potassium carbonate (276 mg) are
 dissolved in DMF (5 mL). 2-Iodobutane (575 .mu.L) is added and the mixture
 is heated to 100.degree. C. for 1 h. The reaction mixture is allowed to
 cool to rt, poured into water (25 mL) and extracted with ethyl acetate
 (2.times.50 mL). The organic layer is washed with sat. aqueous brine (10
 mL). The aqueous layer is back-extracted with ethyl acetate (20 mL). The
 combined organic layers are dried (MgSO.sub.4) and concentrated. The crude
 product is purified by column chromatography (dichloromethane/methanol,
 100/1; 50/1; 20/1) to afford 80 mg (19%) of the title compound as a white
 solid.
 Physical characteristics are as follows:
 Mp 200-201.degree. C. dec; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.27, 8.80,
 8.34, 8.12, 7.84, 7.42-7.35, 5.39, 5.02, 4.55, 4.35, 1.90, 1.51, 0.85; IR
 (drift) 3412, 1657, 1597, 1575, 1547, 1490, 1458, 1422, 1341, 1324, 1213,
 1088, 1047, 812, 804 cm.sup.-1. Anal. Found for C.sub.24 H.sub.23
 ClN.sub.2 O.sub.3 : C, 68.07; H, 5.52; N, 6.45; Cl, 8.15.
 Example 3
 1-(sec-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-8-methoxy-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide
 ##STR55##
 N-((4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolin
 ecarboxamide (300 mg) from Preparation No. 3 and potassium carbonate (310
 mg) are dissolved in DMF (5 mL). 2-Iodobutane (345 .mu.L) is added and the
 mixture is heated to 120.degree. C. for 4 h. Additional 2-Iodobutane (200
 .mu.L) and potassium carbonate (100 mg) is added and the mixture is heated
 for 16 h. The reaction mixture is allowed to cool to rt, poured into water
 (75 mL) and extracted with ethyl acetate (3.times.50 mL). The organic
 layer is washed with sat. aqueous brine (10 mL). The aqueous layer is
 back-extracted with ethyl acetate (20 mL). The combined organic layers are
 dried (MgSO.sub.4) and concentrated. The crude product is purified by
 column chromatography (EtOAc/heptane, 30/1; 10/1) to afford 60 mg (18%) of
 the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 139-142.degree. C. dec; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.20, 8.74,
 7.95, 7.43-7.35, 5.62, 5.40, 4.54, 4.35, 4.04, 1.83, 1.50, 0.77; IR
 (drift) 2480, 2214, 2015, 1909, 1649, 1597, 1550, 1483, 1340, 1327, 1278,
 1211, 1078, 1064, 807 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.25 H.sub.25
 ClN.sub.2 O.sub.4 +H 453.1581, found 453.1593.
 Example 4
 N-(4-Chlorobenzyl)-8-(2-hydroxyethoxy)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide]
 ##STR56##
 To a suspension of
 N-(4-chlorobenzyl)-8-fluoro-6-iodo-3-quinolinecarboxamide from Preparation
 No. 1 (2.28 g) in DMF (75 mL) is added sodium hydride (60% oil dispersion;
 0.600 g) followed by addition of 2-benzyloxyethanol (1.42 mL). The
 reaction is heated to 135.degree. C. and stirred for 1 h. The reaction
 mixture is cooled to room temperature and poured into saturated aqueous
 ammonium chloride (200 mL). The aqueous layer is extracted with
 dichloromethane (4.times.100 mL). The combined organic layers are washed
 with brine (50 mL), dried with MgSO.sub.4, filtered, and concentrated in
 vacuo. The resulting yellow solid is purified by column chromatography
 (dichloromethane/methanol, 98/2). Fractions homogeneous by TLC are
 combined and concentrated in vacuo to yield a yellow solid which is
 recrystallized from ethanol to yield 1.568 g (53%) of the intermediate
 amide as an off-white solid. To a suspension of this material (1.149 g) in
 diethylarnine (24 mL) are added copper iodide (0.111 g) and
 Pd(PPh.sub.3).sub.2 Cl.sub.2 (0.069 g) followed by addition of propargyl
 alcohol (0.16 mL). The reaction is stirred at room temperature for 3 d.
 The reaction mixture is concentrated in vacuo and partitioned between
 H.sub.2 O (50 mL) and dichloromethane (50 mL). The aqueous layer is
 extracted with dichloromethane (3.times.50 mL). Combined organic layers
 are washed with saturated aqueous ammonium chloride (50 mL), dried with
 MgSO.sub.4, filtered, and concentrated in vacuo. The resulting brown solid
 is purified by column chromatography (dichloromethane/methanol, 98/2).
 Fractions homogeneous by TLC are combined and concentrated in vacuo to
 yield a tan solid which is recrystallized from ethanol to yield 0.181 g
 (18%) of the propargyl compound as a tan, crystalline solid. To a solution
 of this material (0.394 g) in DMF (3 mL) is added potassium carbonate
 (0.317 g) followed by iodomethane (0.14 mL). The reaction is heated to
 90.degree. C. and stirred for 18 h. The reaction mixture is concentrated
 in vacuo and the resulting residue is purified by column chromatography
 (dichloromethane; dichloromethane/methanol, 98/2). Fractions homogeneous
 by TLC are combined and concentrated in vacuo to yield a yellow solid
 which is recrystallized from EtOH to yield 0.273 g (67%) of the N-methyl
 pyridone as a yellow solid. The pyridone (0.350 g) is dissolved in 1/1
 dichloromethane/ethanol (100 mL) and hydrogenated over 10% Pd/C (53 mg) at
 35 psi for 18 h. The reaction mixture is filtered through a Celite pad,
 and the filtrate is concentrated in vacuo. The resulting yellow oil is
 dissolved in methanol (60 mL) and hydrogenated over Pd Black (35 mg) for 4
 h. The reaction mixture is filtered through a Celite pad, and the filtrate
 is concentrated in vacuo. The resulting yellow oil is purified by column
 chromatography (dichloromethane/methanol, 98/2; 95/5). Fractions
 homogeneous by TLC are combined and concentrated in vacuo to yield a pale
 yellow solid which is recrystallized from ethyl acetate to yield 0.104 g
 (35%) of the title compound as a pale yellow solid.
 Physical characteristics are as follows:
 Mp 175-179.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.43,
 8.65, 7.75, 7.42-7.34, 7.29, 4.97, 4.57, 4.50, 4.27, 4.18, 3.82, 3.44,
 2.73, 1.77; .sup.13 C NMR (75 MHz, DMSO-d.sub.6) .delta.175.1, 164.9,
 164.8, 150.8, 150.6, 140.7, 140.0, 139.2, 131.8, 129.8, 129.6, 128.9,
 128.8, 127.8, 127.3, 117.5, 117.1, 110.3, 110.2, 72.4, 60.4, 59.9, 48.2,
 42.6, 41.9, 34.4, 31.9; IR (drift) 3341, 3311, 1903, 1657, 1605, 1556,
 1494, 1452, 1346, 1323, 1276, 1084, 1058, 1044, 804 cm.sup.-1 ; MS (ESI+)
 m/z 445 (M+H).sup.+. Anal. Found: C, 62.86; H, 5.87; N, 6.29; Cl, 6.26.
 Example 5
 N-(4-Chlorobenzyl)-8-[2-hydroxy-1-(hydroxymethyl)ethoxy]-6-(3-hydroxypropyl
 )1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR57##
 To a suspension of
 N-(4-chlorobenzyl)-8-fluoro-6-iodo-3-quinolinecarboxamide Preparation No.
 1 (2.28 g) in DMF (75 mL) is added sodium hydride (60% oil dispersion;
 0.600 g) followed by addition of 1,3-dibenzyloxy-2-propanol (2.47 mL). The
 reaction is heated to 135.degree. C. and is stirred for 2 h. The reaction
 mixture is cooled to room temperature and poured into saturated aqueous
 ammonium chloride (200 mL). The aqueous layer is extracted with CH.sub.2
 Cl.sub.2 (4.times.100 mL). The combined organic layers are washed with
 brine (50 mL), dried with MgSO.sub.4, filtered, and concentrated in vacuo.
 The resulting brown oil is purified by column chromatography
 (dichloromethane/methanol, 98/2). Mixed fractions are combined and
 re-purified (ethyl acetate/heptane, 1/1). Fractions homogeneous by TLC are
 combined and concentrated in vacuo to yield a yellow solid which is
 recrystallized from ethyl acetate to yield 1.701 g (48%) of the
 intermediate amide as a pale yellow solid. To a suspension of this
 material (1.330 g) in diethylamine (23 mL) are added copper iodide (0.107
 g) and Pd(PPh.sub.3).sub.2 Cl.sub.2 (0.066 g) followed by addition of
 propargyl alcohol (0.15 mL). The reaction is stirred at room temperature
 for 18 h. The reaction mixture is concentrated in vacuo. The resulting
 brown solid is purified by column chromatography (dichloromethane,
 dichloromethane/methanol, 98/2). Fractions homogeneous by TLC are combined
 and concentrated in vacuo to yield an orange solid which is recrystallized
 from diethyl ether/ethyl acetate to yield 0.727 g (61%) of the propargyl
 derivative as an off-white solid. To a solution of this material (0.500 g)
 in DMF (3 mL) is added potassium carbonate (0.325 g) followed by addition
 of iodomethane (0.15 mL). The reaction is heated to 90.degree. C. and is
 stirred for 18 h. The reaction mixture is concentrated in vacuo, and the
 residue is purified by column chromatography (dichloromethane/methanol,
 98/2). Fractions homogeneous by TLC are combined and concentrated in vacuo
 to yield a yellow solid which is recrystallized from ethyl
 acetate/methanol to yield 0.383 g (75%) of the N-methyl pyridone as a
 yellow solid. A solution of the pyridone (0.310 g) in 1/1
 dichloromethane/ethanol (30 mL) is hydrogenated over 10% Pd/C (62 mg) at
 35 psi for 5.5 h. The reaction mixture is filtered through a Celite pad,
 and the filtrate is concentrated in vacuo. The resulting yellow oil is
 purified by column chromatography (dichloromethane/methanol; 98/2, 95/5,
 90/10). Fractions homogeneous by TLC are combined and concentrated in
 vacuo to yield a pale yellow solid which is recrystallized from ethyl
 acetate/methanol to yield 0.050 g (22%) of the title compound as a white
 solid.
 Physical characteristics are as follows:
 Mp 120-123.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.44,
 8.64, 7.74, 7.42-7.34, 4.92, 4.56,4.50,4.29, 3.77-3.64, 3.44, 2.72, 1.77;
 .sup.13 C NMR (75 MHz, DMSO-d.sub.6) .delta.175.1, 164.9, 150.8, 150.1,
 140.6, 139.2, 131.8, 130.3, 130.0, 129.6, 128.9, 128.8, 127.8, 118.4,
 117.0, 110.1, 82.6, 60.5, 60.2, 48.2, 41.9, 34.5, 31.9, 21.2, 14.6; IR
 (drift) 3388, 3343, 3326, 2350, 1970, 1902, 1651, 1601, 1552, 1499, 1268,
 1118, 1077, 1052, 807 cm.sup.-1 ; MS (ESI+) for m/z 475 (M+H).sup.+. Anal.
 Found: C, 60.59; H, 5.72; N, 5.88.
 Example 6
 N-(4-Chlorobenzyl)-8-fluoro-6-(hydroxymethyl)-4-oxo-1-[3-(tetrahydro-2H-pyr
 an-2-yloxy)propyl]-1,4-dihydro-3-quinolinecarboxamide
 ##STR58##
 To a suspension of NaH (60% dispersion in oil, 11.1 mg) in 2.5 mL anhydrous
 DMF is added
 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxa
 mide from Preparation No. 7 (100 mg). After stirring the reaction mixture
 at room temperature for 15-20 min., 2-(3-bromopropoxy)tetrahydro-2H-pyran
 (89.4 mg) is added. The reaction is stirred at room temperature for 3
 days. The reaction mixture is treated with saturated aqueous NaHCO.sub.3,
 then extracted with CH.sub.2 Cl.sub.2 (3.times.). The combined organic
 layers are washed with 15% K.sub.2 CO.sub.3 and H.sub.2 O (2.times.),
 dried over Na.sub.2 SO.sub.4, and condensed to obtain a yellow residue.
 The residue is chromatographed eluting with 2% MeOH in CH.sub.2 Cl.sub.2.
 Fractions homogenous by TLC are combined and condensed to afford 34.0 mg
 (24%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 148-150.degree. C.; .sup.1 H NMR (300 MHz, DMSO) .delta.10.26, 8.77,
 8.17, 7.65, 7.38, 5.50, 4.60, 4.46, 3.67, 3.35, 2.05, 1.61, 1.53, 1.37; IR
 (drift) 3333, 2940, 2918, 1651, 1603, 1563, 1490, 1352, 1281, 1120, 1069,
 1036, 1018, 990, 805 cm.sup.-1 ; MS (ESI) 503.1 ((M+H).sup.+, 501.1
 (M-H).sup.-. Anal. Found: C, 62.03; H, 5.57; N, 5.58.
 Example 7
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propenyl)-1-[2-(4-morpholinyl)ethyl]-4-ox
 o-1,4-dihydro 3-quinolinecarboxamide
 ##STR59##
 A mixture of
 N-(4-chlorobenzyl)-1,4-dihydro-6-[3-hydroxy-1-propenyl]-4-oxo-3-quinolinec
 arboxamide from Preparations No. 11 and 12 (0.52 g) is dissolved in DMF (4
 mL), and potassium carbonate (0.78 g) and N-(2-chloroethyl)morpholine
 hydrochloride (0.52 g) are added. The mixture is heated at 90.degree. C.
 for 2 h and then partitioned between water and chloroform. The organic
 layer is concentrated in vacuo to give a brown oil. Column chromatography
 (elution with 1-7% MeOH/CHCl.sub.3) followed by crystallization from
 EtOAc/hexane gave the title compound as a mixture of isomers. The mixture
 is then purified by HPLC chromatography on a 0.46.times.25 cm Chiralcel
 OD-H column eluting with EtOH at a rate of 0.5 mL/min. This gave 0.161 g
 of the alkene mixture as approximately a 2:1 mixture of the trans:cis
 isomers, which is crystallized from ethyl acetate to give 0.13 g of the
 title compound as a hydrate.
 Physical characteristics are as follows:
 Mp 146-148.5.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.40,
 8.79, 8.32, 7.77-7.70, 7.45, 7.34-7.28, 7.17-7.10, 6.65, 6.49, 6.53, 6.48,
 4.79, 4.62, 4.35, 4.04-3.67, 3.20-2.46, 2.25, 1.87-1.80, 1.13 ppm; IR
 (drift) 3293, 2956, 1744, 1670, 1648, 1600, 1555, 1512, 1491, 1450, 1229,
 1117, 1092, 1000, 807 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.26 H.sub.28
 ClN.sub.3 O.sub.4 +H 482.1846, found 482.1849.
 Example 8
 N-(4-Chlorobenzyl)-8-fluoro-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide
 ##STR60##
 A mixture of
 N-(4-chlorobenzyl)-8-fluoro-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinec
 arboxamide from Preparation No. 14 (0.600 g), propargyl alcohol (0.11 mL,
 1.90 mmol), CuI (0.048 g, 0.25 mmol), and PdCl.sub.2 (PPh.sub.3).sub.2
 (0.178 g, 0.25 mmol) in diethylamine (42.5 mL) and CH.sub.2 Cl.sub.2 (50
 mL) are warmed to 65.degree. C. overnight. The reaction mixture is then
 concentratred in vacuo. Column chromatography (elution with 5-10%
 MeOH/CH.sub.2 Cl.sub.2) gave the title compound as a solid.
 Physical characteristics are as follows:
 Mp 186-188.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6)
 .delta.10.18-10.13, 8.78, 8.11, 7.77, 7.40, 7.36, 5.45, 4.56, 4.35, 4.16
 ppm; .sup.13 C NMR (100 MHz, DMSO-d.sub.6) .delta.173.8, 182.6, 151.6,
 139.0, 131.8, 129.9, 129.6, 128.7, 125.2, 121.9, 119.7, 111.4, 92.4, 81.9,
 49.8, 46.0, 41.8 ppm; IR (drift) 3410, 1657, 1600, 1569, 1551, 1541, 1493,
 1472, 1362, 1342, 1284, 1127, 806, 799, 726 cm.sup.-1 ; MS (EI) m/z 398
 (M.sup.+); HRMS (EI) calcd for C.sub.21 H.sub.16 ClFN.sub.2 O.sub.3
 398.0833, found 398.0838.
 Example 9
 N-(4-Chlorobenzyl)-8-fluoro-6-[(Z)-3-hydroxy-1-propenyl)-1-methyl-4-oxo-1,4
 -dihydro-3-quinolinecarboxamide
 ##STR61##
 A mixture of
 N-(4-chlorobenzyl)-8-fluoro-1,4-dihydro-6-(3-hydroxy-1-propynyl)-1-methyl-
 4-oxo-3-quinolinecarboxamide from Example No. 8 (0.200 g) and Pd/C (10%,
 0.040 g) in MeOH (10 mL) and CH.sub.2 Cl.sub.2 (10 mL) is placed on a Parr
 shaker under 50 psi of H.sub.2 for 6 h. The reaction mixture is filtered
 through Celite and concentrated in vacuo. Recrystallization from EtOAc
 gave the title compound as a solid.
 Physical characteristics are as follows:
 Mp 182-184.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6)
 .delta.10.28-10.21, 8.76, 7.98, 7.64, 7.40, 7.36, 6.55, 6.00-5.93,
 5.04-5.02, 4.56, 4.30-4.28, 4.18-4.16 ppm; IR (drift) 3048, 1658, 1626,
 1601, 1579, 1552, 1493, 1361, 1284, 1271, 1122, 1039, 1016, 806, 798
 cm.sup.-1 ; MS (EI) m/z 400 (M.sup.+). Anal. found: C, 62.76; H, 4.61; N,
 6.86.
 Example 10
 N-(4-Chlorobenzyl)-1-[2-(diethylamino)ethyl]-8-fluoro-6-(3-hydroxy-1-propyn
 yl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR62##
 A solution of
 N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinoline
 carboxamide from Preparation No. 15 (0.96 g) is dissolved in DMF (7 mL),
 and K.sub.2 CO.sub.3 (1.38 g) and 2-bromo-N,N-diethylethylamine
 hydrobromide (1.30 g) are added. The reaction mixture is heated to
 95.degree. C. for 16. Water is added and an oily solid formed, which is
 isolated by decanting the liquid. Column chromatography (elution with 1-3%
 MeOH/CHCl.sub.3) gave 0.373 g of the title compound which is crystallized
 from ethyl acetate to give 0.163 g of a solid.
 Physical characteristics are as follows:
 Mp 148-150.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.1,
 8.7, 8.2, 7.82, 7.4-7.3, 5.4, 4.5, 4.3, 2.7, 2.4, 0.7 ppm; IR (drift)
 2967, 1650, 1625, 1596, 1580, 1555, 1485, 1369, 1282, 1232, 1083, 1065,
 1018, 1009, 806 cm.sup.-1 ; MS (EI) m/z 483 (M+). Anal. found: C, 64.23;
 H, 5.69; N, 8.49.
 Example 11
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-propyl-1,4-dihydro-3-qu
 inolinecarboxamide
 ##STR63##
 A suspension of 0.50 g of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5, potassium carbonate (0.76 g), and 1-iodopropane
 (0.47 g) in DMF is heated to 100.degree. C. for 6 hrs and stirred at room
 temperature overnight. The reaction mixture is filtered, and the solvent
 is evaporated at reduced pressure leaving a light brown solid. The solid
 is stirred with ethyl acetate for an hour and filtered. The solvent is
 evaporated from the filtrate under reduced pressure, leaving 0.12 g of the
 title compound as a yellowish-white solid.
 Physical characteristics are as follows:
 Mp 183-184.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 8.9, 8.3,
 7.9, 7.8, 7.4, 5.4, 4.5, 4.4, 4.3, 1.8, 0.9; MS (ESI+) for m/z 431.2
 (M+Na).sup.+.
 Example 12
 N-(4-Chlorobenzyl)-1-[2-(diethylamino)ethyl]-6-(3-hydroxy-1-propynyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR64##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.616 g) is dissolved in DMF (4 mL), and K.sub.2
 CO.sub.3 (0.93 g, 6.72 mmol) and 2-bromo-N,N-diethylethylamine
 hydrobromide (0.88 g, 3.35 mmol) are added. The reaction mixture is heated
 to 90.degree. C. for 16. The mixture is partitioned between CHCl.sub.3 and
 water. The organic layer is concentrated in vacuo to give an oil. Column
 chromatography (elution with 1-5% MeOH/CHCl.sub.3) gave 0.10 g of a brown
 oil. Crystallization from ethyl acetate/hexane gave 0.013 g of the title
 compound as a solid.
 Physical characteristics are as follows:
 Mp 145-148.degree. C.; .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.8.7, 8.5,
 7.7, 7.4, 7.3, 4.6, 4.5, 4.2, 2.8, 2.5, 0.9 ppm; MS (EI) m/z 465 (M+);
 HRMS (FAB) calcd for C.sub.26 H.sub.28 ClN.sub.3 O.sub.3 +H 466.1897,
 found 466.1898.
 Example 13
 N-(4-Chlorobenzyl)-1-[2-(dimethylamino)ethyl]-6-(3-hydroxy-1-propynyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide, hydrochloride salt
 ##STR65##
 A solution of
 N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamid
 e from Preparation No. 5 (0.515 g) is dissolved in DMF (10 mL), and K.sub.2
 CO.sub.3 (0.778 g) and diisoproplyaminoethyl chloride-hydrochloride (0.56
 g) are added. The reaction mixture is heated to 95.degree. C. for 14 h,
 then allowed to stir at room temperature overnight. The mixture is then
 poured into H.sub.2 O and an oil formed, which is isolated by decanting
 the liquid. The oil is dissolved in MeOH/CH.sub.2 Cl.sub.2, and etheral
 HCl is added to adjust the pH to 2. The mixture is concentrated in vacuo
 to give the title compound as the hydrochloride salt.
 Physical characteristics are as follows:
 Mp 187-188.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.11.21,
 10.25-10.21, 8.97, 8.31, 8.11, 7.84, 7.40, 7.36, 5.44, 4.93-4.90, 4.57,
 4.36, 3.51-3.49, 2.84 ppm; .sup.13 C NMR (100 MHz, DMSO-d.sub.6)
 .delta.174.8, 163.7, 149.2, 138.5, 138.4, 135.2, 131.3, 129.2, 128.8,
 128.2, 127.1, 119.2, 118.1, 111.6, 91.2, 82.3, 53.6, 49.4, 47.6, 42.6 ppm;
 IR (drift)3332,3281, 3252, 3044, 2591, 2451, 1663, 1599, 1579, 1551, 1489,
 1373, 1228, 813, 808 cm.sup.-1 ; MS (EI) m/z 437 (M.sup.+); HRMS (FAB)
 calcd for C.sub.24 H.sub.24 ClN.sub.3 O.sub.3 +H 438.1584, found 438.1580.
 EXAMPLE 14
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(1-piperidinyl)ethyl]-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR66##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and
 K.sub.2 CO.sub.3 (0.55 g, 4.0 mmol) and 1-(2-chloroethyl)piperidine
 hydrochloride (0.375 g, 2.0 mmol) are added. The reaction mixture is
 heated to 90.degree. C. for 3 h, and then allowed to stir at room
 temperature for 48 h. Water is added and a precipitate formed. The
 precipitate is filtered and allowed to dry at room temperature and then
 under reduced pressure to give 0.171 g of a solid. The solid is dissolved
 in CHCl.sub.3 and filtered. The filtrate is concentrated in vacuo and
 crystallized from ethyl acetate to give 0.066 g of the title compound as a
 solid.
 Physical characteristics are as follows:
 Mp 176-180.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.3,
 8.8, 8.3, 7.9, 7.8, 7.4, 5.4, 4.6-4.5, 4.3, 2.6, 2.4, 1.4, 1.3 ppm; IR
 (drift) 2934, 2919, 1655, 1598, 1579, 1552, 1489, 1452, 1368, 1316, 1227,
 1026, 1016, 816, 806 cm.sup.-1 ; MS (EI) m/z 477 (M+); MS (FAB) m/z 478
 (MH+); HRMS (FAB) calcd for C.sub.27 H.sub.28 ClN.sub.3 O.sub.3 +H
 478.1897, found 478.1907.
 Example 15
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[3-(1-piperidinyl)propyl]-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide
 ##STR67##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and
 K.sub.2 CO.sub.3 (0.55 g) and N-(3chloropropyl)piperidine hydrochloride
 (0.408 g) are added. The reaction mixture is heated to 90.degree. C. for
 10 h, and then allowed to stir at room temperature for 38 h. Water is
 added and a precipitate formed. The precipitate is filtered and allowed to
 dry at room temperature and then under reduced pressure to give 0.187 g of
 a solid. The solid is dissolved in CHCl.sub.3 and filtered to remove 0.045
 g of a precipitate. The filtrate is concentrated in vacuo and crystallized
 from ethyl acetate to give 0.065 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 160-163.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.3,
 8.9, 8.3, 7.9, 7.8, 7.4, 5.4, 4.6, 4.5, 4.4, 2.2-2.1, 1.9, 1.4, 1.3 ppm;
 IR (drift) 3371, 2938, 2918, 1655, 1599, 1569, 1551, 1489, 1374, 1228,
 1089, 1042, 1037, 816, 806 cm.sup.-1 ; MS (EI) m/z 491 (M+); MS (FAB) m/z
 492 (MH+), 494, 493, 492, 491, 490, 126, 124, 98, 96, 45; HRMS (FAB) calcd
 for C.sub.28 H.sub.30 ClN.sub.3 O.sub.3 +H 492.2054, found 492.2061.
