OA11293A - Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands. - Google Patents

Abstract

The present invention encompasses structures of Formula (I) or the pharmaceutically acceptable non-toxic salts thereof wherein: X is hydrogen, halogen, (un)substituted alkyl, (un)substituted alkoxy or amino; and Y is (un)substituted alkyl, aryl, or heteroaryl, which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.

Description

f- 1 * n r-, 7 1 ‘ · ! r 0

SUBSTITUTED 4-OXO-NAPTHYRIDINE-3-CARBOXAMIDES AS GABA BRAIN RECEPTOR LIGANDS

BACKGROUNO O F THE INVENTION

Field of the Invention

This invention relates to substituted 4-oxo-napthyridine- 3-carboxamides and, irr particular, such compounds which selectively bind to GABAa receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses of benzodiazépine - type drugs, Down Syndrome, and sleep, seizure and cognitive disorders.

Description of the Related Art γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain.

Over 40 years hâve elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950). Since that time, an enormous amount of effort has been devoted to implicating GABA in the etiology of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev.

Neuroscience 8.: 21-44, 1985). Widelv, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. GABA médiates many of its actions through a complex of Μ -1 0 0 7 ι I I ζ. > ο proteins localized both on cell bodies and nerve endings;these are called GASAa receptors. Postsynaptic responses to GA3A are mediated through alterations in chloride conductancethat generally, although not invariably, lead to’nyperpolarization of the cell. Drugs that interact at the GA3Aa receptor can possess a spectrum of pharmacologicalactivities depending on their abilities to modify the actions of GA3A.

The 1, 4-Benzodiazépines, such as diazepam, continue tobe among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, andanticonvulsants. A number of these ccmpounds are extremelypotent drugs,· such potency indicates a site of action with ahigh affinity and specificity for individual receptors. Earlyelectro-physiological studies indicated that a major action ofbenzodiazépines was enhancement of GABAergic inhibition.Presently, these compounds possessing activity similar to thebenzodiazépines are called agonists. Compounds possessingactivity opposite to benzodiazépines are called inverseagonists, and the compounds blocking both types of activityhâve been termed antagoniste.

The GABAa receptor subunits hâve been cloned from bovine and human cDNA libraries (Sc'noenfield et al., 1983; Duman et al. , 1989) . A number of diszinct cDNAs were identified as subunits of the GABAa receptor complex by cloninq and expression. These are categorized inro α, β, γ, δ, ε, and -2- 011293 provide a molecular basis for the GASAa receptor heterogeneityand distinctive régional pharmacology (Shiwers et al., 1980;

Levitan et al., 1989) . The γ subunit appears to enable drugslike benzodiazépines to modify the GABA responses (Pritchett 5 et al. , 1989). The presence of lcw Hill coefficients in the binding of ligands to the GABAa receptor indicates uniqueprofiles of subtype spécifie pharmacological action.

With the discovery of the "receptor" for thebenzodiazépines and the subséquent définition of the nature of 10 the interaction between GA3A and the benzodiazépines, itappears that the behaviorally important interactions of thebenzodiazépines with different neurotransmitter Systems aredue in a large part to the enhanced ability of GABA itself tomodify these Systems. Each modified System, in turn, may be 15 associated with the expression of a behavior. Depending on themode of interaction, these compounds are capable of proaucinga spectrum of activities (either sédative, anxiolytic, andanticonvulsant, or wakefulness, seizures, and anxiety).

Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylic 20 acids and esters hâve been disclosed. See, for example, Eur. J. Med. Chem.-C'nim. Ther. (1977), 12 (6), 549-55.

Polish Patent No. 125299 discloses compounds of the formula:

O

-3- CI '1 293 wherein N dénotés a ring nitrogen in the 5- or 6- position,and R is CO2H or CO2Et.

Several 1,4 -dihydro-4-oxo-1,5 -napt’nyridine- 3 -carnoxamide dérivatives of penicillin said to possess antibaoterial 5 activity hâve been disclosed. For example, German Patent No.DD 279887 discloses a compound of the formula

SyMeV Me H CO2H .

Japanese Patent No.72-45118 discloses ampicillindérivatives of 1,4-dihydro-4-oxo-3-naphthyridines. -4 - 0 11293

SUMKA-RY OP THE INVENTION

This invention provides novel compounds of Formula Iwhich interact with a GASAa binding site, the benzodiazépine receptor.

The invention provides pharmaceutical compositionscomprising compounds of Formula I. The invention alsoprovides compounds useful in the diagnosis and treatment ofanxiety, Down Syndrome, sleep, cognitive and seizuredisorders, and overdose with benzodiazépine drugs and forenhancement of alertness, Accordingly, a broad embodiment of the invention is directed to compounds of Formula I :

Λ wnerern: X is hydrogen, halogen, -OR,, C,-C6 alkyl optionally substitutedwith up to three groups selected independently fromhalogen and hydroxy, or -NR2R3; X is p'nenyl, naphthyl, 1- (5,5,7, 8-tetranydro)naphthyl or 4- (1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinoiinyl, 1,2,3,4 -tetranydroisoquinolinyl, benzofuranyl, benzothienvl, each of which is optionally substituted with up to three groups selected from halogen, Cj-Cg alkyl, Ci-C4 alkoxy, 0\-Ο6 alkylthio, -5- 011293 hydroxy, amino, mono or di (C,-Ce) alkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy; or X represents a carbocyclic group ("the X carbocyclic group")containing from 3-7 members, up to two of which membersare optionally hetero atoms selected from oxygen andnitrogen, where the X carbocyclic group is optionallysubstituted with one or more groups selected ' fromhalogen, alkoxy, mono- or dialkylamino, sulfonamide,azacycloalkyl, cycloalkyithio, alkylthio, phenylthio, ora heterocyclic group; Y is lower alkyl having 1-8 carbon atoms optionally substituted with up to two groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkyithio, alkylthio, phenylthio, a heterocyclic group, -OR4,-NR5R6, SR,, or aryl ; or Y is a carbocyclic group ("the Y carbocyclic group") having from 3-7 members atoms, where up to tnree of which members are optionally hetero atoms selected from oxygenand nitrogen and where any member of the Y carbocyclicgroup is optionally substituted with halogen, -0R4,-NRsR.,SR,, aryl or a heterocyclic group; R. is hvdrogen, lower alkyl having 1-6 carbon atoms, orcÿcloalkyl having 3-7 carbon atoms, where each alkyl maybe optionally substituted with -OR4, or -NR5R6; R2 and R3 are the same or different and represent -6- hydrogen, lower alkyl optionally mono- or disubstitutedwith alkoxy, aryl, halogen, or mono- or di-loweralkyl; aryl or aryl (C^Cj) alkyl w’nere each aryl is optionallysubstituted with up to three groups selected fromhalogen, hydroxy, Cj-Ce alkyl, Cj-C6 alkoxy, or mono-or di (Cj-C6) alkylamino; cyçloalkyl having 3-7 carbon atoms optionally mono ordisubstituted with halogen, alkoxy, or mono- or di-lower alkyl; or -S02RB ; R, is as defined for R1Z- r5 and R6 carry the same définitions as R2 and RJ( respectively; *7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; andR8 is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3- 7 carbon atoms, or optionally substituted phenyl.

These compounds are highly sélective agonists,antagonists or inverse agonists for GASAa brain receptors orprodrugs of agonists, antagonists or inverse agonists for GA3Aa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose benzodiazépine drugs and for enhancement of alertness. -7- with p, } P, P\ ~7 U I i DSTAILED DESCRIPTION OF THE INVENTION-

The novei compounds encompassed by the invention can bedescribed· by the general Formula I set forth above.

In Formula I above, “NR2R3 can also represent a 5 heterocyclic group such as, for example, , piperidine in the case where R, and R3 together form a C5-alkvlene group. Further, R2 and R3 together may repres ent an alkylene or alkenylene group optionally containing up to two heteroatomsselected from nitrogen and oxygen. The resulting groups 10 include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl,and piperidinyl.

Similarly, the -NR5R6 group in Formula I above can also represent a heterocyclic group such as, for example,piperidine in the case where R5 and Rs together form a C5- 15 alkylene group. Further, Rs and R6 together may represent analkylene or alkenylene group optionally containing up to twoheteroatoms selected from nitrogen and oxygen. The resultinggroups include imidazolyl, pyrrolidinyl, morpholinyl,piperazinyl, and piperidinyl.

20 Freferred compounds of Formula 1 are those where X represents (C,-C6) alkoxy, more preferably (Cj-C3) alkoxy.Particularly preferred compounds of Formula ï include metnoxy or ethoxy as the X group.

Still other preferred compounds of Formula I include 25 those where the Y is lower alkyl, e.g., methyl or ethyl, substituted with pnenyl, pyridyl, or pyrimidinyl. A more -8-

Γ Ί r· Λ; V U I ! ζ > Û preferred Y group is benzyl optionally substituted withhalogen, (Cj-Cs) alkyl, (C^-Cj) alkoxy, amino, or mono- or di (Cx- C6) alkyl

Where R2 and R3 in Formula I represent optionally5 substituted aryl or aryl (Cj-CJ alkyl, the aryl group ispreferably phenyl, pyridyl, or pyrimidinyl and the alkylgroups are preferably methyl and ethyl. More preferred are benzyl and phenyl. Particularly preferred is benzyl.

Where X is optionally substituted alkyl, the alkyl 10, group is preferably optionally substituted methyl, ethyl, orpropyl. More preferred are perhalomethyl and trihaloethyl.Preferred halogens are fluorine. Particularly preferred is 2,2,2-trifluoroethyl. X in Formula I may be an optionally substituted phenyl,15 naphthyl, 1-(5,6,7,3 -tetrahydro)naphthyl, 4-(1,2- dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl,benzofuranyl, or benzotnienyl group, or preferably a 1,2,3,4- tetrahydroisoquinolinyl group. 20 In addition to the compounds of Formula I, the invention

encompasses compounds of Formula IA

wherein: -9- X is (i) hydrogen, halogen, mono- or dialkylamino, alkoxy, (ii) a group of the formula: 5 where G is lower alkylene having 1-6 carbon atoms, or a cvclic group of the formula (CH2)n

(CH2)m where n is 0, 1, or 2, and m is an integer of from 1to 5, with the proviso that the sum of n + m is not 10 less than 1 or greater than 5; and R. is hydrogen, lower alkyl, or (C3-C7) cycloalkyl, wherethe alkyl or cycloalkyl is optionally substituted withhalogen, lower alkoxy, or mono- or di (Cj-CJ alkylamino ; (iii) a group of the formula: R3R2N'.rx-°\

15 G where G is as defined above for ii; and

Rj and R3 independently represent hydrogen, lower alkylhaving 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, -SO2R6 where Re is (C2-C6) alkyl, (C3- 20 . C7)cycloalkyl, or optionally substituted pnenyl, or R2 and Rj together with the nicrogen atom to which theyare attached form a heterocvclic moiety such asimidazolyl, pyrrolidinyl, morpholinyl, piperazinyl,or piperidinyl; -10- G '11293 (iv) a group of the formula·. r2 where

Rj is as defined above for iii; 5 R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may beoptionally substituted with one or more (C,-C6) alkoxyor mono- or di (C,-C6) alkylamino groups; and G is as defined above for ii; 10 (v) a group of the formula: where R2 and G are as defined above for iv and ii, respectively, and 15 Rs and R6 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, -SO2R8 where Ra is (Cx-C6) alkyl, (C3- C7)cycloalkyl, or optionally substituted phenyl, or

Rs and Rê together with the nitrogen atom to which they 20 are attachée form a heterocyclic moiety ’suc'n as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl; (vi) a group of the formula: -11- 4 /Λ

