LV12539B - 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

LV 12539

SUBSTITUTED 4-OXO-NAPTHYRIDINE-3-CARBOXAMlDES AS GABA BRAIN RECEPTOR LIGANDS BACKGROUND OF THE INVBNTION Field o£ the Invention

This invention relates to substituted 4-oxo-napthyridine-3-carboxamides and, in particular, such compounds w'nich selectiveiv bind to GAEAa receptors. This invention also relates to pharmaceuticai ccmpositions comprising such compounds and to the use of such compounds in enhancing alertness and treating anxiety, overdoses cf ber.zodiazepine-type drugs, Down Svnarome, and sleep, seizure and cognitive disorders.

Description of the Related Art y-Aminobutyric acid (GAŠA) is regarded as one of the major inhibitory amino acid transmitters in the mammalian brain. Over 40 years have elapsed since its presence in the brain was demonstrated (Roberts & Frankel, J. Biol. Chem 187: 55-63, 1550; Udenfriend, J. Biol. Chem. 157: 65-69, 1950). Since that time, an enormous amount of effort has been devotea tc implicating GABA ir, the etiolcgy of seizure disorders, sleep, anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). Widely, although unequally, distributed through the mammalian brain, GABA is said to be a transmitter at approximately 30% of the synapses in the brain. GABA mediates many of its actions through a complex of proteins localized both on celi bodies and nerve endings; these are called GABAa receptors. Postsynaptic responses to GABA are mediated through alterations in chloride conductance that generally, although not invariably, lead to 5 hyperpolarization of the celi. Drugs that interact at the GABAa receptor can possess a spectrum of pharmacological activities depending on their abilities to modify the actions of. GABA.

The 1,4-Benzodiazepines, such as diazepam, continue to 10 be among the most widely used drugs in the world as anxiolytics, sedative-hypnotics, muscle relaxants, and anticonvulsants. A number of these compounds are extremely potent drugs; such potency indicates a site of action with a high affinity and specificity for individual receptors. Early 15 electro-physiological studies indicated that a major action of benzodiazepines was enhancement of GABAergic inhibition. Presently, those compounds possessing activity similar to the benzodiazepines are called agonists. Compounds possessing activity opposite to benzodiazepines are called inverse 20 agonists, and the compounds blocking both types of activity have been termed antagonists.

The GABAa receptor subunits have been cloned from bovine and human cDNA libraries (Scnoenfield et al. , 1988; Duman et al., 1989). A number of distinct cDNAs were identified as 2 5 subunits of the GABAa receptor complex by cloning and expression. These are categorized into a, β, γ, δ, ε, and -2- LV 12539 provide a molecular basis for the GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980; Levitan et al., 1989). The γ subunit appears to enable drugs like benzodiazepines to modify the GABA responses (Pritchett 5 et al., 1989). The presence of low Hill coefficients in the binding of ligands to the GABAa receptor indicates unique profilēs of subtype specific pharmacological action.

With the discovery of the "receptor" for the benzodiazepines and the subsequent definition of the nature of 10 the interaction between GABA and the benzodiazepines, it appears that the behaviorally important interactions of the benzodiazepines with different neurotransmitter systems are due in a large part to the enhanced ability of GABA itself to modify these systems. Each modified system, in turn, may be 15 associated with the expression of a benavior. Depending on the mode of interaction, these compounds are capable of producing a spectrum of activities (either sedative, anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety) .

Various 1,4-dihydro-4-oxo-l, 5-naphthyridine-3-carboxvlic 20 acids and esters have been disclosed. See, for example, Eur. J. Med. Chem.-Chim. Ther. (1977), 12 (6), 549-55.

Polish Patent No. 125299 discloses compounds of the formula: 0

R H -3- vherein N denotes a ring nitrogen in the 5- or 6- position, and R is C02H or COjEt.

Several 1,4-dihydro-4-οχο-1,5-napthyridine- 3 -carboxamide derivatives of penicillin said to possess antibacterial 5 activity have been disclosed. For example, German Patent No. DD 279887 discloses a compound of the formula

Japanese Patent No.72-45118 discloses ampicillir. derivatives of 1,4-dihydro-4-oxo-3-naphthyridines. -4- LV 12539

SUMMARY OP THE INVENTION

This invention provides novel compounds of Formula I which interact with a GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compounds of Formula I. The invention also provides compounds useful in the diagnosis and treatment of anxiety, Down Syndrome, sieep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness. Accordingly, a broad embodiment of the invention is directed to compounds of Formula I:

N H wherein: X is hydrogen, halogen, -OR,, C.-Cs alkyl optionally substituted with up to three groups selected independently from halogen and hydroxy, or -NRZR3; X is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, 1,2,3,4 -tetranydroisoquinolinyl, benzofuranyl, benzothienyi, each of which is optionally substituted with up to three groups selected from halogen, 0χ-06 alkyl, Cx-C4 alkoxy, Cļ-Cg alkylthio, -5- hydroxy, arnino, mono or di (C^-Cj) 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 members are optionally hetero atoms selected from oxygen and nitrogen, where the X carbocyclic group is optionally substituted with one or more groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, or a heterocyclic group; Y is lower alkyl having 1-8 carbon atoms optionally substituted with up to tv/o groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, 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 three of which members are optionally hetero atoms selected from oxygen and nitrogen and where anv member of the Y carbocyclic group is optionally substituted with halogen, -OR4,-NRsR6, SR7, aryl or a neterocyclic group;

Ri is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, where each alkyl may be optionally substituted with -0R4, or -NRSR6; R2 and R3 are the same or different and represent -6- f LV 12539 hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy, aryl, halogen, or mono- or di-lower alkyl; aryl or aryl (C^CJ alkyl where each aryl is optionally substituted with up to three groups selected from halogen, hydroxy, C^-Cj alkyl, Cx-C6 alkoxy, or mono-or di (Cj-Cg) alkylamino; cycloalkyl having 3-7 carbon atoms optionally mono or disubstituted with halogen, alkoxy, or mono- or di-lower alkyl; or - SOjRj ; R4 is as defined for R1(·

Rs and R6 carry the same definitions as R3 and R3, respectively; R7 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; and R8 is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3- 7 carbon atoms, or optionally substituted phenyl.

These 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. -7-

DETAILED DESCRIPTION OP THE INVENTION

The novel compounds encompassed by the invention can be described 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 R2 and R3 together form a Cs-alkylene group. Further, R2 and R3 together may represent an alkylene or alkenylene group optionally containing up to two heteroatoms selected from nitrogen and oxygen. The resulting groups 10 include imidazolvl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinvl.

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

20 Preferred compounds of Formula I are those where X represents (C^-Cj) alkoxy, more preferably (Cj-C3) alkoxy.

Particularly preferred compounds of Formula I include methoxy or ethoxy as the X group.

Stili other preferred compounds of Formula I include 25 those where the Y is lower alkyl, e.g., methyl or ethyl, substituted with phenyl, pyridyl, or pyrimidinyl. A more -8- LV 12539 preferred Y group is benzyl optionally substituted with halogen, (Cj-Cs) alkyl, (Cj-C6) alkoxy, amino, or mono- or ditC^ C6)alkyl.

Where R2 and R3 in Formula I represent optionally 5 substituted aryl or aryl (Ci-C6) alkyl, the aryl group is preferably phenyl, pyridyl, or pyrimidinyl and the alkyl groups are preferably methyl and ethyl. More preferred are benzyl and phenyl. Particularly preferred is benzyl. Vīhere X is optionally substituted C^-Cj alkyl, the alkyl 10 group is preferably optionally substituted methyl, ethyl, or propyl. More preferred are perhalomethyl and trihaloethyl. Preferred halogēns are fluorine. Particularly preferred is 2,2,2-trifluoroethyl. X in Formula I may be an optionally substituted phenyl, 15 naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl, 4-(1,2- dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, or benzothienyl 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

O O

wherein: -9- 5 X is (i) hydrogen, halogen, mono- or dialkylamir.c, alkoxy, (ii) a group of the· formula:

RiOv. where G is lower alkylene having 1-6 carbon atoms, or a cyclic group of the formula (CH2)n

(CH2)m 10 where n is 0, 1, or 2, and m is ar. 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 Rj is hydrogen, lower alkyl, or (C3-C-; cycloalkyl, where the alkyl or cycloalkyl is optionallv substituted with halogen, lower alkoxy, or mono- or di (C.-C6) alkylamino; (iii) a group of the formula:

15 G where G is as defined above for ii; and R2 and Rj inaependentlv represent hyarogen, lower alkyl having 1-6 carbon atoms, cyclcalkyl having 3-7 carbon atoms, -SOjRe where R8 is (C.-Cs) alkyl, (C3- 20 C-,) cycloalkyl, or optionallv substituted phenyi , or R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morphoiinyl, piperazinyl, or piperidinyl; -10- LV 12539 (iv) a group of the formula*. * R4<Xq,Nv where R2 is as defined above for iii; R, is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (C,-Cs) alkoxy or mono- or di (C^-CJ alkylamino groups; and G is as defined above for ii; (v) a group of the formula*. *

RjRsN^N^ where R2 and G are as defined above for iv and ii, respectively, and

Rs and Rs independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -SOxR8 wnere Re is (Cx-C6) alkyl, (C5- C7) cycloalkyl, or optionally substituted phenyl, or

Rs and Rfi together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl; (vi) a group of the formula:

where G is as defined above for ii; or (vii) a group of t'ne formula:

5 where each G is as defined above for ii; and Y is

(viii) lower alkyl having 1-8 carbon atoms or cycloalkyI having 3-7 carbon atoms, any cf which may be optionally 10 substituted with one or more hydroxy, nalogen, (C:- C6)alkoxy, alkoxyalkoxy where each alkoxy is (Cj-CJ alkoxy, (Cļ-Cj alkylthio, (C3-C7) cycloalkylthio, aryl, heteroaryi, or mono- or di (C;-Ce) alkvlamino groups; (ix) a group of the formula:

where K is lower alkvlene having 1-6 carbon atoms optionally substituted with (C,-Cs)alkyl or alkylene, or a cyclic group of the formula K' (CH)m

(CH2)„ where K' independently represents hyarogen 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 -12- 20 LV 12539 sum of n + m is not less than 1 or greater than 5; and R, is hydrogen, lower alkyl, or (C3-C,) cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, 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:

where K is as defined above for ix, and r13 is hydrogen, lower alkyl having 1-6 carbcn 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 (C^-

Cs) alkylamino groups; and (xii) a group of the formula:

K

where K is as defined above for ix, and R7 is hydrogen, lower aikyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms,· and (xiii) a group of the formula·. NR14R15 where K is as defined above for ix; and R14 and RIS independently represent hvdrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -SOjRe where R„ is as defined above, or R14 and R1S together with the nitrogen atom to which they are attached form a heterocycli c moiety such as imidazolyi, pyrrolidinyl, morpholinyl, piperazinvi, or piperidinyl; (xiv) a group of the formula:

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

where K is as defined above for ix; LV 12539 R10 and R10' are the same or different and are selected from hydrogen, (C:-CJ alkyl, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms;

Ru, Rn', and Ria are the same or different and are selected from hydrogen, Cj-C6 alkyl, halogen, hydroxy, -OR,,-CR7(R9)NRSR6, -CR,(R16)OR,, or Rn and Rl2 taken together with the atoms to which they are attached form a (hetero)cyclic ring; and R1S is hydrogen, lower alkyl having 1-6 carbon atoms, or cvcloalkyl 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; Rl0 and R1: are as defined above for xv, and R17 is hydrogen, lower alkyl, or (Cj-C7)cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di(Cj-C,)alkylamino; (xviii) a group of the formula: R10 A .OR u kRi2 Rk- r12, 17 .K. (xix) a group of the formula:

R10 .K

where each K is indepenaently as defined above fcr ix and R10 is defined above; (xx) a group of the formula:

11 NR14R15 10 where K, Rl0, Ru, R14, and R1S are as defined above; (xxi) a group of the formula: R10 ŅR14R15

.K

K where K, R1S, R12, R14, and R;5 are as defined above; 15 (xxii) pyrimidinyl (C.-C6) alkvl or pyridyl {C1-C6) alkyl; cr (xxiii) a group of the formula: -16- LV 12539

Rie where R;e represents hydrogen, -amino, mono-, or di(Cj-Ce) alkylamino, or Cj-Cg alkyl optionally substituted with a R,, where Rlg represents:

where V and V' are inaependently CH or nitrogen; A' ' is Ci-Cj alkylene; and R20 is pnenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted independently with 10 halogen, hydroxy, Cj-C6 alkoxy, amino, or mono- or di (02-Cs) alkylamino.