 Example 16
 N-(4-Chlorobenzyl)-1,4-dihydro-6-(3-hydroxy-1-propynyl)-1-[2-(1-methyl-2-py
 rrolindinyl)ethyl]-4-oxo3-quinolinecarboxamide
 ##STR68##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and
 K.sub.2 CO.sub.3 (0.69 g, 5.0 mmol) and 3-chloromethyl-1-methylpiperidine
 hydrochloride (0.47 g, 2.5 mmol) are added. The reaction mixture is heated
 to 90.degree. C. for 2.5 h. Water is added and a precipitate formed. The
 precipitate is filtered and allowed to dry at room temperature to give
 0.41 g of a solid. The solid is triturated with CHCl.sub.3 and filtered to
 give 0.33 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 154-158.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.3,
 8.9, 8.3, 7.9, 7.4-7.3, 5.4, 4.6, 4.5, 4.3, 2.9, 2.2, 2.1-2.0, 1.9, 1.8,
 1.6, 1.5 ppm; IR (drift) 2963, 2941, 2784, 1656, 1620, 1599, 1551, 1490,
 1457, 1359, 1316, 1222, 1032, 815, 807 cm.sup.-1 ; HRMS (FAB) calcd for
 C.sub.27 H.sub.28 ClN.sub.3 O.sub.3 +H 478.1897, found 478.1907. % Water
 (KF): 4.69. Anal. found: C, 64.67; H, 6.03; N, 8.32.
 Example 17
 N-(4-Chlorobenzyl)-1-[2-(diisopropylamino)ethyl]-6-(3-hydroxy-1-propynyl)-4
 -oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR69##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and
 K.sub.2 CO.sub.3 (0.69 g) and 2-(diisoproplyamino)ethyl chloride
 hydrochloride (0.50 g) are added. The reaction mixture is heated to
 90.degree. C. for 2 h, then allowed to stir at room temperature overnight.
 A drop of water is added and the mixture is heated for 20 h. An additional
 equivalent of 2-(diisoproplyamino)ethyl chloride hydrochloride (0.25 g,
 1.25 mmol) is added and the mixture is heated at 100.degree. C. for 5 h,
 and then stirred at room temperature overnight. Water is added and an oily
 solid formed, which is isolated by decanting the liquid. Column
 chromatography (elution with 1-2% MeOH/CHCl.sub.3) gave 0.45 g of a solid.
 Crystallization by dissolving in CH.sub.2 Cl.sub.2 with a few drops of
 MeOH and adding to a 1:1 solution of pentane/Et.sub.2 O gave 0.22 g of the
 title compound as a solid.
 Physical characteristics are as follows:
 Mp 188-191.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.10.4, 8.7,
 8.4, 7.6, 7.4, 7.3, 4.6, 4.5, 4.2, 3.0, 2.8, 0.9 ppm; IR (drift) 2967,
 1650, 1597, 1575, 1551, 1490, 1366, 1225, 1178, 1165, 1040, 1028, 1019,
 816, 807 cm.sup.-1 ; MS (EI) m/z 493 (M+). Anal. found: C, 67.96; H, 6.59;
 N, 8.33.
 Example 18
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(1-pyrolidinyl)ethyl]-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR70##
 A solution of
 N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamid
 e from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K.sub.2
 CO.sub.3 (0.69 g) and 1-(2-chloroethyl)pyrrolidine hydrochloride (0.425 g)
 are added. The reaction mixture is heated to 90.degree. C. for 3 h. Water
 is added and a dark solid formed, which is isolated by decanting the
 liquid. Column chromatography (elution with 1-5% MeOH/CHCl.sub.3) gave
 0.17 g of a solid. Crystallization by dissolving in CH.sub.2 Cl.sub.2 with
 a few drops of MeOH and adding to a 1:1 solution of pentane/Et.sub.2 O
 gave 0.153 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 189-192.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.2,
 8.8, 8.3, 7.9, 7.8, 7.4, 5.4, 4.6-4.5, 4.3, 2.8, 2.5, 1.6 ppm; IR (drift)
 3358, 2965, 1656, 1598, 1580, 1555, 1489, 1371, 1357, 1229, 1143, 1025,
 819, 806, 746 cm.sup.-1.
 Example 19
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(4-morpholinyl)ethyl]-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR71##
 A solution of
 N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamid
 e from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K.sub.2
 CO.sub.3 (0.69 g) and 4-(2-chloroethyl)morpholine hydrochloride (0.47 g)
 are added. The reaction mixture is heated to 90.degree. C. for 2 h. Water
 is added and a dark solid formed, which is isolated by decanting the
 liquid. Column chromatography (elution with 1-5% MeOH/CHCl.sub.3) gave
 0.183 g of a solid. Crystallization by dissolving in CH.sub.2 Cl.sub.2
 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et.sub.2
 O gave 0.13 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 215-218.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.10.4, 8.7,
 8.4, 7.6, 7.4, 7.3, 4.6, 4.5, 4.3, 3.7, 2.8, 2.5 ppm; IR (drift) 1650,
 1597, 1559, 1491, 1454, 1361, 1353, 1318, 1302, 1231, 1116, 1026, 1016,
 820, 807 cm.sup.-1 ; MS (EI) m/z 479 (M+).
 Example 20
 N-(4-Chlorobenzyl)-1-[3-(dimethylamino)propyl]-6-(3-hydroxy-1-propynyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide
 ##STR72##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and
 K.sub.2 CO.sub.3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride
 (0.42 g) are added. The reaction mixture is heated to 90.degree. C. for 6
 h. Water is added and a dark solid formed, which is isolated by decanting
 the liquid. Column chromatography (elution with 1-20% MeOH/CHCl.sub.3)
 gave 0.103 g of a solid. Crystallization by dissolving in CH.sub.2
 Cl.sub.2 with a few drops of MeOH and adding to a 1:1 solution of
 pentane/Et.sub.2 O gave 0.072 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 172-175.degree. C.; .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.10.5, 8.8,
 8.2, 7.6, 7.5, 7.4-7.3, 4.6, 4.4, 4.3, 2.8, 2.5, 2.2 ppm; IR (drift) 1655,
 1597, 1580, 1556, 1489, 1455, 1379, 1315, 1228, 1092, 1035, 1026, 818,
 805, 747 cm.sup.-1 ; MS (EI) m/z 451 (M.sup.+).
 Example 21
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1-vinyl-1,4-dihydro-3-qui
 nolinecarboxamide
 ##STR73##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (1.83 g) is dissolved in DMF (25 mL), and K.sub.2
 CO.sub.3 (1.38 g) and 1,2-dibromoethane (4.3 mL) are added. The reaction
 mixture is heated to 90.degree. C. for 2 h. Water is added and the mixture
 is extracted with ethyl acetate and then chloroform. The combined organic
 layers are concentrated in vacuo to give 2.5 g of a dark oil. Column
 chromatography (elution with 1-3% MeOH/CHCl.sub.3) gave 0.378 g of
 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide as a solid which is used without further
 purification.
 1-(1-bromoethyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide (0.347 g) is suspended in 1:1 THF/CH.sub.3 CN
 (15 mL) and sodium carbonate (0.16 g) and ethylamine (0.4 mL) are added
 and the mixture is refluxed for 16 h. An additional amount of ethylamine
 (0.80 mL) is added and the mixture is refluxed for 16 h. An additional
 amount of ethylamine (0.80 mL) and DMF (5 mL) is added and the mixture is
 heated at 100.degree. C. for 6 h, and then held at room temperature for 48
 h. Potassium carbonate (0.193 g) is added and the mixture is heated at
 100.degree. C. for 3 h. The mixture is concentrated in vacuo and
 partitioned between ethyl acetate and water. The organic layer is
 concentrated in vacuo to give 0.60 g of an oil. Column chromatography
 (elution with 1-5% MeOH/CHCl.sub.3) gave 0.118 g of the title compound as
 a solid.
 Physical characteristics are as follows:
 Mp 171-174.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.2,
 8.8, 8.3, 7.9-7.8, 7.6, 7.4-7.3, 5.8, 5.6, 5.4, 4.5, 4.3 ppm; IR (drift)
 3299, 1650, 1594, 1578, 1550, 1487, 1355, 1338, 1320, 1227, 1087, 1025,
 821, 807, 688 cm.sup.-1. Anal. found: C, 66.95; H, 4.20; N, 7.05.
 Example 22
 N-(4-chlorobenzyl)-6-[(E)-3-hydroxy-1-propenyl]-1-methyl-4-oxo-1,4-dihydro-
 3-quinolinecarboxamide
 ##STR74##
 A mixture of
 N-(4-Chlorobenzyl)-6-[(1E)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarb
 oxamide from Preparation No. 12 (0.184 g), K.sub.2 CO.sub.3 (0.276 g) and
 iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at
 90.degree. C. for 1 h. Water is added and the mixture is allowed to cool
 and stir at room temperature for 16 h during which a precipitate formed.
 The precipitate is filtered and dried in vacuo at 60.degree. C. for 48 h
 to give 0.164 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 103-106.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.4,
 8.8, 8.2, 8.0, 7.8, 7.4-7.3, 6.7, 6.6-6.5, 4.9, 4.6, 4.2, 4.0 ppm; IR
 (drift) 3044, 1656, 1603, 1552, 1497, 1423, 1362, 1319, 1238, 1128, 1093,
 1017,967,827,807 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.21 H.sub.19
 ClN.sub.2 O.sub.3 +H 383.1162, found 383.1170.
 Example 23
 N-(4-chlorobenzyl)-6-[(Z)-3-hydroxy-1-propenyl]-1-methyl-4-oxo-1,4-dihydro-
 3-quinolinecarboxamide
 ##STR75##
 A mixture of
 N-(4-chlorobenzyl)-6-[(1Z)-3-hydroxy-1-propenyl]-4-hydroxy-3-quinolinecarb
 oxamide from Preparation No. 11 (0.184 g), K.sub.2 CO.sub.3 (0.276 g) and
 iodomethane (0.062 mL) in DMF (2 mL) is heated in a stoppered flask at
 90.degree. C. for 1 h. Water is added and the mixture is allowed to cool
 and stir at room temperature for 16 h during which a precipitate formed.
 The precipitate is filtered and dried in vacuo at 60.degree. C. for 48 h
 to give a solid. Crystallization by dissolving in CH.sub.2 Cl.sub.2 with a
 few drops of MeOH and adding to a 1:1 solution of pentane/Et.sub.2 O gave
 0.085 g of the title compound as a solid.
 Physical characteristics are as follows:
 Mp 137-141.degree. C.; .sup.1 H NMR (400 MHz, DMSO-d.sub.6) .delta.10.4,
 8.8, 8.1, 7.8, 7.7, 7.4-7.3, 6.6, 5.9, 5.0, 4.5, 4.3, 4.0 ppm; IR (drift)
 1656, 1603, 1550, 1497, 1363, 1317, 1242, 1124, 1089, 1037, 1017, 822,
 808, 799, 723 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.21 H.sub.19 CLN.sub.2
 O.sub.3 +H.sub.1 383.1162, found 383.1154.
 Example 24
 N-(4-Chlorobenzyl)-6-[ethyl(2-hydroxyethyl)amino]-1-methyl-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide
 ##STR76##
 To a flask containing ethyl
 6-[[2-(acetyloxy)ethyl](ethyl)amino]-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxylate from Preparation No. 16 (0.22 g) is added p-chlorobenzylamine
 (1.0 mL). The reaction is tightly capped and heated to 190.degree. C.
 overnight. The reaction is cooled to room temperature. The residue is
 adsorbed onto silica and chromatographed on silica eluting with 4% to 8%
 methanol in dichloromethane. The product-containing fractions are
 evaporated to give 0.12 g of the title compound as a off-white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.6, 8.7, 7.6, 7.4, 4.8, 4.5, 4.0,
 3.6, 3.5, 1.1; HRMS (FAB) found 414.1573.
 Example 25
 N-(4-Chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide
 ##STR77##
 To a dry flask under an atmosphere of argon gas containing 0.24 g of
 N-(4-chlorobenzyl)-1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarbo
 xamide from Preparation No. 20, 0.01 g of copper (I) iodide and 0.04 g of
 dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (1.5
 mL) and propargyl alcohol (0.04 mL). After 3 hours reaction is diluted
 with DMF (0.5 mL) and left to stir overnight. The reaction is concentrated
 under reduced pressure, diluted with dichloromethane containing a small
 amount of methanol, and partioned against water. The organic layer is
 washed with brine, dried and concentrated under reduced pressure. The
 residue is adsorbed onto silica and chromatographed on silica eluting with
 2% to 6% methanol in dichloromethane . The product-containing fractions
 are combined and concentrated under reduced pressure to afford 0.17 g of
 the title compound as a solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.2, 8.7, 8.3, 8.2, 7.9, 7.4, 5.4,
 4.5, 4.4, 3.7, 1.3, 1.1; HRMS (FAB) 407.1170 (M+H.sup.+).
 Example 26
 N-(4-Chlorobenzyl)-1-cyclopropyl-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide
 ##STR78##
 To a solution of
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide (0.17 g) from Example No. 25 in THF (3 mL) and
 methanol (3 mL) is added platinuim oxide (0.01 g). The mixture is placed
 under an atmosphere of hydrogen gas. After 1 hour, the mixture is filtered
 through Celite with THF:methanol washes. The filtrate is concentrated
 under reduced pressure. The residue is adsorbed onto silica and
 chromatographed on silica eluting with 2% to 4% methanol in
 dichloromethane. The product-containing fractions are concentrated under
 reduced pressure to afford 0.13 g of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.4, 8.7, 8.1, 7.7, 7.4, 4.5, 3.7,
 3.4, 2.8, 1.7, 1.3, 1.1. Anal. Found: C, 67.05; H, 5.46; N, 6.68.
 Example 27
 N-(4-Chlorobenzyl)-1-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-
 3-quinolinecarboxamide
 ##STR79##
 To a flask containing ethyl
 1-cyclopropyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxy
 late (0.38 g) from Preparation No. 25 is added 4-chlorobenzylamine (2.0
 mL). The reaction is tightly capped and heated to 165.degree. C.
 overnight. The reaction is cooled to room temperature, adsorbed onto
 silica and chromatographed on silica eluting with 1% to 6% methanol in
 dichloromethane. The product-containing fractions are evaporated to give a
 solid which is dissolved in a minimal amount of dichloromethane. The
 solution is added to 1:1 diethyl ether:pentane to precipitate the title
 compound as a white solid. This solid is collected by filtration and dried
 in vacuo to afford 0.36 g of the title compound.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) 10.4, 8.9, 8.4, 8.0, 7.8, 7.3, 4.6, 3.7,
 3.5, 2.5, 1.3, 1.2. Anal. found C, 66.30; H, 6.07; N, 8.97.
 Example 28
 tert-Butyl
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H
 )-quinolinyl]acetate
 ##STR80##
 To a dry flask under an atmosphere of argon gas containing 0.23 g of
 tert-butyl
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-iodo-4-oxo-1(4H)-quinolinyl]aceta
 te from Preparation No. 26, 0.01 g of copper (I) iodide and 0.03 g of
 dichlorobis(triphenylphosphine)palladium (II) is added diethylamine (2.0
 mL) and propargyl alcohol (0.03 mL). After 1 hour the reaction is diluted
 with DMF (1.0 mL) and left to stir overnight. The reaction is concentrated
 under reduced pressure, diluted with dichloromethane containing a small
 amount of methanol, and partioned against water. The organic layer is
 washed with brine, dried and concentrated under reduced pressure. The
 residue is adsorbed onto silica and chromatographed on silica eluting with
 2% to 4% methanol in dichloromethane . The product-containing fractions
 are combined and concentrated under reduced pressure to afford 0.13 g of
 the title compound as a solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.2, 8.9, 8.3, 7.8, 7.6, 7.4, 5.4,
 4.5, 4.3, 3.7, 1.4; MS (ESI) m/z 481 (M+H.sup.+).
 Example 29
 2-[3-{[(4-Chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H)
 -quinolinyl]acetic acid
 ##STR81##
 To a suspension of tert-butyl
 2-[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(3-hydroxy-1-propynyl)-4-oxo-1(4H
 )quinolinyl]acetate (0.07 g) from Example No. 28 in dichloromethane (1 mL)
 is added trifluoroacetic acid (1 mL). After 3 hours, the resulting
 solution is concentrated under reduced pressure. The residue is dissolved
 in a small amount of dichloromethane:methanol:DMF and slowly added to
 vigorously stirring 1:1 diethyl ether:pentane. The resulting precipitate
 is collected filtration to afford 0.05 g of the title compound as a solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.2, 8.9, 8.3, 7.9, 7.8, 7.7, 7.3,
 5.4, 4.5, 4.3 ppm; MS (ESI) m/z 425 (M+H.sup.+).
 Example 30
 N-(4-Chlorobenzyl)-1-(2-hydroxyethyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-di
 hydro-3-quinolinecarboxamide
 ##STR82##
 To a flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de from Preparation No. 5 (0.37 g) is added potassium carbonate (2.75 g)
 and bromoethanol (0.71 mL). The flask is tightly capped and heated to
 100.degree. C. After 4 hours the reaction is cooled to room temperature
 and partioned between dichloromethane containing methanol and water. The
 organic layer is washed with two additional portions of water, brine,
 dried and concentrated under reduced pressure. The residue is adsorbed
 onto silica and chromatographed on silica eluting with 2% to 10% methanol
 in dichloromethane to afford 0.09 g of the title compound as a white
 solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, DMSO-d.sub.6) 10.2, 8.8, 8.3, 7.9, 7.8, 7.4, 5.4,
 5.0, 4.5, 4.3, 3.7 ppm; MS (ESI) m/z 433 (M+Na.sup.+).
 Example 31
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide
 ##STR83##
 A suspension of 6.90 g of
 N-(4-chlorobenzyl-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamid
 e from Preparation No. 5, 10.4 g of potassium carbonate, and 2.3 mL of
 methyl iodide in 40 mL of DMF is stirred at 90.degree. C. for 4 h, then
 cooled and diluted with 350 mL of water. The resulting solid is filtered,
 washed well with water, and dried under vacuum. Flash chromatography of
 the solid on silica using 3-5% methanol in dichloromethane provides 6.02 g
 of the title compound as a yellow solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD) .delta.4.03, 4.45, 4.6, 7.3, 7.6,
 7.8, 8.5, 8.8 ppm; HRMS 381.1006
 Preparation 27
 N-(4-Chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoli
 necarboxamide
 ##STR84##
 A mixture of 0.50 g of
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide from Example No. 31 and 50 mg of 5% platinum on carbon
 catalyst in 20 mL of 1:1 THF-methanol is stirred under 1 atm hydrogen for
 3 h, then filtered through diatomaceous earth. The filtrate is
 concentrated under reduced pressure and the residual solid flash
 chromatographed on silica gel using 4-5% methanol in dichloromethane to
 afford 0.45 g of the title compound as a yellow solid. Further
 purification is achieved by recrystallization of the solid from 15 mL of
 acetonitrile.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD) .delta.1.9, 2.9, 3.6, 4.0, 4.6, 7.3,
 7.5, 7.7, 8.3, 8.8 ppm; HRMS 385.13 10.
 Example 32
 Di(tert-butyl)
 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinol
 inyl)propyl phosphate
 ##STR85##
 To a suspension of 77 mg of
 N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro-3-quinol
 inecarboxamide from Preparation No. 27 and 25 mg of 1H-tetrazole in 2 mL of
 1:1 chloroform-TBF, stirred under argon, is added 90 .mu.L of
 di-tert-butyl diethyl phosphoramidite. After 18 h the solution is cooled
 to 0.degree. C., and a slight excess of m-CPBA (ca 110 mg) is added. After
 10 min, the mixture is partitioned between ethyl acetate and aqeuous
 NaHSO.sub.3. The organic phase is washed with dilute aqueous HCl, water,
 and aqueous NaHCO.sub.3, dried (Na.sub.2 SO.sub.4), and concentrated under
 reduced pressure. Flash chromatography of the residue on silica using 2%
 methanol in dichloromethane provides 111 mg of the title compound as a
 white crystalline solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.49, 2.0, 2.9, 3.94, 4.0, 4.6, 7.3, 7.5,
 7.6, 8.3, 8.8 ppm; IR 2981, 1662, 1609, 1551, 1500, 1369, 1266, 1000, 810
 cm.sup.- ; HRMS 577.2241.
 Example 33
 3-(3-{[(4-Chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinoli
 nyl)propyl dihydrogen phosphate
 ##STR86##
 A solution of 77.8 mg of di(tert-butyl)
 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinol
 inyl)propyl phosphate from Example No. 32 in 1 mL of 1:1
 TFA-dichloromethane is stirred for 1 h, then added slowly to 20 mL of
 rapidly stirred 1:1 ether-hexane. The precipitated solid is filtered,
 washed with hexane, and dried under vacuum to afford 67 mg of the title
 compound as a white solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD+TFA) .delta.2.1, 3.0, 4.0, 4.11, 4.7,
 7.3, 7.7, 8.3, 9.0 ppm; HRMS 465.0981
 Example 34
 Di(tert-butyl)
 3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-cyclopropyl-4-oxo-1,4-dihydro-6-q
 uinolinyl)propyl phosphate
 ##STR87##
 The title compound was prepared from
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide (Example No. 26) following procedures analogous to
 those described in Example No. 32.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) 1.2, 1.3, 1.52, 2.1, 2.9, 3.5, 4.0, 4.6, 7.3,
 7.6, 8.0, 8.3, 8.91, 10.5 ppm; IR 1666, 1606, 1547, 1490, 1266, 1039, 996
 cm.sup.-1 ; HRMS 603.2382.
 Example 35
 Sodium
 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1methyl-4-oxo-1,4-dihydro-6-
 quinolinyl)propoxyl-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate
 ##STR88##
 A solution of 77 mg of
 N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro-3-quinol
 inecarboxamide from Preparation No. 27, 0.46 mL of a 0.65 M solution of
 suleptanic acid triethylammonium salt in acetonitrile, 27 mg of DMAP, and
 38 .mu.L of DIC in 1 mL of DMF is stirred at room temperature for 18 h,
 then concentrated under reduced pressure. Flash chromatography of the
 residue on silica using 5-20% methanol in dichloromethane affords a solid,
 which is dissolved in chloroform and butanol. This solution is stirred
 with 25 mL of saturated aqueous sodium sulfate, then filtered through
 anhydrous sodium sulfate and concentrated under reduced pressure to afford
 113 mg of the title compound as a white solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.3, 1.6, 2.0, 2.3, 2.8-3.2, 3.7, 3.9,
 4.1, 4.6, 7.1-7.3, 7.5, 7.6, 8.3, 8.8 ppm; MS ES- 660; HRMS 662.2289
 Example 36
 Sodium
 2-[{8-[3-(3-{[(4-chlorobenzyl)amino]carbonyl}-1-cyclopropyl-4-oxo-1,4-dihy
 dro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate
 ##STR89##
 The title compound was prepared from
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxypropyl)-4-oxo-1,4dihydro-3-qu
 inolinecarboxamide (Example No. 26) following procedures analogous to those
 described in Example 35.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.3, 1.4, 1.6, 2.0, 2.3, 2.7-3.3, 3.5,
 3.7, 4.1, 4.6, 7.1-7.3, 7.5, 7.9, 8.3, 8.9, 10.5 ppm; IR 2936, 1732, 1664,
 1606, 1547, 1490, 1348, 1192, 1060, 1036, 809, 732 cm.sup.-1 ; MS ES- 686;
 HRMS 688.2447
 Example 37
 Sodium 2-[(8-{[3-(3-{[(.sup.4
 -chlorobenzyl)amino]carbonyl}-1-methyl-4-oxo-1,4-dihydro-6-quinolinyl)-2-p
 ropynyl]oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanesulfonate
 ##STR90##
 The title compound was prepared from
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-q
 uinolinecarboxamide (Example No.31) following procedures analogous to those
 described in Example 35.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3 +CD.sub.3 OD) .delta.1.3, 1.6, 2.3, 3.0-3.4, 3.7,
 4.0, 4.1, 4.6, 4.9, 6.8, 7.3, 7.6, 7.8, 8.1, 8.5, 8.8 ppm; HRMS 680.1797.
 Example 38
 Sodium 2-[(8-{[3-(3-{[(.sup.4
 -chlorobenzyl)amino]carbonyl}-1-cyclopropyl-4-oxo-1,.sup.4
 -dihydro-6-quinolinyl)-2-propynyl]oxy)-8-oxooctanoyl)(methyl)amino]-1-etha
 nesulfonate
 ##STR91##
 The title compound was prepared from
 N-(4-chlorobenzyl)-1-cyclopropyl-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide (Example No. 25) following procedures analogous to
 those described in Example 35.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.1, 1.2-1.4, 1.6, 2.2-2.4, 2.9-3.2, 3.5,
 3.8, 4.6, 4.9, 7.3, 7.8, 7.9, 8.4, 8.9, 10.3 ppm; MS ES- 682; HRMS
 684.2159.
 Preparation 28
 2-Fluoro-5-iodobenzoic acid
 To an argon-covered, stirred solution of 16.8 mL of diisopropylethylamine
 in 200 mL of THF, cooled at -78.degree. C., is added dropwise 67 mL of a
 1.6 M solution of butyllithium in hexane. The solution is allowed to warm
 to 0C and then recooled to -78.degree. C. To this solution is added
 dropwise 11.5 mL of 4-fluoroiodobenzene in 10 mL of THF. The solution is
 stirred for 90 min at -78.degree. C., then cannulated rapidly onto a Dry
 Ice-ether slurry. The mixture is allowed to warm to room temperature, then
 extracted with 300 mL of 0.3 M NaOH. The aqueous phase is chilled in ice
 and acidified with 40 mL of 6N HCl. The precipitate is extracted with two
 portions of ether, and the organic phase dried (MgSO.sub.4) and
 concentrated under reduced pressure. Recrystallization of the residue with
 ethyl acetate-hexane provides 19.57 g of the title compound as white
 needles. A second crop of 3.78 g is obtained by recrystallization of the
 mother liquor residue.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.6.97, 7.88, 8.33 ppm. Anal found: C,
 31.57; H, 1.59.
 Preparation 29
 Ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate
 To a stirred solution of 5.32 g of 2-fluoro-5-iodobenzoic acid from
 Preparation No. 28 in 20 mL of THF, under argon, is added 3.9 g of
 carbonyldiimidazole. In a separate flask, 2.8 mL of chlorotrimethylsilane
 is added to a mixture of 3.74 g of potassium ethyl malonate in 20 mL of
 acetonitrile. The mixture is stirred under argon for 18 h, then cooled to
 0.degree. C. for the dropwise addition of 6.6 mL of DBU. The mixture is
 stirred for 3 h at 0.degree. C., then the solution of acyl imidazolide
 prepared above is added via cannula. After 2 h, the mixture is partitioned
 between ether and excess dilute HCl, and the organic phase is washed with
 dilute HCl and brine and dried (MgSO.sub.4). Removal of the solvent under
 reduced pressure left a colorless oil, which is flash chromatographed on
 silica using 10% ethyl acetate in hexane to provide 5.07 g of the title
 compound as dense pinkish prisms.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.34, 4.27, 5.82, 6.89, 7.7, 8.2 ppm; IR
 1624, 1485, 1419, 1245, 1193, 1070, 1028, 813 cm.sup.-1.