ï z. > O

<TG'N where G is as defined above for ii; or(vii) a group of the formula: r2^~G\ where each G is as defined above for ii; and Y is (viii) lower alkyl having 1-8 carbon atoms or cycloalkylhaving 3-7 carbon atoms, any of which may be optionally 10 substituted with one - or more hyaroxy, ’nalogen, (Cx- C6) alkoxy, alkoxyalkoxy where each alkoxy is (C^-CJ alkoxy,(C,-C6) alkylthio, (C3-C.,) cycloalkylthio, aryl, heteroaryl,or mono- or di (C--C6) alkylamino groups; (ix) a group of the formula:

where K is lower alkylene having 1-6 carbon atomsoptionally substituted with (C^CJ alkyl or alkylene, or acyclic group of the formula K'

20 where K' independently represents hydrogen or (C3- C6) alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the -12- G11-29 3 sum of n + m is no: less than 1 or greater than 5; and R, is hydrogen, lower alkyl, or (C3-C7) cycloalkyl, wherethe alkyl or cycloalkyl is optionally substituted withhalogen, lower alkoxy, or mono- or dialkylamino; (x) a group of the formula: where K is defined as above in ix; (xi) a group of the formula: / O or13 where K is as defined above for ix, and R13 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where the alkyl and cycloalkyl groups are optionally substituted with one or more (C^-CJ alkoxy or mono- or di (¢^-Cj alkylamino groups; and (xii) a group of the formula: SR7 where K is as defined above for ix, and P.7 is hydrogen, lower alkyl having 1-5 cycloalkyl having 3-7 carbon atoms; carbon atoms and -13- (xiii) a group of the formula: ,K„ x NR14R15 where K is as defined above for ix,· and R14 and RlS independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -SO2Rb where Rs is as defined above, or R14 and RiS together with the nitrogen atom to which they are attached form a heterocyclic moiety such asimidazolyl, pyrrolidinyl, morpholinyl, piperazinyl,or piperidinyl; (xiv) a group of the formula:

i

RlS where K and R1S are as defined above in ix and xii, respectivsly; (xv) a group of the formula:

where K is as defined above for ix; -14- R10 and Rl0' are the same or different and are selectedfrom hydrogen, {C,-CJ alkyl, halogen, hydroxy, loweralkoxy having 1-6 carbon atoms, or cvcloalkoxyhaving 3-7 carbon atoms;

Rn, R,/, and R12 are the same or different and areselected from hydrogen, Cj-C6 alkyl, halogen,hydroxy, -OR,, -CR, (.R,) NR5R6, -CR, (R1Ê) OR,, or Rn and R12 taken together with the atoms to which theyare attached form a (netero)cyclic ring; and R16 is hydrogen, lower alkyl having 1-6 carbon atoms, orcycloalkyl having 3-7 carbon atoms; (xvi) a group of the formula:

where K is as defined above for ix; and W is heteroaryl; (xvii) a group of the formula:

where K is as defined above for ix; R10 and Rn are as defined above ’for xv, and R., is hydrogen, lower alkyl, or (C3-C,) cycloalkyl, wherethe alkyl or cycloalkyl is optionally substituted withhalogen, lower alkoxy, or mono- or di (C,-C6) alkylamino; -15- (xviii) a group of the formula: 29z

where K, R10, R12, and Ri7 are as defined above; (xix) a group of the formula·.

where each K is independently as defined above for ix andR10 is defined above; (xx) a group of the formula:

nr14r15 10 where K, R10, Rn, R14, and Rl5 are as defined above; (xxi) a group of the formula:

where K, R10, R,,, Ru, and Rl5 are as defined above; 15 (xxii) _ pyrimidinyl (Cj-Cg) alkyl or pyridyl (Cj-CJ alkyl ; or (xxiii) a group of the formula: -15-

where Rie represents hydrogen, amino, mono-, or di(Cx-Ce) alkylamino, or Cj-Cj alkyl optionally substituted with a R19where R18 represents:

where V and V' are independently CH or nitrogen; A' 1 is Ci-Ci alkvlene; and R20 is phenyl, pyridyl, or pyrimidinyl, each of which isoptionally mono-, di-, or trisubstituted independently with 10 halogen, hydrcxy, Cj-C6 alkoxy, amino, or mono- or difCi-Cfi)alkylamino.

Preferred pyrimidinyl (C^CJ alkyl Y groups are 2- and 4- pyrimiainylmethyl, Preferred pyridyl(Cj-CJ alkyl Y groups are15 2- and 4-pyridylmethyl.

Preferred benzyl Y groups are those where R18 is amino ora substituted methyl or ethyl group. More preferred Riasubstituents are piperazin-1-yl or piperidin-1-yl substituted 20 at the 4-position with a halogenazed benzyl group.

Particularly preferred benzyl Y groups are 4-(1-(4-(4-

Fluorobenzyl)piperazinyl] methyl]benzyl and 4-(1-(4-(4-

Fluorobenzyl)piperidinyl] methyl]benzyl. -17- Γ 4 '1 <' f 7 u 1 i iL j groups in Formula IA are various

Preferred "X" quinolinyl, isoquinolinyl, tetrahydroquinolinyl or :etrahydroisoquinolinyl groups, e.g., groups of the formulas:

CO"' ïXf

NH

The following formulée are preferred embodiments of the invention:

10 wherein Y is defined above.

wherein Z represents halogen and Y is as defined above. 15

wherein Rl and Y are defined above -18- r- .1

U I

' il 7Î I*·"* O

wherein R:,

Rs, and Y are defined above.

-19- r, ·1 λ fi 7i I Δ * Ο

IX wherein Rz, R,, G, and Y are defined above.

XI 10 wherein G and Y are defined above.

XII wherein R,, G, and Y are defined above.

wherein X is defined above and U is (Cj-CJ lower alkylCJ cycloalkyl.

or (C -20- r ί *i r w I I Z.

<A

wherein X, K, and R, are defined above

N OH

wherein X and X are defined above. 10

N O OR,H wherein X, K, and R< are defined above.

-21- C Λ <! r' r- '7

L· i 1 b. O

wherein X K, Rh, and R1S are defined above.

N N'

H R f<15 wherein X, K, and R1S are defined above.

wherein: R10 , R1C' are the same or different and may be selectedfrom hydrogen, (C^CJ alkyi, haiogen, hydroxy, lower alkoxyhaving 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon 15 atoms;

Ru, Ru', and R12 are the same or different and may beselected from hydrogen, (Cx-C.) alkyi, haiogen, hydroxy, -OR4,- CR, (R5)Nr5R6, -CR7(Rs)OR4; or

Rn and R.2 taken together with the atoms to which they are 20 attached form a (hetero)cyclic ring; andRsis as defined above. -22-

011293 wherein X and K are defined above; and W is heteroaryl.

w'nerein X, K, R., R10, and Rn are defined above 10.

wherein X, and R,, are defined above. wherein X,

XXIV

K, and R are defined above. -23- Û1 1 292

and Rn are wherein X, K, R14, R15, Rlo, defined above.

Preferred compounds of the following formulée: he invention are encompassed by

where A is Cx-C6 alkylene;

Ra is phenyl optionally mono-, di-, or trisubstituted withhalogen, lower alkyl, lower alkoxy, or mono- or di- 15 C,-C6 alkylamino, or mono- or di-C1-C6 alkylamino lower alkyl; and

Rb is lower alkyl or lower cycloalkyl.

More preferred compounds of Formula XXVII are those whereA is methylene, R, is phenyl optionally substituted with methyl 20 or ethyl, and Rb is lower alkyl. Particularly preferred -24- <ι *! r, ~r compounds of Formula XXVII are those where A is methylene, Rais phenyl and Rc is C,-C5 aikyl.

Formula XXVIi:

ZAS N R,'H a wherein A is Cj-Cg alkylene;

Ra and Ra' are independently phenyl groups optionallymono-, di-, or trisubstituted with halogen, loweraikyl, lower alkoxy, or mono- or di-C,-C6 alkylamino,or mono- or di-C,-C6 alkylamino lower aikyl; and

Rc is hydrogen or lower aikyl.

More preferred compounds of Formula XXVIII are thosewhere A is methylene, Ra and Ra' are independently phenyloptionally suhstituted with methyl or ethyi, and Rc ïs loweraikyl. Farticularly preferred compounds of Formula XXVII arethose where A is methylene, Ra is phenyl suhstituted in thepara position with lower aikyl, Ra' is phenyl, and R. is C,-C3aikyl. wnerem

-25- A y Re N O e

H A is Cj-C6 alkylene;

Rd and Rs are independently lower alkyl groupa.

More preferred compounds of Formula XXIX are those whereA is C2-C4 alkylene. Particularly preferred compounds of 5 Formula XXIX are those where A is C2-C4 alkylene, Rd is C2-C3alkyl, and Re is C2-C4 alkyl.

Formula XXX

R

,AV

N RfH 10 wherein A is C3-CÉ alkylene;

Rd is lower alkyl; and R, is a group of the formula: pr^-\

M where 3 is oxygen or nitrogen; and 15 M is Cj-Cj alkylene or nitrogen.

More preferred compounds of Formula XXX are those where A is C2-C3 alkylene. Still more preferred compounds of FormulaXXX are those where A is C2-C4 alkylene, Rd is C3-C3 alkyl, andRe is Cj-C4 alkyl. Particularly preferred compounds of Formula 2C XXX are those where A is C2-C4 alkylene, Rd is C2-C3 alkyl, Re isC,-C4 alkyl, and 3 is nitrogen and M is methylene, E is oxygenand M is methylene or ethylene, or S and M are both nitrogen. -26-

Other preferred compounds of Formula XXX are those whereR{ is furanyl, tetrahydrofuranvl, or imidazolyl.

Formula XXXI wherein A is Ca-C6 alkylene;

Rd is lower alkyl optionally substituted with amino ormono- or di (Cj-C6) alkylamino; and

Ra' is phenyl optionally mono-, di-, or trisubstitutedwith halogen, lower alkyl, lower alkoxy, or mono- ordi-C:-C6 alkylamino, or mono- or di-C,-C{ alkylaminolower alkyl.

More preferred compounds of Formula XXXI are those where A is Cj-Cj alkvlene, Ra' is phenyl optionally substituted withmethyl or ethyl, and Rd is C^-Cj alkyl. Still more preferredcompounds of Formula XXXI are where A is methylene, Ra' isphenyl optionally substituted with methyl or ethyl, and Rd isC3-Cs alkyl. Particularly preferred compounds of Formula XXXIare sodium, potassium, or ammonium sales of the corresponding parent compound.

Other preferred compounds of Formula XXXI are those where

Ra' is phenyl substituted with mono- or di-alkylamino lower alkyl. -27- û i ί y

O

A is Ci-Cé alkylene; 5 Rd is lower alkyl; and

Ra" is phenyl, pyridyl, imidazolyl, pyrimidinyl, orpyrrolyl, each of which is optionallysubstituced witn up to two groups selected fromhalogen, lower alkyl, lower alkoxy, mono- or 0 di (C1-C6) alkylamino, or mono- or di-C^-C. alkylamino lower alkyl.

More preferred compounds of Formula XXXIa are those wnereRa" is imidazolyl and Rd is C^-C, alkyl. Still more preferred 5 compounds of Formula XXXI are where A is methylene, Ra" isimidazolyl, and Rd is C3-C6 alkyl.

Formula XXXII

N' "S' e wherein A is C,-C5 alkylene; and

Rd and Re are independently lower alkyl groups. -28-

More preferred compounds of Formula XXXII are those whereA is Ci-Cj aikylene. Particularly preferred compounds of

Formula XXXII are those where A is Cj-C3 aikylene, Rd is C\-C alkyl, and Re is C;-C3 alkyl.

wherein D is nitrogen or CH; D' is nitrogen or oxygen; A is Ci-Cs aikylene; and R,' is phenyl, pyridyl, or thiazolyl, eac’n of wnich is optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di- C,-Cs alkylamino, or mono- or di-C,-C. alkylamino lower alkyl.