Preferred pyrimidinyl (C;-Cs) alkyl Y groups are 2- and 4-pyrimidinylmethyl. Preferred pyridyl (Cļ-Cg) alkyl Y groups are 15 2- and 4-pyridylmethyl.

Preferred benzyl Y groups are those where Rle is amino or a substituted methyl or ethyl group. More preferred R18 substituents are piperazin-1-yl or piperidin-1-yl substituted 20 at the 4-position with a halogenaced benzyl group. Particularly preferred . benzyl Y groups are 4- [1- [4 - (4-Fluorobenzyl)piperazinyl] methyl]benzyl and 4-(l-[4-(4-Fluorobenzyl) piperidiny 1 ] methyl] benzyl. -17- "X" quinolinyl, isoquinolinyl, tetrahydroquinolinyl

Preferred groups in Formula IA are vanous or tetrahydroisoquinolinyl groups, e.g. groups of the f rv* .N. V ί H ArN· k Ak 1 kkk Γι f Y> A H fk H ArN k-1 k AJa k' Λ the

The following formulae are preferred embodiments 02 inventicn: o 0

Λ 10 wherein Y is defined above. O 0

wherein Z represents halogen and Y is as defined above 15

0 O

Λ wherein Rt and Y are defined above. -18- LV 12539

wherein R:, Ra, and Y are defined above.

wherein R,, R3, G, and Y are defined above.

-19-

IX IX 5 wherein RJf R4, G, and Y are defined above.

wherein R2, Rs, R6, G, and Y are defined above.

XII wherein RJf G, and Y are defined above. 15 0 0

wherein X is defined above and U is (Cx-C6)lower alkyl or {C2-Ce) cycloalkyl. -20- LV 12539

,KN N OR, H w’nerein X, K, and R, are defined above. 5

wherein X, K, and R, are defined above. O 0

sr7 wherein X, K, and R- are defined above. -21- 15 ο ο

wherein X, Κ, R,,, and Rl5 are defined above.

N N' H R r15 wherein X( K, and R1S are defined above.

10 wherein R10 / Rl0' are the same or different and may be selected from hydrogen, (Cj-CJalkyl, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon 15 atoms;

Ru, Rn' , and R.2 are the same or different and may be selected from hvdrogen, (C.-Cž) alkyl, halogen, hydroxy, -OR<(-CR7(R9)Nr5R6, -CR, (R,)OR,; or

Ru and R.j taken together with the atoms to which they are 20 attached form a (hetero)cyclic ring; and R9 is as defined above. -22- LV 12539

. ,κ. N W H wherein X and K are defined above; and 5 VJ is heteroaryl.

wherein X, K, R R;c, and R,, are defined above.

wherein X, K, and R1C are defined above. -23- 11ο ο

ĶlO Ķ NR14R15 wherein X, K, R14, Rls, R10> and Ru are defined above.

Preferred compounds of the invention are encompassed by the following formulae:

wnere A is Cl-C6 alkylene;

Ra is phenyl cptionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-15 C.-C6 alkylamino, or mono- or di-C^-Cs alkylamino lower aikyl; and R& is lower alkyl or lower cycloalkyl.

More preferred compounds of Formula XXVII are tnose w’nere A is methylene, R, is phenyl opcionally substitutea with methyl 20 or ethyl, and Re is lower alkyl. Particularly preferred -24- LV 12539 compounds of Formula XXVII are those where A is methylene, R, is phenyl and RB is C,-C, alkyl.

5 wherein A is C1~Ci alkylene;

Ra and Ra' are independently phenyl groups optionally mono-, di-, or trisubst ituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C^-C* alkylamino, 10 or mono- or di-Cj-Cj alkylamino lower alkyl; and

Rc is hydrogen or lower alkyi.

More preferred compounds of Formula XXVIII are those where A is methylene, Ra and Ra' are inaependently phenyl optionally substituted with methyl or ethyl, and Rc is lower 15 alkyl. Particularly preferred compounds of Formula XXVII are those where A is methylene( Ra is phenyl substituted in the para position with lower alkyl, Ra' is phenyl, and R: is C.-C3 alkyl.

-25- A is Cj-C4 alkylene;

Rd and R, are independently lower alkyl groups.

More preferred compounds of Formula XXIX are those where A is C2-C4 alkylene. Particularly preferred compounds of Formula XXIX are those where A is C2-C4 alkylene, Rd is C.-C3 alkyl, and Rt is C2-C4 alkyl.

Formula XXX wherein A is Cj-C6 alkylene;

Rd is lower alkyl; and R. is a group of the formula:

M where E is oxygen or nitrogen; and M is C3-C3 alkylene or nitrogen.

More preferred compounds of Formula XXX are those where A is C-Cj alkylene. Stili more preferred compounds of Formula XXX are those where A is C2-C4 alkylene, Rd is C,-C3 aikyl, and Re is C2-C4 alkyi. Particularly preferred compounds of Formula XXX are those where A is C2-C4 alkylene, Rd is C,-C3 alkyl, Re is C2-C4 alkyl, and E is nitrogen and M is methylene, E is oxygen and M is methyler.e or ethylene, or E and M are both nitrogen. -26- LV 12539

Other preferred compounds of Formula XXX are those where R« is furanyl, tetrahydrofuranyl, or imidazolyl.

Formula XXXI

5 wherein A is Cļ-Cj alkylene;

Rd is lower alkyl optionally substituted with amino or mono- or di (C:-Cs) alkylamino; and R,' is phenyl optionaily mono-, di-, or trisubstituted 10 with halogen, lower alkyl, lower alkoxy, or mono- or di-C,-Ce alkvlamino, or mono- or di-C,-Cs alkylamino lower alkyl.

More preferred compounds of Formula XXXI are those where A is Cj-Cj alkylene, R4' is phenyl optionally substituted with 15 methyl or ethyl, and Rd is C,-C3 alkyl. Stili more preferred compounds of Formula XXXI are where A is methylene, R4' is phenyl optionally substituted with methyl or ethyl, and Rd is C3-Ce alkyl. Particularly preferred compounds of Formula XXXI are sodium, potassium, or ammonium salts of the corresponaing 2 0 parent compound.

Other preferred compounds of Formula XXXI are those where Ra' is phenyl substituted with mono- or di-(Cj-C6) alkvlamino lower alkyl. -27- 5 10 15

Formula XXXla

wherein A is Cļ-Cg alkylene; Rd is lower alkvl; and Ra" is phenyl, pyridyl» imidazolyl, pyrimidinyl, or pyrrolyl, each of which is cptionally subscituted with up to two groups selected from halogen, lower alkvl, lower alkoxy, mono- cr di (C.-Cg) alkylammo, or mono- or di-Cļ-Cg alkyiamino lower alkvl.

More preferred compcur.ds of Formula Ra" is imidazolvl and Rd is C-C3 alkyl. compcunds of Formula XXXI are where A imidazclyl, and Rd is Cj-C.: alkvl. XXXIa are those wnere Stili more preferred is methylene, Ra" is

Formula XXXII 0 wherein A is Cl-Cg alkylene; and Rd and Re are independently

-A. lower alkyl groups. -28- 20 LV 12539

More preferred compounds of Formula XXXII are those where A is Cj-Cj alkylene. Particularly preferred compounds of Formula XXXII are those where A is Cj-Cj alkylēne, Rd is Cļ-Cj alkyl, and Re is C;-C3 alkyl.

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

Rs' is phenvl, pyridyl, or thiazolyl, each of which is optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or ai-C,-Cg alkylamino, cr mono- or di-Cļ-Cg alkylaminc lower alkyl.

More preferred compounds of Formula XXXIII are those where A is Cj-Cj alkylene, Ra' is phenyi optionally substituted with lower alkyl or halogen, and D is nitrogen. Stili more preferred compounds of Formula XXXIII are where A is methylene, R/ is phenyl cptionaily substituted with lower alkyl cr halogen, D is nitrogen, and D' is oxygen. -29- Ο Ο

Formula XXXIV wherein Α is Cļ-Cj alkylene; and

Ra' is hydrogen;

Ra' is thienyl or phenyl, each of which is optionally mono-, di-; or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C^-Cj alkylamino, or mono- or di-C^-Cg alkylamino lower alkyl.

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

A‘ (CH2)r

O wherem A is C,-C6 alkylene; and Rd is lower alkyl; A' represents, oxygen or methylene; and r is an integer of from 1-3. -30- LV 12539

More preferred compounds of Formula XXXV are those where A is Cj-Cj alkylene. Particularly preferred compounds of Formula XXXV are those where A is C3-C3 alkvlene, and Rd is C3-C3 alkyl.

wherein 10 A is Cļ-C6 alkylene; and

Rh and Rh' are independently hydrogen or lower alkyl, where each alkyl is optionally substituted with lower alkoxy; A' represents oxygen or methylene; and 15 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 cf Formula XXXV are those where A is C,-C3 alkvlene, and R;_ is C,-C3 alkyl. 20

Formula XXXVI

wherein A is Cj-C6 alkylene; -31-

Rg is lower alkoxy lower alkyl; and

Ra' is pnenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-Cj-Cj alkylamino, or mono- or di-C^-Cs alkylamino 5 lower alkyl.

wherein R. is halogen or iower alkoxy; and 10 15

Rk is iower alkyl or cycloalkyl each of which is optionally substituted with hydroxy, lower alkyl, or lower alkoxy; or

Rk is phenyl (C^CJ alkyl where the phenyl group is optionally mono-, di-, or trisubstituted with halogen, lower alkvl, lower alkoxy, or mono- or di-C1-C& alkylamino/ or mono- or di-C-C6 alkylaminc lower alkyl.

Formula XXXVIII v/nerein A is Cj-C6 alkylene;

Rx is lower alkoxy, ben2yloxy, lower alkoxy lower alkoxy, amino, or mono- or di-(C1-C6) alkylamino; and -32- 20 LV 12539 R„ is pyranyl, dihydropyranyl, tetrahydropyranyl, or hexahydropyranyl, pyridine, dihydropyridine, tetrahydropyridine, or piperidine.

Preferred compounds of Formula XXXVIII are those where R. 5 is lower alkoxy and R^ is tetrahydropyranyl.

Formula XXXIX

wherein A is C;-Ce alkylene; 10 15 20 R„ is lower alkoxy, lower alkoxy lower alkoxy, benzyl, or a group of the formula: o wnere D is nitrogen or CH; and D' is nitrogen or oxygen; and R0 is pyranyl( 2- or 3-tnienyl; or R0 is 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-imidazolyl, each of which may be cpcionally substituted with lower alkyl.

Preferred compounds of Formula XXXIX are those where -33- 0 Ο Formula ΧΧΧΧ Ν ι

Ν Η wherein Α is Ci-Cj alkylene;

Rb and Rfe' are independently hydrogen or lower alkyl, where each lower alkyl is optinally substituted with lower alkoxy; and

Ra' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C.-C6 alkvlamino, or mono- or di-Cļ-Cs alkylamino lower alkyl; or

Ra' is thienyl opcionally substituted with lov/er alkyl.

Formula ΧΧΧΧΙ

N H wherein A is Ct-C£ alkyler.e; D is nitrogen or CH; D' is nitrogen or oxygen; and

Rp is lower alkvi or lower alkyl optionally substituted with lower aikoxy. -24- LV 12539

wherein A is Cļ-Cg alkylene; X is defined as above for Formula I; and Rie is (i) amino or mono- or di (C;-C6) alkylanu.no; or (ii) lower alkyl optior.ally substituted with

^20 where V and V' are independently CH or nitrogen; A'' is C,-C6 alkylene; and R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or trisubstrtuted independentlv with halogen, hydroxy, Cj-Cs alkoxy, amino, or mono- or di (C,-C6) alkylamino.