 Preparation 30
 Ethyl 1-(tert-butyl)-6-iodo4-oxo-1,4-dihydro-3-quinolinecarboxylate
 A solution of 2.36 g of ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate
 from Preparation No. 29, 2.0 mL of triethyl orthoformate, and 15 mL of
 acetic anhydride is refluxed under argon for 2 h, then the solvents are
 distilled off under reduced pressure. To the residual oil is added 10 mL
 of dry tert-butanol and 0.74 mL of tert-butylamine, and the solution is
 stirred at 80.degree. C. for 2 h. Potassium tert-butoxide (0.87 g) is then
 added, and stirring continued at 80.degree. C. under argon for 18 h. The
 mixture is then cooled and partitioned between dilute HCl and
 chloroform-methanol. The organic phase is dried (MgSO.sub.4) and
 concentrated under reduced pressure. Flash chromatography of the residue
 on silica using 2-4% methanol in dichloromethane provides 1.32 g of the
 title compound as an off-white solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.42, 1.87, 4.4, 7.7, 7.9, 8.9 ppm; HRMS
 400.0414. Anal. Found: C, 48.05; H, 4.50; N, 3.52.
 Preparation 31
 1-(tert-Butyl)-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarbo
 xamide
 ##STR92##
 A slurry of 1.11 g of ethyl
 1-(tert-butyl)-6-iodo4oxo-1,4-dihydro-3-quinolinecarboxylate from
 Preparation No. 30 in 2.0 g of 4-chlorobenzylamine is heated under argon
 at 160.degree. C. for 18 h, then cooled to room temperature and triturated
 with 1N HCl. The solid is filtered, washed well with water, and dried
 under vacuum. Flash chromatography using 20% ethyl acetate in
 dichloromethane provides 1.22 g of the title compound as a white solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.89, 4.6, 7.3, 7.7, 7.9, 8.9, 9.22, 10.4
 ppm; IR 1664, 1536, 1468, 1342, 1180 cm.sup.-1. Anal. Found: C, 51.27; H,
 4.19; N, 5.62.
 Example 39
 1-(tert-Butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl-4-oxo-1,4-dihydro
 -3-quinolinecarboxamide
 ##STR93##
 To a stirred slurry of 1.15 g of
 1-(tert-butyl)-N-(4-chlorobenzyl)-6-iodo4-oxo-1,4-dihydro-3-quinolinecarbo
 xamide from Preparation No. 31, 156 mg of copper (I) iodide, and 66 mg of
 dichlorobis(triphenylphosphine)palladium (II) in 23 mL of diethylamine,
 under argon, is added 0.16 mL of propargyl alcohol. The mixture is stirred
 for 18 h at room temperature, then concentrated under reduced pressure.
 The residue is partitioned between water and chloroform-methanol, and the
 organic phase dried (MgSO.sub.4) and concentrated under reduced pressure.
 Flash chromatography of the residue on silica using 2-4% methanol in
 dichloromethane affords 977 mg of tan solid. Recrystallization from
 ethanol provides 850 mg of the title compound as a beige solid.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.92, 4.47, 4.6, 7.3, 7.7, 8.0, 8.5, 9.19,
 10.5 ppm; HRMS 423.1466. Anal. Found: C, 67.74; H, 5.53; N, 6.61.
 Preparation 32
 1-(tert-Butyl)-N-(4-chlorobenzyl)-6-(3-hydroxypropyl-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide
 ##STR94##
 A mixture of 303 mg of
 i-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide from Example No. 39 and 15 mg of platinum oxide in
 10 mL of 1:1 THF-methanol is stirred under 1 atm of hydrogen gas for 3 h,
 then filtered through diatomaceous earth and concentrated under reduced
 pressure. The mixture was purified by flash chromatography on silica using
 2-3% methanol in dichloromethane to afford 294 mg of the title compound.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.89, 1.9, 2.9, 3.7, 4.6, 7.3, 7.5, 7.9,
 8.4, 9.21, 10.6 ppm; IR 1658, 1596, 1548, 1484, 1349, 1184, 810, 731
 cm.sup.-1 ; HRMS 427.1762
 Example 40
 Sodium
 2-[{8-[3-(1-(tert-butyl)-3-{[(4-chlorobenzyl)amino]-carbonyl}-4-oxo-1,4-di
 hydro-6-quinolinyl)propoxy]-8-oxooctanoyl}(methyl)amino]-1-ethanesulfonate
 ##STR95##
 The title compound was prepared from
 1-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-
 quinolinecarboxamide (Preparation No. 32) following procedures analogous to
 those described in Example 35.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.2-1.4, 1.6, 1.9, 2.0, 2.2-2.4, 2.8-3.2,
 3.7, 4.1, 4.6, 7.1-7.3, 7.5, 7.9, 8.4, 9.2, 10.5 ppm; IR 2937, 1732, 1663,
 1596, 1546, 1484, 1184 cm.sup.-1 ; HRMS 748.2394.
 Example 41
 Sodium
 2-[(8-{[3-(1-(tert-butyl)-3-([(4-chlorobenzyl)amino]-carbonyl}-4-oxo-1,4-d
 ihydro-6-quinolinyl)-2-propynyl]oxy}-8-oxooctanoyl)(methyl)amino]-1-ethanes
 ulfonate
 ##STR96##
 The title compound was prepared from
 1-(tert-butyl)-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihyd
 ro-3-quinolinecarboxamide (Example No. 39) following procedures analogous
 to those described in Example 35.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.3, 1.6, 1.9, 2.2-2.4, 2.6, 2.8-3.2, 3.7,
 4.6, 4.9, 7.1-7.3, 7.7, 7.9, 8.6, 9.2, 10.4 ppm; IR 2936, 1741, 1666,
 1592, 1544, 1482, 1341, 1182 cm.sup.-1 MS ES- 698; HRMS 700.2496
 Example 42
 N-(4-Chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(2-methoxyethoxy)ethyl]-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR97##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No 30-31 and Example No. 39 from ethyl
 l-(tert-butyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
 Physical properties as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.3.29, 3.5, 3.6, 3.8-4.0, 4.34.-4.5, 4.7,
 7.3, 7.5, 8.2, 8.76, 10.4 ppm; MS ES+ 469; HRMS 469.1508. Anal. Found: C,
 63.98; H, 5.42; N, 6.04.
 Preparation 32
 4-(Aminomethyl)benzonitrile
 A mixture of 4-(boromomethyl)benzonitrile (7.1 g) and sodium azide (2.6 g)
 in DMF (40 mL) is stirred for 19 hrs. The reaction mixture is then diluted
 with water (150 mL) and extracted with ether (2.times.50 mL). The organic
 phases are combined, washed with water (50 mL) and brine (50 mL), and
 dried with MgSO.sub.4. Filtration and evaporation of the solvent leaves
 5.5 g of 4-(azidomethyl)benzonitrile as a clear, colorless oil.
 Triphenylphosphine (7.67 g) is added to a solution of
 4-(azidomethyl)-benzonitrile (4.19 g) in THF (30 mL) and stirred for 1 hr.
 Water (10 mL) is added, and the solution is stiffed for 16 hrs. The
 reaction mixture is diluted with ether (50 mL) and extracted with HCl (3
 N, 3.times.25 mL) and water (1.times.25 mL). The aqueous phases are
 combined and washed with ether (50 mL). Sodium hydroxide is added until
 the pH=12. After extracting with ether (2.times.50 mL), the solution is
 dried with MgSO.sub.4 and filtered. The solvent is evaporated under
 reduced pressure. The resulting crude mixture is then purified via bulb to
 bulb distillation at 150.degree. C. and 1 torr to afford 1.74 g (50%) of
 the title compound as a clear, colorless oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.7.7, 7.5, 3.8, 1.9
 Example 43
 N-(4-Cyanobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-qui
 nolinecarboxamide
 ##STR98##
 Ethyl 4-hydroxy-6-iodo-3-quinolinecarboxylate prepared as an intermediate
 in Preparation No. 4 (5.0 g), potassium carbonate (10.4 g) and methyl
 iodide (0.94 mL) are suspended in DMF (100 mL) and heated to 95.degree. C.
 under a nitrogen atmosphere for 6.5 hrs. After the mixture is brought to
 room temperature potassium carbonate is filtered off, and the solvent is
 evaporated under reduced pressure until a white solid precipitates out of
 solution. This white solid is filtered, washed with water and dried in a
 stream of air. A sample of this solid (2.0 g) is suspended in ethanol (12
 mL) and sodium hydroxide (8 mL, 3 N) is added. The mixture is stirred
 overnight. The mixture is then acidified with 3 N HCl. The resulting solid
 is filtered, washed with 3.times.30 mL water and dried in a stream of air.
 A sample of this solid (1.0 g) and 1,1'-carbonyldiimidazole (1.0 g) are
 suspended in DMF (20 mL) and heated to 70.degree. C. for 2 hrs. The
 mixture is brought to room temperature and treated with water (0.054 mL).
 A solution of 0.42 g of 4-(aminomethyl)benzonitrile from Preparation No.
 32b in 10 mL DMF is added to the mixture and allowed to stir at room
 temperature for 24 hrs. Dilution with 30 mL H.sub.2 O causes a white solid
 to precipitate out of solution. The solid is filtered and washed with
 3.times.20 mL 1:1 DMF: water. A sample of this white solid (0.5 g) is
 suspended in diethylamine (17 mL) and treated with copper iodide (0.06 g),
 bis-triphenylphosphine palladium chloride (0.04 g), and propargyl alcohol
 (0.08 mL). The reaction is stirred at room temperature overnight, and the
 volume is reduced by evaporation under reduced pressure to a brown,
 viscous oil. The oil is diluted with CH.sub.2 Cl.sub.2 producing an
 off-white solid. This solid is filtered and then dissolved in hot acetic
 acid. The insoluble impurities are filtered from the solution while still
 hot, and the product precipitates as the solution cools. The solid is
 filtered, washed with 3.times.25 mL water and dried in a stream of air on
 a fritted funnel. The procedure affords 0.31 g of the title compound as an
 off-white solid.
 Physical characteristics are as follows:
 Mp 230-232.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 8.8, 8.3,
 7.8, 7.7, 7.5, 5.4, 4.6, 4.3,4.0.
 Example 44
 6-((Bis(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-1-1-methyl-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide.
 ##STR99##
 Methanesulfonyl chloride (0.048 1L) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide (200 mg) from Preparation No. 10, DMAP (11.5 mg), and
 2,4,6-collidine (0.087 mL) in anhydrous DMF (9.5 mL). The mixture is
 stirred at room temperature until starting material is consumed and
 diethanolamine (0.54 mL) is added. The reaction mixture is heated to
 56.degree. C. for 1.5 h. The reaction mixture is cooled to room
 temperature and partitioned between CH.sub.2 Cl.sub.2 and water. The
 aqueous layer is extracted with CH.sub.2 Cl.sub.2 three times. The
 combined organic layers are washed with brine, dried (Na.sub.2 SO.sub.4),
 and concentrated to afford a yellow residue. The resulting solid was
 adsorbed onto silica and purified by chromatography (eluent 1% MeOH in
 CH.sub.2 Cl.sub.2 (1 L), 2% MeOH in CH.sub.2 Cl.sub.2 (1 L), 3% MeOH in
 CH.sub.2 Cl.sub.2 (1 L), 4% MeOH in CH.sub.2 Cl.sub.2 (2L)). Fractions
 homogenous by TLC were combined and concentrated to afford 69.3 mg (28%)
 of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 165-166.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.45,
 8.86, 8.24, 7.86, 7.79, 7.38, 4.56, 4.38, 4.02, 3.81, 3.46, 2.56; IR
 (drift) 3324, 2935, 2923, 2820, 1667, 1611, 1551, 1491, 1362, 1235, 1087,
 1080, 814, 808, 796 cm.sup.-1 ; Anal. found for C.sub.23 H.sub.26
 ClN.sub.3 O.sub.4 : C, 61.90; H, 5.94; N, 9.35.
 Example 45
 N-(4-Chlorobenzyl)-6-(((2-hydroxyethyl)(methyl)amino)-methyl)-1-methyl-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR100##
 Methanesulfonyl chloride (0.065 mL) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide (0.27 g) from Preparation No. 10, DMAP (0.017 g), and
 2,4,6-collidine (0.12 mL) in anhydrous DMF (14 mL). The mixture is stirred
 at room temperature overnight and 2-(methylamino)ethanol (0.61 mL) is
 added. The reaction mixture is stirred at room temperature for 2 h, poured
 into water, and extracted with CH.sub.2 Cl.sub.2 (3.times.). The organic
 layers are combined, dried (Na.sub.2 SO.sub.4), filtered, and concentrated
 in vacuo. The residue is dissolved in CH.sub.2 Cl.sub.2 /MeOH and adsorbed
 onto silica. Purification by chromatography (eluent CH.sub.2 Cl.sub.2 (1
 L), 1.5% MeOH/CH.sub.2 Cl.sub.2 (1 L), 2.5% MeOH/CH.sub.2 Cl.sub.2 (1 L),
 3.5% MeOH/CH.sub.2 Cl.sub.2 (1 L), 5% MeOH/CH.sub.2 Cl.sub.2 (1 L), 6%
 MeOH/CH.sub.2 Cl.sub.2 (1 L)) affords the product as a clear residue. The
 residue is crystallized by addition of CH.sub.2 Cl.sub.2 /hexanes followed
 by removal of the solvents in vacuo to give 0.21 g (69%) of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 130-131.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.44, 8.86,
 8.23, 7.80, 7.40, 7.36, 4.56, 4.42, 4.02, 3.67, 3.52, 2.46, 2.17; IR
 (drift) 3435, 1665, 1610, 1549, 1497, 1367, 1352, 1316, 1233, 1123, 1090,
 1020, 819, 808, 662 cm.sup.-1 ; Anal. Found for C.sub.22 H.sub.24
 ClN.sub.3 O.sub.3 : C, 63.70; H, 5.98; N, 9.85.
 Preparation 33
 1,4-Oxazepane
 To a stirred solution of tetrahydro4H-pyran-4-one (4.19 mL) in conc. HCl
 (23 mL) cooled to 0.degree. C. is added portion-wise sodium azide (4.42
 mL). After addition was complete, the reaction is stirred at room
 temperature for 4 h. Solid sodium carbonate is added portion-wise until
 the solution was slightly alkaline (pH.dbd.9). Water is added during
 addition of sodium carbonate to dissolve the salt. The alkaline solution
 is diluted with CHCl.sub.3 (125 mL) and the phases are separated. The
 aqueous layer are extracted with CHCl.sub.3 (2.times.75 mL). The combined
 organic layers are dried (Na.sub.2 SO.sub.4), filtered, and concentrated
 to afford 2.5 g (48%) of 1,4-oxazepan-5-one as an orange-brown residue.
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.6.66, 3.80, 3.35, 2.72.
 To a solution of 1,4-oxazepan-5-one (2.5 g) in distilled THF (86 mL) cooled
 to 0.degree. C. is added dropwise a solution of LiAlH.sub.4 in TPF (1M,
 21.9 mL). The reaction mixture is stirred at room temperature for 2.5 h
 during which additional LiAlH.sub.4 (11 mL) is added. The reaction is
 quenched by successive addition of water (4 mL), 15% NaOH (4 mL), and
 water (4 mL). The reaction mixture is filtered, and the filtrate is dried
 (Na.sub.2 SO.sub.4), filtered, and concentrated to obtain 963 mg (44%) of
 1,4-oxazepane as a residue.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.3.82, 3.73, 2.96, 1.88
 Example 46
 N-(4-Chlorobenzyl)-1-methyl-6-(1,4-oxazepan-4-ylmethyl)-4-oxo-1,4-dihydro-3
 -quinolinecarboxamide
 ##STR101##
 Methanesulfonyl chloride (0.080 mL) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide (330 mg) from Preparation No. 10, DMAP (19.1 mg), and
 2,4,6-collidine (0.14 mL) in anhydrous DMF (15.7 mL). The mixture is
 stirred at room temperature until the starting material is consumed and a
 solution of 1,4-oxepane (0.963 g) from Preparation No. 33 in anhydrous DMF
 (3 mL) is added. The reaction mixture is heated to 56.degree. C. for 1.5
 h. The mixture is cooled to room temperature and the product is
 precipitated by addition of water (125 mL). The solid was adsorbed onto
 silica and purified by column chromatography (eluent 100% CH.sub.2
 Cl.sub.2 (1 L), 1% MeOH in CH.sub.2 Cl.sub.2 (2 L), 1.5% MeOH in CH.sub.2
 Cl.sub.2 (1 L), 2% MeOH in CH.sub.2 Cl.sub.2 (3 L)). Fractions homogenous
 by TLC are combined and concentrated to afford 124.5 mg (31%) of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 178-179.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.43,
 8.87, 8.27, 7.81, 7.38, 4.56, 4.02, 3.79, 3.70, 3.61, 2.64, 1.81; IR
 (drift) 2939, 1655, 1606, 1573, 1551, 1502, 1363, 1351, 1344, 1132, 1091,
 1080, 828, 816, 808 cm .sup.-1 ; Anal. found for C.sub.24 H.sub.26
 ClN.sub.3 O.sub.3 : C, 65.14; H, 6.01; N, 9.39.
 Preparation 34
 1,4-Thiazepane
 To a stirred solution of tetrahydrothiopyran-4-one (4.74 g) in conc. HCl
 (20.7 mL) cooled to 0.degree. C. is added portion-wise sodium azide (3.98
 g, 61.2 mmol). After addition is complete, the reaction is stirred at room
 temperature for 4 h. Solid sodium carbonate is then added portion-wise
 until the solution was slightly alkaline (pH=9). Water is added during
 addition of sodium carbonate to dissolve the salt. The alkaline solution
 is diluted with CHCl.sub.3 (125 mL), and the phases are separated. The
 aqueous layer is extracted with CHCl.sub.3 (2.times.75 mL). The combined
 organic layers are dried (Na.sub.2 SO.sub.4), filtered, and concentrated.
 The crude product is recrystallized from CH.sub.2 Cl.sub.2 /hexanes to
 afford 4.30 g (81%) of 1,4-thiazepan-5-one as a white solid.
 Physical characteristics are as follows:
 Mp 114-116.degree. C.; .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.6.41,
 3.66, 2.96, 2.76.
 To a solution of 1,4-thiazepan-5-one (3.0 g) in distilled THF (90 mL)
 cooled to 0.degree. C. is added dropwise a solution of LiAlH.sub.4 in THF
 (1M solution, 22.9 mL). The mixture is stirred at room temperature for 2
 h. The reaction is quenched by successive addition of water (2 mL), 15%
 NaOH (2 mL) and water (2 mL). The reaction mixture is filtered to remove
 the aluminum salt that had precipitated. The filtrate was dried (Na.sub.2
 SO.sub.4), filtered, and concentrated to obtain 2.63 g (98%) of
 1,4-thiazepane as a yellow residue.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.3.07, 2.96, 2.75, 1.92.
 Example 47
 N-(4-Chlorobenzyl)-1-methyl-4-oxo-6-(1,4-thiazepan-4-ylmethyl)-1,4-dihydro-
 3-quinolinecarboxamide
 ##STR102##
 Methanesulfonyl chloride (0.096 mL) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,44dihydro-3-quinolin
 ecarboxamide (400 mg) from Preparation No. 10, DMAP (23 mg), and
 2,4,6-collidine (0.17 mL) in anhydrous DMF (19 mL). The mixture is stirred
 at room temperature until the starting material is consumed and 1,4
 thiazepane (1.13 g) from Preparation No. 34 is added. The reaction mixture
 is heated to 65.degree. C. for 1.5 h. The mixture is cooled to room
 temperature and the product is precipitated by addition of water (125 mL).
 The solid is adsorbed onto silica and purified by column chromatography
 (eluent 100% CH.sub.2 Cl.sub.2 (1 L), 0.5% MeOH in CH.sub.2 Cl.sub.2 (1
 L), 1% MeOH in CH.sub.2 Cl.sub.2 (2.5 L), 1.5% MeOH in CH.sub.2 Cl.sub.2
 (2.5 L)). Fractions homogenous by TLC are combined and concentrated to
 afford 338.7 mg (66%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 166-167.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.44,
 8.86, 8.28, 7.84, 7.80, 7.38, 4.56, 4.02, 3.88, 2.91, 2.83, 2.76, 2.68,
 1.80; IR (drift) 2919, 1656, 1605, 1573, 1551, 1501, 1420, 1363, 1317,
 1240, 1131, 1109, 819, 808, 661 cm.sup.-1 ; Anal. found for C.sub.24
 H.sub.26 ClN.sub.3 O.sub.2 S: C, 63.13; H, 5.73; N, 9.15.
 Example 48
 N-(4-Chlorobenzyl)-1-methyl-6-(2-oxa-5-azabicyclo(2.2.
 1]-hept-5-ylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR103##
 Methanesulfonyl chloride (0.06 mL) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide (250 mg) from Preparation No. 10, DMAP (14.4 mg), and
 2,4,6-collidine (0.11 mL) in anhydrous DMF (12 mL). The mixture is stirred
 at room temperature until the starting material is consumed. (1S,
 4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane hydrochloride (475.9 mg) and
 Et.sub.3 N (0.49 mL) are added to the solution. The reaction mixture is
 heated to 65.degree. C. overnight. The mixture is cooled to room
 temperature and filtered to remove the salt that had precipitated out of
 solution. The filtrate is diluted with water (125 mL) to precipitate the
 product. The solid is adsorbed onto silica and purified by column
 chromatography (eluent 1% MeOH in CH.sub.2 Cl.sub.2 (1 L), 2% MeOH in
 CH.sub.2 Cl.sub.2 (1 L), 3% MeOH in CH.sub.2 Cl.sub.2 (2.5 L)). Fractions
 homogenous by TLC are combined, concentrated, and recrystallized from
 CH.sub.2 Cl.sub.2 /hexanes to afford 164.0 mg (53%) of the title compound
 as a white solid.
 Physical characteristics are as follows:
 Mp 162-163.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.44,
 8.86, 8.28, 7.84, 7.79, 7.38, 4.56, 4.36, 4.02, 3.94, 3.88, 3.54, 3.46,
 2.73, 2.43, 1.84, 1.61; IR (drift) 1655, 1605, 1573, 1550, 1500, 1364,
 1316, 1222, 1131, 1091, 844, 822, 810, 721, 662 cm.sup.-1 ;
 [.alpha.]D.sup.25 =+35 (c=0.89, methanol); Anal. found for C.sub.24
 H.sub.24 ClN.sub.3 O.sub.3 : C, 65.86; H, 5.58; N, 9.58.
 Example 49
 N-(4-Chlorobenzyl)-6-(2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl)-1-methyl-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR104##
 A solution of LiAlH.sub.4 (34 mL, 1M in THF) is added dropwise via addition
 funnel to a cold (0.degree. C.) solution of (2H)1,4-benzoxazin-3(4H)-one
 (5.04 g) in freshly distilled THF (110 mL). The LiAlH.sub.4 is added at
 such a rate to keep the reaction temperature below 10.degree. C. The
 mixture is stirred at room temperature for 2 h and then is quenched
 successively with water (5 mL), 15% NaOH (5 mL), and water (5 mL) again.
 The resulting precipitate is filtered and the filtrate is concentrated in
 vacuo. The residue is dissolved in CH.sub.2 Cl.sub.2 and dried (Na.sub.2
 SO.sub.4), filtered, and concentrated to afford the product
 benzomorpholine as a yellow oil which was used without further
 purification in the next step.
 Methanesulfonyl chloride (0.10 mL) is added to a cold (0.degree. C.)
 solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide (0.41 g) from Preparation No. 10, DMAP (0.030 g), and
 2,4,6-collidine (0.19 mL) in anhydrous DMF (15 mL). The mixture is stirred
 at room temperature for 12 h and then benzomorpholine (1.60 g) from above
 is added. The reaction mixture is stirred at room temperature for 2 h and
 is then heated to 65.degree. C. overnight. The mixture is cooled to room
 temperature and poured water. The solid is dissolved in CH.sub.2 Cl.sub.2
 /MeOH and adsorbed onto silica. Purification by column chromatography
 (eluent CH.sub.2 Cl.sub.2 (1 L), 1% MeOH/CH.sub.2 Cl.sub.2 (2 L)) and then
 recrystallization from CH.sub.2 Cl.sub.2 /hexanes affords 0.56 g (100%) of
 the title compound as a pale gold solid.
 Physical characteristics are as follows:
 Mp 193-194.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.40, 8.86,
 8.24, 7.82, 7.39, 7.35, 6.68, 6.53, 4.65, 4.54, 4.24, 4.01, 3.44; IR
 (drift) 1653, 1604, 1576, 1551, 1502, 1365, 1347, 1329, 1307, 1254, 1235,
 1214, 818, 811, 733 cm.sup.-1 ; Anal. Found for C.sub.27 H.sub.24
 ClN.sub.3 O.sub.3 : C, 68.06; H, 5.09; N, 8.80.
 Example 50
 6-((Benzyl(2-hydroxyethyl)amino)methyl)-N-(4-chlorobenzyl)-1-methyl-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide
 ##STR105##
 Methanesulfonyl chloride (0.193 mL) is added to a solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3uinolinec
 arboxamide (357 mg) from Preparation No. 10, DMAP (20 mg), and
 2,4,6-collidine (0.33 mL) in DMF (20 mL). The mixture is stirred at room
 temperature for 3 h and then N-benzylethanolamine (1.42 mL) is added. The
 reaction mixture is stirred at room temperature for 20 h, poured into
 water (60 mL), and extracted with ethyl acetate (3.times.50 mL). The
 organic layers are washed with sat. aq. sodium bicarbonate (10 mL) and
 brine (10 mL), dried (Na.sub.2 SO.sub.4), and concentrated. The crude
 product was purified by column chromatography (CH.sub.2 Cl.sub.2
 /methanol, 100/1; 50/1) to afford 0.35 g (71 %) of the title compound as a
 white solid.