More preferred compounds of Formula XXXIII are those where A is Cx-C3 aikylene, R/ is phenyl optionally substitutedwith lower alkyl or halogen, and D is nitrogen. Still more preferred compounds of Formula XXXIII are where A is methyl-ene, Râ' is phenyl optionally substituted with lower alkyl or halogen, D is nitrogen, and D' is oxygen. -29- 011293

Formula XXXIV

wnsrem A is Cj-C6 alkylene; and

Ra' is hydrogen,· R.' is thienyl or phenyl, each of which is optionallymono-, ai-, or trisubstituted with halogen, loweraikyl·, lower alkoxy, or mono- or di-C1-CÊ alkylamino,or mono- or di-C^Cj alkylamino lower alkyl.

More preferred compounds of Formula XXXIV are those where A is Cl-C-j alkylene, and Ra' is phenyl optionally substitutedwith lower alkyl or halogen. Still more preferred compoundsof Formula XXXIV are where A is methylene, Ra' is phenyloptionally substituted with lower alkyl, lower alkoxy or halogen.

Formula XXXV

wherein A is C,-C6 alkylene; and

Rd is lower alkyl; A' représenta oxygen or merhyiene; and r is an integer of from 1-3. -30- 011293

More preferred compounds of Formula XXXV are those where A is C^-Cj alkylene. Particularly preferred compounds of

Formula XXXV are those where A is C,-C. alkylen alkyl. e, and Rd is Cj-C^ Rn 1 0 0 /N Rh > .N. JLîr i Formula XXXVa n 1 I Γ « χ (CH2)r wherein H ^O A is Cx-C6 alkylene; and Rh and Rn' are independently hydrogen or lower alkyl, where each alkyl is op ttonally suhstituted with louer alkoxy; A' représente oxygen or methylene; and r is an integer of from 1-3.

More preferred compounds of Formula XXXVa are those where A is Cj-Cj alkylene. Particularly preferred compounds o

Formula XXXV are those where A is C,-C, alkylene, and Rh is C,-C3alkyl.

Formula XXXVI wherein A is C^-C. alkylene; rn

-31- Λ N Ra‘ 5 011293

Rg is lower alkoxy lower alkyl; and

Ra' is phenyl optionally mono-, di-, or trisubstitutedwith halogen, lower alkyl, lower alkoxy, or mono- ordi-C^-Cj alkylamino, or mono- or di-Cx-C6 alkylaminolower alkyl.

Formula XXXVII

10 wnerern R3 is halogen or lower alkoxy; and RK is lower alkyl or cycloalkyl each of which is optionally substituted with hydroxv, lower alkyl, orlower alkoxy; or

Rk is phenyl (CX.C6) alkyl where the phenyl group is optionally mono-, di-, or trisubstituted with 15 halogen, lower alkyl, lower alkoxy, or mono- or di-

Cj-Cs alkylamino, or mono- or di-C1-Ci alkylamino lower alkyl. 20

Formula XXXVIII wnerern

N Rn A is Cj-C6 alkylene;

Rx is lower alkoxy, benzyloxy, lower alkoxy lower alkoxy,amino, or mono- or di-(Cj-CJ alkylamino; and -32- 011293

O O

R™ is pyranyl, dihydropyranyl, tetrahydropyranyl, orhexahydropyranyl, pyridine, dihydropyridine, tetrahydropyridine, or piperidine.

Preferred compounds of Formula XXXVIII are those where Rxis lower alkoxy and R^ is tetrahydropyranyl.

Formula XXXIX wherein A is Cx-C6 alkylene; R, is lower alkoxy, lower alkoxy lower alkoxy, benzyl, or a group of the formula: w'nere D is nitrogen or CH; and D' is nitrogen or oxyaen; andRo is pyranyl, 2- or 3-thienyl; or

Ra is 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-imidazolyl,each of which may be optionally substituted withlower alkyl.

Preferred compounds of Formula XXXIX are those where -33- 10

Formula XXXX

N

H wherein A is Ct-C6 alkylene;

Rh and Rb' are independentîy hydrogen or lower alkyl,where each lower alkyl is optinally substituted withlower alkoxy; and

Ra' is phenyl optionally mono-, di-, or trisubstitutedwith halogen, lower alkyl, lower alkoxy, or mono- ordi-C;-C6 alkylamino, or mono- or di-C^Cg alkylaminolower alkyl; or

Ra' is thienyl optionally substituted with lower alkyl.

15 wherein A is C1-Ci alkylene; D is nitrogen or CH; D' is nitrogen or oxygen; and

Rp is lower alkyl or lower alkyl optionallywith lower alkoxy. substituted -34- 20 011293

Formula XXXXII

,A

R

13 wherein A is Cj-Cg alkylene; X is defined as above for Formula I; and R1B is (i) amino or mono- or di (C.-C6) alkylamino; or (ii) lower alkyl optionally substituted with A" rm w ) where .0 V and V' are independently CK or nitrogen; A'' is C;-C6 alkylene; and R20 is phenyl, pyridyl, or pyrimidinyl, eacn of whicn is optionally mono-, di-, or trisubstituted independently with halogen, hydroxy, Cj-C6 alkoxy,L5 amino, or mono- or di (Cj-C6) alkylamino.

More preferred compounds of Formula XXXXII are thosewhere V is nitrogen and X is C,-C6 alkoxy or Cj-C6 alkyloptionally substituted with up to three halogen atoms.

Particularly preferred compounds of XXXXII are those where V2G and V' are nitrogen; X is Cj-Cj alkoxy or C.-C. alkyl optionallysubstituted with up to three halogen atoms; A' ' is methyleneor ethylene; and R20 is halogenated phenyl. A preferred R20 -35- Ü1 'i 295 group is 4 - flucropnenyl. Highly preferred ccmpounds of XXXXIIare those where X is 2,2,2-trifiuoroethyl,- V and V' arenitrogen,· R20 is halogenated pnenyl; and A and A' are methyleneor ethylene.

In certain situations, compounds of Formula I may containone or more asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds canbe, for example, racemates or optically active forms. Inthese situations, the single enantiomers, i.e., opticallyactive forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

Représentative compounds of the présent invention, whicn are encompassed by Formula I, include, but are not limited tothe compounds in Table I and their pharmaceutically acceptableacid and base addition salts. In addition, if the compound of the invention is obtained as an acid addition sait, the free base can be obtained by basifying a solution of the acid sait.

Conversely, if the product is a free base, an addition sait,particularly a pharmaceutically acceptable addition sait, maybe produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance -36- 4 4 r, π 7r λ _i ' f -- .. j with conventional procedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acidssuch as hydrochloric, phosphoric, hydrobrotr.ic, sul furie, 5 sulfinic, formic, toluenesulfonic, methanesulfonic, nitric,benzoic, citric, tartaric, maleic, hvdroiodic, alkanoic such as acetic, KOOC- (CH2) n-ACOOH where n is 0-4, and the like.

Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the 10 like. Those skilled in the art will recognize a v/ide variety of non-toxic pharmaceutically acceptable addition salts.

The présent invention also encornasses the acylated prodrugs of the compounds of Formula I. Those skilled in theart will recognize various synthetic méthodologies which may 15 be employed to préparé non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compoundsencompassed bv Formula I.

By lower alkyl in the présent invention is meant straightor branched Chain alkyl groups having 1-5 carbon atoms, such 20 as, for example, methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, terc-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. -37- 3y cycloalkyl in the présent invention is meant cycloalkyl groups having 3-7 atoms such as, for example 2 5 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. G ! 1 2 9 3

By aryl is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl), multiple rings (e.g., biphenyl),or multiple ccndensed rings in which at least one is aromatic,(e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, ortrisubstituted with, e.g., halogen, lower alkyl, lower alkoxy,lower alkylthio, ' trifluoromethyl, lower’ acyloxy, aryl,heteroaryl, and hydroxy.

By lower alkoxy in the présent invention is meantstraight or branched chain alkoxy groups having 1-6 carbonatoms, such as, for example, methoxy, ethoxy, propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxv, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. 3y cycloalkoxy in the présent invention is meant cycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl is defined above.

By halogen in the présent invention is meant fluorine, bromine, chlorine, and iodine.

By heteroaryl (aromatic heterocycle) in the présentinvention is meant one or more aromatic ring Systems of 5-, 6- , or 7-membered rings containing at least one and up to fourhetero" atoms selected from nitrogen, oxygen, or sulfur. Suchheteroaryl groups include, for example, thienyl, furanyl,thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, -38- 011293 (iso)quinolinyl, naphthyridinyl, benzimidazolyl, andbenzoxazolyl.

Spécifie examples of heteroaryl groups are the following:

wherein Q is nitrogen or -CR9; T is -NR,, oxygen, or sulfur; and R9, R10 , R,o 1 , R11Z R:1 ' , R12 are as defined above.

Where Y représenta a carbocyciic group, it is attached to the amide nitrogen by a single bond. The resuit is an amide of the formula:

where X is defined as above anc

Yx) reoresents

:he Y carbocyciic group.

Where X is a carbocyciic group, such moiety or group includes both aromatic heterocycles (heteroaryl), unsaturatedheterocylic ring Systems, and saturated heterocyclic ring -39-

Systems. Examples of such groups are imidazolyl,pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl.Preferred X carbocyclic groups are linked to the parentnaphthyridine moiety by a nitrogen atom in the X carbocyclicgroup. Thus, for example, when pyrrolidinyl is the Xcarbocyclic group, it is preferably a 1-pyrrolidinyl group of the formula :

Wnere Y is a carbocyclic group, such moiety or groupincludes both aromatic heterocycles (heteroaryl groups) ,unsaturated heterocylic ring Systems, and saturatedheterocyclic ring Systems. Examples of such groups areimidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, orpiperidinyl. Preferred Y carbocyclic groups are linked to the parent naphthyridine carboxamide group by a nitrogen atom inthe Y carbocyclic group. Thus, for exemple, when piperidinylis the Y carbocyclic group, it is preferably a 1- piperidinylgroup of the formula: -40-

Sy "optionally substituted phenyl" as used herein is meant phenyl groups that are unsubstituted or substituted with up to 3 groups selected independently from halogen, hydroxy, lower alkyl, lower alkoxy, triflucromethvl, and mono- or di- lower alkylamino.

Représentative compounds of the invention are shown below in Table 1.

Table 1

Compound 2

Ccmpound 3

-41- 10

1S 20 0i1293

Comoound 5 V-o

Compound 6

Comoound 7

O O

Comoound 3 OMe

Compound 9

iz -42-

r * *î C f” 7· -- ί î t*: O

The pharmaceutical utility of compounds of this inventionis indicated by the following assays for GA3Aa receptoractivity.

Assays are carried out as described in Thomas and Tallman 5 (J. Sio. Chem. 15 6 : 9838-9842, J. Neurosci. 2: 433-440, 1983).

Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer (pH 7.4 at 4°C) . The tissuehomogenate is centrifuged in the cold (4°) at 20,000 x g for20'. The supernatant is decanted and the pellet is 10 rehomogenized in the same volume of buffer and againcentrifuged at 20,000 x g. The supernatant is decanted and the pellet is frozen at -20°C overnight. The pellet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice. The pellet is 15 finally resuspended in 50 volumes (w/vol of 0.05 M Tris HCl buffer (pH 7.4 at 4 0°C).