More preferred compounds of Formula ΧΧΧΧΙΙ are those where V is r.itroger. and X is C.-C6 alkoxy or C.-Cs alkvl optionally subscituted with up to three halogen atoms. Particularly preferred compounds of ΧΧΧΧΙΙ are those where V and V' are nitrogen; X is C-Cj alkcxy or C:-C5 alkyl cptionallv substituted with up to three halogen atoms; A' ' is methylene or ethylene; and RJ0 is halogenated phenyl. A preferred RĪ0 -35- group is 4-fluorophenyl. Highly preferred compounds of ΧΧΧΧΙΙ are those where X is 2,2,2 -trifluoroethyl; V and V' are nitrogen ; R20 is halogenated phenyl; and A and A' are methylene or ethylene. 5

In certain situations, compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In 10 these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric syntnesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving aģent, or 15 chromatography, using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid and base addition salts. Ir. addition, if the compound of 20 the invention is obtained as ar. acid addition salt, the free base can be obtained by basifyinc a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic 25 solvent and treating the solution with an acid, in accordance -36- LV 12539 with conventional procedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include' salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, H00C- (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 like. Those skilled in the art will recoanize a wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methocclogies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.

By lower alkyl in the present invention is meant straight or branched Chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butvl, pentyl, 2-pentyl, isoper.tyl, r.eopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

By cycloalkyl in the present invention is meant cycloalkyl groups having 3-7 atoms such as, fcr example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. -37-

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

By lower alkoxy in the present invention is meant straight or brancned chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, et'noxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By cycloalkoxy in the present invention is meant cycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl is defined above.

By halogen in the present invention is meant fluorine, bromine, chlorine, and iodme. 3y heteroaryl (aromatic heterocvcle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl,

-38- LV 12539 (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.

Specific examples of heteroaryl groups are the following:

wherein Q is nitrogen or -CR9; T is -NR7, oxygen, or sulfur; and 10 R,, R10 , Rjo', Rn/ Rn' , R;j are as defined above.

Where Y represents a carbocyclic group, it is actac’ned co the amide nitrogen by a single bond. The result is an amide of the formula:

reoresents the Y where X is defined as above an carbocyclic group.

Where X is a carbocyclic group, such moiety or group includes both aromatic heterocycles (heteroaryl), unsaturated heterocylic ring systems, and saturated heterocyclic ring -39- 15 systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. Preferred X carbocyclic groups are linked to the parent naphthyridine moiety by a nitrogen atom in the X carbocyclic 5 group. Thus, for example, when pyrrolidinyl is the X carbocyclic group, it is preferably a l-pyrrolidinyl group of the formula:

v-V

Where Y is a carbocyclic group, such moiety or group 10 includes both aromatic heterocycles (heteroaryl groups), unsaturatea heterocylic ring systems, and saturated heterocyclic ring systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyi. Preferred Y carbocyclic groups are linked to the 15 parent naphthyridine carboxamide group by a nitroger. atom in the Y carbocyclic group. Thus, for example, when piperidinyl is the Y carbocyclic group, it is preferably a 1- piperidinyl group of the formula:

By "optionally substituted phenyl" as used herein is meant phenyl groups that are unsubstituted or substituted wit’n up to 3 groups selected independently from halogen, hydroxy, -40- 20 LV 12539 lower alkyl, lower alkoxy; trifluoromethyl, and mono- or di-lower alkylamino.

Represencative compounds of the invention are shown belov in Table 1. 10 15

Compound 1

Compound 2

ComDOund 3 J) Ύ

Compound 4 -41- 5 15 ο ο

Compound 5

Compound 6

Compound 7

OMe

Compound S

-42- LV 12539

The pharmaceutical utility of compounds of this invention is indicated by the following assays for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chern. I£6: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HC1 buffer (pH 7.4 at 4°C) . The tissue homogenate is centrifuged in the cold (4°) at 20,000 x g for 20'. The supernatant is decar.ted and the peliet is rehomogenized in the same volume of buffer and again centrifuged at 20,000 x g. The supernatant is decanted and the peliet is frozen at -20°C overnight. The peliet is then thawed and rehomogenized in 25 volume (original wt/vol) of buffer and the procedure is carried out twice. The peliet is finallv resuspended in 50 volumes (w/vol of 0.05 M Tris HCl buffer (pH 7.4 at 40°C) .

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand 0.5 nM (3H-RoI5-1788 [3H-Flumazenil] specific activitv 80 Ci/mmol) , drug cr blocker and buffer to a total

volume of 500 ml. Incubations are carried for 30 min at 4°C ther. are rapidly filterea through GFB filters to separate free and bound ligand. Filters are washed twice with fresh 0.05 M

Tris KCl buffer (pH 7.4 at 4cC) and counted in a liquid scintillation counter. 1.0 mM diazepam is added to some tubes to cetermine nonspecific bindir.g. Data are collected ir. -43- triplicate determinations, averaged and % inhibition of total specific binding is calculated. Total Specific Binding = Total - Nonspecific. In some cases, the amounts of unlabeled drugs is varied and total displacement curves of binding are carried out. Data are converted to K/s. Compounds of the invention when tested in the assay described above have K/s of less than ΐμΜ.

In addition, the following assay may be used to determine if the compounds of the invention are agonists, antagonists, or inverse agonists, and, therefore, their specific pharmaceutical utility. The fcllowing assay can be eirployed to determine specific GABAa receptor activity.

Assays are carried out as described in White and Gurley (NeuroReņort 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Xenopus Laevis oocytes are enzymatically isolated and injected with nor.-polyadenylated cRNA mixed in a ratio of 4:1:4 for human derived α, β, and y subunits, respect ively. For each subunit combination, sufficient message is injected to resul t in current amplitudes cf >10 nA w'nen 1 μΜ GABA is appl ied.

Eiectrophysiological reccrdings are carried out usir.g the two electrode voltage-clamp technicue at a membrane r.oldinc potential of -70 mV.

Compounds are evaluated against a GABA concentraticn that evokes <10% of the maximal evokable GABA current. Each oocyte LV 12539 is exposed 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 Ic is the GABA evoked current 5 amplitude observed in the presence of compound and I is the GABA 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 10 curve. After washing the oocyte sufficiently to remove previously applied compound, the oocyte is exposed to GABA + l μΜ Rol5-1788, followed by exposure to GABA + 1 μΜ Rol5-1788 ...+ compound. Percent change due to addition of compound is calculated as described above. Anv percent change observed in 15 the presence of Rol5-1788 is subtracted from the percent changes in current amplitude observed in the absence of 1 μΜ Rol5-1788. These net values are used for the caiculation of average efficacy and EC50 values.

To evaluate average efficacy and ECS0 values, the 20 concentration/ef fect data are averaaed across celis and fit tc the logistic equation. Average values are reported as mean ± Standard error.

The substituted 4-oxo-napthyridine-3-carboxamides of Formula I and their salts are suitable for the diagnosis and 25 treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose witn benzodiazepine drugs and

-45- for enhancement of alertness, both in human and non-human animals and domestic pets, especially dogs and cats and farm animals such as sheep, swine and cattle.

The compounds of general Formula I may be administered 5 orally, topically< parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, 10 intrasternal injection or infusion technicrues. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic 15 pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. 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, 20 dispersible powders or granules, emulsion, hara or scft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may 25 contain one or more aģents selected from the group consisting of sweetening aģents, flavoring aģents, coloring aģents and -46- LV 12539 preserving aģents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture 5 of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating aģents, for example, corn starch, or alginic acid; binding aģents, for example starch, gelatin or 10 acacia, and lubricating aģents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to del;ay disintegration and absorption in the gastrointestinal tra;ct and thereby provide a sustained action over a longer period-15 For example, a time aelay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, 20 calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liouid paraffin or olive oil.

Aqueous suspensions contain the active materiāls in admixture with excipients suitable for the manufacture of 25 aaueous suspensions. Such excipients are suspending aģents, for example sodium carboxymethylcellulose, methylcellulose, -47 - hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting aģents may be a naturally-occurring phosphatide, for examplef lecithin, or condensation products 5 of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids 10 and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The agueous suspensions may also contain one or more preservatives, for example ethyl, or 15 n-propyl p-hydroxybenzoate, one or more coloring aģents, one or more flavoring aģents, and one or more sweetening aģents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis 20 oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liauid paraffin. The oily suspensions may contain a thickening aģent, for exampie beeswax, hard paraffin or cetyi alcohol. Sweetening aģents such as those set forth above, and flavoring aģents may be added to provide palatable oral 25 preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. -48- LV 12539

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or vetting aģent, suspending aģent and one or more preservatives. Suitable dispersing or wetting aģents and suspending aģents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring aģents, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying aģents may be naturally-occurring gums, .-ļ&Ā for example gum acacia or gum tragacanth, natūraily-occurring 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, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring aģents.

Syrups and elixirs may be formulated with sweetenina aģents, for example glycerol, propylene givcol, sorbitol cr sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring aģents. The pharmaceutical compositions may be in the form of a sterile injectable agueous or oleaginous suspension. This suspension -49- may be formulated according to the known art using those suitable dispersing or wetting aģents and suspending aģents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or 5 suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally 1C employed as a solvent or suspending medium. For this purpose any bland fixea oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be 15 administered in the form of suppositories for rectal administrat ion of the drug. These compositions can be prepared by mixing the drug wit’n a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the 2C rectum to release the drug. Such materiāls are cocoa butter and polyethylene glycols.

Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or 25 dissolved in the vehicle. Advantageouslv, adjuvants such as -50- LV 12539 local anesthetics, preservatives and buffering aģents can be dissolved in the vehicle.

Dosage Ievels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) . The amount of active ingredient that may be combined with the carrier materiāls to producē a single dosage form will vary depending upon the species of the host animal to be treated, the particular mode of administration, and the body weight of the host. Dosage unit forms will generaliy contain between from about 1 mg to about 500 mg of an active ingredient.

It will be understood, however, that the specific dose Ievel for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, bocy weight, general health, sex, diet, time of administration, route of administration, and rāte of excretion, drug combination and the severity of the particular disease undergoina therapy.

For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will 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 of the composition along with its diet. It will also be convenient to present -51- the composition as a premix for addition to the feed or drinking water.

An illustration of the preparation of compounds of the present invention is given in Scheme I.

C02H

1) Et3N, CICOjEt, OMF

2) H2NY 3) H2NY (XS) or h2NCH2CH2NMe2 Of 1N NaOH, EtOH. Δ

In Scheme I, the substituents X and Y carrv the definitions set forth above for formula I.

Those naving skill in the art wili recognize that the 10 starting materiāls may be varied and additional steps employed to producē compounds encompassed by the present inventions, as demonstrated by the following examples. In some cases, -52- LV 12539 protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for such protecting grdups will be apparent to those skilled in the art of organic synthesis as well as 5 the conditions necessary to attach and remove such groups.

The invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. 10 EXAMPLE 1

Preparation of starting materiāls and intermediates

The starting materiāls and various intermediates may be obtained from commercial sources, preparec from commercially 15 available organic compounds, or prepared using weil known synthetic methods.