 Physical characteristics are as follows:
 Mp 133-135.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.44, 8.86,
 8.29, 7.89-7.79, 7.42-7.21, 4.56, 4.42, 4.02, 3.76, 3.62, 3.5; .sup.13 C
 NMR (DMSO-d.sub.6) .delta.175.4, 164.4, 148.6, 139.4, 138.9, 138.7, 136.9,
 133.5, 131.4, 129.1, 128.5, 128.3, 128.2, 126.8, 126.7, 125.2, 117.5,
 110.4, 59.2, 58.1, 57.5, 55.2, 41.4, 41.2; IR (drift) 1653, 1606, 1549,
 1499, 1456, 1362, 1318, 1234, 1224, 1128, 1062, 817, 810, 799, 739
 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.28 H.sub.28 ClN.sub.3 O.sub.3 +H
 m/z 490.1897, found 490.1900. Anal. Found for C.sub.28 H.sub.28 ClN.sub.3
 O.sub.3 68.62; H, 5.89; N, 8.54; Cl, 7.17.
 Preparation 35
 N-(4-Chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinec
 arboxamide
 ##STR106##
 A solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide from Preparation No. 10 (1.0 g), collidine (0.44 mL), and DMAP
 (57.9 mg) in anhydrous DMF (48 mL) is cooled to 0.degree. C.
 Methanesulfonyl chloride (0.24 mL) is added dropwise. The reaction is
 stirred at room temperature. The crude product is precipitated by addition
 of water and is filtered. The resulting solid is adsorbed onto silica and
 purified by chromatography (eluent 100% CH.sub.2 Cl.sub.2 (1 L), 1% MeOH
 in CH.sub.2 Cl.sub.2 (1 L)). Product-containing fractions were combined
 and concentrated to afford 948.8 mg (90%) of the title compound as a white
 solid.
 Physical characteristics are as follows:
 Mp 241-242.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.36,
 8.89, 8.39, 7.92, 7.86, 7.36, 4.98, 4.57, 4.03; IR (drift) 1658, 1605,
 1578, 1550, 1544, 1503, 1364, 1348, 1275, 1222, 820, 808, 798, 694, 656
 cm.sup.-1 ; Anal. found for C.sub.19 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2 :
 C, 60.81; H, 4.16; N, 7.49.
 Example 51
 6-(Azidomethyl)-N-(4-chlorobenzyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolineca
 rboxamide
 ##STR107##
 A solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide from Preparation No. 35 (200 mg) and sodium azide (176.8 mg) in
 anhydrous DMF (7 mL) is heated at 60.degree. C. overnight. The reaction is
 cooled to room temperature and poured into water to precipitate the
 product. The solid is adsorbed onto silica and purified by chromatography
 (eluent 100% CH.sub.2 Cl.sub.2 (1 L), 0.5% MeOH in CH.sub.2 Cl.sub.2 (1
 L), and 1% MeOH in CH.sub.2 Cl.sub.2 (1 L)). Fractions homogenous by TLC
 were combined and concentrated to afford 182.7 mg (90%) of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 219-220.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.38,
 8.90, 8.33, 7.88, 7.38, 4.67, 4.57, 4.04; IR (drift) 2107, 2075, 1656,
 1603, 1580, 1550, 1543, 1501, 1362, 1241, 1221, 822, 808, 798, 722
 cm.sup.-1 ; Anal. found for C.sub.19 H.sub.16 ClN.sub.5 O.sub.2 : C,
 59.62; H, 4.15; N, 18.08.
 Preparation 36
 t-Butyl 4,4-difluoro-1-piperidinecarboxylate and t-butyl
 4-fluoro-3,6-dihydro-1 [2H]-pyridinecarboxylate
 Diethylaminosulfur trifluoride (4.39 mL) is added to a solution of
 1-(t-butoxycarbonyl) 4-piperidone in distilled THF (41 mL). The reaction
 is heated at 60.degree. C. for 6 hrs, then allowed to cool to room
 temperature overnight. The reaction mixture is poured into 120 mL ice
 water. The phases are separated, and the aqueous layer is extracted with
 EtOAc three times. The combined organic layers are dried over Na.sub.2
 SO.sub.4, filtered, and concentrated to afford yellow crystals. The crude
 product is adsorbed onto silica and purified by chromatography (eluent 1%
 EtOAc in hexanes (1 L), 2% EtOAc in hexanes (1 L), 3% EtOAc in hexanes (1
 L)). Fractions homogenous by TLC are combined and concentrated to yield a
 mixture of two products. The products are separated by HPLC to afford
 543.8 mg (16%) of t-butyl 4,4-difluoro-1-piperidine-carboxylate [.sup.1 H
 NMR (300 MHz, CDCl.sub.3) .delta.3.56, 1.94, 1.48] as a white solid and
 196 mg (7%) of t-butyl
 4-fluoro-3,6-dihydro-1[2H]-pyridinecarboxylate[.sup.1 H NMR (300 MHz,
 CDCl.sub.3) .delta.5.21, 3.93, 3.62, 2.31, 1.48] as a yellow residue.
 Preparation 37
 4,4-Difluoropiperidine
 To a solution of t-butyl 4,4-difluoro-1-piperidinecarboxylate from
 Preparation No. 36 (510 mg) in CH.sub.2 Cl.sub.2 (2 mL) is added
 trifluoroacetic acid (0.71 mL). The reaction is stirred at room
 temperature for 2.5 hours, and is then partitioned between saturated
 NaHCO.sub.3 and CH.sub.2 Cl.sub.2. The aqueous layer is extracted with
 CH.sub.2 Cl.sub.2 (3.times.). The combined organic layers are dried
 (Na.sub.2 SO.sub.4), filtered, and concentrated until product began to
 evaporate (vigorous bubbling seen). At least 50 mg (18%) of
 4,4-difluoropiperidine was obtained as a clear liquid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.2.98, 1.94, 1.84.
 Example 52
 N-(4-chlorobenzyl)-6-((4,4-difluoro-1-piperidinyl)methyl)-1-methyl-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide
 ##STR108##
 To a solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide from Preparation No. 35 (50 mg) in 1-methyl-2-pyrrolidinone (3
 mL) is added N,N-diisopropylethylamine (0.03 mL) and
 4,4-difluoropiperidine from Preparation No. 37 (50 mg). The reaction
 mixture is stirred at room temperature overnight and then heated at
 50.degree. C. for 4 hrs. The mixture is cooled to room temperature and
 poured into water to precipitate the product. The crude solid is
 recrystallized from CH.sub.2 Cl.sub.2 /hexanes to afford 51.5 mg (84%) of
 the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 214-215.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.43,
 8.88, 8.25, 7.81, 7.38, 4.56, 4.02, 3.72, 2.51, 1.96; IR (drift) 2823,
 1655, 1606, 1574, 1551, 1502, 1490, 1362, 1132, 1085, 1017, 949, 830, 808,
 802 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.24 H.sub.24 CIF.sub.2 N.sub.3
 O.sub.2 +H 460.1603, found 460.1598; Anal. found for C.sub.24.sub.24
 ClF.sub.2 N.sub.3 O.sub.2 : C, 62.12; H, 5.26; N, 8.99.
 Preparation 38
 4-Fluoro-1,2,3,6-tetrahydropyridine hydrochloride
 Dry HCl is passed over the surface of a cold (0.degree. C.) solution of
 t-butyl 4-fluoro-3,6-dihydro-1[2H]-pyridinecarboxylate from Preparation No
 36 (196 mg) in MeOH (3 mL) for 1 min. The reaction mixture is stoppered
 and stirred at 0.degree. C. for 15 min., then at room temperature for 15
 min. The mixture is concentrated to afford 119 mg (100%) of
 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride as an orange-brown
 residue.
 Example 53
 N-(4-Chlorobenzyl)-6-((4-fluoro-3,6-dihydro-1(2H)-pyridinyl)methyl)-1-methy
 l-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR109##
 To a solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide from Preparation No. 35 (60 mg) in 1-methyl-2-pyrrolidinone (3
 mL) is added N,N-diisopropylethylamine (0.075 mL) and
 4-fluoro-1,2,3,6-tetrahydropyridine hydrochloride from Preparation No. 38
 (119 mg). The reaction mixture is stirred at room temperature overnight
 and then heated at 60.degree. C. for 4 hrs. The mixture is cooled to room
 temperature and poured into water to precipitate the product. The crude
 solid is adsorbed onto silica and purified by chromatography (eluent 100%
 CH.sub.2 Cl.sub.2 (1 L), 0.25% MeOH in CH.sub.2 Cl.sub.2 (1 L), 0.5% MeOH
 in CH.sub.2 Cl.sub.2 (1 L), 0.75% MeOH in CH.sub.2 Cl.sub.2 (1 L), 1% MeOH
 in CH.sub.2 Cl.sub.2 (1 L), 1.25% MeOH in CH.sub.2 Cl.sub.2 (1 L), 1.5%
 MeOH in CH.sub.2 Cl.sub.2 (2 L)). Fractions homogenous by TLC are combined
 and concentrated to afford 32.2 mg (46%) of the desired product as a white
 solid.
 Physical characteristics are as follows:
 Mp 221-223.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.43,
 8.88, 8.25, 7.82, 7.38, 5.24, 4.57, 4.03, 3.75, 2.94, 2.66, 2.26; IR
 (drift) 1656, 1607, 1574, 1553, 1501, 1364, 1131, 1119, 1109,
 832,819,808,781,730,661 cm.sup.-1 ; Anal. found for C.sub.24 H.sub.23
 ClFN.sub.3 O.sub.2 : C, 65.29; H, 5.27; N, 9.44.
 Preparation 39
 N-(4-Chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR110##
 N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide (12.07 g) from
 Preparation No. 4 and potassium carbonate (5.70 g) are disolved in DMF (90
 mL). lodomethane (2.1 mL) is added and the mixture is stirred at room
 temperature for 1 h. The resulting suspension is poured into water (500
 mL) and filtered. The crude solid is washed with water (50 mL) and diethyl
 ether (100 mL) and then is recrystallized from ethanol to afford 10.6 g
 (85%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 205-208.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.25, 8.89,
 8.59, 8.14, 7.66, 7.42-7.33, 4.55, 4.00; .sup.13 C NMR (CF.sub.3 CO.sub.2
 D) .delta.173.3, 167.6, 147.9, 147.3, 140.1, 135.5, 135.4, 133.9, 129.6,
 123.3, 119.1, 106.7, 95.3, 44.5, 44.2; IR (drift) 3044, 1656, 1602, 1575,
 1551, 1493, 1469, 1438, 1361, 1312, 1241, 1126, 810, 801, 663 cm.sup.-1.
 Anal. Found for C.sub.18 H.sub.14 ClIN.sub.2 O.sub.2 : C, 47.71; H, 3.23;
 N, 6.08; Cl, 7.67; I, 28.52.
 Example 54
 N-(4-Chlorobenzyl)-1-methyl-4-oxo-6-vinyl-1,4-dihydro-3-quinolinecarboxamid
 e [32112-mes-57B]
 ##STR111##
 Tributylvinylstannane (0.32 mL) is added to a solution of
 N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamid
 e (0.45 g) from Preparation No. 39 and PdCl.sub.2 (PPh.sub.3).sub.2 (70
 mg). The mixture is stirred at room temperature for 1 h and then is heated
 to 60.degree. C. for 30 min. After cooling to room temperature, the
 reaction mixture is poured into water (60 mL), filtered, and washed with
 water (20 mL) and diethyl ether (20 mL). The crude product is purified by
 recrystallization from acetonitrile to afford 0.20 g (57%) of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 193-196.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.40, 8.86,
 8.31, 8.04, 7.82, 7.42-7.35, 6.93, 5.99, 5.39, 4.56, 4.03; .sup.13 C NMR
 (CF.sub.3 CO.sub.2 D) .delta.173.9, 167.7, 146.7, 141.1, 140.0, 135.9,
 135.4, 133.4, 129.6, 129.5, 123.1, 122.4, 119.8, 118.2, 106.2, 44.4, 44.2;
 IR (drift) 1654, 1618, 1602, 1550, 1541, 1498, 1362, 1318, 1238, 1225,
 911, 822, 806, 798, 717 cm.sup.-1 ; MS (EI) m/z 352 (M.sup.+, 26). Anal.
 Found for C.sub.20 H.sub.17 ClN.sub.2 O.sub.2 : Found: C, 68.08; H, 4.92;
 N, 7.91; Cl, 10.01.
 Preparation 40
 N-(4-Chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 ##STR112##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide
 (1.71 gm) from Preparation No. 9 in DMF (50 mL) at 0.degree. C. under a
 drying tube is treated with 4-dimethylaminopyridine (0.12 gm),
 2,4,6-collidine (1.05 mL) and methanesulfonylchloride (0.60 mL). The
 mixture is allowed to slowly warm to room temperature overnight. The
 reaction mixture is then treated with morpholine (8.0 mL) and stirred for
 4 hrs. The reaction mixture is poured into water (250 mL) and extracted
 with dichloromethane (5.times.50 mL). The combined organic layers are
 washed with water, brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by recrystallization from
 methanol-acetonitrile (1/1, 150 mL) to afford 1.7 gm of the title compound
 as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.12.7, 10.4, 8.7, 8.1, 7.8-7.6, 7.4-7.3,
 4.5, 3.6, 2.3; MS (ESI+) m/z 412, MS (ESI-) m/z 410.
 Example 55
 N-(4-Chlorobenzyl)-1-[2-(2-hydroxyethoxy)ethyl]-6-(3-hydroxy-1-propynyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR113##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxami
 de (0.37 gm) from Preparation No. 5 in DMF (10 mL) is treated with
 potassium carbonate (2.75 gm), potassium iodide (1.66 gm) and
 2-(2-chloroethoxy)ethanol (1.0 mL). The mixture is tightly capped and
 heated to 100.degree. C. for 48 hrs. The reaction mixture is allowed to
 cool to room temperature, poured into water and extracted with
 dichloromethane. The layers are separated and the aqueous layer is
 re-extracted with dichloromethane containing a small amount of methanol
 and finally again with dichloromethane. The combined organic layers are
 washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by flash column
 chromatography eluting with 3% to 15% methanol in dichloromethane and then
 by recrystallization from methanol to afford 82 mg of the title compound
 as a light yellow solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.2, 8.8, 8.3, 7.9, 7.8, 7.4-7.3, 5.4,
 4.6, 4.5, 3.8, 3.4; MS (ESI+) m/z 455.
 Example 56
 N-(4-Chlorobenzyl)-1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-6-(4-morpholinylm
 ethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR114##
 A dry flask containing
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (165 mg), triethyleneglycol
 monomethyl ether (0.10 mL) and diethyl azodicarboxylate (0.10 mL). The
 mixture is stirred at room temperature for 2 hrs. The reaction mixture is
 concentrated under reduced pressure. The crude product is purified by
 flash column chromatography eluting with 2% to 8% methanol in
 dichloromethane and then by recrystallization from ethyl acetate-heptane
 to afford 164 mg of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4, 7.8, 7.5, 7.3-7.2, 4.6,
 4.4, 3.9, 3.7-3.3, 2.4; MS (ESI+) m/z 558. Anal. found for C.sub.29
 H.sub.36 ClN.sub.3 O.sub.6 : C, 62.17; H, 6.64; N, 7.63.
 Example 57
 N-(4-Chlorobenzyl)-1-[2-(2-hydroxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide
 ##STR115##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (165 mg), diethyleneglycol (0.20
 mL) and diethyl azodicarboxylate (0.10 mL). The mixture is stirred at room
 temperature for 2 hrs. The reaction mixture is concentrated under reduced
 pressure. The crude product is purified by flash column chromatography
 eluting with 10% to 40% methanol in ethyl acetate and then by
 recrystallization from ethyl acetate to afford 68 mg of the title compound
 as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.9, 8.4, 7.8, 7.5, 7.3-7.2, 4.6,
 4.4, 3.9, 3.7-3.5, 2.4; MS ESI+) m/z 500; Anal. found for C.sub.26
 H.sub.30 ClN.sub.3 O.sub.5 : C, 62.23; H, 6.12; N, 8.29.
 Example 58
 N-(4-Chlorobenzyl)-1-[2-(2-ethoxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR116##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (164 mg),
 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10
 mL). The mixture is stirred at room temperature overnight. The reaction
 mixture is again treated with triphenylphosphine (164 mg),
 2-ethoxy-(2-ethoxy)ethanol (0.09 mL) and diethyl azodicarboxylate (0.10
 mL). After 4 hours, the reaction mixture is concentrated under reduced
 pressure. The crude product is purified by flash column chromatography
 eluting with acetone and then by recrystallization from ethyl
 acetate-heptane to afford 0.18 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4, 7.8, 7.5, 7.3-7.2, 4.6,
 4.4, 3.9, 3.7-3.4, 2.5, 1.1; MS (ESI+) m/z 528. Anal. found for C.sub.28
 H.sub.34 ClN.sub.3 O.sub.5 : C, 63.67; H, 6.55; N, 7.90.
 Example 59
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(2-propynyl)-1,4-dihydro
 -3-quinolinecarboxamide
 ##STR117##
 A dry flask containing
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (393 mg), propargyl alcohol (0.09
 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room
 temperature overnight. The reaction mixture is concentrated under reduced
 pressure and adsorbed onto silica gel. The crude product is purified by
 flash column chromatography eluting with 2% to 6% methanol in
 dichloromethane and then by recrystallization from acetonitrile to afford
 0.20 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 221-224.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 8.9,
 8.4, 7.8, 7.6, 7.3, 5.0, 4.6, 3.7, 3.6, 2.4; MS (ESI+) m/z 450. Anal.
 found for C.sub.25 H.sub.24 ClN.sub.3 O.sub.3 : C, 66.57; H, 5.41; N,
 9.28.
 Example 60
 N-(4-Chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR118##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (393 mg), ethyl
 2-hydroxyethylsulfide (0.16 mL) and diethyl azodicarboxylate (0.18 mL).
 The mixture is stirred at room temperature overnight then concentrated
 under reduced pressure. The crude product is purified by flash column
 chromatography eluting with 2% to 6% methanol in dichloromethane and then
 by recrystallization from ethanolcyclohexane to afford 0.21 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 Mp 140-142.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 8.8, 8.4,
 7.8, 7.5, 7.3, 4.6, 4.4, 3.7, 3.6, 3.0, 2.6, 2.4, 1.3; MS (ESI+) m/z 500.
 Anal. found for C.sub.26 H.sub.30 ClN.sub.3 O.sub.3 S: C, 62.36; H, 6.16;
 N, 8.37.
 Example 61
 N-(4-Chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide
 ##STR119##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (396 mg), 3-methylthiolpropanol
 (0.16 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred
 at room temperature 48 hours and then concentrated under reduced pressure.
 The crude product is purified by flash column chromatography eluting with
 2% to 6% methanol in dichloromethane and then by recrystallization from
 toluene-cyclohexane to afford 0.14 gm of the title compound as a white
 solid.
 Physical characteristics are as follows:
 Mp 102-104.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4,
 7.8, 7.6, 7.3-7.2, 4.6, 4.4, 3.7, 3.6, 3.0, 2.6, 2.5, 2.2; MS (ESI+) m/z
 500; HRMS (FAB) found 500.1779 for C.sub.26 H.sub.30 ClN.sub.3 O.sub.3
 S+H.
 Example 62
 N-(4-Chlorobenzyl)-1-(4-hydroxy-2-butynyl)-6-(4-morpholinylmethyl)-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide
 ##STR120##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (393 mg), 1,4-butyne diol (0.45 gm)
 and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room
 temperature overnight, concentrated under reduced pressure and adsorbed
 onto silica gel. The crude product is purified by flash column
 chromatography eluting with 2% to 6% methanol in dichloromethane and then
 by recrystallization from methanol-acetonitrile to afford 0.16 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 Mp 215-217.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 8.9,
 8.4, 7.8, 7.6, 7.3, 5.0, 4.6, 4.3, 3.7, 3.6, 2.5; MS (ESI+) m/z 480; Anal.
 found for C.sub.26 H.sub.26 ClN.sub.3 O.sub.4 : C, 64.68; H, 5.52; N,
 8.62.
 Example 63
 N-(4-Chlorobenzyl)-6-{[(2-hydroxy-2-phenylethyl)(methyl)-amino]methyl}-1-me
 thyl-4-oxo-1,4-dihydro-3quinolinecarboxamide
 ##STR121##
 A solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide (0.06 gm) from Preparation No. 35 in dry NMP (2 mL) containing
 diisopropylethylarnine (0.04 mL) is treated with
 .alpha.-(methylaminomethyl)-benzyl alcohol (0.04 gm). The reaction mixture
 is shaken at room temperature for 3 days then concentrated under reduced
 pressure. The residue is partioned between dichloromethane and water. The
 separated organic layer is washed with two additional portions of water,
 brine, dried (Na.sub.2 SO.sub.4) and concentrated under reduced pressure.
 The residue is adsorbed onto silica and purified by flash column
 chromatography eluting with 2% to 6% methanol in dichloromethane and then
 by recrystallization from ethyl acetate-hexanes to afford 0.05 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 8.8, 8.4, 7.8, 7.5, 7.3, 5.0, 4.8,
 4.6, 4.0, 3.9-3.6, 2.6, 2.3; MS (ESI+) m/z 490; HRMS (FAB) found for
 C.sub.28 H.sub.28 ClN.sub.3 O.sub.3 +H: 490.1895.
 Example 64
 1-{2-[Bis(2-hydroxyethyl)amino]ethyl}-N-(4-chlorobenzyl)-6-(4-morpholinylme
 thyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR122##
 A dry flask containing
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.20 gm) from Preparation No.40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (363 mg), triethanolamine (1.3 mL)
 and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room
 temperature for 4 days. The reaction mixture is concentrated under reduced
 pressure and the crude product is purified by flash column chromatography
 eluting with 3% to 9% methanol in dichloromethane. The product fractions
 are concentrated under reduced pressure, dissolved in a small volume of
 ethyl acetate-diethyl ether and added dropwise to a large volume of
 hexanes. The resulting precipitant is collected by filtration, washed with
 diethyl ether followed by hexanes to afford 0.04 gm of the title compound
 as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 9.0, 8.4, 7.8, 7.5, 7.3, 4.6, 4.3,
 3.7-3.4, 3.0, 2.7, 2.4; MS (ESI+) m/z 543; HRMS (FAB) found 543.2369 for
 C.sub.28 H.sub.35 ClN.sub.4 O.sub.5 +H.
 Example 65
 N-(4-Chlorobenzyl)-1-[3-(methylsulfinyl)propyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4-dihydro-3-quinolinecarboxamide
 ##STR123##
 A solution of
 N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 61 in
 dichloromethane (2 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid
 (.about.85%)(0.045 gm). The mixture is stirred for 0.5 hrs. The reaction
 mixture is diluted with dichloromethane, washed with saturated aqueous
 sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried
 (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The crude
 product is purified by flash column chromatography eluting with 3% to 9%
 methanol in dichloromethane. The product fractions are combined and
 recrystallized from ethyl acetate-methanol-hexanes to afford 0.07 gm of
 the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.2, 7.9, 7.8, 7.4, 4.6, 3.6,
 2.9-2.7, 2.5, 2.4, 2.0; MS (ESI+) m/z 516; HRMS (FAB) found 516.1729 for
 C.sub.26 H.sub.30 ClN.sub.3 O.sub.4 S+H.
 Example 66
 N-(4-Chlorobenzyl)-1-{3-[(3-hydroxypropyl)sulfanyl]propyl}-6-(4-morpholinyl
 methyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR124##
 A dry flask containing
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (314 mg), 3,3'-thiodipropanol (0.7
 mL) and diethyl azodicarboxylate (0.18 mL). The mixture is stirred at room
 temperature overnight. The reaction mixture is concentrated under reduced
 pressure and the crude product is purified by flash column chromatography
 eluting with 5% to 15% methanol in dichloromethane. The product fractions
 are concentrated under reduced pressure and recrystallized from ethyl
 acetate-hexanes to afford 0.20 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.2, 7.9, 7.8, 7.3, 4.5, 4.3,
 3.6, 3.4, 2.5-2.3, 2.0, 1.6; MS (ESI+) m/z 544; Anal. found for C.sub.28
 H.sub.34 ClN.sub.3 O.sub.4 S: C, 61.69; H, 6.30; N, 7.67.
 Example 67
 N-(4-Chlorobenzyl)-1-[3-(methylsulfonyl)propyl]-6-(4-morpholinylmethyl)-4-o
 xo-1,4dihydro-3-quinolinecarboxamide
 ##STR125##
 A solution of
 N-(4-chlorobenzyl)-1-[3-(methylsulfanyl)propyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 61 in
 dichloromethane (2 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.09 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by flash column chromatography eluting with 3% to 6% methanol in
 dichloromethane to afford 0.07 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 8.8, 8.4, 7.8, 7.6, 7.3, 4.6, 4.5,
 3.7, 3.6, 3.1, 2.5; MS (ESI+) m/z 532; Anal. found for C.sub.26 H.sub.30
 ClN.sub.3 O.sub.5 S: C, 58.29; H, 5.72; N, 7.77.
 Example 68
 N-(4-Chlorobenzyl)-1-[2-(ethylsulfinyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR126##
 A solution of
 N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in
 dichloromethane (2 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.045 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by flash column chromatography eluting with 3% to 9% methanol in
 dichloromethane and then by recrystallization from acetonitrile to afford
 0.05 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.3, 7.9, 7.8, 7.4-7.3, 4.9,
 4.6, 3.6, 3.3, 3.1, 2.8-2.7, 2.4, 1.2; MS (ESI+) m/z 516; HRMS (FAB) found
 516.1729 for C.sub.26 H.sub.30 ClN.sub.3 O.sub.4 S+H; Anal. found for
 C.sub.26 H.sub.30 ClN.sub.3 O.sub.4 S: C, 60.55; H, 5.95; N, 8.04.