Incubations contain 100 ml of tissue homogenate, 100 mlof radioligand 0.5 nM (3H-Rol5-1788 pH-Flumazenil] spécifieactivity 80 Ci/mmol) , drug or blocker and buffer to a total

20 volume of 500 ml. Incubations are carried for 30 min at 4°C

then are rapidly filtered through GF3 filters to separate freeand bound ligand. Filters are washed twice with fresh. 0.05 M

Tris HCl buffer (pH 7.4 at 4°C) and ccunted in a liquid scintillation counter. 1.0 mM diazepam is added to some tubes 25 to détermine nonspecific binding. Data are collected in -43- ϋ ί ι 2 > ό triplicate déterminations, averaged and % inhibition of totalspécifie binding is caiculated. Total Spécifie Binding =

Total - Nonspecific. In some cases, the amounts of unlabeleddrugs is varied and total displacement curves of binding are 5 carried out. Data are converted to K/ s. Compounds of theinvention when tested in the assay described above hâve K/s of less than ΙμΜ.

In addition, the following assay may be used to détermineif the compounds of the invention are agonists, antagonists, IC or inverse agonists, and, therefore, their spécifiepharmaceutical utility. The following assay can be employedto détermine spécifie GA3Aa receptor activity.

Assays are carried out as described in White and Gurley (NeuroRepcrt 6.: 1313-1316, 1995} and White, Gurley, Hartnett, 15 Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995} with modifications. Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1-.4 for human derived cl, β, and γ subunits, respectively. For each subunit combination, sufficient

20 message is injected to resuit in current amplitudes of >10 nA when 1 μΜ GABA is applied.

Electrcphysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potentiel of -70 mV. 25 Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current. Each oocyte -44- ü 11 2 9 3 is expcsed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is expressed as a percent-change in current amplitude: 100*((Ic/I)-1), where le is the GA3A evoked current amplitude observed in the presence of compound and I is the GA3A evoked current amplitude observed in the absence of compound.

Specificity of a compound for the Rol5-1788 site is determined following completion of the concentration/effect curve. After washing the oocyte sufficiently to removepreviously appiied compound, the oocyte is exposed to GASA + 1 pM Rol5-1788, followed by exposure to GA3A + 1 pM Rol5-1788 + compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in the presence of Rol5-1788 is subtracted from the percent

changes in current amplitude observed in the absence of 1 pM

Rol5-1788. These net values are used for the calculation of average efficacy and ECS0 values.

To evaluate average efficacy and ECS0 values, the concentration/effect data are averaged across cells and fit to the logistic équation. Average values are reported as mean ± standard error.

The substituted 4-oxo-napthyridine-3-carboxamides ofFormula I and their salts are suitable for the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazépine drugs and -45- for enhancement of 011293 alertness, both in human and non-human animais and domestic pets, especially dogs and cats and farmanimais such as sheep, swine and cattle.

The compounds of general Formula I may be administeredorally, topically, parenterally, by inhalation or spray orrectally in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parentéral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising acompound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be présent in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired otner active ingrédients. The pharmaceutical compositions containing compounds of general

Formula I may be in a form suitable for oral use, for example,as tablets, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, émulsion, hard or soft capsules, or syrups or élixirs.

Compositions intended fer oral use may be preparedaccording to any method known to the art for the manufactureof pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and -46- - fj I ί Z > -jC ΐ ί _ preserving agents in order to provide pharmaceutically élégantand palatable préparations. Tablets contain the activeingrédient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufactureof tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnésiumstéarate, stearic acid or talc. The tablets may be uncoatedor they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.For example, a time delay matériel such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingrédient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, -47- hydrcpropylmethylcellulose sodium l .1 i i Z > .· alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurringphosphatide, for example, lecithin, or condensation productsof an alkvlene oxide with fatty acids, for examplepolyoxyethylene stéarate, or condensation products of ethyleneoxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acidsand a hexitol suc'n as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial estersderived from fatty acids and hexitol anhydrides, for examplepolyethylene sorbitan monooleate. The aqueous suspensions mayalso contain one or more preservatives, for example ethyl, orn-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending theactive ingrédients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a minerai oil such as liquid paraffin. The oily suspensions may contain athickening agent, for example beeswax, nard paraffin or cetylalconol. Sweetening agents such as those set forth above, andflavoring agents may be added to provide palatable oralpréparations. Tnese compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. -48- r- ,ι λ <> -7 υ I ! δ > 3

Dispersible powders and granules suitable for préparationof an aqueous suspension by the addition of water provide theactive ingrédient in admixture with a dispersing or wettingagent, suspending agent and one or more preservatives. 5 Suitable dispersing or wetting agents and suspending agentsare exemplified by those already mentioned above. Additionalexcipients, for example sweetening, flavoring and coloringagents, may also be présent.

Pharmaceutical compositions of the invention may also be 10 in the form of oil-in-water émulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or aminerai cil, for example liguid paraffin or mixtures of these.Suitable emulsifying agents may be naturelly-occurring gums,for example gum acacia or gum tragacanth, naturally-occurring 15 phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation

Products of the said partial esters with ethylene oxide, forexample polyoxyethylene sorbitan monooleate. The émulsions 20 may also contain sweetening and flavoring agents.

Syrups and élixirs may be fcrmulated with sweetening agents, for example glycercl, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative and flavoring and coloring agents. The 25 pharmaceutical compositions may be in the form of a stérile injectable aqueous or oleaginous suspension. This suspension -49- may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agentswhich bave been mentioned above. The stérile injectablepréparation may also be stérile injectable solution orsuspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonie sodium chloridesolution. In addition, stérile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acidfind use in the préparation of injectables.

The compounds of general Formula I may also be administered in the form of sunoositories for rectal administration of the drug ?hese comDositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary températures but liquid at the rectal température and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administeredparenterally in a stérile medium. The drug, depending on thevehicle and concentration used, can either be suspended ordissolved in the vehicle. Advantageously, adjuvants such as -50- r 4 ί f' r 7 <> ! ί - local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about14 0 mg per kilogram of body weight per day are useful in thetreatment of the above-indicated conditions (about 0.5 mg toabout 7 g per patient per day) . The amount of activeingrédient that may be combined with the carrier materials toproduce a single dosage form will vary depending upon thespecies of the host animal to be treated, the particular modeof administration, and the body weight of the host. Dosageunit forms will generally contain between from about 1 mg toabout 500 mg of an active ingrédient.

It will be understood, however, that the spécifie doselevel for anv particular patient will dépend upon a variety offactors including the activity of the spécifie compoundemployed, the âge, body weight, general health, sex, diet, time of administration, route of administration, and rate ofexcrétion, drug combination and the severity of the particulardisease undergoing therapy.

For administration to non-human animais, the compositionmay also be added to the animal feed or drinking water. Itwill be convenient to formulate these animal feed and drinking water 'compositions with a mullet-dose of the drug so that the animal takes in an appropriate quantity cf the composition along with its diet. It will also be convenient to présent -51- the composition as a premix for addition to the feed or drinking water.

An illustration of the préparation of compounds of theprésent invention is given in Scheme I. 5 Scheme I:

NO,

RtOH, KOH or HNR2R3, i-PrûH, Δ

X. .N

Pd/C, h2

EtOH NO,

X. .N

'EtO2C^c°2EtEK? ' Δ

CO2Et

CO2H

-Y and carry the 1N NaOH, EtOH, Δ

In Scheme I, the substituents X définitions set forth above for formula I.

Those having skill in the art will recognize that thestarting materials may be varied and additional steps employed to produce compounds encompassed by the présent inventions, as demonstrated by the following examples. In some cases, -52- 10 011293 protection of certain reactive functionalities may be necessary to achieve some of the above transformations. Ingeneral, the need for such protecting groups will be apparentto those skilled in the art of organic synthesis as well asthe conditions necessary to attach and remove such groups.

The invention is illustrated further bv the followingexamples which are not to be construed as limiting theinvention in scope or spirit to the spécifie procedures described in them. EXAMPLE 1

Préparation of starting materials and intermediates

The starting materials and various intermediates may beobtained from commercial sources, prepared from commerciallyavailable organic compounds, or prepared using well known synthetic methods.

Représentative examples of methods for preparing intermediates of the invention are set forth below. 1 2-Benzvlamino-5-nitropvridine A solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) and benzylamine (2.3 mL, 21 mmol) in éthanol (10 mL) was heated at reflux for 2 h. The reaction mixture was allowed to ambient température, 1.2 N HCl was added, the precipitate collected, rinsed with water, and dried to give 2.02 g of 2- benzylamino-5-nitropyridine as a yellow solia. -53- .011 9 f ' Z- 2 . 2-Benzylamino-5 -aminopyridine A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and10% Pd/C (202 mg) in éthanol (20 mL) was placed in a Paarbottle and shaken under ’nydrogen (50 PSI) for 3 h. Themixture was filtered through Celite using dichloromethane andconcentrated in vacuo to afford 1.76 g of 2-benzylamino-5-aminopyridine as a burgundy oil. 3. Diethyl(2-benzylamino-5-pyridylaminomethylene)malonate A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethyl ethoxymethylenemalonate (1.78 mL, 8.82 mmol) was heated at 130° C for 2 h. While warm, the mixture wasevacuated. After cooling, the product was triturated with 2:1hexanes/ether and collected to give 2.74 g of diethyl (2-benzylamino-5-pyridylaminomethylene) malonate as a gold solid. 4. Sthyl 6-benzylamino-4-oxo-l, 4-dihydro- 1,5-naphthvridine-3-carboxvlate

Diethyl (2-benzylamino- 5-pyridylaminomethylene) malonate (2.23 g) was added to diphenyl ether (10 mL) preheated to 230° C. Keating was continued for 0.5 h, the reaction flask removed from the oil bath, and the mixture allowed to cool to ambient température. The product was triturated with 1:1ether:hexanes, collected, rinsed with ether, and dried to give -54- 011293u I i z y : 1.47 g of ethyl 6-benzylamino-4-oxo-l,4-dihydro-l,5- naphthyridine-3-carboxylate as a brown solid. 5. 6-Benzvlamino-4-oxo-1,4-dihvdro-1,5-naphthvridine-3-carboxvlic acid A mixture of ethyl 6-benzylamino-4-oxo-l,4-dihydro-l,5- naphthyridine-3-carboxylate (60 mg) , IN NaOH (2 mL), and éthanol (0.5 mL) was heated at reflux for 2 h. The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride was added. The resulting precipitate was collected, rinsed with water and ether, then dried to afford35 mg of 6-benzylamino-4-oxo-1,4-dihydro-l,5-naphthyridine-3-carboxylic acid as a brown solid. 6. 2-Ethoxv-5-nitropyridine 2-Chloro-5-nitropyridine was added to a homogeneous solution of potassium hydroxide (3.93 g, 70 mmol) in éthanol (35 mL) at ambient température. The reaction mixture was stirred for 1 h, then diluted with saturated aqueous ammoniumchloride and cooled in an ice bath. The precipitate wascollected, rinsed with water and dried to give 3.50 g of 2-ethoxy-5-nitropyridine as a beige solid. 7 . 2-Ethoxv-5-aminopvridine A mixture of 2-ethoxy-5-nitropyridine (3.60 g) and 10%

Pd/C (360 mg) in éthanol (40 mL) was placed in a Paar bottle -55- 011293 and shaken under hydrogen {50 PSI) for 15 h. The mixture was filtered through Celite using dichloromethane and concentratedto give 2.892 g of 2- ethoxy-5-aminopyridine as a gold solid. 8 . Diethvl ( 2 -ethoxy-5-pyridylaminomethylene) malonate A mixture of 2- ethoxy-5-aminopyridine (2.89 'g, 20.9 mmol) and diethyl ethoxymetnylenemalonate (4.23 mL, 20.9 mmol)was heated at 130° C for 4.5 hours. While warro, the mixturewas evacuated. After cooling, the product was triturated with2:1 hexanes:ether and collected to afford 6.04 g of diethyl(2-ethoxy-5-pyridylaminomethylene) malonate as a beige solid. 9. Ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5 -naohthyridine- 3 -oarboxvlate

Diethyl (2-ethoxy-5-pyridylaminomethylene) malonate (6.04 g) was added to diphenyl ether (20 mL) preheated to 230° C.