Representative examples of methods for preparina intermediates of the invention are set forth below. 20 1. 2-Benzvlamino-5-nicropvridine A solution of 2-chloro-5-nitropyridine (1.59 a, 10 mmol) and benzylamine (2.3 mL, 21 mmol) in ethanoi (10 mL) was heated at reflux for 2 h. The reaction mixture was allowed to ambient temperature, 1.2 N HC1 was added, the precipitate 25 collected, rinsed with water, and dried to give 2.02 g of 2-benzylamino-5-nitropyridine as a yellow solia. -53- 2 . 2-Benzvlamino-5-aminopvridine A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and 10% Pd/C (202 tng) in echanol (20 mL) was placed in a Paar 5 bottle and shaken under hydrogen (50 PSD for 3 h. The mixture v/as filtered through Celite using dichloromethane and concentrated in vacuo to afford 1.76 g of 2-benzylamino-5-aminopyridine as a burgundy oil. 10 3. Diethyl(2-benzylamino-5- ovridvlaminomethvler.e'’ malonate A r.ixture of 2-benzylamino-5-aminopyridine (1.75 g) and diethvl ethoxymethylenemaionate (1.78 nu., S.82 trmol) was 15 heated at 130° C fcr 2 h. VJhile warm, the mixture was evacuated. After cooling, the product was criturated with 2:1 hexanes/ether and collec ted zo give 2.74 g of diethvl (2- benzylanino-5-pyridylaT.inomethylene) malcnate as a gold solid. 20 4. Sthyi 6-benzylamino-4-οχο-1,4-dihvdro- 1,5-nachthvridine-3-carboxvlate

Diethvl (2 - ber.zy 1 amino - 5 - py r i dy 1 arr.i ncrr.e t hy 1 er.e) ma 1 cna t e (2.23 g) was added to diphenvl ether (10 iri-) preheated tc 230L 25 C. Heating was continued for 0.5 h, the reaction flask removed frcm the oil bath, and the mixture allowed to oocl tc ambient temperature. The product was triturated with 1:1 ether:hexanes, collected, rinsed with ether, and dried to give -54- LV 12539 1.47 g of ethyl 6-benzylamino-4-oxo-1,4-dihydro-l, 5 - naphthyridine-3-carboxylate as a brown solid. 5 · 6-Benzvlamino-4-oxo-l.4-dihvdro-l.5-naphthvridine-3-carboxvlic acid A mixture of ethyl 6-benzylamino-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylate (60 mg) , 1N NaOH (2 mL) , and ethanol (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 precipitace was collected, rinsed with water and ether, then dried to afford 35 mg of 6-benzylamino-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylic acid as a brown solid. 6. 2-Ethoxv-5-nitropvridine 2-Chloro-5-nitropyridine was added to a homogeneous solution of potassium hydroxide (3.93 g, 70 mmol) in ethanol (35 mL) at ambient temperature. The reaction mixture was stirred for 1 h, then diluted with saturated aqueous ammonium chloride and cooled in an ice bath. The precipitate was collected, rinsed with water and dried to give 3.60 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 ethanol (40 mL) was placed in a Paar bottle -55- and shaken under hydrogen (50 PSI) for 16 h. The mixture was filtered through Celite using dichloromethane and concentrated to give 2.892 g of 2- ethoxy-5-aminopyridine as a gold solid. 5 8 . Diethvl (2-ethoxv-5-pvridvlaminomethvlene)malonate A mixture of 2- ethoxy-5-aminopyridine (2.89 g, 20.5 mmol) and diethyl ethoxymethyienemalonate (4.23 mL, 20.9 mmol; was heated at 13 0° C for 4.5 hours. While warm, the mixture 10 was evacuated. After cooling, the product was triturated with 2:1 hexanes: ether and collected to afford 6.04 g of diethvl (2-ethoxy-5-pyridylaminomethylene)malonate as a beige solid. 9. Ethyl 6-ethoxy-4-oxo-l,4-dihydro-15 1.5-naphthvriaine-3-carboxvlate

Diethyl (2-ethoxy-5-pyridylaminomethylene)malonate (6.C4 g) was added to diphenyl ether (20 mL) preheated to 230° C. Heating was continued for 0.5 h, the reaction flask removed 20 from the oil bath, and the mixture allowed to cool to ambier.c temperature. The product was triturated with 1:1 ether:hexanes, collected, rinsed witn ether, and criea to give 2.98 g cf ethyl 6-ethoxy-4-oxo-l,4-dihvdro-l, 5-naphthyridine-. 3-carboxylate as a tan solid. 10. 6-Ethoxy-4-ΟΧΟ-1,4-aihydro- 1.5-naohthvridine-3-carboxvlic acid -56- 25 LV 12539 A mixture of ethyl 6-ethoxy-4-oxo-l,4-dihydro-l,5-naphthyridine-3-carboxylate (2.98 g) , IN NaOH (50 mL) , and ethanol (10 mL) was heated at reflux- for 2 h. The reaction mixture was cooled in an ice bath, acidified, and the resulting precipitate collected, rinsed with water and dried to 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) - methvlaminomethvl)benzvlamine hvdrochloride a) A solution of a-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 0e 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 N,N-bis (4-benzonitrile) methvl-amine . The aqueous was adjusted to pH>8 and extracted 2X with 9:1 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 coioriess oil. -57- b) Di-tert-butyl dicarbonate (1.77 g, 8.1 mmol) was added to a stirring mixture of 4 -(methylaminomethyl)-benzonitrile -(1.13 g, 7.7 mmol) and 1N NaOH (15 mL) in 1,4-dioxane (15 mL) at ambient temperature. The reaction mixture was stirred for 2 h, poured into saturated aqueous sodium chloride, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.81 g of crude 4-{N-(tert-butoxycarbonyl) -methylaminomethyi] benzonitrile. The crude material was filtered through a 1" silica gel pad, first eluting with hexane, then with ether. The ether filtrate was concentrated to give pure 4-{N-(tert-butoxycarbonyl)-methylaminomethyl] benzonitrile as a colorless oil. To this was added 10% ?d/C (170 mg) and ethanol in a Paar bottle. The mixture was shaken under hydroaen (50 PSI) for 4.5 h, then filtered through Celite and concentrated in vacuo. The residue was taken up in etnanol, cooled in an ice bath, and 1.0 M HCl in ether (10 mL) was added dropwise. The resulting precipitate was filtered and dried in a vacuum oven to give 1.346 g of 4- [(N-tert-butoxvcarbonyl)-methylaminomethyl)-benzylamine hydroc’nloride as a pele aray solid. EXAMPLE 2 1. N-n-Butvl-6-benzvlamino-4-oxo-l.4-dihvdro 1.5-naphthvridine-3-carboxamide -58- LV 12539

To a solution of 6-benzylamino-4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxylic acid {59 mg, 0.2 mmol) and triethylamine (59 ml, 0.42 mmol) in N,N-dimethylformamide (1 mL) 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 precipitate collected, rinsed with water and ether, then dried to afford 10 49 mg of N-n-butyl 6-benzyiamino-4-oxo-l, 4-dihydro-l, 5- naphthyridine-3-carboxamide as a brown solid. Compound l. An alternate 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-l. 5-napththvridine-3-carboxamide

To a solution of 6-methoxy-4-oxo-l,4-dihydro-l,5-naphthyridine-3-carboxylic acid (55 mg, 0.25 mmol) and 20 triethylamine (73 mL, 0.53 mmol) in N,N-dimethylformamide (2 mL) at 0e C was added ethyl chloroformate (49 mL, 0.52 mmol) . After stirring at 0° C for 0.5 h, 2-(et’nylthio) ethylamine hydrochloride (172 mg, 1 mir.cl) and triet'nvlamine (139 ml, 1 mmol) was added. The reaction mixture was stirred for 0.5 h 2 5 at 0° C, then poured into 1.2 N HC1, cooled in an ice bath, and the resulting precipitate collected, rinsed with water and dried to give 57 mg of N- [2- (et'nylthio) ethyl] 6-methoxy-4-oxo- -59- 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] 6-5 (2-methoxyethoxy) -4-oxo-l, 4-dihydro-l, 5 naphthvridine-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) and 10 triethylamine (117 mL, 0.84 mmol) in 4:1 tetrahydrofuran: N,N-

dimethylformamide (2 mL) at 0° C was added ethyl chloroformace (66 mL, 0.82 mmol). After stirring at 0° C for 1.25 h, 4-((N-tert-butoxycarbonyl) -methylaminomethyl) ber.zylamine hydrochloride (120 mg, 0.42 mmol) and triethylamine (5S mL, 15 0.42 mmol) was added. The reaction mixture was stirred at 0° C for 0.75 h, then allcwed to ambient temperature and stirred for 20 h. N,N-Dimethylethyleneaiamine (132 mL, 1.2 mmol) was added, the reaction mixture stirred for 1 h, then concentrated in vacuo. The residue was cooled in an ice bath, saturated 20 aoueous ammonium chloride was added and the mixture extracted with dicnlcromethane. The crganic layer was washed with saturated agueous sodium chloride, dried over sodium sulfate, filtered, and concentrated to give 177 mg of crude N-[4-(N-tert butoxycarbonyl)-methvlamincmethvl) benzyl] 6-(2- 25 methoxyethoxy) -4-oxo-l, 4-dihydro-l, 5-naphthyridine-3-carboxamide.

To crude N-[4-(N- tert -butoxycarbcnyl)- methylaminomethyl)benzyl] 6-(2-methoxyethoxy) -4-οχο-1,4- -60- LV 12539 dihydro-l,5-naphthyridine-3-carboxamide in dichloromethane (1 mL) was added 1:1 trifluoroacetic acid:dichloromethane (2 mL) dropwise at ambient temperature. The reaction mixture was stirred for one hour, concentrated in vacuo, the residue dissolved in ethanol, and 1.0M HC1 in ether (0.8 mL) was added. The precipitate was collected to afford 68 mg of N-[4-(methylaminomethyl)benzyl] 6- (2-methoxyethoxy) -4-oxo-l,4- dihydro-l,5-naphthyridine-3-carboxamide hydrochloride.

Compound 10. 4. N-(4-Methoxybenzyl) 6-pyrrolidino- 4-oxo-1.4-dihvdro-l. 5-naphthvridine-3-carboxamide

To a solution of 6-pyrrolidino-4-oxo-l,4-dihydro-l,5-naphthyridine-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 0eC was added ethvl chloroformate (0.09 mL, 0.9 mmol). After stirring at C°C for 0.5 h, 4-methoxybenzylamine (0.1 mL, 0.8 mmol) was added. The reaction mixture was allowed to ambient temperature and stirred for 0.5 h. Water was added and the resulting precipitate collected, washed wit'n water and ether and dried. The solid was combined with IN NaOH (5 mL·) and ethanol (2 mL) and heated at reflux for 0.25 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 69 mg -61- 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-l,4-tetrahydro-l,5-5 napthvridine-3-carboxamide. sodium salt N-Benzyl 6 -ethoxy-4 -oxo-l, 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 10 is heated until homogenous, subsequently cooled and concentrated. The resulting solid is treated with ethyl acetate (5 mL) and ethyl alcohol (250 mL) , and the resulting mixture is stirred for 22h. The precipitate is collected, rinsed with ethyl acetate and aried to give the sodium salt of 15 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 salt; (Compound 13) m.p. 20 286-288 °C. EXAMPLE 3