 Example 69
 N-(4-Chlorobenzyl)-1-[2-(ethylsulfonyl)ethyl]-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR127##
 A solution of
 N-(4-chlorobenzyl)-1-[2-(ethylsulfanyl)ethyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 60 in
 dichloromethane (2 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.04 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.085 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by recrystallization from acetonitrile to afford 0.08 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.3, 7.8, 7.4-7.3, 4.9, 4.6,
 3.7, 3.6, 3.2, 2.4, 1.2; MS (ESI+) m/z 532; HRMS (FAB) found 532.1677 for
 C.sub.26 H.sub.30 ClN.sub.3 O.sub.5 S+H.
 Example 70
 N-(4-Chlorobenzyl)-1-(3-[(3-hydroxypropyl)sulfinyl]propyl)-6-(4-morpholinyl
 methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR128##
 A solution of
 N-(4-chlorobenzyl)-1-(3-[(3-hydroxypropyl)sulfanyl]propyl)-6-(4-morpholiny
 lmethyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.27 gm) from Example No.
 66 in dichloromethane (5 mL) at 0.degree. C. is added p-toluenesulfonic
 acid hydrate (0.10 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.10 gm). The mixture is stirred for 0.5 hrs. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by flash column chromatography eluting with 3% to 25% methanol in
 dichloromethane to afford 0.17 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4, 7.8, 7.6, 7.3, 4.6, 4.5,
 3.8-3.5, 3.0-2.7, 2.5, 2.0; MS (ESI+) mnz 560; HRMS (FAB) found 560.1988
 for C.sub.28 H.sub.34 ClN.sub.3 O.sub.5 S+H.
 Example 71
 N-(4-Chlorobenzyl)-1-(3-[(3-hydroxypropyl)sulfonyl]propyl)-6-(4-morpholinyl
 methyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR129##
 A solution of
 N-(4-chlorobenzyl)-1-(3-[(3-hydroxypropyl)sulfanyl]propyl)-6-(4-morpholiny
 lmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.27 gm) from Example
 No. 66 in dichloromethane (5 mL) at 0.degree. C. is added
 p-toluenesulfonic acid hydrate (0.10 gm) followed by m-chloroperoxybenzoic
 acid (.about.85%) (0.20 gm). The mixture is stirred for 0.5 hrs. The
 reaction mixture is diluted with dichloromethane, washed with saturated
 aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried
 (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The crude
 product is purified by flash column chromatography eluting with 3% to 9%
 methanol in dichloromethane and then by recrystallization from
 acetonitrile to afford 0.08 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4, 7.8, 7.6, 7.3, 4.9, 4.6,
 4.5, 3.8-3.6, 3.2-3.1, 2.5, 2.1; MS (ESI+) m/z 576; Anal. found for
 C.sub.28 H.sub.34 ClN.sub.3 O.sub.6 S: C, 58.12; H, 6.06; N, 7.33.
 Example 72
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[2-phenylsulfanyl)ethyl]
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR130##
 A dry flask containing
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.20 gm) from Preparation No. 40 in dry THF (5 mL) under an argon
 atmosphere is added triphenylphosphine (284 mg), 2-hydroxyethyl phenyl
 sulfide (0.27 mL) and diethyl azodicarboxylate (0.17 mL). The mixture is
 stirred at room temperature overnight. The reaction mixture is
 concentrated under reduced pressure and the crude product is purified by
 flash column chromatography eluting with 5% to 15% methanol in
 dichloromethane. The product fractions are concentrated under reduced
 pressure and recrystallized from acetonitrile to afford 0.21 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 Mp 166-167.degree. C.; .sup.1 H NMR (DMSO-d.sub.6), 10.4, 8.9, 8.2, 7.9,
 7.8, 7.3, 4.5, 4.3, 3.6, 3.4, 2.5-2.3, 2.0, 1.6; MS (ESI+) m/z 544; Anal.
 found for C.sub.28 H.sub.34 ClN.sub.3 O.sub.4 S: C, 61.69; H, 6.30; N,
 7.67.
 Example 73
 N-(4-Chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(morpholinylmethyl-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide
 ##STR131##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium
 carbonate (0.33 gm) and chlormethyl methyl sulfide (0.05 mL). The mixture
 is tightly capped, stirred at room temperature for 3 hrs and then heated
 to 90.degree. C. for 1 hr. The reaction mixture is allowed to cool to room
 temperature, diluted with dichloromethane (50 mL) and washed with water
 (2.times.), brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by flash column
 chromatography eluting with 2% to 4% methanol in dichloromethane and then
 by recrystallization from acetonitrile to afford 0.1 gm of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 199-201.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.0, 8.2,
 7.9, 7.8, 7.4-7.3, 5.7, 4.5, 3.6, 2.4, 2.1; MS (ESI+) m/z 472; Anal. found
 for C.sub.24 H.sub.26 ClN.sub.3 O.sub.3 S: C, 61.00; H, 5.62; N, 8.92.
 Example 74
 N-(4-Chlorobenzyl)-6-([(2-hydroxy-2-[4-hydroxyphenyl]-ethyl)
 [methyl]amino]methyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR132##
 A solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing
 diisopropylethylamine (0.07 mL) is treated with synephrine (0.05 gm). The
 reaction mixture is stirred overnight. The reaction mixture is diluted
 with dichloromethane (50 mL) and washed with water (2.times.10 mL), brine
 (10 mL), dried (Na.sub.2 SO.sub.4) and concentrated under reduced
 pressure. The residue is purified by flash column chromatography eluting
 with 3% to 6% methanol in dichloromethane and then by recrystallization
 from toluene to afford 0.09 gm of the title compound as a tan solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.5, 8.8, 8.4, 7.8, 7.5, 7.3, 7.1, 6.7,
 4.6, 3.9, 3.8, 3.6, 2.6-2.4, 2.3; MS (ESI+) m/z 506; HRMS (FAB) found
 506.1848 for C.sub.28 H.sub.28 ClN.sub.3 O.sub.4 +H.
 Example 75
 N-(4-Chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-di
 hydro-3-quinolinecarboxamide
 ##STR133##
 A solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-1,4-dihydro-3-quinolinecarbox
 amide (0.09 gm) from Preparation No. 35 in dry NMP (2 mL) containing
 diisopropylethylamine (0.14 mL) is treated with 3-azetidinol hydrochloride
 (0.04 gm) (prepared as described in Helv. Chim. Acta 1988, 1035). The
 reaction mixture is stirred overnight. The reaction mixture is diluted
 with dichloromethane (50 mL) and washed with water (2.times.10 mL), brine
 (10 mL), dried (Na.sub.2 SO.sub.4) and concentrated under reduced
 pressure. The residue is purified by flash column chromatography eluting
 with 5% to 20% methanol in dichloromethane and then by recrystallization
 from methanol-acetonitrile to afford 0.08 gm of the title compound as an
 off-white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.8, 8.2, 7.8, 7.4, 5.3, 4.5, 4.2,
 4.0, 3.7, 3.5, 2.8; MS (ESI+) m/z 412; HRMS (FAB) found 412.1412 for
 C.sub.22 H.sub.22 ClN.sub.3 O.sub.3 +H.
 Example 76
 N-(4-Chlorobenzyl)-6-(morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl]-1
 ,4-dihydro-3-quinolinecarboxamide
 ##STR134##
 A solution of
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.21 gm) from Preparation No. 40 in DMF (4 mL) is treated with cesium
 carbonate (0.30 gm) and chloromethyl phenyl sulfide (0.08 mL). The mixture
 is tightly capped and heated to 75.degree. C. for 8 hrs. The reaction
 mixture is allowed to cool to room temperature, diluted with
 dichloromethane (50 mL) and washed with water (2.times.10 mL), brine,
 dried (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The
 crude product is purified by flash column chromatography eluting with 2%
 to 4% methanol in dichloromethane and then by recrystallization from ethyl
 acetate-hexanes to afford 0.19 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.2, 8.4, 8.2, 7.9, 7.8, 7.4-7.3, 6.0,
 4.5, 3.6, 2.4; MS (ESI+) m/z 534; Anal. found for C.sub.29 H.sub.28
 ClN.sub.3 O.sub.3 S: C, 64.88; H, 5.27; N, 7.75.
 Example 77
 N-(4-Chlorobenzyl)-6-([(2-hydroxy-2-[4-hydroxy-3-methoxyphenyl]ethyl)[methy
 l]amino]methyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR135##
 A solution of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinoline
 carboxamide (0.09 gm) from Preparation No. 35 in dry DMF (2 mL) containing
 diisopropylethylamine (0.18 mL) is treated with dl-metanephrine
 hydrochloride (0.12 gm). The reaction mixture is stirred at room
 temperature for 3 days. The reaction mixture is diluted with
 dichloromethane (50 mL) and washed with water (2.times.10 mL), brine (10
 mL), dried (Na.sub.2 SO.sub.4) and concentrated under reduced pressure.
 The residue is purified by flash column chromatography eluting with 2% to
 5% methanol in dichloromethane and then by recrystallization from
 methanol-toluene to afford 0.08 gm of the title compound as an off-white
 solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.7, 8.2, 7.7, 7.4, 6.8, 6.7,
 4.9, 4.6, 4.0, 3.7, 2.5, 2.2; MS (ESI+) m/z 536; HRMS (FAB) found 536.1949
 for C.sub.29 H.sub.30 ClN.sub.3 O.sub.5 +H.
 Example 78
 N-(4-Chlorobenzyl)-6-[(3,3-dihydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,
 4-dihydro-3-quinolinecarboxamide
 ##STR136##
 A solution of
 N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-d
 ihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 75 in dry DMSO (3
 mL) containing triethylamine (0.35 mL) is treated with pyridine-sulfar
 trioxide complex (0.25 gm). The reaction mixture is stirred at room
 temperature for 2 hrs. The reaction mixture is diluted with ethyl acetate
 and washed with water (2.times.), brine, dried (Na.sub.2 SO.sub.4) and
 concentrated under reduced pressure. The residue is purified by
 recrysrallization from acetonitrile to afford 0.06 gm of the title
 compound as a tan solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.9, 8.3, 7.8, 7.4, 4.6, 4.2, 4.0;
 MS (ESI+) m/z 442 (MeOH adduct); HRMS (FAB) found 428.1381 for C.sub.22
 H.sub.22 ClN.sub.3 O.sub.4 +H.
 Example 79
 N-(4-Chlorobenzyl)-1-[(methylsulfinyl)methyl]-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR137##
 A solution of
 N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide (0.14 gm) from Example No. 73 in
 dichloromethane (4 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.06 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by recrystallization from methanol-acetonitrile to afford 0.11 gm
 of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.3, 8.9, 8.4, 7.8, 7.6, 7.3, 5.3, 4.6,
 3.7, 3.6, 2.8, 2.5; MS (ESI+) m/z 488; Anal. found for C.sub.24 H.sub.26
 ClN.sub.3 O.sub.4 S: C, 58.71; H, 5.38; N, 8.57.
 Example 80
 N-(4-Chlorobenzyl)-1-[(methylsulfonyl)methyl]-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR138##
 A solution of
 N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide (0.14 gm) from Example No. 73 in
 dichloromethane (4 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.06 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.13 gm). The mixture is stirred for 1 hr. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by flash column chromatography eluting with 3% to 9% methanol in
 dichloromethane and then by recrystallization from ethyl acetate-hexanes
 to afford 0.08 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.4, 9.1, 8.4, 7.8, 7.7, 7.3, 5.6, 4.7,
 3.7, 3.6, 3.0, 2.5; MS (ESI+) m/z 504. Anal. found for C.sub.24 H.sub.26
 ClN.sub.3 O.sub.5 S: C, 56.85; H, 5.20; N, 8.20.
 Example 81
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfinyl)methyl]
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR139##
 A solution of
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl
 )-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in
 dichloromethane (2 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.03 gm). The mixture is stirred for 1 hr. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by recrystallization from acetonitrile to afford 0.06 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.2, 8.4, 7.8, 7.6, 7.3, 5.2, 4.6, 3.7,
 3.6, 2.4; MS (ESI+) m/z 550; HRMS (FAB) found 550.1569 for C.sub.29
 H.sub.28 ClN.sub.3 O.sub.4 S+H.
 Example 82
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfonyl)methyl]
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR140##
 A solution of
 N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-[(phenylsulfanyl)methyl
 ]-1,4-dihydro-3-quinolinecarboxamide (0.08 gm) from Example No. 76 in
 dichloromethane (4 mL) at 0.degree. C. is added p-toluenesulfonic acid
 hydrate (0.03 gm) followed by m-chloroperoxybenzoic acid (.about.85%)
 (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is
 diluted with dichloromethane, washed with saturated aqueous sodium
 sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na.sub.2
 SO.sub.4) and concentrated under reduced pressure. The crude product is
 purified by recrystallization from acetonitrile to afford 0.07 gm of the
 title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.10.1, 8.3, 7.8-7.5, 7.3, 5.5, 4.6, 3.7,
 3.6, 2.5; MS (ESI+) m/z 566; HRMS (FAB) found 566.1516 for C.sub.29
 H.sub.28 ClN.sub.3 O.sub.5 S+H.
 Example 83
 N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide
 ##STR141##
 The title compound is prepared from
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-[2-(2-methoxyethoxy)ethyl]-4
 -oxo-1,4-dihydro-3-quinolinecarboxamide, which is the product of Example
 No. 42, according to the procedure described in Preparation No. 27.
 Preparation 41
 N-(4Chlorobenzyl)-6-(hydroxymethyl)-1-[2-(2-methoxyethoxy)-ethyl]-4-oxo-1,4
 -dihydro-3-quinolinecarboxamide
 ##STR142##
 A stirred mixture of
 N-(4-chlorobenzyl-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide (3.3
 g) from Preparation No. 9, cesium carbonate (6.33 g), and
 2-(2-methoxyethoxy)ethyl p-toluenesulfonate (4.0 g) in of DMF (10 mL) is
 heated at 50.degree. C. for 18 h, then cooled and partitioned between
 ethyl acetate and dilute HCl. The organic phase is washed with water and
 brine, dried over MgSO.sub.4, and concentrated under reduced pressure.
 Flash chromatography of the residue on silica using 4-5% methanol in
 dichloromethane provides 3.0 g of the title compound.
 Physical characteristics are as follows:
 Mp 161-162.5.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.3.29, 3.45, 3.57,
 3.88, 4.39, 4.61, 4.77, 7.2-7.4, 7.58, 8.30, 8.55, 10.4 ppm; IR 3381,
 2876, 1655, 1605, 1551, 1495, 1226, 1106 cm.sup.-1. HRMS (m+H) 445.1525;
 Anal. Found for C.sub.23 H.sub.25 N.sub.2 O.sub.5 Cl.sub.1 : C, 62.06; H,
 5.72; N, 6.42.
 Example 84
 N-(4-Chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-6-(4-morpholinylmethyl-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR143##
 To a stirred solution of
 N-(4-chlorobenzyl)-6-(hydroxymethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4
 -dihydro-3-quinolinecarboxamide (197 mg) from Preparation No. 41 in DMF (1
 mL) is added 2,4,6-collidine (0.14 mL) and DMAP (8 mg). The solution is
 cooled to 0.degree. C., and methanesulfonyl choride (69 .mu.L) is added.
 After 18 h, the mixture is added to 20 mL of rapidly stirred water
 containing 0.75 mL of 1N HCl. The resulting precipitate is filtered,
 washed well with water, and dried in vacuo to afford 183 mg of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]4-oxo-1,4-
 dihydro-3-quinolinecarboxamide.
 To a solution of the above chloride (93 mg) in DMF (1 mL) is added
 morpholine (53 .mu.L). The solution is stirred for 18 h, then concentrated
 under reduced pressure. Flash chromatography of the residue on silica
 using 3-4% methanol in dichloromethane provides 98.7 mg of the title
 compound as a white crystalline solid. An analytical sample may be
 prepared by recrystallization from ethyl acetate in hexane.
 Physical characteristics are as follows:
 Mp 116-118.degree. C.; .sup.1 H NMR .delta.2.46, 3.46, 3.58, 3.63, 3.70,
 3.91, 4.45, 4.64, 7.3, 7.54, 7.77, 8.41, 8.82, 10.5 ppm; IR 2815, 1662,
 1606, 1549, 1494, 1224, 1116 cm.sup.-1. HRMS (M+H) 514.2114; Anal. Found
 for C.sub.27 H.sub.32 N.sub.3 O.sub.5 Cl: C, 63.00; H, 6.28; N, 8.09.
 Example 85
 N-(4-Chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-6-[(4-oxo-1-piperidin
 yl)methyl]-1,4-dihydro-3-quinolinecarboxamide
 ##STR144##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.2.45, 2.77, 3.30, 3.46, 3.58, 3.76, 3.92,
 4.47, 4.64, 7.3, 7.59, 7.80, 8.01, 8.45, 8.83, 10.5 ppm; IR 3060, 2912,
 1717, 1663, 1606, 1550, 1494, 1224, 1091 cm.sup.-1. HRMS (M+H) 526.2107.
 Example 86
 N-(4-Chlorobenzyl)-6-{[(cyanomethyl)(methyl)amino]methyl}-1-[2-(2-methoxyet
 hoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR145##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 Mp 118-120.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.2.43, 3.29,
 3.4-3.5, 3.58, 3.75, 3.91, 4.46, 4.64, 7.3, 7.58, 7.71, 8.45, 8.83, 10.5
 ppm. IR 3062, 2877, 1662, 1606, 1550, 1495, 1224, 1107, 811 cm.sup.-1.
 HRMS (M+H) 497.1950; Anal. Found for C.sub.26 H.sub.29 N.sub.4 O.sub.4
 Cl.sub.1 : C, 62.71; H, 5.96; N, 11.24.
 Example 87
 N-(4-Chlorobenzyl)-6-{[(3R)-3-hydroxypyrrolidinyl]methyl}-1-[2-(2-methoxyet
 hoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR146##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 Mp 106-109.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.74, 2.20, 2.35,
 2.56, 2.66, 2.87, 3.29, 3.45, 3.58, 3.76, 3.90, 4.33, 4.45, 4.63, 7.3,
 7.54, 7.77, 8.39, 8.81, 10.5 ppm; IR 3239, 2915, 1659, 1605, 1550, 1494,
 1225, 1093, 810 cm.sup.-1 ; HRS (M+H) 514.2114; Anal Found for C.sub.27
 H.sub.32 N.sub.3 O.sub.5 Cl.sub.1 : C, 62.89; H, 6.34; N. 8.10.
 Example 88
 N-(4-Chlorobenzyl)-6-{[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl](methyl)am
 ino]methyl}-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarbo
 xamide
 ##STR147##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 Mp 106-109.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.05, 2.20, 2.94,
 3.29, 3.46, 3.57, 3.74, 3.89, 4.43, 4.63, 4.87, 7.3, 7.46, 7.54, 8.33,
 8.80, 10.5 ppm; IR 3404,2876, 1658, 1605, 1549, 1494, 1106, 810 cm.sup.-1
 ; HRMS (M+H) 592.2576.
 Example 89
 N-(4-Chlorobenzyl)-6-{[(2-hydroxy-2-phenylethyl)(methyl)amino]methyl}-1-[2-
 (2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinoline-carboxamide
 ##STR148##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.2.33, 2.6, 3.29, 3.46, 3.58, 3.67, 3.89,
 4.45, 4.63, 4.78, 7.3, 7.57, 7.76, 8.38, 8.83, 10.5 ppm; IR 3240, 2878,
 1661, 1606, 1550, 1494, 1225, 1093, 810 cm.sup.-1 ; HRMS (M+H) 578.2410.
 Example 90
 N-(4-Chlorobenzyl)-6-{[[2-hydroxy-2-(4-hydroxyphenyl)ethyl](methyl)amino]me
 thyl}-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR149##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.2.30, 2.4-2.7, 3.28, 3.45, 3.55, 3.63,
 3.84, 4.40, 4.65, 6.74, 7.11, 7.3, 7.53, 7.73, 8.36, 8.80, 10.55 ppm; IR
 3240, 2879, 1654, 1605, 1550, 1495, 1226, 811, 731 cm.sup.-1 ; HRMS (M+H)
 594.2363.
 Example 91
 1-{2-[2-(tert-Butoxy)ethoxy]ethyl}-N-(4-chlorobenzyl)-6-(4-morpholinylmethy
 l)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR150##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 Mp 130-132.5.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.1.10, 2.46, 3.41,
 3.53, 3.63, 3.70, 3.92, 4.44, 4.64, 7.3, 7.56, 7.77, 8.41, 8.81, 10.50
 ppm; IR 2972, 1663, 1506, 1550, 1494, 1364, 1224, 1117, 1092, 809
 cm.sup.-1 ; HRMS (M+H) 556.2578; Anal. Found for C.sub.30 H.sub.38 N.sub.3
 O.sub.5 Cl: C, 64.79; H, 6.87; N, 7.51.
 Example 92
 1-{2-[2-(tert-Butoxy)ethoxy]ethyl}-N-(4-chlorobenzyl)-6-{[[2-hydroxy-2-(4-h
 ydroxyphenyl)ethyl](methyl)amino]methyl}-4-oxo-1,4-dihydro-3-quinolinecarbo
 xamide
 ##STR151##
 The title compound is prepared in a manner analogous to that described in
 Example No. 84.
 Physical characteristics are as follows:
 .sup.1 H NMR (CDCl.sub.3) .delta.1.12, 2.32, 2.5-2.7, 3.43, 3.54, 3.6, 3.8,
 4.41, 4.64, 4.70, 6.77, 7.13, 7.3, 7.52, 7.75, 8.36, 8.80, 10.51 ppm; IR
 3238, 2974, 1654, 1605, 1550, 1494, 1365, 1226, 1092, 811,731 cm.sup.-1.
 Example 93
 N-(4-Chlorobenzyl)-1-[2-(2-methoxyethoxy)ethyl]-6-[(methylsulfanyl)methyl]-
 4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR152##
 To a suspension of
 N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4
 -dihydro-3-quinolinecarboxamide (175 mg) prepared as described in Example
 No. 84, in DMF (1.5 11) is added sodium thiomethoxide (40 mg). The mixture
 is stirred for 18 h, then added to 25 ml of rapidly stirred water. The
 solid is filtered, washed well with water, dried in vacuo, and
 recrystallized from acetonitrile to afford 139 mg of the title compound as
 pale yellow crystals.
 Physical characteristics are as follows:
 Mp 154-155.degree. C.; HRMS m/z 475.1457; Anal. Found for C.sub.24 H.sub.27
 N.sub.2 O.sub.4 CIS: C, 60.63; H, 5.75; N, 5.91.
 Preparation 42
 N-(4-Chlorobenzyl-4-hydroxy-6-iodo-3-quinolinecarboximidoyl chloride.
 ##STR153##
 A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide
 (0.75 g) from Preparation No. 4 in dichloroethane (15 mL) is heated to
 65.degree. C. Phosphorus pentachloride (0.57 g) is added in one portion.
 After 1.25 h, the reaction mixture is cooled to room temperature and the
 solvent is evaporated in a stream of nitrogen. Dichloromethane (20 mL) is
 added followed by toluene (6 mL) and the resulting solid is filtered and
 dried to give N-(4-chlorobenzyl-4-hydroxy-6-iodo-3-quinolinecarboximidoyl
 chloride (0.77 g).
 Physical characteristics are as follows:
 Mp 172-174.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.14.44,
 13.13, 10.29, 8.76, 8.52, 8.05, 7.57, 7.40, 7.35, 4.55 ppm; IR (drift)
 3025, 2410, 1660, 1615, 1573, 1556, 1529, 1494, 1462, 1398, 1367, 1324,
 1316, 1302, 928 cm.sup.-1 ; MS (FAB) m/z 439, 577, 576, 575, 442, 441,
 440, 439, 298, 127, 125.
 Preparation 43
 N-(4-Chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide.
 ##STR154##
 Hydrogen sulfide is bubbled for 30 minutes into a solution of anhydrous
 pyridine (40 mL) cooled to 0.degree. C.
 N-(4-Chlorobenzyl)-4hydroxy-6-iodo-3-quinolinecarboximidoyl chloride (1.14
 g) from Preparation No. 42 is added in one portion. After 15 minutes, the
 ice bath is removed and the reaction is stirred at room temperature for 18
 h with continuous bubbling of H.sub.2 S. The reaction mixture is poured
 into ice water and the resulting solid is filtered and dried. The solid is
 dissolved in CH.sub.2 Cl.sub.2 /MeOH, adsorbed onto silica, and purified
 by chromatography (eluent CH.sub.2 Cl.sub.2 (1 L), 0.5% MeOH:CH.sub.2
 Cl.sub.2 (1 L), 0.75% MeOH:CH.sub.2 Cl.sub.2 (6 L)) to give
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.90 g) as
 a yellow solid.
 Physical characteristics are as follows:
 Mp 275-276.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.09,
 9.44, 8.55, 8.09, 7.56, 7.44, 5.02 ppm; IR (drift) 3069, 3061, 1620, 1607,
 1557, 1534, 1518, 1493, 1381, 1352, 1344, 1288, 1194, 813, 745 cm.sup.-1 ;
 MS (FAB) m/z 455 (MH.sup.+), 531, 457, 455, 454, 417, 262, 247, 125, 124,
 107.
 Preparation 44
 N-(4-Chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioam
 ide
 ##STR155##
 To a suspension of
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.20 g)
 from Preparation No. 43 and triphenylphosphine (0.15 g) in freshly
 distilled tetrahydrofuran (5 mL) is added MeOH (0.027 mL) followed by
 diethyl azodicarboxylate. After an initial exotherm, the reaction is
 stirred at room temperature for 3 h. To drive the reaction to completion,
 additional triphenylphosphine (0.030 g), methanol (0.010 mL), and diethyl
 azodicarboxylate (0.020 mL) are added. The reaction is stirred at room
 temperature overnight. The reaction is concentrated in vacuo. The residue
 is dissolved in CH.sub.2 Cl.sub.2 and adsorbed onto silica. Purification
 by chromatography (eluent CH.sub.2 Cl.sub.2 (1 L), 1% MeOH:CH.sub.2
 Cl.sub.2 (1 L)) affords
 N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioa
 mide (0.065 g) as a yellow solid.
 Physical characteristics are as follows:
 Mp 153-155.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.04,
 9.50, 8.61, 8.18, 7.71, 7.44, 5.02, 4.06 ppm; IR (drift) 1619, 1597, 1576,
 1528, 1489, 1385, 1365, 1352, 1332, 1307, 1220, 1180, 1117, 812, 650
 cm.sup.-1 ; MS (FAB) m/z 469 (MH.sup.+), 547, 545, 471, 470, 469, 468,
 371, 328, 125, 123.