Heating was continued for 0.5 h, the reaction flask removed from the oil bath, and the mixture allowed to cool to ambient température. The product was triturated with 1:1 ether-.hexanes, collected, rinsed with ether, and dried to give2.98 g of ethyl 6-ethoxy-4-oxo-l, 4-dihydro-l, 5-naphthyridine-3-carboxylate as a tan solid. 10. 6-Ethoxy-4-oxo-1,4-dihydro- 1,5-naphthvridine-3-carboxvlic acid -56- 011295 A mixture of ethyl 6-ethoxy-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylate (2,98 g), IN NaOH (50 mL) , and éthanol (10 mL) was heated at reflux for 2 h. The reaction mixture- was cooled in an ice bath, acidified, and theresulting precipitate collected, rinsed with water and driedto give 2.42 g of 6-ethoxy-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylic acid as a beige solid. 11. 4-[(n-tert-Butoxycarbonyl)- methvlaminomethyl)benzvlamine hvdrochloride a) A solution of α-bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile (50 mL) was added dropwise to a stirring solution of 40% aqueous methylamine (21.5 mL, 250 mmol) in acetonitrile (50 mL) at 0° C. The reaction mixture was stirred 0.5 h, then concentrated in vacuo. Water was added to the residue and extracted 2X with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.41 g of 4- (methylaminomethyl)benzonitrile as a yellow oil containing-30% of Ν,Ν-bis (4-benzonitrile)methyl-amine. The aqueous was extracted

2X with 9:1 adjusted to pH>8 and dichloromethane :methanol.. The combined extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.13 g of pure 4- (methylamino)benzonitrile as a colorless oil. -57- b) Di-tert-butyl dicarbonate (1.77 g, 8.1 mmol) wasadded to a stirring mixture of 4- (methylaminomethyl) -benzonitrile (1.13 g, 7.7 mmol) and IN NaOH (15 mL) in 1,4- dioxane (15 mL) at ambient température. The reaction mixture was stirred for 2 h, poured into saturated açueous sodium chloride, and extracted with dichloromethane. The organiclayer was dried over sodium sulfate,’ filtered, and concentrated in vacuo to give 1.81 g of crude 4-{N-(tert-butoxycarbonyl)-methylaminomethyl 3 benzonitrile. The crudematerial was filtered through a 1" . silica gel pad, firsteluting with hexane, then with ether. The ether filtrate wasconcentrated to give pure 4-{N-(tert-butoxycarbonyl)-methylaminomethyl]benzonitrile as a colorless oil. To thiswas added 10% Pd/C (170 mg) and éthanol in a Paar bottle. The mixture was shaken under hydrogen (50 PSI) for 4.5 h, then filtered through Celite and concentrated in vacuo. The residue was taken up in éthanol, cooled in an ice bath, and1.0 M HCl in ether (10 mL) was added dropwise. The resuitingprecipitate was filtered and dried in a vacuum oven to give1.346 g of 4-[(N-tert-butoxycarbonyl)-methylaminomethyl) -benzylamine hydrochloride as a pale gray solid. EXAMPLE 2 1. N-n-Butvl-6-benzvlamino-4-oxo-l, 4-dihvdro- 1,5-naohthvridine-3 - carboxamide -58-

Το a solution of 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (59 mg, 0.2 mmol) andtriethylamine (59 ml, 0.42 mmol) in N,N-dimethylformamide (1mL) at 0° C was added ethyl chloroformate (39 mL, 0.41 mmol). 5 After stirring at 0° C for 1 h, n-butylamine 99 mL, 1.0 mmol) was added. The reaction mixture was stirred an additional 2 h at 0° C, then poured into saturated aqueous sodium chloride.The mixture was cooled in an ice bath, the precipitatecollected, rinsed with water and ether, then dried to afford 10 49 mg of N-n-butyl 6-benzylamino-4-oxo-1,4-dihydro-1,5- naphthyridine-3-carboxamide as a brown solid. Compound 1. Analternats name for this compound is: N-butyl (4-oxo-6- (benzylamino) (3-hydro-5-azaquinolyl) ) formamide. 15 2. N-[2-(Ethylthio) ethyl] 6-methoxy-4-oxo- 1,4-dihvdro-1,5-napththvridlne-3-carboxamide

To a solution of 6-methoxy-4-oxo-l,4-dihydro-1,5- naphthyridine-3-carboxylic acid (55 mg, 0.25 mmol) and 20 triethylamine (73 mL, 0.53 mmol) in N,N-dimethylformamide (2mL) at 0° C was added ethyl chloroformate (4 9 mL, 0.52 mmol) .After stirring at 0° C for 0.5 h, 2-(ethylthio) ethyl aminehydrochloride (172 mg, 1. mmol) and triethylamine (13 9 ml, 1 mmol) was added. The reaction mixture was stirred for 0.5 h 25 at 0° C, then poured into 1.2 N HCl, cooled in an ice bath, andthe resulting precipitate collected, rinsed with water anddried to give 57 mg of N-[2-(ethylthio) ethyl] 6-methoxy-4-oxo- -59- 011293 1.4- dihydro-l, 5-napththyridine-3-carboxamide as a beige solid;m.p. 257-259° C (d). Compound 5. 3. N-[4-(Methylaminomethyl)benzyl] 6- (2-methoxyethoxy)-4-oxo-1,4-dihydro-l, 5naphthvridine-3-carboxamide hvdrochloride

To a solution of 6-(2-methoxyethoxy)-4-oxo-l,4-dihydro- 1.5- naphthyridine-3-carboxylic acid (106 mg, 0.4 mmol) andtriethylamine (117 mL, 0.84 mmol) in 4:1 tetrahydrofuran: N,N-dimethylformamide (2 mL) at 0° C was added ethyl chloroformate(66 mL, 0.82 mmol). After stirring at 0° C for 1.25 h, 4-((N-tert-butoxycarbonyl) -methylaminomethyl) benzylamine hydrochloride (120 mg, 0.42 mmol) and triethylamine (59 mL,

0.42 mmol) was added. The reaction mixture was stirred at 0° C for 0.75 h, then allowed to ambient température and stirred for 20 h. N,N-Dimethylethylenediamine (132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, then concentrated in vacuo. The resiaue was cooled in an ice bath, saturated aqueous ammonium chloride was added and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated to give 177 mg of crude N-(4-(N- tert butoxycarbonyl)-methylaminomethyl)benzyl] 6-(2- methoxyethoxy) -4-oxo-1,4-dihydro-l, 5-naphthyridine-3- carbcxamide.

To crude N-[4-(N- tert -butoxycarbonyl)- methylaminomethyl)benzyl) 6- (2-methoxyethoxy) -4-oxo-l,4- -60- 011293 dihydro-1,5-naphthyridine-3-carboxamide in dichloromethane (1 mL) was added 1:1 trifluoroacetic acid:dichloromethane (2 mL) dropwise at ambient température. The reaction mixture was stirred for one hour, concentrated in vacuo, the residue dissolved in éthanol, and 1.0M HCl in ether (0.8 mL) wasadded. The precipitate was collected to afford 68 mg of N- [4-(methylaminomethyl) benzyl] 6- (2-methoxyethoxy)-4-oxo-l,4- dihydro-1,5-naphthyridine-3-carboxamide hydrochloride.

Compound 10. 4. N- (4-Methoxybenzyl) 6-pyrrolidino- 4-oxo-1,4-dihydro-l,5-naohthvridine-3-carboxamide

To a solution of 6-pyrrolidino-4-oxo-l,4-dihydro-l,5- naphthvridine-3-carboxylic acid (80 mg, 0.3 mmol) and triethylamine (0.11 mL, 0.8 mmol) in 5:1 tetrahydrofuran: N,N- dimethylformamide (6 mL) at 0°C was added ethyl chloroformate (0.09 mL, 0.9 mmol) . After stirring at 0°C for 0.5 h, 4- methoxybenzylamine (0.1 mL, 0.8 mmol) was added. The reaction mixture was allowed to ambient température and stirred for 0.5 h. Water was added and the resulting precipitate collected, washed with water and ether and dried. The solid was combined with IN NaOH (5 mL) and éthanol (2 mL) and heated at reflux for Ό".25 h. The reaction mixture was cooled in an ice bath, 3N HCl was added to achieve pH 8, and the precipitate collected, rinsed with water and ether and dried to give 6 9 mg -61- 011293 of N-(4-methoxybenzyl) 6-pyrrolidino-4-oxo-l,4-dihydro-l,5-naphthyri-dine-3-carboxamide; m.p. 270-272’ C. Compound 8. 5a. N-Benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthvridine-3-carboxamide, sodium sait N-Benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-l,5-napthyridine-3-carboxamide (914 mg, 2.83 mmol) is suspended in ethyl alcohol (9 mL) and 10 N NaOH (0.27 mL) is added. The mixture is heated until homogenous, subsequently cooled andconcentrated. The resulting solid is treated with ethylacetate (5 mL) and ethyl alcohol (250 mL) , and the resultingmixture is stirred for 22h. The precipitate is collécted,rinsed with ethyl acetate and dried to give the sodium sait of N-benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-napthyridine-3- carboxamide (Compound 12) (960 mg) as a tan solid. 5b. N-benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- napthyridine-3-carboxamide, potassium sait; (Compound 13) m.p. 286-288 °C. EXAMPLE 3

The following compounds were prepared essentiallyaccording to the procedures described in Examples 1-2: . (a) N'-n-Butyl 6-chloro-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide; (Compound 14) m.p. 330° C (d) . -62-

CM 011 29 (b) N-Propan-3-ol 6-methoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 15) m.p. 271-272° C. (c) N-n-Sutyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 16) tn.p. 274-276° C. (d) N- (2-Ethylthio) ethyl 6-methoxy-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 17) m.p. 257-259° C. (e) N-n-Sutyl 6-(N-benzylamino)-4-oxo-l, 4-tetrahydro- 1,5-naphthyridine-3-carboxamide (Compound 18). (f) N- n-Pentyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 19) m.p.265-265° C. (g) N-(3-Isopropoxy)propyl 6-ethoxy-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 20). (h) N-Benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 21) m.p.275-27 8° C. (i) N-2-Pentyl 6-ethoxy-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 22). -63- Ü11293 (j) N-(2-Tetrahydrofuranyl)methyl 6-ethoxy-4-oxo-l,4- tetrahydro-1,5- naphthyridine- 3 -carboxamide ; m.p.235-237°C. (Compound 4). (k) N-(3-Methoxy)propan-2-ol 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 23). (l) N- (3-Methoxy)propyl 6-ethoxy-4-oxo-l.4-tetrahyd.ro- 1,5-naphthyridine-3-carboxamide (Compound 24). (m) N-(2-Methoxy) ethyl 6-ethoxy-4-oxo-l, 4-tetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 25). (n) N-Isoamyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napnthyridine-3-carboxamide; (Compound 26) m.p. 279-281° C. (o) N-(2-Furanyl)methyl 6-et'noxy-4-oxo-l, 4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 27) m.p. 245 (d)° C. (p) N-(3-Methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; m.p. 250-253’ C. (Compound 11) . -64- (q) N-(3-Ethoxy)propyl 6-etnoxy-4-oxo-l, 4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 28) m.p. 224-225° C.