The following compounds were prepared essentially 25 according 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- LV 12539 (b) N-Propan-3-ol 6-methoxy-4-οχο-1,4-tetrahydro-l, 5-naphthyriaine-3-carboxamide; (Compound 15) m.p. 271-272° C. (c) N-n-Butyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide(· (Compound 16) m.p. 274-276° C. (d) N- (2-Ethyltnio)ethyl 6-methoxy-4-oxo-l,4-tetrahydro-l, 5-naphchyridine-3-carboxanu.de; (Compound 17) m.p. 257-259° C. (e) N-n-Butyl 6 -(N-benzyiamino)-4-οχο-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 18). (f) N- n-Pentyl c-etnoxy-4-οχο-1,4-tecrahvaro-l, 5-naphthyridine-3-carboxamiae; (Compound 19) m.p.265-265° C. (g) N- (3-Isoprcpoxy)prcņyi 6-e£hoxy-4-oxo-l,4-tecranydro-l, 5-naphthyridine-3-carboxanu.de (Compound 20) . (h) N-Benzyi 6-ethoxy-4-cxo-1,4-cecrahvdro-1,5-naphthyridine-3-carboxamide; (Compound 21) m.p.275-273° C. (i) N-2-Pentyl 6-ethoxy-4-οχο-1,4-cetrahydro-l, 5-naphthyriaine-3-carbcxamide (Compound 22). -63- (j) N-(2-Tetrahydrofuranyl)methyl 6-ethoxy-4-oxo-l,4- tetrahydro-l, S-naphthyridine-3-carboxanu.de; m.p.235-237eC. (Compound 4). (k) N-(3-Methoxy)propan-2-ol 6-ethoxy-4-oxo-l,4-cetrahydro-1,5-naphthyridine-3-carboxamide (Compound 23). (l) N-(3-Methoxy)propyl 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 24). (m) N-(2-Methoxy)ethyl 6-ethoxy-4-oxo-l,4-cetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 25). (n) N-Isoamyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 26) m.p. 279-231° C. (ο) N-(2 -Furany1)methy1 6-ethoxy-4-oxo-l,4-tecrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 27) m.p. 245 (d)° C. (p) N- (3-Methoxybenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- napht'nyridine-3-carboxamide; m.p. 250-253° C. (Compound 11) . (q) N- (3-Ethoxy)propyl 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 28) m.p. 224-225° C. -64- LV 12539 (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) Ν-2-Pentan-l-ol 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxanu.de; (Compound 30) m.p. 232-234° C. (t) Ν-5-Pentanol 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 31) m.p. 223-224° C. (u) N-l-Cyclo'nexan-2-ol 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxanu.de; (Compound 32) m.p.268-270eC. (v) N-Benzyl 6-methoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxanu.de; (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-tetra’nydro- 1.5- naphthyridine-3-carboxamide; (Compound 35) m.p.281eC. (y) N-(4-Fluorobenzyl) 6-mechoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 36) m.p.283-286°C. (z) N-(Imidazol-4-ylmethyl) 6-echoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide . (Compound 6). -65- [Alternate name: (6-ethoxy-4-oxo(3-hydro-5-azaquinolyl))-N-(imidazol-4-ylmethyl)formamide] (aa) N-4-Tetrahydropyranyl 6-ethoxy-4-οχο-l, 4-tetrahydro- 1.5- naphthyridine-3-carboxanu.de; (Compound 37) m.p. 303-305eC. (bb) N-(3-Thienyl)methyl 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 38) m.p. 324-325°C. (cc) N-2-(6-Methyl)heptan-6-ol 6-ethoxy-4-oxo-lf4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 39) m.p.281eC. (dd) N- (2-Tetrahydropyranyl)methyl 6-ethoxy-4-oxo-l,4-tetrahyaro-1,5-naphthyridine-3-carboxamide; (Compound 40) m.p.204-206°C. (ee) N-(2-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 41) m.p. 157-162‘C. (ff) N-(3-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide; (Compound 42) m.p. 2S7-302’C. (gg) N-(4-Fluorobenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 43). -66- LV 12539 (hh) N- (4-Methoxybenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 44) m.p.l86°C. (ii) N-(3-Fluorobenzyl) 6-methoxy-4-oxo-l, 4-tetrahydro-5 1,5-naphthyridine-3-carboxamide; (Compound 45) m.p.301eC. (jj) N-Benzyl 6-{N-methyl, N-toluenesulfonyl-ami.no)-4-oxo-1,4 - tetrahydro-1,5-naphthyridine - 3 - carboxamide. (Compound 2). [Alternate name: (6-(methyl((4 -10 methylphenyl) sulfonyl) amino) -4-oxo (3-hydro-5-azaquinolyl)) -N-benzylformamide] (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-meohoxy-4-oxc-l, 4-tetrahydro-l, 5-20 naphthyridine-3-carboxamide; (Compound 47) m.p.l86°C. (nn) N-2-(Imidazol-4-yletnyl) 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridir.e-3-carboxamide ; (Compound 48) m.p.268eC. -67- 25 (οο) Ν- (4-Methylbenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 49) m.p.270-271eC. (pp) N-Benzyl 6-(2-methoxyethoxy)-4-οχο-l, 4-tetrahydro- 5 1,5-naphthyridine-3-carboxamide; (Compound 50) m.p.>300eC. (qq) N-Benzyl 6-dimethylamino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 51) m.p.246-249eC. 10 (rr) N-Isoamyl 6-morpholino-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide; (Compound 52) m.p.295-298eC. (ss) N-Benzyl 6-morpholino-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 53) m.p. 88-90° C. 15 (tt) N-(2-Fluorobenzyl) 6-morpholino-4-oxo-l<4-t e trahydro-1,5-naphthyri di ne-3 -carboxami de; m.p.l37-139°C. 9Compound 7). 20 (uu) N-(3-Ethoxy) prcpyl 6-morp'nolino-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 54) m.p.150-152eC. (vv) N-n-Butyl 6-morpholino-4-οχο-1,4-tetrahydro-l,5- 25 naphthyridine-3-carboxamide; (Compound 55) m.p.275-277°C. -68- LV 12539 (ww) N-(2-Pyridyl)methyl 6-morpholino-4-οχο-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 56) m.p.125-127eC. 5 (xx) N-(2-Thienyl)methyl 6-(2-methoxyethoxy)-4-oxo-l, 4 - tecrahydro-1,5-naphthyridine-3-carboxamide; (Compound 57) m.p.235-236eC. (yy) N-Isoamyl 6-dimethylamino-4-oxo-l,4-tetrahydro-l,5- 10 naphthyridine-3-carboxamide; (Compound 58) m.p. 254-256’C. (zz) N- (2-Thienyl)methyl 6-morpholino-4-oxo-l,4-tetrahydro-l, 5-naphthyriaine-3-carboxamide; (Compound 59) m.p.277-279°C. 15 (aaa) N- (2-Thienyl)methyl 6-dimechylamino-4-oxo-l/4- tecrahydro-l, 5-naphthyridine-3-carbcxamide; (Compound 60) m.p. 240 C. 20 (bbb) N-(2-Thiazolyl}methyl 6-morpholino-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 61) m.p.270-272eC. (ccc) N- (4-Methylaminomet.hyl)benzyl 6-ethoxy-4-oxo- 25 l,4-tetrahydro-l,5-naphthyridine-3-carboxamide (Compound 62). -69- (ddd) N-[4-(1-Methylami.no) ethyl] benzyl 6-ethoxy-4- οχο-1,4 -tetrahydro-1,5-naphthyridine-3-carboxami.de; (Compound 63) m.p. 259-262 C. (eee) N-(2-Tetrahydrofuranyl)methyl 6-dimethylamino-4-0X0-1,4 -tetrahydro-1,5-naphthyridine-3 -carboxamide; (Compound 64) m.p. 285-288’C. (fff) N-n-Pentyl 6-morpholino-4-oxo-l,4-tetrahydro- l, 5-naphthyridine-3-carboxamide; (Compound 65) m.p.278-280°C. (ggg) N-(3-Methoxybenzyl) 6-morpholino-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 66) m. p.204-205eC. (hhh) N-(3-Fluorobenzyl) 6-morpholino-4-oxo-l,4- tetrahydro-l,5-naphthyriaine-3-carboxamide; (Compound 67) m.p.263-265eC. (iii) N-(4-Methylaminomethyl) benzyl 6-(2- methoxyethoxy)-4-οχο-1,4 -tetrahydro-l,5-naphchyridine-3-carboxamide; (Compound 68) m.p. 275-277'C. (jjj) N-n-Butyl 6-pyrrolidino-4-oxo-l,4-tetrahydro- 1,5-naphthyridine-3-carboxamide; (Compound 69) m.p.57-58eC. LV 12539 (kkk) N- (4-Methoxybenzyl) 6-pyrrolidino-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 70) m.p.270-272°C. 5 (111) N-(2-Thienyl)methyl 6-pyrrolidino-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 71) m.p.265-267ec. (mmm) N- (4- (l-Methylamino)ethyl]benzyl 6-dimethylamino-4-10 οχο-1,4-tetrahyaro-l, 5-naphthvridine-3-carboxamide (Compound 72) . (nnn) N- (4-Methylaminometnyl)benzyl 6-n-propoxy-4- oxo-l, 4-1etrahydro-1,5-naphthvridine- 3-carboxamide 15 hydroc'nlcride; (Compound 73) m.p. 270-271eC. (ooo) N- [4-(l-Methylamino)ethyl]benzyl 6-chioro-4- oxo-l, 4-tetrahydro-l, 5-naphthyridine-3 -carboxamide; (Compound 74) m.p.260-263eC. 20 (ppp) N- [4-(l-Methvlamino)ethyl]benzyl 6- pyrrolidino-4 - οχ© -1,4-tecrahvdro-1,5-naphthyridine-3-carboxamide nydrochloride; (Compound 75) m.p.298-302eC. -71- (qqq) N-(4-Ethoxybenzyl) 6-morpholino-4-oxo-l,4- tetrahydro-l, S-naphthyridine-3-carboxamide; (Compound 76) m.p.278-281eC. 5 (rrr) N-(4-Ethoxybenzyl) 6-pyrrolidino-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 77) m.p.265-267°C. (sss) N-(4-Chlorobenzyl) 6-morpholino-4-oxo-l,4- 10 tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 78) m.p.295-297°C. (tcc) N-(3-Chlorobenzyl) 6-morpholino-4-oxo-l,4-

Cetrahydro-l,5-naphthyridine-3-carboxamide; (Compound 79) 15 m.p.276-278°C. (uuu) N-Piperonyl 6-dimethylamino-4-οχο-1,4- tetrahydro-l,5-naphthyridine-3-carboxamide hydrochloride; (Compound 80) m.p.246-247eC. 20 ivw) N-3enzyl 6-(2-methylamino)ethoxy-4-oxo-l,4- tetrahydro-l, 5-napht'nyridine-3-carboxamide (Compound 81). (www) N-Benzyl 6-(2-dimethylarnino)ethoxy-4-οχο-1,4-25 tetrahydro-l, 5-naphthyridine-3-carboxanu.de; (Compound 82) m.p.194-198eC. -72- 5 LV 12539 (χχχ) N- (4-Ethylaminomethyl)benzyl S-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 83) m.p.194eC (d) . (yyy) N-Benzyl 6-(2-methoxy)ethylamino-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide; (Compound 84) m.p.254-257®C. 10 (zzz) N- (3-Methylaminome~hyl)benzvl 6-ethoxy-4-oxo- 1,4-cetrahydrc-l, 5-naphthyridine-3-carboxamide hydrcchloride; (Compound 85) m.p.lBTT (d) . (aaaa) N-(4-DimethyIaminomethyl)benzyl 6-ethoxy-4-oxo-15 1,4-tetrahydro-l, 5-naphthyridine-3-carboxamide hydrochloride; (Compound 86) m.p.20 0‘C (d) . (bbbb) N-(3-Kec.hylar\inomewhyl) benzvl 6-n-propcxy-4- oxo-l, 4 - tetrahydro-l, 5-naphthvridine-3 -carboxamide 20 hydrochloride; (Compound 57} m.p.l84°C (d) . (cccc) N-[4-(l-Imidazolylme“hy)]benzyl 6-echcxv-4-oxo- l, 4-tetrahycro-l, 5-naphthvridine-2 -carbcxamide; (Compound 88) m. p. 14 3-14 5°C. -73- 25 (dddd) N-[4-(1-morpholinomethyl)]benzyl 6-ethoxy-4-0x0-1,4-tetrahydro-l, 5-napthyridine-3-carboxamide; (Compound 89) m.p. - 215-218°C. 5 (eeee) N-[3-(l-morpholinomethyl))benzyl 6-ethoxy-4- oxo-l, 4 - tetrahydro-1,5 -napthyridine- 3 -carboxamide; (Compound 90) m.p. 195- 198°C. (ffff) N-{4 - [1- (4-methylpipera2inomethyl) ]benzyl 6- 10 ethoxy-4 -oxo-1,4 -1etrahydro-1,5 -napthyridine-3 -carboxamide (Compound 91) . (9999) N- (4 - (1,2,4 -triazol- l-ylmethyl) ] benzyl 6-ethoxy-4 - 0x0-1,4-tetrahydro-l, 5-napthyridine-3-carboxamide; 15 (Compound 92) m.p. 195-200'C. (hhhh) N-Benzyl 6-benzylamino-4-oxo-l,4-tetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 93). 20 (iiii) N-Cyclohexyl 6-ethoxy-4-oxo-l, 4-tetrahyarc-1,5- naphthyridine-3-carboxamide (Compound 94) . (jjjj) N-Cyclohexylmethyl 6-ethoxy-4-oxo-l,4-cetrahydro- 1.5- naphthyridine-3-carboxamide (Compound 95). -74- 25 LV 12539 (kkkk) N- (4-Aminobenzyl) -6-ethoxy-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide (Compound 96). (1111) N-(4-Pyridylmethyl) 6-ethoxy-4-oxo-l,4-tetrahydro 5 -1,5-naphthyridine-3-carboxamide (Compound 97). (mmmm) N-Benzyl 6-tetrahyarolsoquinolinyl-4-oxo-l,4- tetrahydro-l, 5-naphthyridine-3-carboxamide (Compound 98). 10 (nnnn) N-{4 -[1-[4 -(4-Fluorobenzvl)piperazinyl] methyl] benzyl} 6-(2,2,2-crif luorcethyi) -4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3-carboxamide, (Compound 99) m.p. 234-236eC. (oooo) N-(3 -isopropoxypropyl) 6-ethoxy-4-oxo-l, 4- 15 tetrahvdro-l, S-naphthyridine-3-carboxamide Compound 3 [alcernative name: (6-ethoxv-4-cxohydropyridino [3,2-b]pyridin-3-yl) -N- [3- (methylethoxy)propyl] carboxarru.de] .