 Example 94
 N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl4-oxo-1,4-dihydro-3-qui
 nolinecarbothioamide
 ##STR156##
 A suspension of
 N-(4-chlorobenzyl)-6-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarbothioa
 mide (0.20 g) from Preparation No. 44, propargyl alcohol (0.030 mL), copper
 iodide (0.028 g), and bis(triphenylphosphine)palladium(II)chloride (0.0095
 g) in diethylamine (10 mL) is stirred at room temperature for 18 h. The
 solid in the reaction mixture is filtered, then dissolved in CH.sub.2
 Cl.sub.2 /MeOH, and adsorbed onto silica. Purification by chromatography
 (eluent 1% MeOH:CH.sub.2 Cl.sub.2 (1 L), 2% MeOH:CH.sub.2 Cl.sub.2 (1 L))
 affords the title compound as a yellow solid (0.12 g).
 Physical characteristics are as follows:
 Mp 200-201.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.04,
 9.47, 8.30, 7.89, 7.44, 5.42, 5.04, 4.35, 4.08 ppm; IR (drift) 3311, 1625,
 1602, 1572, 1535, 1490, 1392, 1368, 1352, 1337, 1312, 1030, 1015, 831, 801
 cm.sup.-1 ; MS (ESI) m/z 397.0 (M+H).sup.+
 Preparation 45
 Methyl
 3-{[(4-Chlorobenzyl)amino]carbothioyl}-4-hydroxy-6-quinolinecarboxylate.
 ##STR157##
 Dimethylformamide (anhydrous, 5 mL) is added to a flame-dried flask. The
 solution is purged with nitrogen for 15 minutes. To this solution is added
 N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarbothioamide (0.25 g)
 from Preparation No. 44, methanol (0.90 mL), triethylamine (0.16 mL), and
 dichlorobis(triphenylphosphine)palladium (0.068 g). The reaction is placed
 under a CO balloon and stirred at 70.degree. C. for 3 h. The reaction is
 cooled to room temperature and poured into 1N HCl (40 mL). The resulting
 solid is filtered and dried. The solid is dissolved in CH.sub.2 Cl.sub.2
 /MeOH and adsorbed onto silica. Purification by chromatography (eluent
 CH.sub.2 Cl.sub.2 (1 L), 1% MeOH:CH.sub.2 Cl.sub.2 (2 L), 3% MeOH:CH.sub.2
 Cl.sub.2 (1 L)) affords methyl
 3-{[(4-chlorobenzyl)amino]carbothioyl}-4-hydroxy-6-quinolinecarboxylate
 (0.090 g) as a yellow solid.
 Physical characteristics are as follows:
 Mp 259-261.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.24,
 13.03, 9.46, 8.85, 8.28, 7.84, 7.45, 5.04, 3.91 ppm; IR (drift) 1713,
 1630, 1572, 1564, 1539, 1519, 1494, 1483, 1436, 1296, 1275, 1237, 1201,
 799, 769 cm.sup.-1 ; MS (FAB) m/z 387 (MH.sup.+), 389, 388, 387, 386, 371,
 246, 127, 125, 92, 45.
 Preparation 46
 N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarbothioamide.
 ##STR158##
 To a suspension of methyl
 3-{[(4-chlorobenzyl)amino]carbothioyl})-4-hydroxy-6-quinolinecarboxylate
 (0.062 g) from Preparation No. 45 in freshly distilled THF (8 mL) at room
 temperature is added lithium aluminum hydride (1M in THF, 0.34 mL)
 dropwise. After 45 minutes, the reaction is quenched sequentially with 1
 mL water, 1 mL 15% NaOH, and 1 mL water. The reaction mixture is
 concentrated in vacuo. The residue is adsorbed onto silica. Purification
 by chromatography (eluent 1% MeOH:CH.sub.2 Cl.sub.2 (1 L), 2%
 MeOH:CH.sub.2 Cl.sub.2 (1 L), 3% MeOH:CH.sub.2 Cl.sub.2 (1 L)) affords
 N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarbothioamide
 (0.038 g).
 Physical characteristics are as follows:
 Mp 240-242.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.35,
 13.01, 9.41, 8.23, 7.75, 7.70, 7.45, 5.42, 5.04, 4.64 ppm; IR (drift)
 2962, 2943, 2907, 2889, 1631, 1588, 1530, 1493, 1439, 1414, 1217, 1003,
 883, 822, 812 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.18 H.sub.15 ClN.sub.2
 O.sub.2 S+H.sub.1 359.0621, found 359.0638.
 Preparation 47
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarbothioam
 ide.
 ##STR159##
 To a solution of
 N-(4-chlorobenzyl-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarbothioamide
 (0.082 g) from Preparation No. 46 in anhydrous dimethylformamide (4 mL) in
 a flame-dried flask is added dimethylaminopyridine (0.011 g),
 2,4,6-collidine (0.035 mL), and methanesulfonyl chloride (0.017 mL). The
 reaction mixture is stirred at room temperature for 1 h after which time
 thin layer chromatography indicates starting material is nearly consumed.
 Morpholine (0.20 mL) is added in one portion. The reaction is stirred for
 1.5 h and then poured into water. The aqueous solution is extracted
 2.times. with CH.sub.2 Cl.sub.2 and 2.times. with 3% MeOH:CH.sub.2
 Cl.sub.2. The organics are combined, dried over Na.sub.2 SO.sub.4,
 filtered, and concentrated. Residual DMF is removed on the vacuum pump.
 The residue is dissolved in CH.sub.2 Cl.sub.2 and hexanes was added to
 give a solid (starting material) which is filtered and dried. Upon
 allowing this filtrate to evaporate overnight, a second solid is obtained.
 This solid is dissolved in CH.sub.2 Cl.sub.2 and adsorbed onto silica.
 Purification by chromatography (eluent CH.sub.2 Cl.sub.2 (1 L), 1%
 MeOH:CH.sub.2 Cl.sub.2 (1 L), 2% MeOH:CH.sub.2 Cl.sub.2 (1 L) 2.5%
 MeOH:CH.sub.2 Cl.sub.2 (1 L), 3% MeOH:CH.sub.2 Cl.sub.2 (2 L)) affords
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarbothioa
 mide (0.028 g) as a yellow solid.
 Physical characteristics are as follows:
 Mp 215-216.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.35,
 13.04, 9.41, 8.18, 7.75, 7.70, 7.45, 5.03, 3.60, 3.57, 2.37 ppm; IR
 (drift) 1621, 1591, 1575, 1540, 1524, 1490, 1352, 1297, 1287, 1115, 1107,
 923, 855, 831, 798 cm.sup.- ; HRMS (FAB) calcd for C.sub.22 H.sub.22
 ClN.sub.3 O.sub.2 S+H.sub.1 428.1199, found 428.1198.
 Example 95
 N-(4-Chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-qui
 nolinecarbothioamide
 ##STR160##
 A flame-dried flask is charged with
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarbothioa
 mide (0.060 g) from Preparation No. 47, triphenylphosphine (0.045 g), and
 freshly distilled THF (1.5 mL). To this solution is added methanol (8.00
 .mu.L) and diethyl azodicarboxylate (28.00 .mu.L). The reaction is stirred
 at room temperature for 18 h. Monitoring of the reaction still shows a
 significant amount of starting material left. Additional PPh.sub.3 (0.025
 g), methanol (5.00 .mu.L), and diethyl azodicarboxylate (14.00 .mu.L) are
 added and the reaction is stirred for 18 h. Since monitoring of the
 reaction still shows some starting material, 10 equivalents each of
 PPh.sub.3, methanol, and diethyl azodicarboxylate are added. A reasonable
 exotherm is seen after adding diethyl azodicarboxylate. The reaction is
 immediately monitored by TLC and starting material is consumed. The
 solvents are removed and the residue is dissolved in CH.sub.2 Cl.sub.2
 /MeOH and adsorbed onto silica. Purification by column chromatography
 (eluent CH.sub.2 Cl.sub.2 (1 L), 1% MeOH:CH.sub.2 Cl.sub.2 (1 L), 2%
 MeOH:CH.sub.2 Cl.sub.2 (2 L), 4% MeOH:CH.sub.2 Cl.sub.2 (1 L), 7%
 MeOH:CH.sub.2 Cl.sub.2 (1 L)) affords the title compound contaminated with
 triphenylphosphine oxide. These fractions are combined and concentrated
 and the residue is again adsorbed onto silica. Purification by a second
 chromatography (eluent 1:1 hexanes:ethyl acetate (1 L), 45:55
 hexanes:ethyl acetate (1 L), 4:6 hexanes:ethyl acetate (1 L), 35:65
 hexanes:ethyl acetate (1 L), 1:3 hexanes:ethyl acetate (1 L), 2:8
 hexanes:ethyl acetate (1 L), 1:9 hexanes:ethyl acetate (1 L), 100% ethyl
 acetate (1 L), 2% MeOH:CH.sub.2 Cl.sub.2 (1 L), 4% MeOH:CH.sub.2 Cl.sub.2
 (1 L)) affords the title compound as a light yellow residue. The residue
 is dissolved in CH.sub.2 Cl.sub.2 and hexanes are added until cloudy. The
 solution is placed in the freezer overnight and the title compound as a
 solid is subsequently filtered and dried (0.020 g).
 Physical characteristics are as follows:
 Mp 167-169.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.13.24,
 9.45, 8.25, 7.84, 7.42, 5.01, 4.07, 3.62, 3.55, 2.35 ppm; HRMS (FAB) calcd
 for C.sub.23 H.sub.24 ClN.sub.3 O.sub.2 S+H, 442.1356, found 442.1357.
 Preparation 48
 N-(4-Corobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamride
 ##STR161##
 A solution of 2-iodoaniline (8.22 g) and diethyl ethoxymethylenemalonate
 (8.00 mL) is heated at 130.degree. C. for 1 h. The reaction is cooled to
 room temperature. Diphenyl ether (100 mL) is added and the reaction is
 heated at 250.degree. C. for 1.25 h. The reaction is cooled to room
 temperature and the resulting solid is filtered, washed thoroughly with
 hexanes, and dried to give ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate
 (6.84 g).
 A portion of the resulting ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate
 (4.01 g) and 4-chlorobenzylamine (20.00 mL) are heated at 180.degree. C.
 for 1.5 h. The reaction is cooled to room temperature. Ethyl acetate is
 added, followed by hexanes, and the solid is filtered, washed with
 hexanes, and dried to give
 N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (3.98 g).
 A suspension of the above
 N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (0.88 g),
 K.sub.2 CO.sub.3 (1.12 g), and iodomethane (0.14 mL) in anhydrous
 dimethylformamide (25 mL) is heated at 90.degree. C. until the reaction is
 complete by TLC. The reaction mixture is cooled to room temperature and
 poured into water (150 mL). The resulting solid is filtered and dried. The
 solid is dissolved in CH.sub.2 Cl.sub.2 /MeOH and adsorbed onto silica.
 Purification by chromatography (eluent CH.sub.2 Cl.sub.2 (1 L), 0.5%
 MeOH:CH.sub.2 Cl.sub.2 (1 L), 1% MeOH:CH.sub.2 Cl.sub.2 (1 L), 1.5%
 MeOH:CH.sub.2 Cl.sub.2 (1 L), 2% MeOH:CH.sub.2 Cl.sub.2 (1 L)) affords the
 title compound as a white solid (0.50 g).
 Physical characteristics are as follows:
 Mp 222-223.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.16,
 8.77, 8.51, 8.36, 7.38, 7.34, 7.21, 4.53, 4.38 ppm; IR (drift) 1662, 1600,
 1574, 1551, 1536, 1489, 1436, 1418, 1358, 1116, 1105, 798, 779, 750, 724
 cm.sup.-1 ; MS (EI) m/z 452, 285, 159, 156, 140, 130, 128, 103, 102, 77,
 76.
 Example 96
 N-(4-Chlorobenzyl)-8-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-qu
 inolinecarboxamide
 ##STR162##
 A solution of
 N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamid
 e (0.21 g) from Preparation No. 48, copper iodide (0.029 g),
 bis(triphenylphosphine)palladium(II) chloride (0.012 g), and propargyl
 alcohol (0.035 mL) in diethylamine (15 mL) is stirred at room temperature
 for 18 h. Dichloromethane followed by hexanes is added to the reaction
 mixture. The resulting solid is filtered, washed thoroughly with hexanes,
 and dried. The solid is dissolved in CH.sub.2 Cl.sub.2 /MeOH and adsorbed
 onto silica. Purification by chromatography (eluent CH.sub.2 Cl.sub.2 (1
 L), 0.5% MeOH:CH.sub.2 Cl.sub.2 (1 L), 1% MeOH:CH.sub.2 Cl.sub.2 (1 L),
 1.5% MeOH:CH.sub.2 Cl.sub.2 (1 L), 2% MeOH:CH.sub.2 Cl.sub.2 (1 L), 3%
 MeOH:CH.sub.2 Cl.sub.2 (1 L)) affords the title compound as a yellow solid
 (0.13 g).
 Physical characteristics are as follows:
 Mp 228-230.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.26,
 8.78, 8.38, 7.92, 7.51, 7.40, 7.36, 5.44, 4.56, 4.44, 4.39 ppm; IR (drift)
 3358, 1660, 1606, 1551, 1492, 1431, 1360, 1243, 1123, 1042, 801, 784, 758,
 750, 695 cm.sup.-1 ; MS (ESI) for m/z 381.0 ((M+H).sup.+, 379.0
 (M-H).sup.-.
 Example 97
 N-(4-Chlorobenzyl)-8-(4-hydroxy-1-butynyl)-1-methyl-4-oxo-1,4-dihydro-3-qui
 nolinecarboxamide
 ##STR163##
 A solution of
 N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamid
 e (0.22 g) from Preparation No. 48, copper iodide (0.029 g),
 bis(triphenylphosphine)palladium(II) chloride (0.013 g), and 3-butyn-1-ol
 (0.040 mL) in diethylamine (15 mL) is stirred at room temperature for 18
 h. Hexanes are added to the reaction mixture and the resulting solid is
 filtered and dried. The solid is dissolved in CH.sub.2 Cl.sub.2 /MeOH and
 adsorbed onto silica. Purification by chromatography (eluent CH.sub.2
 Cl.sub.2 (1 L), 1.5% MeOH:CH.sub.2 Cl.sub.2 (1 L), 2% MeOH:CH.sub.2
 Cl.sub.2 (2 L), 3% MeOH:CH.sub.2 Cl.sub.2 (1 L)) affords the title
 compound as a light yellow solid (0.16 g).
 Physical characteristics are as follows:
 Mp 195-197.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.27,
 8.77, 8.35, 7.91, 7.48, 7.41, 7.36, 4.97, 4.55, 4.45, 3.64, 2.65 ppm; IR
 (drift) 1661, 1604, 1555, 1489, 1427, 1359, 1242, 1118, 1090, 1073, 839,
 803, 782, 753, 695 cm.sup.-1 ; MS (ESI) for m/z 395.0 (M+H).sup.+.
 Preparation 49
 (4-Nitrobenzyl)triphenylphosphonium bromide.
 To a solution of triphenylphosphine (15.34 g) in Et.sub.2 O (150 mL) is
 added 4-nitrobenzylbromide (12.96 g). The solution is allowed to stir
 overnight and the resulting solid is filtered and dried to yield 10.95 g
 of (4-nitrobenzyl)(triphenyl)phosphonium bromide as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.7.79,7.63, 7.48, 5.99 ppm.
 Preparation 50
 4-(4-Nitrobenzylidene)tetrahydro-2H-pyran.
 To a 100 mL flask under N.sub.2 is added NaH (0.40 g of a 60% solution in
 mineral oil) and anhydrous DMSO (7 mL). The resulting solution is heated
 at 80.degree. C. for 1 h and then cooled in an ice-water bath. To this is
 added a suspension of the phosphonium bromide (4.78 g) from Preparation
 No. 49 in warm DMSO (40 mL). The mixture is stirred at room temperature
 for 10 min. Tetrahydro4H-pyran-4-one (0.92 mL) is then added dropwise. The
 mixture is allowed to stir at room temperature overnight and then at
 80.degree. C. for 8 h. The mixture is poured over ice and extracted with
 Et.sub.2 O. The combined extracts are combined and concentrated. The crude
 product is chromatographed (Biotage flash 40 M, eluent gradient from
 hexane to 60/40 CH.sub.2 Cl.sub.2 /hexanes) to yield 0.464 g of
 4-(4-nitrobenzylidene)tetrahydro-2H-pyran as a yellow solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.8.20, 7.36, 6.39, 3.83, 3.70,
 2.55, 2.46 ppm.
 Preparation 51
 Ethyl 4-Hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate.
 ##STR164##
 A mixture of 4-(4-nitrobenzylidene)tetrahydro-2H-pyran (400 mg) from
 Preparation No. 50 and platinum (IV) oxide (40 mg) in MeOH (40 ml) is
 hydrogenated at 40 psi H.sub.2 for 4 h. The reaction mixture is filtered
 through Celite and concentrated. CH.sub.2 Cl.sub.2 (50 mL) and diethyl
 ethoxymethylenemalonate (0.37 mL) are then added to the residue and the
 mixture was concentrated at 40.degree. C. To this residue is then added
 diphenyl ether (20 mL). The mixture is heated to 250.degree. C. for 1 h.
 The mixture is then cooled and diluted with hexanes. The resulting product
 is collected, washed with hexanes and dried to yield 0.453 g of ethyl
 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate.
 Physical characteristics are as follows:
 Mp 275-280.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.12.30,
 8.49, 7.90, 7.52, 4.18, 3.78, 3.20, 2.61, 1,73, 1,43, 1.25 ppm; IR (drift)
 2952, 2928, 1699, 1615, 1581, 1562, 1524, 1377, 1296, 1208, 1175, 1103,
 1096, 808, 610 cm.sup.4 l; MS (ESI+) for C.sub.18 H.sub.21 NO.sub.4 m/z
 316.2 (M+H).sup.+.
 Preparation 52
 N-(4-Chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinoline
 carboxamide.
 ##STR165##
 A solution of ethyl
 4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxylate (0.315
 g) from Preparation No. 51 and 4-chlorobenzylamine (0.61 nL) is heated to
 180.degree. C. for 1 h. The reaction mixture is cooled to 65.degree. C.
 and diluted with CH.sub.2 Cl.sub.2. Hexanes are added to initiate
 precipitation of the product. The resulting solid is collected and dried
 to yield 0.33 g of
 N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolin
 ecarboxamide as an off-white solid.
 Physical characteristics are as follows:
 Mp 184-185.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.12.71,
 10.50, 8.71, 7.99, 7.60, 7.36, 4.53, 3.78, 3.19, 2.64, 1.74, 1.43, 1.21
 ppm; IR (drift) 2968, 2959, 2924, 2916, 2842, 1660, 1620, 1538, 1489,
 1365, 1094, 851, 833, 806, 797 cm.sup.-1 ; MS (ESI+) for C.sub.23 H.sub.23
 ClN.sub.2 O.sub.3 m/z 411.1 (M+H).sup.+.
 Example 98
 N-(4-Chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-di
 hydro-3-quinolinecarboxamide
 ##STR166##
 To a solution of
 N-(4-chlorobenzyl-4-hydroxy-6-(tetrahydro-2H-pyran4-ylmethyl)-3-quinolinec
 arboxamide (0.200 g) from Preparation No. 52 in anhydrous DMF (10 mL) is
 added K.sub.2 CO.sub.3 (0.269 g) and CH.sub.3 I (0.04, mL). The mixture is
 stirred for 15 min. Water (10 mL) is then added and the resulting solid is
 collected and dried. The crude product is chromatographed (Biotage flash
 40 S, gradient CH.sub.2 Cl.sub.2, then 1% MeOH/CH.sub.2 Cl.sub.2 then 2%
 MeOH/CH.sub.2 Cl.sub.2) to yield 0.161 g of the title compound as a white
 solid.
 Physical characteristics are as follows:
 Mp 219-221.degree. C.; .sup.1 H NMR (300 MHz, DMSO-d.sub.6) .delta.10.45,
 8.83, 8.08, 7.75, 7.68, 7.36, 4.54, 3.99, 3.78, 3.19, 2.67, 1.76, 1.43,
 1.22 ppm; IR (drift) 2929, 2914, 2850, 1655, 1606, 1572, 1551, 1501, 1487,
 1364, 1133, 1088, 847, 826, 808 cm.sup.-1.
 Example 99
 N-(4-Chlorobenzyl)-6-{[3-(ydroxyimino)-1-azetidinyl]methyl}-1-methyl-4-oxo-
 1,4-dihydro-3-quinolinecarboxamide
 ##STR167##
 A suspension of
 N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-d
 ihydro-3-quinolinecarboxamide (0.09 gm) of Example No. 75 in methyl
 sulfoxide (3 mL) is treated with triethylamine (0.35 mL) and cooled in a
 water bath. The mixture is treated with sulfur trioxide pyridine complex
 (0.25 gm) and allowed to stir for 2 hours. The mixture is diluted with
 diethyl ether containing a small amount of methanol and dichloromethane.
 The organic phase is washed with three portions of water, brine, dried
 over sodium sulfate, filtered, and concentrated under reduced pressure.
 The residue is suspended in ethanol (95%, 2 mL) and treated with
 hydroxylamine hydrochloride (0.03 gm) and sodium hydroxide (0.02 gm). The
 flask is tightly capped and heated at 65.degree. C. overnight. The
 reaction mixture is cooled to room temperature and partitioned between
 dichloromethane containing methanol and water. The aqueous phase is
 extracted with dichloromethane containing methanol and dichloromethane.
 The combined organic phase is washed with water, brine, dried over sodium
 sulfate, and concentrated under reduced pressure. The residue is purified
 by flash column chromatography on silica gel eluting with a small amount
 of methanol in dichloromethane and then by recrystallization from
 acetonitrile-methanol to afford 14 mg of the title compound as a tan
 solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.7, 10.4, 8.9, 8.2, 7.8, 7.4, 4.6,
 4.0, 3.9, 3.3; MS (ESI+) m/z 425; HRMS (FAB) found 425.1379 for C.sub.22
 H.sub.21 ClN.sub.4 O.sub.3 +H.
 Example 100
 N-(4-Chlorobenzyl)-1-{2-[2-(4-morpholinyl)ethoxy]ethyl}-6-(4-morpholinylmet
 hyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR168##
 A solution of
 N-(4-chlorobenzyl)-1-[2-(2-hydroxyethoxy)ethyl]-6-(4-morpholinylmethyl)-4-
 oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) of Example No. 57 and
 4-dimethylaminopyridine (0.002 gm) in pyridine (2 mL) at 0.degree. C. is
 treated with tosyl chloride (0.05 gm). The mixture is allowed to warm to
 room temperature overnight. The mixture is treated with an additional
 portion of tosyl chloride (0.05 gm), stirred 4 hours, then treated with
 morpholine (0.20 mL) and allowed to stir overnight. The mixture is
 concentrated under reduced pressure and the residual pyridine
 azeotropically removed with toluene. The residue is purified by flash
 column chromatography on silica gel eluting with 2% to 10% methanol
 containing ammonia in dichloromethane and then by recrystallization from
 ethyl acetate-hexanes to afford 29 mg of the title compound as a white
 solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.8, 8.2, 7.9, 7.7, 7.4, 4.6, 4,5,
 3.7, 3.6, 3.5, 3.4, 3.3, 2.4, 2.3, 2.2; MS (ESI+) m/z 569; HRMS (FAB)
 found 569.2531 for C.sub.30 H.sub.37 ClN.sub.4 O.sub.5 +H.
 Example 101
 N-(4-Chlorobenzyl)-1-([(4-chlorophenyl)sulfanyl]methyl)-6-(4-morpholinylmet
 hyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR169##
 A suspension of
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.25 gm) from Preparation No. 40 and cesium carbonate (0.39 gm) in DMF (3
 mL) is treated with chloromethyl 4-chlorophenyl sulfide (0.13 mL). The
 mixture is tightly capped and heated to 105.degree. C. for 2 hrs. The
 reaction mixture is allowed to cool to room temperature, diluted with
 dichloromethane (50 mL), washed with water (2.times.10 mL), brine, dried
 (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The crude
 product is purified by flash column chromatography eluting with 1% to 3%
 methanol in dichloromethane and then by trituration with ethyl acetate to
 afford 0.26 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.2, 8.5, 8.2, 7.9, 7.8, 7.4-7.3, 6.0,
 4.5, 3.6, 3.5, 2.4; MS (ESI+) m/z 568; Anal. Found: C, 61.14; H, 4.77; N,
 7.30.
 Example 102
 N-(4-Chlorobenzyl)-1-([(4-chlorophenyl)sulfinyl]methyl)-6-(4-morpholinylmet
 hyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR170##
 A solution of
 N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfanyl]methyl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.11 gm) from Example No.
 101 in dichloromethane (2 mL) at 0.degree. C. is treated with
 p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic
 acid (.about.85%) (0.04 gm). The mixture is stirred for 0.75 hr. The
 reaction mixture is diluted with dichloromethane, washed with saturated
 aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried
 (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The crude
 product is purified by recrystallization from acetonitrile to afford 0.10
 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.2, 8.7, 8.2, 7.8, 7.7, 7.5, 7.4, 6.0,
 4.5, 3.6, 2.3; MS (ESI+) m/z 584; HRMS (FAB) found 584.1171 for C.sub.29
 H.sub.27 Cl.sub.2 N.sub.3 O.sub.4 S+H.
 Example 103
 N-(4-Chlorobenzyl)-1-([(4-chlorophenyl)sulfonyl]methyl)-6-(4-morpholinylmet
 hyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR171##
 A solution of
 N-(4-chlorobenzyl)-1-([(4-chlorophenyl)sulfanyl]methyl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.11 gm) from Example No.
 101 in dichloromethane (2 mL) at 0.degree. C. is treated with
 p-toluenesulfonic acid hydrate (0.04 gm) followed by m-chloroperoxybenzoic
 acid (.about.85%) (0.09 gm). The mixture is stirred for 0.75 hr. The
 reaction mixture is diluted with dichloromethane, washed with saturated
 aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried
 (Na.sub.2 SO.sub.4) and concentrated under reduced pressure. The crude
 product is purified by recrystallization from acetonitrile to afford 0.09
 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.1, 8.7, 8.2, 7.7, 7.6, 7.5, 7.4, 6.4,
 4.5, 3.5, 2.3; MS (ESI+) nzz 600; HRMS (FAB) found 600.1121 for C.sub.29
 H.sub.27 Cl.sub.2 N.sub.3 O.sub.5 S+H.