Cl 1293 (r) N-2-(2-Methyl)butyl 6-ethoxy-4-oxo-l,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 29) m.p. 282-283° C. (s) N-2-Pentan-l-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 30) m.p. 232-234° C. (t) N-5-Pentanol 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide ; (Compound 31) m.p. 223-224° C. (u) N-l-Cyclohexan-2-ol 6-ethoxy-4-oxo-l,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 32) m.p.268-270eC. (v) N-Benzyl 6-methoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 33) m.p. 273-274° C. (w) N-(2-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 34) m.p. 266-27l'C. (x) N-(3-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide ; (Compound 35) m.p.281°C. (y) N-(4-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 36) m.p.283-286°C. (z) N-(Imidazol-4-ylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. (Compound 6). -65-

Ci 1223 [Alternate name: (6-ethoxy-4-oxo(3-hydro-5-azaquinolyl)) -N-(imidazol-4-ylmethyl) formamide] (aa) N-4-Tetrahydropyranyl 6-ethoxy-4-oxo-l,4-tetrahydro-5 1,5-naphthyridine-3-carboxamide; (Compound 37) m.p.303-305°C. (bb) N-(3-Thienyl)methyl 6-ethoxy-4-oxo-l,4-tetrahydro- l, 5-naphthyridine-3-carboxamide; (Compound 38) m.p.324-325eC. 10 (cc) N-2-(6-Methyl)heptan-6-ol 6-ethoxy-4-oxo-1,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 39) m. p.281°C. (dd) N-(2-Tetrahydropyranyl)methyl 6-ethoxy-4-oxo-1,4-15 tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 40) m.p.2Q4-2Q6eC. (ee) N-(2-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (Compound 41) m.p. 157-162'C 20 (ff) N-(3-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-

1,5-naphthyridine-3-carboxamide; (Compound 42) m.p. 297-302C (gg) N-(4-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-25 1,5-naphthyridine-3-carboxamide (Compound 43). -66- 011293 ύ II 2 > ύ (hh) N-(4-Methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 44) m.p,186°C. (ii) N-(3-Fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-5 1,5-naphthyridine-3--carboxamide; (Compound 45) m.p.301eC. (jj) N-Benzyl 6-(N-methyl, N-toluenesulfonyl-amino)-4-oxo-l, 4-tetrahydro-l,5-naphthyridine-3-carboxamide. (Compound2). [Alternate name: (6-(methyl((4- 10 metnylphenyl ) sulfonyl) amino) -4-oxo (3-hydro-5-azaquinolyl) ) -N-benzylf ormamide] (kk) N-Benzyl 6-(methylamino)-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide (Compound 46). 15 (11) N-Piperonyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide; m.p.l90°C. (Compound 9). (mm) N-Piperonyl 6-methoxy-4-oxo-1,4-tetrahydro-l,5 -20 naphthyridine-3-carboxamide; (Compound 47) m.p.l86°C. (nn) N-2-(Imidazol-4-ylethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 48) m.p.268°C. -67- 011293 (oo) N-(4-Methylbenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 49) m.p.270-271°C. (pp) N-Benzyl 6- (2-methoxyethoxy)-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 50) m.p.>300“C. • (qq) N-Benzyl 6-dimethylamino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 51) m.p.246-249eC. (rr) N-ïsoamyl 6-morpholino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 52) m.p.295-298’C. (ss) N-Benzyl 6-morpholino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 53) m.p. 88-90° C. (tt) N-(2-Fluorobenzyl) 6-morpholino-4-oxo-l, 4-tetrahydro-1,5- naphthyridine - 3 - carboxamide ; m.p.l37-139°C. 9Compound 7) . (uu) N-(3-Ethoxy)propyl 6-morpholino-4-oxo-1,4- tetrahydro-1,5-naphthyridine-3-carboxamide ; (Compound 54) m.p.150-152°C. (w) N-n-Butyl 6-morpholino-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide ; (Compound 55) m.p.275-277eC. -68- Ü11293 (ww) N-(2-Pyridyl)methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 56) m.p. 125-127’C. (xx) N-(2-Thienyl)methyl 6-(2-methoxyethoxy)-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 57) m. p.235-236’C. (yy) N-Isoamyl 6-dimethylamino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 58) m.p. 254-256’C. (zz) N-(2-Thienyl)methyl 6-morpholino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 59) m.p.277 - 279°C. (aaa) N-(2-Thienyl)methyl 6-dimethylamino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 60) m.p. 240 C. (bbb) N-(2-Thiazolyl)methyl 6-morpholino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 61) m. p.270 - 272eC. (ccc) N-(4-Methylaminomethyl)benzyl 6-ethoxy-4-oxo- 1,4-tetrahydro-l, 5-naphthyridine-3-carboxamide (Compound 62). -69- 011223 (ddd) N-[4-(l-Methylamino) ethyl]benzyl 6-ethoxy-4- oxo-1,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound63) m.p. 259-262 C. (eee) N-(2-Tetrahydrofuranyl) methyl 6-dimethylamino-4-oxo-1,4 -tetrahydro-1,5-naphthyridine-3-carboxamide;(Compound 64) m.p. 285-288C. (fff) N-n-Pentyl 6-morpholino-4-oxo-l,4-tetrahydro- l, 5-naphthyridine-3-carboxamide; (Compound 65) m.p.278-280eC. (gag) N-(3-Methoxybenzyl) 6-morpholino-4-oxo-1,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 66) m. p.204-205’C. (hhh) N-(3-Fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 67)m.p.263-265°C. (iii) N-(4-Methylaminomethyl)benzyl 6-(2- metnoxyethoxy)-4-oxo-1,4-tetrahydro-l,5-naphthyridine-3 -carboxamide; (Compound 68) m.p. 275-277'c. (jjj) N-n-3utyl 6-pyrrolidino-4-oxo-l, 4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 69) m.p.57-58°C. -70-

Ci 1293 (kkk) N-(4-Methoxybenzyl) 6-pyrrolidino-4-oxo-l, 4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 70) m.p.270 -272°C. (111) N- (2-Thienyl)methyl 6-pyrrolidino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 71) m.p.265-267°C. (mmm) N-[4- (1-Methylamino)ethyl]benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-l,5-naphthyridine-3-carboxamide (Compound 72) . (nnn) N-(4-Methylaminomethyl)benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 73) m.p.270-271°C. (ooo) N-[4-(1-Methylamino)ethyl] benzyl 6-chloro-4- oxo-1,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 74) m.p.260-263°C. (ppp) N-(4 -(1-Methylamino)etnyl] benzyl 6- pyrrolidino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-,carboxamide hydrochloride; (Compound 75) m.p.298-302eC. -71- G Ί Ί 2 2 3 (qqq) N-(4-Ethoxybenzvl) 6-morpholino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 76)m.p.278-281’C. (rrr) N- (4-Ethoxybenzyl) 6-pyrrolidino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 77)m.p.265-267°C. (sss) N-(4-Chlorobenzyl) 6-morpholino-4-oxo-l, 4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 78) m.p.295-297®C. (ttt) N-(3-Chlorobenzyl) 6-morpholino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 79) m.p.276-278°C. (uuu) N-Piperonyl. 6-dimethylamino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 80) m.p.246-247°C. (wv) N-Benzyl 6-(2-methylamino) ethoxy-4-oxo-1,4- tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 81) . (www) N-Benzyl 6-(2-dimethvlamino)ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 82) m.p.194-198°C. -72- (xxx) N-(4-Ethylaminomethyl)benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 83)m.p.194 °C (d). (yyy) N-Benzyl 6-(2-methoxy)ethylamino-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 84)m.p.254-257°C. (zzz) N- (3-Methylaminomethyl) benzyl ô-ethoxv-4-oxo- 1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride;(Compound 85) m.p.l87°C (d) . (aaaa) N-(4-Dimethylaminomethyl)benzyl 6-ethoxy-4-oxo- 1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride ;(Compound 8c) m.p.2 00°C (d) . (bbbb) N- (3-Methylaminomethyl ) benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 87) m.p.l84°C (d) . (cccc) N-[4-(1-Imidazolylmethy)]benzyl 6-ethoxy-4-oxo l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 88) m. p. 143-145’C. -73- 011223 (dddd) N-[4- (1-morpholinomethyl)]benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1, 5-napthyridine-3-carboxamide ; (Compound 89) m.p. 215-218°C. (eeee) N-[3-(1-morpholinomethyl)]benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide; (Compound 90) m.p. 195-198°C. (ffff) N-{4-[1-(4-methylpiperazinomethyl)]benzyl 6-ethoxy-4 -oxo-1,4-tetrahydro-1,5-napthyridine-3-carboxamide (Compound 91). (9999) N-[4-(1,2,4-triazol-1-ylmethyl)]benzyl 6-ethoxy-4 - oxo-1,4 - tetrahydro-1,5-napthyridine-3-carboxamide ;(Compound 92) m.p.l95-200'c. (hhhh) N-Benzyl 6-benzylamino-4-oxo-1,4-tetrahydrΟ-Ι ,5-naphthyridine-3-carboxamide (Compound 93). (iiii) N-Cyclohexyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 94) . (jjjj) N-Cyclohexylmethyl 6-ethoxy-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide (Compound 95). -74-

Ci (kkkk) N- (4 -Aminobenzyl)- 6-ethoxy-4-cxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 96). (1111) 14-(4 - Pyridvlmethyl ) 6-ethoxy-4-oxo-1,4-tetrahydro 5 -1, 5-naphthyridine~3-carboxamide (Compound 97). (mmmrn) N-Benzyl 6 -1etrahydrolsoquinolinyl-4-oxo-1,4 -tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 99). 10 (nnnn) N-{4 -[1 -[4 -(4-Fluorobenzyl)piperazinyl] methyl] benzyl} 6-(2,2,2-trifluoroethyl)-4-oxo-1,4-tetrabydro-1,5-naphthyridine-3-carboxamide, (Compound 99) m.p. 234-236°C. (oooo) 14-( 3 - i sopropoxypropyl ) 6-ethoxy-4-oxo-1,4 - 15 tetrahydro-1,5-naphthyridine-3-carboxamide Compound 3 [alternative name: (6-ethoxy-4-oxohydropyridino[3,2-b] pyridin- 3-yl)-N- [3 -(methylethoxy)propyl]carboxamide] .