The invencion and the manner and process of making and 20 using it, are now described in such full, clear, conoise and exact terms as to enable any person skilled in the art to which it pertains, tc make and use the same. It is to be understood that the foregoma aescribes preferred embodiments of the present invention and that modifications may be made 25 therein without aeparting from the spirit or scope of the present invention as set forth in the claims. To particularly -75- point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification. -76- L.V 12539 WHAT IS CLAIMED IS: 1. A compound of the formula: 0 0

or the pharmaceutically acceptable salts thereof wherein: 5 X is hydrogen, halogen, -ΟΡ^, Cj-C* alkyl optionally substituted vrith up to three groups selected independently from halogen and hydroxy, cr -NR2R3; X is phenyl, naphthvl, 1- (5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, 10 isoquinolinyl, l,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, or ber.zothienyl, each of which is optionally substituted with up to three groups selected from halogen, C:*C6 alkvi, C:-C4 alkoxy, Cj-Cs alkylthio, hydroxy, amino, tr.ono cr ai (C,-C6) alkylamino, cyar.o, nitro, 15 trifluoromethyl or trifluoromethoxy; or X represents a carbocvclic group containing from 3-7 members, up to two of which members are optionallv hetero atoms selected from cxygen and nitrogen, where the X carbocyclic group is optionaliy substituted with one or 20 more groups selected from halogen, C,-Cs alkoxy, mono- or di (C:-C6) alkylamino, sulfonamiae, aza (C3-C-,) cycloalkyl, C3- C, cycloalkylthio, C,-C6 alkylthio, phenylthio, or a heterocyclic group; -77- Υ is lower alkyl having 1-8 carbon atoms optionally substituted with up to tv/o groups selected from halogen, C3-C, cycloalkyl, C^-Cs alkoxy, mono- or di(Cj-C6) alkylanu.no, sulfonamide, aza (C3-C7) cycloalkyl, C3-C7 5 cycloalkylthio, Cj-Cg alkylthio, phenylthio, a heterocyclic group, -OR4,-NRsRs, SR7, or optionally substituted aryl; or Y is a carbocyclic group having from 3-7 members atoms, where up to three of which members are optionally hetero atoms 10 selected from oxygen and nitrogen and where any member of the Y carbocyclic group is optionally substituted with halogen, -0R4,-NRSRS, SR7, aryl or a heterocyclic group; R. is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbcr. atoms, where each alkyl may 15 be optionally substituted with -OR4, or -NRSRS; R2 and R3 are the same or different and represent hydrogen, lower alkyl optionally mono- or disubstituted with alkoxy, aryl, halogen, or mono- or ai-lower alkyl; 20 aryl or aryl {C1-C6) alkyl where each aryl is optionallv substituted with up to three groups selected from halogen, hyaroxy, C.-C6 alkyi, Cj-Cs alkoxy, or mono-or di (C^Cg) alkylanu.no; cycloalkyl having 3-7 carbon atoms optionally mono or 25 disubstituted with halogen, alkoxy, or mono- or di- lower alkyl; or -78- LV 12539 R4 is as defined for Rlf-

Rs and Rs carry the same definitions as Rz and RJ( respectively; R, is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms; and R, is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or optionally substituted phenyl. 2. A compound of the formula: 0 o

H or the pharmaceuticaily acceptable salts thereof wherein: X is (i) hydrogen, halogen, mono- or dialkvlamino, alkoxy, (ii) a aroup cf the formula:

where G is lower alkylene having 1-6 carbon atoms, or a cyclic group of the formula (CH2)n

(CH2)m where n is 0, 1, or 2, and m is an integer cf from 1 to 5, with the proviso that the sum of n + m is not less than 1 or greater than 5; and -79- r2 is hydrogen, lower alkyl, or (C3-C7) cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di {Cl-C6) alkylamino'; (iii) a group of the formula: R3R2N.r/0^

5 G where G is as defined above for ii; and r2 and R3 independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -SO,Re where R3 is (C3-Ce) alkyl, (C3- 10 c7) cycloalkyl, or optionally substituted phenyl, or R. and R3 together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperiainyl; 15 (iv) a group of the formula: R40^g,N^ where R2 is as defined above for iii; R4 is hydrogen, lower alkyl having 1-6 carbon atoms, or 2 0 cycloalkyl having 3-7 carbon atoms, and may be optionally substituted with one or more (Cj-C6) alkoxy or mono- or di (C.-C6) alkylamino groups; and G is as defined above for ii; (v) a group of the formula: -80- LV 12539

where

Rj and G are as defined above for iv and ii, respectively, and

Rs and Re independently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -S02Rg where R, is (C^-CJ alkyi, (C3- C,) cycloalkyl, or optionally substituted phenyl, or R5 and R6 together with the nitrogen atom to which thev are attached form a heterocyclic moiety; (vi) a group of the formula:

where G is as defined above for ii; or (vii) a group of the formula: /"“G,

w'nere each G is as defined above for ii; and Y is (viii) lower alkyi having 1-8 carbon atoms or cycioalkyl having 3-7 carbon atoms, anv of which may be optionally substituted with one or more halogen, (C3-Cs) alkoxy, alkoxyalkoxy where each alkoxy is (Cj-CJ alkoxy, (Cx-Ce) alkylthio, (C3-C7) cycloalkylthio, aryl, heteroaryl, or mono- or di (C^-CJ alkylamino groups; (ix) a group of the formula:

'ORg where K is lower alkylene having 1-6 carbon atoms optionally substituted with (C1-C6)alkyl or alkylene, or a cyclic group of the formula κ· (CHJh,

(CH2)n where K' independently represents hydrogen or (C.-Ce)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 R9 is hydrogen, lower alkyi, or (C3-C,) cycloalkyl, where the alkyl or cycloalkyl is optionally substituted with halogen, 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: LV 12539 where K is as defined above for ix, and

Rn 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,-Ce) alkoxy or mono- or dKCj-Cs)alkylamino groups; and (xii) a group of the formula:

where K is as defined above for ix, and R, is hydrogen, Iower alkyl having 1-6 carbon atoms, or cycioalkyl having 3-7 carbon atoms; and (xiii) a group of the formula: x nr14r15 where K is as defined above for ix; and R.4 and R1S inaependently represent hydrogen, lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, -SOjR„ where Ra is as defined above, or R,, and R1S toget'ner with the nitrogen atom to whicn thev are attached form a heterocyclic moiety; (xiv) a group of the formula: -83-

where K and R1S are as defined above in ix and xii, respectively; group of the formula R-io Rio,-^y ^Rl2 R,1' where K is as defined above for ix; R10 and R10' are the same or different and are selected 10 from hydrogen, halogen, hydroxy, lower alkoxy having 1-6 carbon atoms, or cycioalkoxy having 3-7 carbon atoms;

Ru, Ru' , and Ru are the same or different and are selected from hyarogen, halogen, nydroxy, -OR4,-15 CR7 (R,)NRSRS, -CR, (R16)OR4, or R,,-R,2 taken together with the atoms to which they are attached form a (hetero)cyciic ring; and Ru is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms (xvi) a group of the formula: -84- 20 LV 12539

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

K is as defined above for ix; R10 and Ru are as defined above for xv, and

Rl7 is hydrogen, lower alkyl, or (C3-C,) cycloalkyl, where 10 the alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di (C3-C6) alkylanu.no; (xviii) a group of the formula: Ķ10 -N xOR17 n Ri2 where K, R10, R12, and R17 are as defined above; (xix) a group of the formula: ĶlO -°Λ 1 'J where each K is indepenaently defined as above R10 is defined above; (xx) a group of the formula: -85-

Rm

R11 Ķ NR14R15 where K, R10, Rn, Rl4, and R1S are as defined above; and (xxi) a group of the formula:

5 where K, R10, Ri2, R14, and R.s are as defined above. 3. A compound according to claim 1, which is

Rb where 10 A is Cj-Cg alkylene;

Ra is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-Cļ-Cg alkviaminc, or mono- or di-Cj-Cg alkylamino lower alkyl; and 15 Rb is lower alkyl or lower cycloalkyl. 4. A compound according to claim 1, which is -86- LV 12539

N H wherein A is Ci-Cj alkylene;

Ra and Ra' are independently phenyl groups optionaliy mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-Cj-Cg alkylamino, or mono- or di-C.-C6 alkylamino lower alkyl; and

Rc is hydrogen or lower alkyl. 5. A compound according to claim 1, which is wherein O 0

H

n σ H A is C.-C6 alkylene;

Rd and Re are independently lower alkvl groups. 6. A compound according to claim 1, which is 0 0

H wherein A is Cj-Cj alkylene;

Ra is lower alkyl; and

Rf is a group of the formula:

where E is oxygen or nitrogen; and M is Ci-Cļ alkylene or nitrogen. 7. A compound according to claim 1, which is 0 0

N H wherein A is Ci-Cj alkylene;

Rd is lower alkyl; and

Ra' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, cr mono- or di-C^-Cg alkylamino, or mono- or di-C.^-Cj a!kylamino lower alkyl. 8. A compound according to claim 1, which is O 0

H wherein A is C^Cj alkylene; and

Rd and Re are independently lower alkyl groups. LV 12539 9. A compound according to claim 1, which is

N H wherein D is nitrogen or CH; D' is nitrogen or oxvgen; A is Cļ-Cg alkylene; and R,' is phenyl optionaliv mono-, di-, or trisubstituted with halogen, lower alkyl, iower alkcxy, or mono- or di-C^-Cg alkylamino, or mono- or di-C,-Cs alkylamino lower alkyl. 1C. A compound according to claim 1, which is

H wherein A is C,-C6 alkylene; and R,' is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C;-Cg alkylamino, or mono- or di-C,-C6 alkylamino lower alkyl. -89- 5 11. A compound according to claim 1, which is R„ V-

H (CH2)r 0 wherein A is Cj-C6 alkylene; and Rd is lower alkyi; 10 A' represents oxyger. or methylene; and r is an integer cf from 1-3. 12. A compound according to claim 1, whicn is 15

20 A is Cj-Cg alkvler.e;

Rg is lower alkyloxy lcwer alkyl; and Ra' is phenyl cptionaIIy mono-, di-, or trisii with haloger., lower alkyl, lcwer alkcxv, or di-Cj-Cj alkvlaminc, or mono- cr di-C,-C.; a lower alkyl. bstituted mono- or ikylamino -90- LV 12539 13. A compound according to claim 1, which is N-n-Butyl 6-benzylamino-4-oxo-l, 4 -dihydro-l, 5-naphthyridine-3-carboxamide. 14. A compound according to claim l, which is N-t2-5 (Ethylthio) ethyl] 6-methoxy-4-oxo-l,4-dihydro-l, 5- napththyridine-3-carboxamide. 15. A compound according to claim 1, which is N-[4-(Methylaminomethyl)benzyl] 6- (2-methoxyethoxy) -4-oxo-l,4-dihydro-l, 5-naphthyridine-3-carboxamide. 10 16. A compound according tc claim 1, which is N-(4-