 Example 104
 N-(4-Chlorobenzyl)-1-[(4-chlorophenoxy)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR172##
 A suspension of
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.21 gm) from Preparation No. 40 and cesium carbonate (0.33 gm) in DMF
 (2 mL) is treated with .alpha.,4-dichloroanisole (0.13 gm). The mixture is
 tightly capped and heated to 100.degree. C. for 3 hrs. The reaction
 mixture is allowed to cool to room temperature, diluted with
 dichloromethane (50 mL) and washed with water. The aqueous phase is
 extracted with two additional portions of dichloromethane. The combined
 organic phase is washed with brine, dried (Na.sub.2 SO.sub.4) and
 concentrated under reduced pressure. The crude product is purified by
 flash column chromatography eluting with 1% to 4% methanol in
 dichloromethane and then by recrystallization with acetonitrile to afford
 0.20 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.2, 9.0, 8.2, 8.0, 7.8, 7.4, 7.1, 6.5,
 4.5, 3.6, 3.5, 2.4; MS (ESI+) m/z 552; Anal. Found: C, 62.92; H, 4.94; N,
 7.66.
 Example 105
 N-(4-Chlorobenzyl)-1-[(2-methoxyethoxy)methyl]-6-(4-morpholinylmethyl)-4-ox
 o-1,4-dihydro-3-quinolinecarboxamide
 ##STR173##
 A suspension of
 N-(4-chlorobenzyl-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamide
 (0.21 gm) from Preparation No. 40 and cesium carbonate (0.34 gm) in DMF (2
 mL) is treated with 2-methoxyethoxymethyl chloride (0.07 mL). The mixture
 is tightly capped and heated to 100.degree. C. for 3 hrs. The reaction
 mixture is allowed to cool to room temperature, diluted with
 dichloromethane and washed with water. The aqueous phase is extracted with
 two additional portions of dichloromethane. The combined organic phase is
 washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by flash column
 chromatography eluting with 1% to 5% methanol in dichloromethane and then
 by recrystallization with acetonitrile to afford 0.08 gm of the title
 compound as a white solid.
 Physical characteristics are as follows:
 Mp 150-152.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.0, 8.2,
 7.9, 7.8, 7.4, 5.8, 4.5, 3.6, 3.4, 3.1, 2.4; MS (ESI+) m/z 500; Anal.
 Found: C, 62.49; H, 6.03; N, 8.50.
 Example 106
 2-{[3-{[(4-Chlorobenzyl)amino]carbonyl}-6-(4-morpholinylmethyl)-4-oxo
 -1(4H)-quinolinyl]methoxy}ethyl benzoate
 ##STR174##
 A suspension of
 N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxamid
 e (0.41 gm) from Preparation No. 40 and cesium carbonate (0.65 gm) in DMF
 (5 mL) is treated with benzoyloxyethylchloromethylether (.about.85%, 0.31
 mL). The mixture is tightly capped and heated to 110.degree. C. for 3 hrs.
 The reaction mixture is allowed to cool to room temperature, diluted with
 dichloromethane and washed with water (3.times.). The organic phase is
 washed with brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by flash column
 chromatography eluting with 2% to 6% methanol in dichloromethane and then
 by recrystallization with acetonitrile to afford 0.08 gm of the title
 compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.0, 8.2, 7.9, 7.7, 7.6, 7.4, 5.9,
 4.6, 4.3, 3.9, 3.5, 3.3, 2.3; MS (ESI+) m/z 590; HRMS (FAB) found 590.2046
 for C.sub.32 H.sub.32 ClN.sub.3 O.sub.6 +H.
 Example 107
 N-(4-Chlorobenzyl)-1-[(2-hydroxyethoxy)methyl]-6-(4-morpholinylmethyl-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide
 ##STR175##
 A flask containing
 2-{[3-{[(4-chlorobenzyl)amino]carbonyl}-6-(4-morpholinylmethyl)-4-oxo-1(4H
 )-quinolinyl]methoxy}ethyl benzoate (0.12 gm) from Example No. 106 is
 treated with methanol saturated with ammonia (5 mL). The mixture is
 tightly capped and stirred at room temperature for 3 days. The reaction
 mixture is concentrated under reduced pressure. The crude product is
 purified by flash column chromatography eluting with 2% to 10% methanol in
 dichloromethane and then by recrystallization with acetonitrile to afford
 0.07 gm of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.0, 8.2, 7.9, 7.8, 7.4, 5.8, 4.7,
 4.5, 3.6, 3.5, 3.3, 2.4; MS (ESI+) m/z 486; Anal. Found: C, 61.69; H,
 5.85; N, 8.61.
 Example 108
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran-4-yl
 -1,4-dihydro-3-quinolinecarboxamide (formula W-5; Z=O)
 ##STR176##
 A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22
 (0.48 g) is treated with methanol (5 mL) and a few dozen dry molecular
 sieves (3 .ANG.). The mixture is treated with acetic acid (1 mL) and
 terahydro-4H-pyran-4-one (0.24 mL). After 1 hour, the mixture is carefully
 treated with sodium cyanoborohydride (0.6 g) and heated to reflux under an
 argon atmosphere. After 1 hour, the mixture is cooled to room temperature
 and filtered with methanol washes. The filtrate is diluted with diethyl
 ether and washed with aqueous sodium hydroxide (2N). The aqueous is
 back-extracted with dichloromethane. The combined organic layers are
 washed with brine, dried over sodium sulfate, and concentrated under
 reduced pressure. The residue is flash column chromatographed on silica
 eluting with 2% to 5% methanol in dichloromethane. The product-containing
 fractions are combined and evaporated to afford 0.34 g of
 N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine as a white
 solid.
 A flask containing
 N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine (0.34 g) is
 treated with diethyl ethoxymethylenemalonate (0.30 mL) and pyridine (0.20
 mL). The flask is tightly capped and heated to 140.degree. C. for 2 hours.
 The reaction is cooled to room temperature and azeotroped under reduced
 pressure with toluene (3.times.). The residue is dissolved in
 dichloromethane and washed with water, brine, dried and concentrated under
 reduced pressure. The residue is chromatographed on silica eluting with 2%
 to 6% methanol in dichloromethane. The product-containing fractions are
 evaporated to give 0.41 g of diethyl
 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-pyran-4-yl)anilino]methylene}mal
 onate as a tan oil.
 A flask containing diethyl
 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-pyran-4-yl)anilino]methylene}mal
 onate (0.41 g) is treated with polyphosphoric acid (1.5 g). The reaction
 mixture is heated to 100.degree. C. under a flow of nitrogen gas. After 1
 hour the reaction is cooled to room temperature. The reaction mixture is
 carefully added to a vigorously stirred mixture of dichloromethane and
 saturated aqueous bicarbonate. The layers are separated and the basic
 aqueous layer is extracted with three additional portions of
 dichloromethane. The combined organic layers are washed with water, brine,
 dried over sodium sulfate and concentrated under reduced pressure. The
 residue is chromatographed on silica eluting with 2% to 6% methanol in
 dichloromethane to afford 0.24 g of ethyl
 6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran4-yl-1,4-dihydro-3-quin
 olinecarboxylate as a tan solid.
 A flask containing ethyl
 6-(4-morpholinylmethyl)-4-oxo-1-tetrahydro-2H-pyran-4-yl-1,4-dihydro-3-qui
 nolinecarboxylate (0.21 g) is treated with 4-chlorobenzylamine (2.0 mL).
 The reaction is tightly capped and heated to 190.degree. C. for 1 hour.
 The reaction is cooled to room temperature, adsorbed onto silica and
 chromatographed on silica eluting with 2% to 6% methanol in
 dichloromethane and then by recrystallization from ethyl acetate to afford
 0.14 g of the title compound.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.8, 8.3, 8.1, 7.8, 7.4, 5.0, 4.5,
 4.0, 3.7, 3.6, 3.5, 2.4, 2.0; MS (ESI+) m/z 496; Anal. Found: C, 65.20; H,
 6.17; N, 8.23.
 Example 109
 N-(4-Chlorobenzyl)-1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo
 -1,4-dihydro-3-quinolinecarboxamide (formula W-5; Z=NMe)
 ##STR177##
 A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22
 (0.48 g) is treated with tetrhydrofuran (10 mL) and N-methyl-4-piperidone
 (0.37 mL) under an argon atmosphere. The solution is treated with acetic
 acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After
 stirring overnight, the mixture is partitioned between diethyl ether and
 saturated aqueous sodium bicarbonate containing sodium hyroxide. The
 aqueous is back-extracted with additional portions of dichloromethane. The
 combined organic layer is washed with brine, dried over sodium sulfate,
 and concentrated under reduced pressure. The residue is purified by flash
 column chromatography on silica gel eluting with 2% to 5% methanol
 saturated with ammonia in dichloromethane to afford 0.52 g of
 1-methyl-N-[4-(4-morpholinylmethyl)phenyl]-4-piperidinamine as a tan
 solid.
 A flask containing
 1-methyl-N-[4-(4morpholinylmethyl)phenyl]-4-piperidinamine (0.52 g) is
 treated with diethyl ethoxymethylenemalonate (0.55 mL). The flask is
 tightly capped and heated to 150.degree. C. for 1 hour. The reaction is
 cooled to room temperature, treated with diethyl ethoxymethylenemalonate
 (0.55 mL) and heated to 180.degree. C. for 2 hours. The reaction is cooled
 to room temperature and flash column chromatographed on silica eluting
 with 5% to 20% methanol in dichloromethane. The product-containing
 fractions are evaporated to give 0.75 g of diethyl
 2-{[(1-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)anilino]methylene}malo
 nate as tan solid.
 A flask containing diethyl
 2-{[(1-methyl-4-piperidinyl)-4-(4-morpholinylmethyl)anilino]methylene}malo
 nate (0.36 g) is treated with polyphosphoric acid (1.8 g). The reaction
 mixture is heated to 130.degree. C. under a flow of nitrogen gas. After 4
 hours the reaction is cooled to room temperature. The reaction mixture is
 carefully added to a vigorously stirred mixture of dichloromethane and
 saturated aqueous bicarbonate. The layers are separated and the basic
 aqueous layer is extracted with three additional portions of
 dichloromethane. The combined organic layers are washed with brine, dried
 over sodium sulfate and concentrated under reduced pressure to afford 0.32
 g of crude ethyl
 1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-qui
 nolinecarboxylate as a tan solid.
 A flask containing crude ethyl
 1-(1-methyl-4-piperidinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-qui
 nolinecarboxylate (0.31 g) is treated with 4-chlorobenzylarnine (2.0 mL).
 The reaction is tightly capped and heated to 165.degree. C. overnight. The
 reaction is cooled to room temperature, adsorbed onto silica and
 chromatographed on silica eluting with 2% to 10% methanol saturated with
 ammonia in dichloromethane and then by recrystallization from ethyl
 acetate-hexanes to afford 0.11 g of the title compound.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.8, 8.3, 8.0, 7.8, 7.4, 4.8, 4.5,
 3.6, 3.5, 2.9, 2.4, 2.2, 2.0; MS (ESI+) m/z 509; Anal. Found: C, 65.71; H,
 6.56; N, 10.85.
 Example 110
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dihy
 dro-3-quinolinecarboxamide (formula W-5; Z=NH)
 ##STR178##
 A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22
 (0.48 g) is treated with tetrahydrofuran (10 mL) and tert-butyl
 4-oxo-1-piperidinecarboxylate (0.60 gm) under an argon atmosphere. The
 solution is treated with acetic acid (0.20 mL) followed by sodium
 triacetoxyborohydride (0.80 g). After stirring 3 days, the mixture is
 concentrated under reduced pressure. The residue is partitioned between
 dichloromethane and dilute aqueous sodium hydroxide. The aqueous is
 back-extracted with additional portions of dichloromethane. The combined
 organic layer is washed with brine, dried over sodium sulfate, and
 concentrated under reduced pressure. The residue is flash column
 chromatographed on silica gel eluting with 2% to 6% methanol in
 dichloromethane to afford 0.96 g of tert-butyl
 4-[4-(4-morpholinylmethyl)anilino]-1-piperidinecarboxylate as a tan solid.
 A flask containing tert-butyl
 4-[4-(4-morpholinylmethyl)anilino]-1-piperidinecarboxylate (0.94 g) is
 treated with diethyl ethoxymethylenemalonate (1.0 mL). The flask is
 tightly capped and heated to 150.degree. C. for 2 hours. The reaction is
 then heated to 175.degree. C. for 2 hours. The reaction is cooled to room
 temperature and flash column chromatographed on silica eluting with 2% to
 5% methanol in dichloromethane. The product-containing fractions are
 evaporated to give 0.78 g of diethyl
 2-{[1-(tert-butoxycarbonyl)-4-piperidinyl]-4-(4-morpholinylmethyl)anilino]
 methylene}malonate as tan solid.
 A flask containing a solution of diethyl
 2-{[[1-(tert-butoxycarbonyl-4-piperidinyl]-4-(4-morpholinylmethyl)anilino]
 methylene}malonate (0.36 g) in toluene (2 mL) is treated with
 polyphosphoric acid (2.1 g). The reaction mixture is heated to 120.degree.
 C. under a flow of nitrogen gas. After 1 hour the reaction is cooled to
 room temperature. The reaction mixture is carefully added to a vigorously
 stirred mixture of dichloromethane and saturated aqueous bicarbonate. The
 layers are separated and the basic aqueous layer is extracted with three
 additional portions of dichloromethane. The combined organic layers are
 washed with brine, dried over sodium sulfate and concentrated under
 reduced pressure to afford 0.14 g of crude ethyl
 6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dihydro-3-quinolinecar
 boxylate as a tan oil.
 A flask containing crude ethyl
 6-(4-morpholinylmethyl)-4-oxo-1-(4-piperidinyl)-1,4-dihydro-3-quinolinecar
 boxylate (0.14 g) is treated with 4-chlorobenzylamine (1.0 mL). The
 reaction is tightly capped and heated to 180.degree. C. for 2 hours. The
 reaction is cooled to room temperature and flash column chromatographed on
 silica eluting with 2% to 10% methanol saturated with ammonia in
 dichloromethane and then by recrystallization from acetonitrile to afford
 0.10 g of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.4, 8.8, 8.3, 8.1, 7.8, 7.4, 4.9, 4.5,
 3.6, 3.5, 3.1, 2.8, 2.4, 2.0, 1.8; MS (ESI+) m/z 495; Anal. Found: C,
 65.11; H, 6.38; N, 11.23.
 Example 111
 N-(4-Chlorobenzyl)-1-(1,1-dioxohexahydro-thiopyran-4-yl)-6-(4-morpholinylme
 thyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (formula W-5; Z=SO.sub.2)
 ##STR179##
 A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22
 (0.48 g) is treated with tetrahydrofuran (10 mL) and
 terahydrothiopyran-4-one (0.35 gm) under an argon atmosphere. The solution
 is treated with acetic acid (0.20 mL) followed by sodium
 triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is
 concentrated under reduced pressure. The residue is partitioned between
 dichloromethane and dilute aqueous sodium hydroxide. The aqueous is
 back-extracted with dichloromethane. The combined organic layers are
 washed with brine, dried over sodium sulfate, and concentrated under
 reduced pressure. The residue is purified by flash column chromatography
 on silica eluting with 2% to 6% methanol in dichloromethane and then by
 recrystallization from cyclohexane to afford 0.53 g of
 N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine as a tan
 solid.
 A flask containing
 N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine (0.44 g)
 is treated with diethyl ethoxymethylenemalonate (0.35 mL). The flask is
 tightly capped and heated to 160.degree. C. for 2 hours. The reaction is
 cooled to room temperature, treated with diethyl ethoxymethylenemalonate
 (0.35 mL) and pyridine (0.35 mL) and heated to 150.degree. C. for 1 hour
 in a tightly sealed flask. The reaction is cooled to room temperature and
 azeotroped under reduced pressure with toluene (3.times.). The residue is
 flash column chromatographed on silica gel eluting with ethyl acetate. The
 product-containing fractions are evaporated to give 0.59 g of diethyl
 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-thiopyran-4-yl)anilino]methylene
 }malonate as a tan solid.
 A solution of diethyl
 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-thiopyran-4-yl)anilino]methylene
 }malonate (0.30 gm) in dichloromethane (5 mL) at 0.degree. C. is treated
 with p-toluenesulfonic acid hydrate (0.57 gm) followed by
 m-chloroperoxybenzoic acid (.about.85 %) (0.32 gm). The mixture is stirred
 for 3 hr. The reaction mixture is diluted with dichloromethane, washed
 with saturated aqueous sodium sulfite, saturated aqueous sodium
 bicarbonate, brine, dried (Na.sub.2 SO.sub.4) and concentrated under
 reduced pressure. The crude product is purified by flash column
 chromatography on silica gel eluting with 2% to 6% methanol in
 dichloromethane to afford 0.12 gm of
 4-[4-(4-morpholinylmethyl)anilino]tetrahydrothiopyran-1,1(2H)-dione as a
 white solid.
 A flask containing
 4-[4-(4-morpholinylmethyl)anilino]tetrahydro-thiopyran-1,1(2H)-dione (0.11
 g) is treated with diethyl ethoxymethylenemalonate (0.15 mL). The flask is
 tightly capped and heated to 155.degree. C. for 2 hours. The reaction is
 cooled to room temperature, treated with diethyl ethoxymethylenemalonate
 (0.15 mL) and pyridine (0.15 mL) and heated to 120.degree. C. for 2 hour
 in a tightly sealed flask. The reaction is cooled to room temperature and
 azeotroped under reduced pressure with toluene (3.times.). The residue is
 treated with diethyl ethoxymethylenemalonate (0.5 mL) and heated to
 190.degree. C. After 2 hours, the reaction is cooled to room temperature
 and flash column chromatographed on silica gel eluting with 2% to 6%
 methanol in dichloromethane. The product-containing fractions are
 evaporated to give 0.11 g of diethyl
 2-{[(1,1-dioxohexahydrothiopyran-4-yl)-4-(4-morpholinylmethyl)anilino]meth
 ylene}malonate as a tan solid.
 A flask containing a solution of diethyl
 2-{[(1,1-dioxohexahydro-thiopyran-4-yl)-4-(4-morpholinylmethyl)anilino]met
 hylene}malonate (0.11 g) in toluene (2 mL) is treated with polyphosphoric
 acid (1.5 g). The reaction mixture is heated to 120.degree. C. under a
 flow of nitrogen gas. After 2 hours the reaction is cooled to room
 temperature. The reaction mixture is carefully added to a vigorously
 stirred mixture of dichloromethane and saturated aqueous bicarbonate. The
 layers are separated and the basic aqueous layer is extracted with two
 additional portions of dichloromethane. The combined organic layers are
 washed with brine, dried over sodium sulfate and concentrated under
 reduced pressure. The residue is purified by flash column chromatography
 on silica gel eluting with 2% to 10% methanol in dichloromethane to afford
 0.06 g of crude ethyl
 1-(1,1-dioxohexahydro-thiopyran-4-yl)-6-(4-morpholinylmethyl)-4-oxo-1,4-di
 hydro-3-quinolinecarboxylate as an off-white solid.
 A flask containing ethyl
 1-(1,1-dioxohexahydro-thiopyran-4-yl)-6-(4-morpholinylmethyl)-4-oxo-1,4-di
 hydro-3-quinolinecarboxylate (0.06 g) is treated with 4-chlorobenzylamine
 (0.6 mL). The reaction is tightly capped and heated to 190.degree. C. for
 2 hours. The reaction is cooled to room temperature, adsorbed onto silica
 gel, flash column chromatographed on silica eluting with 2% to 10%
 methanol in dichloromethane. The product-containing fractions are
 concentrated under reduced pressure and triturated with diethyl ether. The
 resulting residue is dissolved in a small amount of dichloromethane and
 added dropwise to stirring diethyl ether (40 mL). The resulting
 precipitant is collected by suction filtration to afford 0.05 g of the
 title compound as an off-white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 8.7, 8.3, 8.0, 7.8, 7.4, 5.3, 4.5,
 3.6, 3.5, 3.3, 2.4; MS (ESI+) m/z 544; HRMS (FAB) found 544.1665 for
 C.sub.27 H.sub.30 ClN.sub.3 O.sub.5 S+H.
 Preparation 53
 4-(3-bromo-4-fluorobenzyl)morpholine
 Morpholine (0.96 mL) and acetic acid (0.57 mL) are added to a solution of
 3-bromo-4-fluorobenzaldehyde (2.03 g) in dichloroethane (40 mL). Sodium
 triacetoxyborohydride (3.18 g) is added in portions over an hour, and the
 reaction is stirred at room temperature for 18 hours. The reaction is
 quenched with a 1 N solution of NaOH (10 mL) and diluted with CH.sub.2
 Cl.sub.2 (100 mL). The organic layer is washed with 1 N NaOH (3.times.35
 mL). The aqueous layers are back-extracted with CH.sub.2 Cl.sub.2 (20 mL).
 The combined organic layers are extracted with 0.1 N HCl (6.times.25 mL).
 The combined aqueous layers are basified (pH=12) with 2 N NaOH, and the
 product is extracted with CH.sub.2 Cl.sub.2 (6.times.25 mL). The combined
 organic layers are washed with brine (20 mL) and dried (MgSO.sub.4). The
 solution is concentrated in vacuo to afford 2.23 g (82%) of the title
 compound as a clear, colorless oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.) 7.62, 7.35, 7.32, 3.57, 3.45, 2.34;
 HRMS (FAB) calcd for C.sub.11 H.sub.13 BrFNO+H 274.0243, found 274.0243.
 Anal. Found for C.sub.11 H.sub.13 BrFNO: C, 48.15; H, 4.83; N, 5.10.
 Preparation 54
 1-[2-Fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone
 A solution of 4-(3-bromo-4-fluorobenzyl)morpholine (35.5 g) of Preparation
 No. 53 in THF (400 mL) is cooled to -75.degree. C., and n-butyllithium is
 added via addition funnel maintaining the temperature below -65.degree. C.
 A solution of N-methyl-N-methoxyacetamide (16.0 g, prepared as described
 in Tetrahedron Lett. 1983, 24, 1857) in THF (50 mL) is added via addition
 funnel, again maintaining temperature below -65.degree. C. The reaction is
 stirred at -75.degree. C. for 1 hour and then is allowed to warm to room
 temperature overnight. The reaction mixture is quenched with 1 N HCl (150
 mL) and diluted with ethyl acetate (400 mL). The layers are separated, and
 the aqueous layer is basified with sat. sodium bicarbonate solution. The
 aqueous layer is extracted with ethyl acetate (2.times.100 mL). The
 combined organic layers are washed with sat. sodium bicarbonate
 (2.times.100 mL) and brine (50 mL). The aqueous layers are back-extracted
 with ethyl acetate (100 mL). The combined organic layers are dried
 (Na.sub.2 SO.sub.4) and concentrated in vacuo to a yellow oil. The oil is
 purified by fractional distillation at 135-140.degree. C./0.3 torr to
 afford 19.7 g (64%) of the title compound as a clear, colorless oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.7.72, 7.58, 7.31, 3.56, 3.48, 2.58,
 2.34; IR (liq.) 2421, 2259, 1996, 1979, 1919, 1688, 1612, 1492, 1417,
 1361, 1291, 1281, 1212, 1118, 865 cm.sup.-1 ; MS (ESI+) m/z 238
 (M+H).sup.+. Anal. Found for C.sub.13 H.sub.16 FNO.sub.2 : C, 65.43; H,
 6.75; N, 5.84.
 Preparation 55
 Ethyl 3-[2-Fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate
 A solution of 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1-ethanone (19.6
 g) of Preparation No. 54 in diethyl carbonate (150 mL) is cooled to
 0.degree. C., and sodium hydride (60% dispersion, 6.6 g) is added slowly
 to the reaction mixture. The reaction is stirred at 0.degree. C. for 3
 hours, and then is allowed to warm to room temperature overnight. The
 reaction mixture is quenched with acetic acid (10 mL), diluted with water
 (200 mL) and then basified with sat. sodium carbonate. The solution is
 then extracted with ether (3.times.200 mL). The combined organic layers
 are washed with sat. sodium bicarbonate (100 mL) and brine (50 mL). The
 combined aqueous layers are back-extracted with ether (50 mL). The
 combined organic layers are then dried (Na.sub.2 SO.sub.4) and
 concentrated in vacuo to an orange oil. The crude product is purified in 2
 batches by column chromatography (heptane/IPA, 8/1; 4/1) to afford 20.2 g
 (79%) of the title compound as a yellow oil.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.7.78, 7.62, 7.32, 4.21, 4.05, 3.57,
 3.50, 2.34, 1.16; IR (liq.) 2419, 2261, 1996, 1979, 1744, 1689, 1626,
 1611, 1493, 1331, 1260, 1215, 1147, 1117, 865, cm.sup.-1 ; MS (ESI+) m/z
 310 (M+H).sup.+ ; Anal. Calcd for C.sub.16 H.sub.20 FNO.sub.4 : C, 62.12;
 H, 6.52;N, 4.53. Found: C, 61.96; H, 6.67; N, 4.44.
 Preparation 56
 Ethyl
 1-(4-Morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecar
 boxylate
 ##STR180##
 Ethyl 3-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-3-oxopropanoate (10.0 g)
 of Preparation No. 55, triethylorthoformate (10.8 mL) and acetic anhydride
 (10.7 mL) are combined in a flask equipped with a Dean-Stark trap and
 condenser. The reaction is heated to 150.degree. C. for 3.5 hours. The
 excess acetic anhydride and triethylorthoformate are distilled off at
 100.degree. C. and 0.2 torr leaving a burgundy oil containing a mixture of
 E- and Z-isomers of
 ethyl-3-ethoxy-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-2-propenoate.