The invention and the manner and process of making and 20 using it, are now described in such full, clear, concise and. exact ternis as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the présent invention and that modifications may be made 25 therein without departing from the spirit or scope of theprésent invention as set forth in the daims. To particularlypoint out and distinctly claim the subject matter regarded asinvention, the following daims conclude this spécification. 75

Claims (90)

1. 011293 WHAT IS CLAIMED IS:

   1. A compound of the formula:

   <Y or the pharmaceutically acceptable salts thereof wherein: 5 X is hydrogen, halogen, -ORX, Cx-Ct alkyl optionally substitutedwith up to three groups selected independently fromhalogen and hydroxy, or -NRjR3; X is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, 10 isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, or benzothienyl, each of which is optionally substituted with up to three groups selectedfrom halogen, Ci~C6 alkyl, Ci~C4 alkoxy, Cj-Cj alkylthio,hydroxy, amino, mono or di (C\-C6) alkylamino, cyano, nitro, 15 trifluoromethyl or trifluoromethoxy; or X represents a carbocyclic group containing from 3-7 members, up to two of which members are optionally hetero atomsselected from oxygen and nitrogen, where the Xcarbocyclic group is optionally substituted with one or 20 more groups selected from halogen, Cj-Cj alkoxy, mono- or di (Cx-C6) alkylamino, sulfonamide, aza (C3-C7) cycloalkyl, C3- C7 çycloalkylthio, . C1-Ci alkylthio, phenyltnio, or aheterocyclic group; 76 011293 Y is lower alkyl having 1-8 carbon atoms optionally substituted with up to two groups selected from halogen,C3-C, cycloalkyl, Ci-C6 alkoxy, mono- or di {CrC6) alkylamino, sulfonamide, aza (C3-C7) cycloalkyl, C3-C, cycloalkylthio, Cj-Cê alkylthio, phenylthio, aheterocyclic group, -OR,,-NRSR6, SR,, or optionallysubstituted aryl; or Y is a carbocyclic group having from 3-7 members atoms, where up to three of which members are optionally hetero atomsselected from oxygen and nitrogen and where any member ofthe Y carbocyclic group is optionally substituted withhalogen, -OR,,-NR5R6, SR7, aryl or a heterocyclic group; Rx is hydrogen, lower alkyl having 1-5 carbon atoms, orcycloalkyl having 3-7 carbon atoms, where each alkyl maybe optionally substituted with -OR,, or -NR5R6; R2 and R3 are the same or different and represent hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy, aryl, halogen, or mono- or di-lower alkyl; aryl or aryl (C3-C6) alkyl where each aryl is optionallysubstituted with up to three groups selected from.halogen, hydroxy, Cj-C6 alkyl, Cj-Cj alkoxy, or mono-or di (Cj-CJ alkylamino; cycloalkyl having 3-7 carbon atoms optionally mono ordisubstituted with halogen, alkoxy, or mono- or di-lower alkyl; or 77 011293 Rx is hydrogen, lower alkyl, or (C,-C7) cycloalkyl, wherethe alkyl or cycloalkyl is optionally substituted withhalogen, lower alkoxy, or mono- or di (C^-CJ alkylamino; (iii) a group of the formula: R3R2Nxp/O\ 5 where G is as defined above for ii; and R2 and Rj independently represent hydrogen, lower alkylhaving 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, -SO2Re where R8 is (Cj-CJ alkyl, (C3- 10 C7) cycloalkyl, or optionally substituted phenyl, or R2 and Rj together with the nitrogen atom to which theyare attached form a heterocyclic moiety such asimidazolyl, pyrrolidinyl, morpholinyl, piperazinyl,or piperidinyl; 15 (iv) a group of the formula:

   where Rj is as defined above for iii; R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or2 0 cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (Cj- Cs) alkoxy or mono- or di (C.-CJ alkylamino group s ; and G is as defined above for ii; (v) a group of the formula: 79 011293

   where R2 and G are as defined above for iv and ii, respectively, and Rs and R6 independently represent hydrogen, lower alkylhaving 1-6 carbon atoms, cycloalkyl having 3-7carbon atoms, -SO2R6 where R„. is (Cj-CJ alkyl, (C,- C,) cycloalkyl, or optionally substituted phenyl, or Rs and R6 together with the nitrogen atom to which theyare attached form a heterocyclic moiety; (vi) a group of the formula: O

   where G is as defined above for ii; or (vii) a group of the formula: r2n

   where each G is as defined above for ii; and (viii) lower alkyl having 1-8 carbon atoms or cycloalkyl having' 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen, (C^-Cg) alkoxy, QÛ 011293 alkoxyalkoxy where each alkoxy is (C^-CJ alkoxy, (Οχ-CJ alkylthio, (Cj-C,) cycloalkylthio, aryl, heteroaryl, ormono- or di (Cx-C6) alkylamino groups; (ix) a group of the formula:

   where K is lower alkylene having 1-6 carbon atomeoptionally substituted with (Cj-C6) alkyl or alkylene, or acyclic group of the formula K' f (CH)m

   (CH2)n 10 where K' independently represents hydrogen or (Cj- C6) alkyl or alkylene, n is 0, 1, or 2, and m is an integer of from 1 to 5, with the proviso that the sum of n + m is not less than 1 or greater than 5; and 15 R9 is hydrogen, lower alkyl, or (C3-C7) cycloalkyl, where the alkyl or cycloalkyl is optionally substituted withhalogen, lower alkoxy, or mono- or dialkylamino; (x) a group of the formula: 20 where K is defined as above in ix; (xi) a group of the formula:

   OR13 81 011223 where K is as defined above for ix, and Rn is hydrogen, lower alkyl having 1-6 carbon atoms, orcycloalkyl having 3-7 carbon atoms, where the alkyland cycloalkyl groups are optionally substitutedwith one or more (C,-C6) alkoxy or mono- or di(Cx-C6) alkylamino groups; and (xii) a group of the formula:

   where K is as defined above for ix, and R, is hydrogen, lower alkyl having 1-6 carbon atoms, orcycloalkyl having 3-7 carbon atoms; and (xiii) a group of the formula: . x nr14r,5 where K is as defined above for ix; and R14 and R1S independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, - SOjR8 where R8 is as defined above, or Rh and R15 together with the nitrogen atom to which they are attached form a heterocyclic moiety; 32 (xiv) a group of the formula: 01I293

   where K and R15 are as defined above in ix and xii,respectively; 5 (xv) a group of the formula:

   10 15 where K is as defined above for ix; R10 and R10' are the same or different and are selectedfrom hydrogen, halogen, hydroxy, lower alkoxy having1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms; Ru, Ru' , and R12 are the same or different and areselected from hydrogen, halogen, hydroxy, -OR,,-CR,(R9)NR5R6, -CR7(R16)OR4, or Ru-R12 taken together with the atoms to which they areattached form a (hetero)çyclic ring; and R16 is hydrogen, lower alkyl having 1-6 carbon atoms, orcycloalkyl having 3-7 carbon atoms (xvi) a group of the formula: 20 63 Ü1 » 29 3

   where K is as defined above for ix; and W is heteroaryl;

   where K is as defined above for ix; Rl0 and Ru are as defined above for xv, and R17 is hydrogen, lower alkyl, or (C3-C7)cycloalkyl, where10 the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di (Cj-C6) alkylamino;(xviii) a group of the formula:

   where K, R10, R13, and R17 are as defined above; 15 (xix) a group-of the formula:

   flt» where each K is independently defined as above for ix and R10 is defined above; (xx) a group of the formula: 01129

   NR)4Ri5 where K, Rlo, Ru, R14, and R1S are as defined above; and(xxi) a group of the formula:

   5 where K, R10 ' ^12 ' R14, and Rl5 are as defined above.
2. 3. A compound according to claim 1, which is

   where 10 A is Ci-Cj alkylene; Ra is phenyl optionally mono-, di-, or trisubstituted withhalogen, lower alkyl, lower alkoxy, or mono- or di-C1-CÉ alkylamino, or mono- or di-Cj-Cj alkylaminolower alkyl; and 15 Rb is lower alkyl or lower cycloalkyl.
3. 4. A compound according to claim 1, which is 65

   wherein 10 A is C^-Cg alkylene; R# and R/ are independently phenyl groups optionallymono-, di-, or trisubstituted with' halogen, loweralkyl, lower alkoxy, or mono- or di-C\-Cs alkylamino,or mono- or di-Cj-Cg alkylamino lower alkyl; and Rc is hydrogen or lower alkyl.
4. 5. A compound according to claim 1, which is

   wherein A is Ci-Cg alkylene; Rd and Re are independently lower alkyl groups. 15
5. 6. A compound according to claim 1, which is

   N R»H wherein A is Cj-Cg alkylene; as Ü11293 Rd is lower alkyl; and R( is a group of the formula: M where E is oxygen or nitrogen; andM is Cx-Cj alkylene or nitrogen. A compound according to claim 1, which is

   N R' H 3 10 15 wherein A is Cx-C6 alkylene; Rd is lower alkyl; and Ra' is phenyl optionally mono-, di-, or trisubstitutedwith halogen, lower alkyl, lower alkoxy, or mono- ordi-Ci-Cj alkylamino, or mono- or di-Cx-C6 alkylaminolower alkyl. 20
6. 8. A compound according to claim 1, which is O O Rd wherein A is Ci-Cj alkylene; and Rd and Re are independently lower alkyl groups. 87 011293
7. 9. .A compound according to claim 1, which is

   wherein D is nitrogen or CH; D' is nitrogen. or oxygen; A is Ci-Cg alkylene; and 10 Ra' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- ordi-Ci-Cg alkylamino, or mono- or di-Cj-Cs alkylaminolower alkyl. 15

   is wherein A is Cx-C6 alkylene; and Ra' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- ordi-Cj-Cg alkylamino, or mono- or di-Cj-Cg alkylaminolower alkyl. 88 20

   wherein A is Ci~Cs alkylene; and Rd is lower alkyl; A' represents oxygen or methylene; and r is an inteqer of from 1-3. A compound according to claim 1, which is