Methoxybenzyl) 6-pyrrolidino-4-oxo-l,4-dihydro-l, 5-naphthyridine-3 -carboxamide. 17. A compound according to claim 1, which is N-n-3utyl 6 - chloro - 4 - oxo -1,4 -1 e t ranvdro -1,5- napht hyr idine - 3 - carboxamide. 15 IS. A compound according to claim 1, which is N-Propan- 3 -oi 6-methoxy-4 -ΟΧΟ-1,4 - tetrahydro-1,5 -naphthyridir.e-3-carboxamide. 19. A compound according to claim l, which is N-n-Butyl 6-ethoxy-4 -0X0-1,4 - tetrahvdro-1,5-naphthyridine-3 - carboxamide . 2 0 2 0. A compound according to claim 1, which is N- (2-

Ethvlthio)ethyl 6-methoxy-4-οχο-1,4 -tetrahydro-1,5-naphthyridine-3-carboxamide. 21. A compound according to claim 1, which is N-n-Butyl 6- (N-benzylamino) -4 - οχο-1,4 - tetrahyaro-1,5 -naphthyridine-3 -25 carboxamide. -91- 22. A compound according to claim 1, which is N- n-Pentyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide. 23. A compound according to claim 1, which is N-(3-5 Isopropoxy)propyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3 -carboxamide. 24. A compound according to claim 1, which is N-Benzyl 6 -ethoxy-4-oxo-l, 4 - tetrahydro-1,5-naphthyridine-3-carboxamide. 25. A compound according to claim 1, which is N-2-Pentyl 10 6 - ethoxy-4 - oxo-l, 4 - tetrahydro-l, 5-naphthyridine-3 - carboxamide. 26. A compound according to claim 1, which is N-(2-Tetrahydrofuranyl) methyl 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 27. A compound according to claim 1, whic‘n is N-(3-15 Methoxy) propan-2-ol 6-ethoxy-4-οχο-1,4-tetrahydro-l,5- naphthyridine-3-carboxamide. 28. A compound according to claim 1, which is N-{3-Methoxy)propyl 6-ethoxy-4-οχο-1,4-tetrahvdro-1,5-naphthyridine-3-carboxanu.de. 20 29. A compound according to claim 1, which is N-(2-

Methoxy)ethyl 6-ethoxy-4-οχο-1,4 -tetrahydro-1,5-naphthyridine 3-carboxamide. 30. A compound according to claim 1, which is N-Isoamyl 6 - e t hoxy- 4 - οχο-1,4 -1 e t rahydro -1,5- naphthyridine - 3 - carboxamide -92- LV 12539 31. A compound according to claim 1, which is N-(2-Furanyl)methyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 32. A compound according to claim 1, which is N-(3-5 Methoxybenzyl) 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide. 33. A compound according to claim 1, which is N-(3-

Et hoxy) propy 1 6 - e t hoxy- 4 -oxo -1,4-t etrahydro-1,5-napht hyr idine -3 - carboxarru.de. 10 34. A compound according to claim 1, which is N-2-I2-

Methyl) butyl 6 -ethoxy-4 -οχο-1,4 -tetrahydro-l, 5-naphthyridine-3 -carboxamide. 35. A compound according to claim 1, which is N-2-Pentan-l-ol 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3- 15 carboxamide. 36. A compound according to claim 1, vrhich is N-5-Pentanol 6-ethoxy-4-oxo-l, 4-tetrahydro -1,5-naphthyridine-3-carboxanu.de. 37. A compound according to claim 1, which is N-l-20 Cyclohexan-2-ol 6-ethcxy-4-οχο-1,4-tetrahvdro-l, 5- naphthyridine-3-carboxamide. 38. A compound according to claim 1, which is N-Senzyl 6-methoxy-4-oxo-l, 4-tetrahydro-l, 5-naphthyridine-3-carboxanu.de. -93- 39. A compound according to claim 1, which is N-(2-Fluorobenzyl) 6-methoxy-4-oxo-l, 4-tetrahydro-l,5-naphthyridine-3-carboxamide. 40. A compound according to claim 1, which is N-(3- 5 Fluorobenzyl) 6-methoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3 -carboxamide. 41. A compound according to claim 1, which is N-(4-Fluorobenzyl) 6-methoxy-4-oxo-l, 4-tetrahydro-l,5-naphthyridine-3 - carboxamide. 10 42. A compound according to claim 1, which is n-(4/5-

Imidazolyl)methyl 6-ethoxy-4-οχο-1,4-tetrahydro-l,5-naphthyridine- 3 -carboxamide. 43. A compound according to claim 1, which is N-4-Tetrahydropyranyl 6-ethoxy-4-οχο-1,4-tetrahydro-l,5- 15 naphthyridine-3-carboxamide. 44. A compound according to claim i, which is N-(3-Thienyl)methyi 6-ethoxy-4-oxo-1,4-tetrahydro-l,5-naphthyridine - 3 - carboxamide . 45. A compound according to claim l, which is N-2-(6-20 Methyl)heptan-6-ol 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide. 46. A compound according to claim 1, which is N-(2-Tetrahydropyranyl) methvl 6-ethoxy-4-oxo-l, 4-tetrahydro -1,5-naphthyridine- 3 -carboxamide. -94- LV 12539 47. A compound according to claim 1, which is N-(2-Fluorobenzyl) 6-ethoxy-4-οχο-1,4 -tetrahydro-l,5-naphthyridine-3 - ca-rboxamide. 48. A compound according to claim 1, which is N-(3- 5 Fluorobenzyl) 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 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-naphthyriaine-3-carboxamide. 10 50. A compound according to claim 1, which is N-(4-

Methoxybenzyi) 6 -ethoxy-4-οχο-1,4 -tetrahydro-1,5 -naphthyriaine-3-carboxamide . 51. A compound according to claim 1, which is N-(3-Fluorcbenzyl) 6-methoxy-4-οχο-1,4 -tetrahydro-1,5- 15 naphthyridine-3-carboxamide. 52. A compound according to claim 1, which is N-Benzyl 6-(N-methyl, N-toluenesulfonyl-amino)-4-oxo-1,4-tetrahydro- 1,5-naphthyridine-3-carboxamide. 53. A compound according to claim l, wnich is N-Benzyl 20 6-(methy!amino)-4-oxo-l,4-tetrahyaro-l,5-naphthyridine-3- carboxamiae. 54. A compound according to claim 1, which is N-Piperonvl 6-ethoxy-4-oxo-l, 4 - tetrahydro-1,5-naphthyridir.e-3 -carboxamide. -95- 55. A compound according to claim 1, which ia N-Piperonyl 6-methoxy-4-oxo-l, 4-tetrahvdro-l, 5-naphthyridine-3-carboxamide. 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-carboxanu.de. 57. A compound according to claim 1, which is N-(4-Methylbenzyl) 6-ethoxy-4-οχο-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 - οχο -1,4 - tetrahydro-l, 5-naphthyridine-3 -carboxamide. 59. A compound according to claim 1, which is N-Benzyl 6 -dimethylamino-4-oxo -1,4-tetrahydro-l, 5-naphthyridine-3 - 15 carboxamide. 60. A compound according to claim l, which is N-Isoamyl 6-morpholino-4-oxo-l, 4 -tetrahydro-l, 5-naphthyridine-3-carboxamiae. 61. A compound according to claim l, which is N-Benzyl 20 6-morpholino-4 -oxo-l, 4 -tetrahydro-l, 5-naphthyridine-3- carboxamide. 62. A compound according to claim 1, which is N-(2-Fluorobenzyl) 6-morpholino-4-οχο-1,4-tetrahydro-l, 5-naphthyridine-3-carboxamide. -96- LV 12539 63. A compound according to claim 1, which is N- (3 -Ethoxy)propyl 6-morpholino-4-οχο-1,4 -tetrahydro-1,5 -naphthyridine-3 -carboxamide. 64. A compound according to claim 1, which is N-n-Butyl 5 6-morpholino-4-οχο-1,4-tetrahydro-1,5-naphthyridine-3- carboxamide. 65. A compound according to claim 1, which is N-(2-Pyridyl)methyl 6-morpholino-4-oxo-l,4 -tetrahydro-l,5-naphthyridine-3 -carboxamide. 10 66. A compound according to claim 1, which is N-(2-

Thienyl)methyl 6-(2-methoxyethoxy) -4-oxo-l,4-tetrahydro-l,5-napht hyridine - 3 - carboxamide. 67. A compound according to claim 1, which is N-Isoamyl 6-dimethylamino-4-οχο -1,4 -tetrahydro -1,5-naphthyridine-3-15 carboxamide. 67. A compound according to claim 1, whicn is N-(2-Thienyl) methyl 6-morpholino-4-oxo-l, 4-tetrahydro-1,5-naphthyridine-3 -carboxamide. 68. A compound according to claim 1, which is N-(2-20 Tnienyl)methvl 6-dimethylamino-4-οχο-1,4-tetrahydro-l, 5- nap’nthyridine-3 - carbcxamide. 69. A compound according to claim 1, which is N-(2-Thiazolyl) methyl 6-morpholino-4-οχο-1,4 -tetranydro-l, 5-naphthyridine-3-carboxamide. -97- 70. A compound according to claim 1, which is N-(4-Methylaminomethyl)benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l, 5-naphthyridine-3-carboxamide. 71. A compound according to claim 1, which is N-[4-(l-5 Methylamino) ethyl]benzyl 6-ethoxy-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide. 72. A compound according to claim 1, which is N-(2-Tetrahydrofuranyl) methyl 6-dimethylamino-4-oxo-l, 4-tetrahydro-1,5- napht hyr idine - 3 - carboxamide. 10 73 . A compound according to claim 1, which is N-n-Pentyl 6 -morphol ino - 4 - oxo -1,4-1 e t rahydro -1,5- naphthyr idine - 3 -carboxamide. 74. A compound according to claim 1, which is N-(3-Methoxybenzyl) 6-morpholino-4-οχο-1,4-tetrahydro-l, 5- 15 naphthyriaine-3 -carboxamide. 75. A compound according to claim 1, which is N-(3-Fluorobenzyl) 6-morpholino-4 -οχο-1,4 -tetrahydro-l, 5-napht hyr idine - 3 - carboxamide. 76. A compound according to claim 1, which is N-(4-20 Methylaminomethyl)benzyl 6-(2-methoxyethoxy)-4-oxo-l,4- tetrahydro-1,5-naphthyridine-3-carboxamide. 77. A compound according to claim l, which is N-n-3utyl 6 - pyrroliaino-4-oxo-l, 4 - tetrahydro -1,5 - napht hyr idine-3 -carboxamide. -98- LV 12539 78. A compound according to claim 1, which is N-(4-Methoxybenzyl) 6-pyrrolidino~4-oxo-l,4-tetrahydro-l,5- .naphthyridine - 3 -carboxamide. 79. A compound according to claim 1, which is N-(2-5 Thienyl)methyl 6-pyrrolidino-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3 -carboxamide. 80. A compound according to claim 1, which is N-[4-(l-Methylamino)ethyl]benzyl 6-dimethylamino-4-oxo-l,4 -tetrahydro- 1.5- naphthyr idine - 3 - carboxamide. 10 81. A compound according tc claim I, which is N-{4-