 This crude mixture is dissolved in ethanol (50 mL), and 4-aminomorpholine
 (4.7 mL) is added. The reaction mixture is stirred at room temperature for
 2.5 hours and concentrated in vacuo. The resulting burgundy oil is
 purified in two batches by column chromatography (MeOH/CH.sub.2 Cl.sub.2 :
 1%, 2%; 5%) to give ethyl (E)- and
 (Z)-2-[2-fluoro-5-(4-morpholinylmethyl)benzoyl]-3-(4-morpholinylamino)-2-p
 ropenoate as a yellow oil.
 The crude enamine is dissolved in THF, and sodium hydride is slowly added
 to the solution. After heating the mixture to 70.degree. C. for 2 hours,
 the reaction is quenched with water (5 mL) and concentrated in vacuo to a
 burgundy slurry. More water (100 mL) is added, and the remaining THF
 removed in vacuo. The resulting yellow precipitate suspended in an aqueous
 solution is filtered on a fritted funnel and washed twice with water and
 once with ether to afford 5.9 g (55%) of the title compound as a powdery,
 yellow solid.
 Physical characteristics are as follows:
 Mp 209-211.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.8.87, 8.20, 8.11,
 7.74, 4.23, 3.97, 3.78, 3.59, 3.57, 3.03, 2.37, 1.30; MS (ESI+) m/z 402
 (M+H).sup.+ ; Anal. Found for C.sub.21 H.sub.27 N.sub.3 O.sub.5 : C,
 62.83; H, 6.75; N, 10.44.
 Example 112
 N-(4-Chlorobenzyl)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihy
 dro-3-quinolinecarboxamide
 ##STR181##
 Ethyl
 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecar
 boxylate (5.0 g) from Preparation No. 56 and 4-chlorobenzylamine (7.6 mL)
 are combined and heated to 190.degree. C. for 7 hours. After cooling to
 room temperature, the mixture solidifies. The solid is triturated with a
 10:1 mixture of EtOAc/MTBE (30 mL) and filtered on a frit. The crude solid
 is triturated again, this time with a hot mixture of 10:1 EtOAc/MTBE (110
 mL). The suspension is cooled to room temperature and filtered on a frit
 to afford 4.9 g (79%) of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 195-196.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.30, 9.14,
 8.28, 8.20, 7.81, 7.40, 4.56, 3.98, 3.80, 3.62, 3.57, 3.28, 3.08, 2.37; IR
 (mull) 2286, 1969, 1952, 1926, 1652, 1599, 1585, 1524, 1489, 1352, 1283,
 1111, 862, 808, 724 cm.sup.-1 ; MS (ESI+) for m/z 497 (M+H).sup.+. Anal.
 Found for C.sub.26 H.sub.29 ClN.sub.4 O.sub.4 : C, 62.69; H, 5.94; N,
 11.22; Cl, 7.11.
 Example 113
 N-(4Chlorobenzyl)-1-(4methyl-1-piperazinyl)-6-(4-morpholinylmethyl)-4-oxo-1
 ,4-dihydro-3-quinolinecarboxamide
 ##STR182##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No. 56 employing 1-amino-4-methylpiperazine and
 Example No. 112. The crude product is purified by recrystallization in
 EtOH to afford 0.87g of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 135-139.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.32, 8.97,
 8.18, 7.80, 7.36, 4.54, 3.59, 3.55, 3.21, 3.05, 2.88, 2.36, 2.27; IR
 (drift) 2796, 2309, 1934, 1659, 1597, 1568, 1544, 1489, 1352, 1323, 1289,
 1115, 1008, 865, 809 cm.sup.-1 ; MS (ESI+) m/z 510 (M+H).sup.+. HRMS (FAB)
 calcd for C.sub.27 H.sub.32 CLN.sub.5 O.sub.3 +H 510.2272, found 510.2290.
 Anal. Found for C.sub.27 H.sub.32 ClN.sub.5 O.sub.3 : C, 63.59; H, 6.40;
 N, 13.33; Cl, 6.86.
 Example 114
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(1-piperidinyl)-1,4-dihy
 dro-3-quinolinecarboxamide
 ##STR183##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No. 56 employing 1-aminopiperadine and Example
 No. 112. The crude product is purified by recrystallization in
 acetonitrile to afford 0.73 g of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 161-164.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.38, 9.07,
 8.22, 8.20, 7.81, 7.40, 4.56, 3.61, 3.57, 3.10, 2.37, 1.81, 1.40; IR
 (drift) 2942, 2853, 1657, 1597, 1574, 1549, 1531, 1488, 1354, 1326, 1291,
 1115, 807, 796, 680 cm.sup.-1 ; MS (ESI+) for m/z 495 (M+H).sup.+ ; Anal.
 Calcd for C.sub.27 H.sub.31 ClN.sub.4 O.sub.3 : C, 65.51; H, 6.31; N,
 11.32; Cl, 7.16. Found: C, 65.50; H, 6.23; N, 11.40; Cl,7.19.
 Example 115
 N-(4-Chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-(1-pyrrolidinyl)-1,4-dih
 ydro-3-quinolinecarboxamide
 ##STR184##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No. 56 employing 1-amiinopyrrolidine and Example
 No. 112. The crude product is purified by recrystallization in methanol to
 afford 0.39 g of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 211-214.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.) 10.35, 9.08,
 8.16, 8.13, 7.78, 7.36, 4.54, 3.59, 3.55, 3.14, 2.35, 2.05, 1.93; IR
 (drift) 2857, 2805, 1966, 1944, 1655, 1600, 1576, 1545, 1488, 1361, 1324,
 1134, 1113, 863, 809 cm.sup.-1 ; MS (ESI+) for m/z 481 (M+H).sup.+ ; Anal.
 Found for C.sub.26 H.sub.29 ClN.sub.4 O.sub.3 : C, 64.57; H, 6.13; N,
 11.53; Cl, 7.19.
 Example 116
 N-(4-Chlorobenzyl)-1-[(2R)-2-(methoxymethyl)pyrrolidinyl]-6-(4-morpholinylm
 ethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR185##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No. 56 employing
 (R)-(+)-1-amino-2-(methoxymethyl)pyrrolidine and Example No. 112. The
 crude product is purified by column chromatography (MeOH/CH.sub.2 Cl.sub.2
 : 0.5%, 1.5%, 2.5%) and trituration with ether to afford 0.79 g of the
 title compound as a white solid.
 Physical characteristics are as follows:
 MP 98-100.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.) 10.35, 9.15,
 8.22, 8.18, 7.77, 7.39, 4.56, 3.61, 3.57, 3.39, 3.25, 2.89, 2.37, 2.16,
 2.01, 1.70; IR (drift) 2350, 1663, 1597, 1580, 1549, 1488, 1351, 1325,
 1203, 1116, 1093, 867, 831, 807, 800 cm.sup.-1 ; HRMS (FAB) calcd for
 C.sub.28 H.sub.33 ClN.sub.4 O.sub.4 +H 525.2268, found 525.2275.
 Example 117
 N-(4-Chlorobenzyl)-1-(dimethylamino)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihy
 dro-3-quinolinecarboxamide
 ##STR186##
 The title compound is prepared according to procedures analogous to those
 described in Preparation No. 56 employing 1,1-dimethylhydrazine and
 Example No. 112. The crude product is purified by recrystallization in
 methanol to afford 0.2 g of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 170-171.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.38, 9.10,
 8.20, 8.14, 7.82, 7.39, 4.57, 3.61, 3.57, 2.92, 2.37; IR (drift) 1962,
 1932, 1661, 1597, 1551, 1489, 1462, 1360, 1352, 1323, 1113, 913, 866, 811,
 804 cm.sup.-1 ; MS (ESI+) for m/z 455 (M+H).sup.+ ; HRMS (FAB) calcd for
 C.sub.24 H.sub.27 ClN.sub.4 O.sub.3 +H 455.1850, found 455.1857.
 Preparation 57
 1-Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR187##
 A suspension of N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide
 (2.0 g) of Preparation No. 4 and of potassium carbonate (2.0 g) in DMF (40
 mL) is stirred at room temperature for 5 hrs and then treated with of
 O-(mesitylsulfonyl)hydroxylamine (1.5 g). After 24 hrs, the solvent is
 evaporated under reduced pressure and the residue is diluted with
 water(150 mL). The resulting solid is filtered and washed with water
 (3.times.) and ether (2.times.). Recrystallization from hot acetic
 acid/water affords 1.35 g of the title compound as a tan solid.
 Physical characteristics are as follows:
 Mp 230-235.degree. C. (dec). .sup.1 H NMR (DMSO-d.sub.6) .delta.8.81, 8.54,
 8.13, 7.89, 7.40-7.32, 6.69, 4.54.
 Example 118
 1-Amino-N-(4-chlorobenzyl)-6(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-quin
 olinecarboxamide
 ##STR188##
 1-Amino-N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 (0.25 g) from Preparation No. 57, copper (I) iodide (32 mg), and
 bis(triphenylphosphine)palladium (II) chloride (19 mg) are suspended in
 diethylamine (8 mL). Propargyl alcohol (39 .mu.L) is added and the mixture
 is allowed to stir at room temperature for 16 h. The mixture is diluted
 with ethanol and then concentrated in vacuo. The crude solid is triturated
 with dichloromethane and recrystallized in acetic acid to affording 76 mg
 of the title compound as a beige solid.
 Physical properties are as follows:
 Mp 230-235.degree. C. (dec); .sup.1 H NMR (DMSO-d.sub.6) .delta.10.25,
 8.79, 8.22, 8.07, 7.85, 7.35, 6.70, 5.39, 4.52, 4.32; HRMS (FAB) calcd for
 C.sub.20 H.sub.16 ClN.sub.3 O.sub.3 +H 382.0958, found 382.0952;
 Example 119
 1-Amino-N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydro-3-quinolin
 ecarboxamide
 ##STR189##
 1-Amino-N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydro-3-qui
 nolinecarboxamide (0.21 g) from Example No. 118 is dissolved in a 1:1
 mixture of methanol/DMF. To the solution is added 5% platinum on carbon
 (0.11 g) and acetic acid (0.5 mL). The reaction is shaken under a hydrogen
 atmosphere (35 psi) for 4.5 hours. The catalyst is removed by filtration
 through Celite. The filtrate is concentrated in vacuo, and the resulting
 white solid is triturated with dichloromethane. The crude product is then
 purified by column chromatography (MeOH/CH.sub.2 Cl.sub.2 : 3%, 5%)
 yielding 0.10 g of the title compound as a white solid.
 Physical properties are as follows:
 Mp 187-188.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.44, 8.77,
 8.06, 7.98, 7.71, 7.36, 6.67, 4.54, 4.50, 3.40, 2.77, 1.74; IR (drift)
 3272, 3183, 2941, 1916, 1644, 1598, 1559, 1491, 1433, 1242, 1093, 842,
 805, 740, 724 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.20 H.sub.20 ClN.sub.3
 O.sub.3 +H 386.1271, found 386.1282.
 Preparation 58
 Butyl 1-(Dimethylamino)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 ##STR190##
 A solution of of the TBDMS ketene acetal of butyl acetate (8.1 g) and
 triethylamine (5.6 mL) in THF (20 mL) is added in one portion to a
 solution of 2-chloro-5-iodobenzoyl chloride in THF (40 mL). The mixture is
 stirred 24 h and then the solvent was evaporated in a stream of nitrogen.
 The residue is diluted with ether (30 mL) and filtered. The resulting
 filtrate is concentrated to afford 8.2 g of an oil which is dissolved in
 THF (100 mL) and treated with of 3 N hydrochloric acid (10 mL). After 5 h
 the volume of this mixture is reduced by two thirds by evaporation at
 reduced pressure. The residue is diluted with dichloromethane (100 mL).
 The phases are separated and the organic layer dried over MgSO.sub.4. The
 mixture is filtered and dissolved in toluene. The solvent was evaporated
 and the process was repeated until TBDMS is no longer detectable in the
 mixture by .sup.1 H NMR. The residual oil is purified by column
 chromatography (gradient 30-45% dichloromethane in hexanes) to afford 7.9
 g of butyl 3-(2-chloro-5-iodophenyl)-3-oxopropanoate as an orange oil.
 A mixture of the above ketoester (3.3 g) and ethyl orthoformate (2.2 mL) in
 acetic anhydride (2 mL) is refluxed for 2 h. The excess triethyl
 orthoformate and acetic anhydride are removed by evaporation at reduced
 pressure followed by concentration from xylene (75 mL) to afford butyl
 2-(2-chloro-5-iodobenzoyl)-3-ethoxy-2-propenoate as a crude oil.
 Dimethylhydrazine (1.1 mL) is added to a solution of the above crude enol
 ether (4.0 g) in ethanol (10 mL). The mixture is allowed to stirr for 4 h.
 The reaction mixture is then concentrated to afford 4 g of butyl
 2-(2-chloro-5-iodobenzoyl)-3-(2,2-dimethylhydrazino)-2-propenoate as an
 amber oil.
 The above hydrazide is dissolved in dioxane (50 mL) and treated with sodium
 hydride (0.6 g, 60% in mineral oil). The mixture is refluxed 2 hours,
 cooled to room temperature, and is filtered washing with absolute ethanol
 (2.times.10 mL). The combined filtrate and washes are briefly refluxed
 with 5 g of DARCO, and the solution is filtered through Celite. The
 solvent was evaporated at reduced pressure, and the residue is purified by
 column chromatography (gradient 5-15% ethyl acetate in dichloromethane) to
 afford 1.2 g of the title compound as a white solid.
 Physical characteristics are as follows:
 .sup.1 H NMR (DMSO-d.sub.6) .delta.8.87, 8.43, 8.06, 7.86, 4.18, 2.85,
 1.70-1.55, 1.50-1.30, 0.91; MS (ESI+) m/z 415 (M+H.sup.+).
 Example 120
 N-(4-Chlorobenzyl)-1-(dimethylamino)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dih
 ydro-3-quinolinecarboxamide
 ##STR191##
 Butyl 1-(dimethylamino)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 (0.50 g) from Preparation No. 58 and 4-chlorobenzylamine (0.29 mL) are
 heated to 170.degree. C. for 7 hours. The reaction is cooled to rt, and
 the crude solid is recrystallized in acetic acid yielding 0.54 g of the
 amide. The resulting amide (0.25 g), copper (I) iodide (30 mg), and
 bis(triphenylphosphine)palladium (II) chloride (18 mg) are suspended in
 diethylamine (8 mL). Propargyl alcohol (36 .mu.L) is added and the mixture
 is allowed to stir at room temperature for 16 h. The mixture is diluted
 with ethanol and then concentrated in vacuo. The crude solid is triturated
 with dichloromethane and purified by column chromatography (2%
 MeOH/CH.sub.2 Cl.sub.2), affording 9 mg of the title compound as a beige
 solid.
 Physical properties are as follows:
 Mp 210-214.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.52, 9.34,
 8.50, 8.39, 8.05, 7.62, 5.64, 4.83, 4.63, 3.19; IR (drift) 2225, 1928,
 1912, 1646, 1592, 1572, 1549, 1486, 1462, 1357, 1346, 1032, 1026, 836, 806
 cm.sup.-1 ; HRMS (FAB) calcd for C.sub.22 H.sub.20 ClN.sub.3 O.sub.3 +H
 410.1271, found 410.1283.
 Preparation 59
 Ethyl 1-(Dimethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 ##STR192##
 Ethyl 3-(2-fluorophenyl)-3-oxopropanoate (15.0 g) is refluxed with
 triethylorthoformate (17.8 mL) in acetic anhydride (16.8 mL) for 4 hrs.
 The reaction mixture is diluted with xylenes (75 mL) and is concentrated
 under reduced pressure to give 19.1 g of an amber oil. A solution of this
 oil (4.0 g) in ethanol (10 mL) is treated with 1,1-dimethylhydrazine (1.1
 mL) and stirred for 10 min. The reaction mixture is concentrated and
 agitated with 4:1 hexanes/ether. The solvent is decanted, and the final
 traces of solvent are removed at high vacuum to leave an amber oil of
 ethyl 3-(2,2-dimethylhydrazino)-2-(2-fluorobenzoyl)-2-propenoate.
 The resulting hydrazide (4.0 g) is dissolved in dioxane (20 mL) and treated
 with 60% sodium hydride in oil (0.60 g). The mixture is refluxed under
 nitrogen for 2 hrs and then cooled to 25.degree. C. The reaction mixture
 is diluted with ethanol (10 mL) and water (75 mL) and is then extracted
 with ethyl acetate (3.times.75 mL). The organic phases are combined,
 washed with brine, dried with calcium chloride and filtered. The volume of
 the filtrate is reduced by evaporation at reduced pressure almost to
 dryness, and the residue is diluted with diethyl ether (150 mL). The solid
 is filtered and washed with diethyl ether (2.times.20 mL) to afford 0.75 g
 of ethyl 1-(dimethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate as an
 orange solid.
 Physical characteristics are as follows:
 Mp 119-120.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.8.89, 8.19, 8.09,
 7.79, 7.47, 4.24, 3.30, 1.29; MS (ESI+) m/z 283 (M+Na.sup.+); HRMS (FAB):
 calcd for C.sub.14 H.sub.17 N.sub.2 O.sub.3 +H.sup.+ : 261.1239. Found:
 261.1234.
 Example 121
 N-(4-Chlorobenzyl)-1-(dimethylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxami
 de
 ##STR193##
 Ethyl 1-(dimethylamino-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.21 g) of
 Preparation No. 59 and 4-chlorobenzylamine (1.2 mL) are heated to
 180.degree. C. for 10 hrs under nitrogen. The product is precipitated from
 the cooled reaction mixture by dilution with a mixture of toluene and
 hexanes. The crude product is then recrystallized from aqueous acetic acid
 to give 0.030 g of the title compound.
 Physical characteristics are as follows:
 Mp 170-172.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.1, 8.3,
 8.2, 7.9, 7.5, 7.4, 4.6, 2.9; MS (FAB)(M+H).sup.+ : calcd 356.1165, found
 356.1173.
 Preparation 60
 Ethyl 1-(Allyloxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate
 ##STR194##
 O-Allylhydroxylamine hydrate (1.52 g) is dissolved in ethanol (50 mL) and
 treated with 3 N aqueous sodium hydroxide until a phenolphthalien endpoint
 is achieved. Ethyl 3-ethoxy-2-(2-fluorobenzoyl)-2-propenoate (3.7 g,
 prepared from ethyl 3-(2-fluorophenyl)-3-oxopropanoate as in Preparation
 No. 59) is added, and the mixture is stirred for 3 h. The mixture is
 filtered and the resulting filtrate is concentrated. The crude enamine
 intemediate is treated with sodium hydride in refluxing dioxane according
 to the procedures analogous to those described in Preparation No. 58. The
 crude product is is purified by column chromatography (30-40% ethyl
 acetate in dichloromethane). Fractions containing the major product are
 combined and concentrated at reduced pressure. The residue is dissolved in
 a minimum volume of ethyl acetate and stored at -15.degree. C. overnight
 followed by the addition of ether (20 mL) and cyclohexane (20 mL). The
 solid is collected by filtration and washed with two portions of ether to
 afford 1.0 g of the title compound as a pale yellow solid.
 Physical characteristics are as follows:
 Mp 98-100.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta.8.89, 8.20, 7.85,
 7.76, 7.51, 6.3-6.1, 5.50, 5.42, 4.88, 4.22, 1.28; MS (ESI+) m/z 296 (M
 +H.sup.+). Anal. Found for C.sub.15 H.sub.15 NO.sub.4 : C, 65.80; H, 5.64;
 N, 5.09.
 Example 122
 1-(Allyloxy)-N-(4-chlorobenzyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR195##
 Ethyl 1-(allyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.5 g) of
 Preparation No. 60 is treated with sodium hydroxide (3 N, 2 mL) in ethanol
 (2 mL) and stirred for 30 min. The reaction mixture is neutralized with
 hydrochloric acid and filtered, washing the filtrant with water (3.times.)
 and ether (1.times.). The crude carboxylic acid is dried in a stream of
 air to give 0.31 g of a white powder which is suspended in DMF (15 mL) and
 treated with 1,1'-carbonyldiimidazole (0.46 g). The reaction mixture is
 heated to 65.degree. C. for 5 hrs, cooled and treated with H.sub.2 O (0.03
 mL). After 5 minutes, 4-chiorobenzylamine (0.19 mL) is added. The mixture
 is stirred for 3 days, diluted with water (15 mL) and filtered to afforded
 0.19 g of the title compound as a white solid.
 Physical characteristics are as follows:
 Mp 113-114.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.3, 9.0, 8.3,
 7.9, 7.6, 7.4, 6.2, 5.5, 5.4, 4.9, 4.5; MS (FAB)(M+H).sup.+ : calcd
 369.1006, found 369.1000.
 Example 123
 N-(4-Chlorobenzyl)-1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxamide
 ##STR196##
 Ethyl 3-ethoxy-2-(2-fluorobenzoyl)-2-propenoate (4.0 g, prepared from ethyl
 3-(2-fluorophenyl)-3-oxopropanoate as in Preparation No. 59) and
 O-methylhydroxylamine (16 mmol, prepared by mixing 1 eq of sodium ethoxide
 with 1 eq of O-methylhydroxylamine hydrochloride in ethanol) are stirred
 in ethanol (20 mL) for 1 hour at rt. The mixture is concentrated, diluted
 with dioxane (75 mL) and re-concentrated to remove any remaining ethanol.
 The resulting enamine is diluted in dioxane (70 mL) and sodium hydride
 (60% dispersion, 0.64 g) is added. The mixture is heated to reflux for 2.5
 hours, cooled to rt and concentrated in vacuo. The remaining residue is
 partially dissolved in ethanol (100 mL) and filtered. The filtrate is
 concentrated in vacuo and chromatographed (7% MeOH/CH.sub.2 Cl.sub.2). The
 combined fractions are concentrated, leaving a residue which is
 recrystallized in a 1:1 ether/hexanes mixture to afford 0.95 g of ethyl
 1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (Mp 120-121.degree. C.)
 as a white solid.
 The resulting carboxylate ester (0.48 g) is stirred with a solution of 3 N
 NaOH (aqueous, 5 mL) in ethanol (6 mL) for 15 minutes. The reaction
 mixture is neutralized with 3 N HCl, filtered, and washed with ethanol to
 give the carboxylic acid as a white solid. The carboxylic acid (0.16 g)
 and N,N'-carbonyldiimidazole (0.18 g) are dissolved in DMF (10 mL) and
 heated to 65.degree. C. for 5 hours. The reaction mixture is cooled to
 0.degree. C., quenched with water (0.01 mL) and stirred for 5 minutes.
 After warming to room temperature, 4-chlorobenzylamine (0.10 mL) is added.
 The reaction mixture is then stirred for 16 hours at room temperature.
 Water (15 mL) is added, and the precipitate is filtered off and washed
 with 1:1 DMF/H.sub.2 O (2.times.25 mL) and H.sub.2 O (2.times.25 mL) to
 afford 50 mg of the title compound as a white solid.
 Physical properties are as follows:
 Mp 155-160.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.10.30, 9.08,
 8.32, 7.91, 7.62, 7.39, 4.56, 4.21; IR (drift) 1941, 1920, 1650, 1603,
 1549, 1489, 1463, 1350, 1221, 1013, 954, 840, 801, 751, 713 cm.sup.-1 ;
 HRMS (FAB) calcd for C.sub.18 H.sub.15 ClN.sub.2 O.sub.3 +H 343.0849,
 found 343.0867.
 Example 124
 N-(4-Bromobenzy)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydr
 o-3-quinolinecarboxamide
 ##STR197##
 4-Bromobenzylamine hydrochloride (2.22 g) is suspended in water (5 mL) and
 neutralized with 2N aqueous NaOH (5 mL). The free amine is extracted with
 dichloromethane (2.times.25 mL). The organic layers are combined, washed
 with brine (5 mL), and dried with Na.sub.2 SO.sub.4. The solution is
 concentrated in vacuo to afford 1.48 g of a clear, colorless oil which is
 then combined with ethyl
 1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecar
 boxylate (0.48 g) from Preparation No. 56 and heated to 190.degree. C. for
 3 hours. The reaction mixture is allowed to cool to room temperature, and
 the resulting solid is recrystallized in ethyl acetate to afford 0.44 g of
 the title compound as a white solid.
 Physical properties are as follows:
 Mp 200-202.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta.) 10.35, 9.03,
 8.28, 8.21, 7.81, 7.54, 7.31, 4.55, 3.96, 3.80, 3.62, 3.59, 3.28, 3.08,
 2.37. IR (drift) 1966, 1926, 1652, 1597, 1585, 1549, 1522, 1487, 1359,
 1351, 1283, 1111, 862, 807, 799 cm.sup.-1. MS (ESI+) m/z 541 (M+H).sup.+ ;
 HRMS (FAB) calcd for C.sub.26 H.sub.29 BRN.sub.4 O.sub.4 +H 541.1451,
 found 541.1447.
 Example 125
 N-(4-Fluorobenzyl)-1-(4-morpholinyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihy
 dro-3-quinolinecarboxamide
 ##STR198##
 Ethyl
 1-(4-morpholinyl)-6-(4-morpbolinylmethyl-4-oxo-1,4-dihydro-3-quinolinecarb
 oxylate (0.33 g) from Preparation No. 56 and 4-fluorobenzylamine (0.55 mL)
 are combined and heated to 180.degree. C. for 3 hours. The reaction is
 allowed to cool to room temperature. The crude solid is triturated with
 ether, filtered, and recrystallized in methanol to afford 0.14 g of the
 title compound as a white solid.
 Physical properties are as follows:
 Mp 165-167.degree. C. .sup.1 H NMR (DMSO-d.sub.6) .delta.10.33, 9.06, 8.27,
 8.21, 7.81, 7.39, 7.17, 5.76, 4.57, 3.97, 3.80, 3.62, 3.57, 3.08, 2.37. IR
 (drift) 1661, 1598, 1549, 1510, 1488, 1355, 1324, 1288, 1269, 1223, 1110,
 864, 842, 829, 809 cm.sup.-1. MS (ESI+) m/z 481 (M+H).sup.+ ; HRMS (FAB)
 calcd for C.sub.26 H.sub.29 FN.sub.4 O.sub.4 +H 481.2251, found 481.2245.
 All cited publications, patents, and patent documents are incorporated by
 reference herein, as though individually incorporated by reference. The
 invention has been described with reference to various specific and
 preferred embodiments and techniques. However, it should be understood
 that many variations and modifications may be made while remaining within
 the spirit and scope of the invention.