   wherein A is C!-C6 alkylene; Rg is lower alkyloxy lower alkyl; and Ra' is phenyl optionally mono-, di-, or trisubstitutedwith halogen, lower alkyl, lower alkoxy, or mono- ordi-C1-C6 alkylamino, cr mono- or di-C,-Ct alkylaminolower alkyl. 89 011293
8. 13. A compound according to claim 1, which is N-n-Butyl6-benzylamino-4 -oxo-1,4-dihydro-1,5-naphthyridine-3- carboxamide.
9. 14. A compound according to claim 1, which is N-[2-(Ethylthio)ethyl] 6-methoxy-4-oxo-l, 4-dihydro-1,5-napththyridine-3-carboxamide.
10. 15. A compound according to claim 1, which is N-[4-(Methylaminomethyl)benzyl] 6- (2-methoxyethoxy) -4-oxo-1,4-d i hydro-1,5-napht hyr i d i ne-3 -c arboxami de.
11. 16. A compound according to claim 1, which is N-(4-Me thoxybenzy1) 6-pyrroli dino-4 -oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide.
12. 17. A compound according to claim 1, which is N-n-Butyl6-chloro-4-oxo-1,4-tetrahydro-l, 5-naphthyridine-3 - carboxamide.
13. 18. A compound according to claim 1, which is N-Propan- 3- ol 6-methoxy-4-oxo-1,4-tetrahydro-l, 5-naphthyridine-3 - carboxamide.
14. 19. A compound according to claim 1, which is N-n-Butyl 6 - e t hoxy - 4 - oxo -1,4 -1 e t r ahydro -1,5- naph t hy r i di ne - 3 - c arboxami de .
15. 20. A compound according to claim 1, which is N- (2- Ethylthio)ethyl 6-methoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide.
16. 21. A compound according to claim 1, which is N-n-Butyl6 -(N-benzylamino)-4-oxo-1,4 -tetrahydro-1,5-naphthyridine-3- carboxamide. 90 011293
17. 22. A compound according to claim 1, which is N- n- Pentyl 6-ethoxy-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3- carboxamide.
18. 23. A compound according to claim 1, which is N-(3-5 Isopropoxy)propyl 6-ethoxy-4-oxo-l, 4-tetrahydro-1,5- naphthyridine-3 -carboxamide.
19. 24. A compound according to claim 1, which is N-Benzyl6-ethoxy-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3 -carboxamide.
20. 25. A compound according to claim 1, which is N-2-PentyI10 6-ethoxy-4-oxo-l, 4- tetrahydro-1,5-naphthyridine- 3 - carboxamide.
21. 26. A compound according to claim 1, which is N-(2-Tetrahydrofuranyl)methyl 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-napht nyr idine-3-c arboxami de.
22. 27. A compound according to claim 1, which is N-(3- 15 Methoxy)propan-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide.
23. 28. A compound according to claim 1, which is N-(3- Methoxy) propyl 6-ethoxy-4 - oxo -1,4-tetrahydro - 1,5- naphthyridine-3-carboxamide. 20 29. A compound according to claim 1, which is N-(2- Methoxy)ethyl 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine 3-carboxamide.
24. 30. A compound according to claim 1, which is N-Isoamyl6 - e thoxy- 4 - oxo -1,4 -1 e t r ahydro -1,5- napnthyridine - 3 - carboxamide 91 011293
25. 31. A compound according to claim 1, which is N-(2- Furanyl)methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide.
26. 32. A compound according to claim 1, which is N-(3-Methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
27. 33. A compound according to claim 1,'which is N-(3-Ethoxy) propyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine- 3-carboxamide.
28. 34. A compound according to claim 1, which is N-2-(2-Methyl)butyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine- 3-carboxamide.
29. 35. A compound according to claim 1, which is N-2-Pentan-l-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3- carboxamide.
30. 36. A compound according to claim 1, which is N-5- Pentanol 6 -ethoxy-4 -oxo-1,4-tetrahydro-1,5-naphthyridine-3 - carboxamide.
31. 37. A compound according to claim 1, which is N-l- Cyclohexan-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine- 3 -carboxamide .
32. 38. A compound according to claim 1, which is N-Benzyl6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3- carboxamide. 92 -93- 0112
33. 39. A compound according to claim 1, which is N-(2-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide.
34. 40. A compound according to claim 1, which is N-(3-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
35. 41. A compound according to claim 1, which is N-(4-Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide.
36. 42. A compound according to claim 1, which is N-(4/5-Imi da zoly1)methy1 6-et hoxy- 4 -oxo-1,4 -1 e t rahydro-1,5-naphthyridine-3-carboxamide.
37. 43. A compound according to claim 1, which is N-4-Tetrahydropyranyl 6-ethoxy-4-oxo-i,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
38. 44. A compound according to claim 1, which is N-{3-Thienyl)methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
39. 45. A compound according to claim 1, which is N-2-(6-Methyl)heptan-6-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
40. 46. A compound according to claim 1, which is N-(2-Tetrafiydropyranyl)methyl 6- ethoxy-4- oxo -1,4- tetrahydro-1,5-naphthyridine-3-carboxamide. 93 011293
41. 47. A compound according to claim 1, which is N-(2-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine- 3-carboxamide.
42. 48. A compound according to claim 1, which is N-(3- 5 Fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine 3-carboxamide. .49. A compound according to claim 1, which is N-(4-Fluorobenzyl) 6-ethoxy-4-oxo-1,4 - tetrahydro-1,5-naphthyridine 3-carboxamide. 10 50. A compound according to claim 1, which is N-(4- Methoxybenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide .
43. 51. A compound according to claim 1, which is N-(3-Fluorobenzyl) 6-methoxy-4 -oxo-1,4-tetrahydro-1,5- 15 naphthyridine-3-carboxamide.
44. 52. A compound according to claim 1, which is N-Benzyl6- (N-methyl, N-toluenesulfonyl-amino) -4-oxo-1,4 - tetrahydro- 1,5-naphthyridine-3-carboxamide .
45. 53. A compound according to claim 1, which is N-Benzyl 20 6- (methylamino) -4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3 - carboxamide.
46. 54. A compound according to claim 1, which is N- Piperônyl 6-ethoxy-4-oxo-1,4-tetra'nydro-l, 5-naphthyridine-3- carboxamide. 94 011293
47. 55. A compound according to claim 1, which is N-Piperonyl 6-methoxy-4-oxo-1,4-tetrahydro-l,5-naphthyridine-3- carboxamide.
48. 56. A compound according to claim 1, which is N-2-(4/5-5 Imidazolyl)ethyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide.
49. 57. A compound according to claim 1, which is N-(4-Methylbenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-l,5-naphthyridine- 3-carboxamide C. 10 58. A compound according to claim 1, which is N-Benzyl 6- (2-methoxyethoxy) -4-oxo-l,4-tetrahydro-l,5-naphthyridine-3- carboxamide.
50. 59. A compound according to claim 1, which is N-Benzyl6-dimethylamino-4-oxo-1,4-tetrahydro-l,5-naphthyridine-3- 15 carboxamide.
51. 60. A compound according to claim 1, which is N-Isoamyl 6 - morphol ino - 4 - oxo -1,4 -1 e t r ahydro -1,5- napht hyr i dine - 3 - carboxamide.
52. 61. A compound according to claim 1, which is N-Benzyl 6-morpholino-4-oxo-1,4-tetrahydro-l,5-naphthyridine-3- carboxamide.
53. 62. A compound according to claim 1, which is N-(2- Fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-l,5-naphthyricine-3-carboxamide. 95 C1'l 292 €3. A compound according to daim 1, which is N-(3-Ethoxy)propyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
54. 64. A compound according to daim 1, which is N-n-Butyl6-morpholino-4-oxo-1,4 -tetrahydro-1,5-naphthyridine-3- carboxamide.
55. 65. A compound according to daim 1, which is N-(2-Pyridyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
56. 66. A compound according to daim 1, which is N-(2-Thienyl)methyl 6- (2-methoxyethoxy) -4-oxo-l,4-tetrahydro-l,5-napht hyr idine - 3 - carboxamide.
57. 67. A compound according to daim 1, which is N-Isoamyl6-dimethylamino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3- carboxamide.

    67. A compound according to claim 1, which is N-(2-Thienyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
58. 68. A compound according to claim 1, which is N-(2-Thienyl)methyl 6-dimethylamino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
59. 69. A compound according to daim 1, which is N-(2-Tniaz'olyl) methyl 6-morpholino-4-oxo-1,4 - tetrahydro-1,5-naphthyridine-3-carboxamide. 96 011293
60. 70. A compound according to claim 1, which is N-(4-Methylaminomethyl) benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyr i'dine - 3 - carboxamide.
61. 71. A compound according to claim 1, which is N-[4-(l-5 Methylamino) ethyl] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5- naphthyridine- 3 -carboxamide.
62. 72. A compound according to claim 1, which is N-(2-Tetrahydrofuranyl) methyl 6-dimethylamino-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3 -carboxamide. 10 73. A compound‘according to claim 1, which is N-n-Pentyl 6 -morphol ino- 4 - oxo-1,4 - tetrahydro-1,5 -naphthyridine -3 - carboxamide.
63. 74. A compound according to claim 1, which is N-(3-Methoxvbenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5- 15 naphthyridine-3-carboxamide.
64. 75. A compound according to claim 1, which is N-(3-Fluorobenzyl) 6-morpholino-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide.
65. 76. A compound according to claim 1, which is N-(4-20 Methylaminomethyl)benzyl 6- (2-methoxyethoxy) -4-oxo-1,4- tetrahydro-1,5-naphthyridine-3-carboxamide.
66. 77. A compound according to claim 1, which is N-n-Sutyl6 -pyrrol i dino - 4 - oxo -1,4 - tetrahydro -1,5 - naphthyridine - 3 - carboxamide. 97 011 29
67. 78. A compound according to claim 1, which is N-{4-Methoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
68. 79. A compound according to claim 1, which is N-(2-5 Thienyl) methyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide. \ 80. A-compound according to claim 1, which is K-[4-(l-Methylamino) ethyl 3 benzyl 6-dimethylamino-4-oxo-1,4 - tetrahydro 1.5- naphthyridine-3-carboxamide. 10 81. A compound according to claim 1, which is N-(4- \ Methylamino)benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride.
69. 82. A compound according to claim 1, which is N-[4-(1-Methylaminomethyl)ethyl]benzyl 6-chloro-4-oxo-l,4-tetrahydro- 15 1,5-naphthyridine-3-carboxamide.
70. 83. A compound according to claim 1, which is N-[4-(l·Methylamino) ethyl] benzyl 6-pyrrolidino-4 -oxo-1,4 -tetrahydro- 1.5- naphthyridine-3-carboxamide hydrochloride.
71. 84. A compound according to claim 1, which is N-(4- 20 Ethoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide.
72. 85. A compound according to claim 1, which is N-(4-Ethoxÿbenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 98 011293
73. 86. A compound according to claim 1, which is N-(4-Chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
74. 87. A compound according to claim 1, which is N-(3-5 Chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide.
75. 88. A compound according to claim 1, which is N-P i p e rony1 6-di me thy1amino-4 -oxo-1,4-1 e trahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 10 89. A compound according to claim 1, which is N-Berizyl 6-(2-methylamino)ethoxy-4-cxo-1,4-tetrahydro-l, 5-naphthyridine-3-carboxamide.
76. 90. A compound according to claim 1, which is N-Benzyl6-(2-dimethylamino)ethoxy-4-oxo-1,4-tetrahydro-1, Ξ- Ι 5 naphthyr i dine-3 -c arboxami de.
77. 91. A compound according to claim 1, which is N-(4-Ethylaminomethyl)benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.
78. 92. A compound according to claim 1, which is N-Benzyl 20 6-(2-methoxy)ethylamino-4-oxo-1,4-tetrahydro-l, 5- naphthyridine- 3 -carboxamide.
79. 93. A compound according to claim 1, which is N-(3-Methÿlaminomethyl)benzyl 6-ethoxy-4-oxo-1,4-tetrahydro - 1,5-naphthyridine-3-carboxamide hydrochloride. 99 CI1293
80. 94. A compound according to claim 1, which is N-(4-Dimethylaminomethyl)benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine- 3 -carboxamide hydrochloride.
81. 95. A compound according to claim 1, which is N-(3- 5 Methylaminomethyl)benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride.
82. 96. A compound according to claim 1, which is N- [4-(1-Imidazolylmethy)]benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide.
83. 97. A compound according to claim 1, wherein Y is pyrimidinylmethyl, pyridylmetnyl, or a group of the formula: where R1B represents hydrogen, amino, mono-, or di (C,- C6) alkylamino, or Cx-C6 alkyl optionally substituted with a Rl915 where R18 represents:

    where V and V' are independently CH or nitrogen; A' ' is Cj-Cg alkylene; and R20 is phenyl, pyridyl, or pyrimidinyl, each of which is20 optionally mono-, di-, or trisubstituted independently withhalogen, hydroxy, C^Cg alkoxy, amino, or mono- or di(C.- Cs) alkylamino. 100 G11293
84. 98. A compound according ta claim 1, which is 10 1 10 1 15 20 15 20 O X

    N H wherein A is C\-Ce alkylene; X is defined as above for Formula I; andRie is (i) amino or mono- or di (Cj-Cj) alkylamino; or (ii) lover alkyl optionally substituted with

    where V and V' are independently CH or nitrogen; A'', is Cj-Ce alkylene; and R20 is phenyl, pyridyl, or pyrimidinyl, each of which isoptionally mono-, di-, or trisubstituted independently withhalogen, hydroxy, alkoxy, amino, or mono- or dHCj- Ce) alkylamino.
85. 99. A compound according to claim 1, which is N-Benzyl 6 - benzyl amino - 4 - oxo-1,4 -1 et r ahydro -1,5 -naphthyr idine - 3 - carboxamide. 101
86. 100. A compound according co claim 1, which is N-Cyclohexyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 011 29 3
87. 101. A compound according to claim l, which is N- 5 Cyclohexylmethyl 6-ethoxy-4-oxo-l,4-tetrahvdro-l,5- naphthyridine-3-carboxamide.
88. 102. A compound according to claim 1, which is N-(4-Aminobenzyl)-6-ethoxy-4-oxo-l,4-tetrahydro-1, 5-naphthyridine- 3-carboxamide.
89. 103. A compound according to claim 1, which is N-(4-Pyridylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro -1,5-naphthyridine 3 -carboxamide. 15
90. 104. A compound according to claim 1, which is N- Benzyl S-tetrahydroisoquinolinyl-4-oxo-l,4-tetrahydro-1,5- naphthyridine-3-carboxamide. 20 105. A compound according to claim 1, which is N-{4- [1-[4-(4-Fluorobenzyl)piperazinyl] methyl]benzyl} 6-(2,2,2-tri fluoroethyl)-4-oxo-1,4 -tetrahydro-1,5-naphthyridine-3 - carboxamide. 102