Mechylamino) benzyl 6-n-propoxy-4-οχο-1,4 -tecrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 82. A compound according to claim 1, which is N-[4-(l-Methy1aminomethy 1)ethyl]benzvl € -chicro-4 -oxo-1,4 -1etrahydro- 15 1, S-naphthyridine-2-carboxamide. 83. A compound according to claim 1, which is N-[4-(l-Methylamino) ethyl] benzyl 6-pvrrolidino-4 -oxo-l, 4-tetrahydro- 1.5- naphthyridine-3-carboxamiae hvdrochloride. 84. A compound according to claim 1, which is N-{4-20 Ethoxybenzyl) 6-morņholino-4-oxc-l,4-tetrahvdro-l,5- naphthyridine - 3-carboxamide . 85. A compound according cc claim 1, which is N-(4-Ethoxybenzyl) 6-pyrrolidino-4-oxo-l,4-tetrahydro-l,5-naphtnyridine-3-carboxamide. -99- 86. A compound according to claim l, which is N-(4-Chlorobenzyl) 6-morpholino-4-oxo-l,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 87. A compound according to claim 1, which is N-(3-5 Chlorobenzyl) 6-morpholino-4-oxo-l,4-tetrahydro-l,5- naphthyridine-3-carboxamide. 88. A compound according to claim 1, which is N-Piperonyl 6-dimethylamino-4-oxo-l,4-tetrahydro-l, 5-naphthyridine - 3 -carboxamide hydrochloride. 1C 89. A compound according to claim 1, which is N-Benzyl 6- (2-methylamino) etnoxy-4-oxo-1,4-tetrahydro-l, 5-naphthyridine-3 -carboxamide. 90. A compound according to claim 1, which is N-Benzyl 6 -(2-dimethylamino)ethoxy-4-οχο-1,4-tetrahydro-l, 5- 15 naphthyridine-3-carboxamide. 91. A compound according to claim 1, which is N-(4-Ethylaminomet’nyl) benzyl 6-ethoxy-4 - οχο -1,4 -tetrahyaro -1,5 -naphthyridine-3 -carboxanu.de. 92. A compound according to claim 1, which is N-3enzyl 2 0 6-(2-methoxy)ethylamino-4-οχο-1,4-tetrahydro-1,5- naphthyridine-3-carboxamide. 93. A compound according to claim 1, which is N-(3-Methylaminomethyl) benzyl 6 -et'noxy-4 - οχο -1,4 - cetrahydro-1,5 -naphthyridine-3-carboxamide hydrochloride. -100- LV 12539 94. A compound according to claim 1, which is N-(4-Dimethylaminomethyl)benzyl 6-ethoxy-4-οχο-1,4 -tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 95. A compound according to claim 1, which is N-(3- 5 Methylaminomethyl)benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-l,5-naphthyridine- 3-carboxamide hyarochloride. 96. A compound according to claim 1, which is N-[4-(1-Imidazolylmethy)]benzyl 6-ethoxy-4-οχο-1,4-tetrahydro-l,5-napht hyr idine - 3 - carboxanu.de. 10 97. A compound according to claim 1, wherein Y is pyrimidinylmethyl, pyridylmethyl, or a group cf the formula*.

where Rl8 repressnts hydrogen, amino, mono-, or di(C.-C5) alkylamino, or C.-C£ alkyi optionallv substituted with a R.9 15 where Rie represents:

where V and V' are independently CH or nitrogen,· A' ' is C,-C£ alkvlene; and R;o is phenyi, pyndyl, or pyrimidinyl, each cf which is 20 optionally mono-, di-, or trisubstituted ir.dependently with halogen, hydroxy, C,-Cs alkoxy, amino, or mono- or di (C.-C6)alkylamino. -101- 98. A compound according to claim l, which is

wherein A is Cj-Cg alkylene; 5 X is defined as above for Formula I; and (i) amino or mono- or di (Ci-Cg) alkylamino; or (ii) lower alkyl optionally subscituted with

where 1 V and V' are independently CH or nitrogen; A' ' is Cj-Cg alkylene; and 20 10 15 R2c is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted indepenaently vith halogen, hydroxy, C,-C6 alkoxy, amino, or mono- or diiC;-Cg) alkylamino. 99. A compound according to claim 1, v/hich is N-Benzyl 6-benzylamino-4-oxo-i, 4-tetrahydro-l, 5-naphthyridine-3 -20 carboxamide. -102- f LV 12539 100. A compound according to claim 1, which is N-Cyclohexyl 6-ethoxy-4-ΟΧΟ-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 101. A compound according to claim 1, which is N- 5 Cyclohexylmethyl 6-ethoxy-4-oxo-l, 4-tetrahydro-l, 5- naphthyridine-3-carboxamide. 102. A compound according to claim 1, which is N-(4-Aminobenzyl)-6-ethoxy-4-οχο-1,4 -tetrahydro-1,5-naphthyridine- 10 3-carboxamide. 103. A compound according to claim 1, which is N-(4-Pyridylmethyl) 6-ethoxy-4-oxo-l,4-tetrahydro -1,5-naphthyridine-3-carboxamide. 15 104. A compound according to claim 1, which is N-Benzyl 6-tetrahydroisoquinolinyl-4-oxo-l,4-tetrahydro-l,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-trifluoroethyl)-4-oxo-l,4-tetrahydro-l,5-naphthyridine-3-carboxamide. -103- LV 12539 Ābstract of the Discloaure

The present invention encompasses structures of the Formula

N H -Y 5 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, 10 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, 15 cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness. -104-

Claims (105)

EN 12539 INVENTION FORMULA 1. A compound of the formula: N 'H Y Ν H or a pharmaceutically acceptable salt thereof, wherein: X is hydrogen, halogen, -OR 1, C 1 -C 6 alkyl optionally substituted with up to three groups independently selected from halogen and oxo or -NR 2 R 3; X is phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl or 4- (1,2-dihydro) indenyl, pyridinyl, pyrimidyl, isoquinolinyl, 1,2,3 , 4 - tetrahydroisoquinolinyl, benzofuranyl or benzothienyl, each of which is optionally substituted with up to three groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 alkylthio, oxy, amino, mono- di (C 1 -C 6) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; or X represents a 3-7 membered carbocyclic group, where up to two of its members are optionally heteroatoms selected from oxygen and nitrogen atoms, wherein the carbocyclic group X is optionally substituted with one or more groups selected from halogen, C 1 -C 6 alkoxy -, mono- or di (C 1 -C 6) alkylamino, sulfamido, aza (C 3 -C 7) cycloalkyl, C 3 -C 7 cycloalkylthio, C 1 -C 6 alkylthio, phenylthio or heterocyclic groups; X is lower alkyl of 1-8 carbon atoms optionally substituted with up to two groups selected from halogen, (C3-C7) cycloalkyl, C1-C6 alkoxy, mono- or di (C1-C6) alkylamino, sulfamide -, aza (C3-C7) cycloalkyl, C3-C7 cycloalkylthio, C1-C6 alkylthio, phenylthio, heterocyclic, -OR4, -Nr5R6, SR7 or optionally substituted aryl; or Y is a carbocyclic group of 3-7 membered atoms, where up to three of its members are optionally heteroatoms selected from oxygen and nitrogen, and wherein any member of the carbocyclic group Y is optionally substituted by halogen, -OR4i -NR5R6, SR7i aryl or heterocyclic group; R 1 is hydrogen, lower alkyl of 1-6 carbon atoms, or cycloalkyl of 3-7 carbon atoms, each alkyl being optionally substituted by -OR 4 or -NR 5 R 6; R2 and R3 are the same or different and are hydrogen, lower alkyl optionally mono- or dialyzed with alkoxy, aryl, halogen, or mono- or di-lower alkyl; aryl or aryl (C1-C6alkyl, wherein each aryl is optionally substituted with up to three groups selected from halogen, oxy, C1-C6 alkyl, C1-C6 alkoxy, or mono- or di (C1-C6) cycloalkyl with 3-7 carbon atoms optionally mono or dialyzed with halogen, alkoxy, or mono- or di-lower alkyl, or -SO 2 Re; R 4 is as defined for R 1, R 5 and R 6 are the same as R 2 and R 3 respectively R7 is hydrogen, lower alkyl of 1-6 carbon atoms or cycloalkyl of 3-7 carbon atoms, and 2R5 is lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-7 carbon atoms or optionally substituted phenyl. 2. Connection to formula: N 'H Y or a pharmaceutically acceptable salt thereof, wherein: X is (i) hydrogen, halogen, mono- or dialkylamino, alkoxy, (ii) a group of the formula: R1 ° N xO ^ J- g r " wherein G is the lower alkylene of 1-6 carbon atoms or a cyclic group of formula (CH9) n - < > - (CH2) m where n is 0, 1 or 2, and m is an integer from 1 to 5, provided that the sum of n + m is not less than 1 or greater than 5; and R 1 is hydrogen, lower alkyl or (C 3 -C 8) cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by halogen, lower alkoxy, or mono- or di (C 1 -C 6) alkylamino; (iii) a group of the formula: R 3 R 2 N g 0 O wherein G is as defined above for (ii); and R 2 and R 3 are independently hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-7 carbon atoms, -SO 2 R 8, wherein R 8 is (C 1 -C 6 alkyl, (C 3 -C 7) cycloalkyl, or optionally substituted phenyl, or R2 and R3 together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl, (iv) a group of formula R wherein R2 is as defined above for iii; 12539 R4 is hydrogen, lower alkyl of 1-6 carbon atoms or cycloalkyl of 3-7 carbon atoms, and may be optionally substituted with one or more (C1-C6) alkoxy or mono- or di (C1-C6) alkylamino groups; and G is as defined above for (ii), (v) a group of the formula: r 2 -N r 6 r 5 nx wherein R 2 and G are as defined above for iv and ii, respectively, and R 5 and R 6 are independently hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, -SO2R8, wherein Re is (C1-C6alkyl, (C3-C7) cycloalkyl, or optionally substituted phenyl, or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic moiety; (vi) a group of formula: Ο N where G is as defined above for case ii; or (vii) a group of formula: r2n G N where each G is as defined above for case ii; and Y is (viii) lower alkyl of 1-8 carbon atoms or cycloalkyl of 3-7 carbon atoms, any of which may be optionally substituted with one or more halogen atoms, (C1-C6) alkoxy, alkoxyalkoxy, each alkoxy are (C1-C6) alkoxy, (C1-C6alkylthio, (C3-C7) cycloalkylthio, aryl, heteroaryl, or mono- or di (C1-C6) alkylamino; (ix) a group of the formula: " " or9 where K is the lower alkylene of 1-6 carbon atoms optionally substituted with (C1-C6alkyl or alkylene or a cyclic group of the formula 4 4I (CHo) m - < > - (CH2) n where K 'is independently hydrogen or (C 1 -C 6 alkyl or alkylene, n is 0, 1 or 2, and m is an integer from 1 to 5, provided that the sum of n + m is not less than 1 or greater than 5, and R g is hydrogen, lower alkyl or (C3-C7) cycloalkyl, where alkyl or cycloalkyl is optionally substituted by halogen, lower alkoxy, or mono- or dialkylamino (x) a group of formula: wherein K is as defined above for ix; (xi) a group of formula: K 'OR 13 wherein K is as defined above for ix, and Ris is hydrogen, lower alkyl of 1-6 carbon atoms, or cycloalkyl of 3-7 carbon atoms, wherein alkyl and cycloalkyl are alkyl; optionally substituted with one or more (C1-C6) alkoxy or mono- or di (C1-C6) alkylamino groups; and (xii) a group of formula: sr7 wherein K is as defined above for ix, and R7 is hydrogen, lower alkyl of 1-6 carbon atoms, or cycloalkyl of 3-7 carbon atoms; and (xiii) a group of the formula: K > NR14R15 where K is as previously defined for ix case; and R14 and R15 are independently hydrogen, lower alkyl of 1-6 carbon atoms, cycloalkyl of 3-7 carbon atoms, -SO2R8 > wherein R 8 is as defined above, or 5 LV 12539 R 14 and R 15 together with the nitrogen atom to which they are attached form a heterocyclic moiety; (xiv) a group of formula: R 15 wherein K and R 15 are as defined above for ix and xii, respectively; (xv) Group with formula: R 11 R 12 wherein K is as defined above for ix; R10 and R10 'are the same or different and selected from hydrogen, halogen, oxo, lower alkoxy of 1-6 carbon atoms, or cycloalkoxy having 3-7 carbon atoms; R11, R11 and R12 are the same or different and selected from hydrogen, halogen, oxo, -OR *. The -CR 7 (R 9) NR 5 R 6, -CR 2 R 6 -ROR * groups, or R 11 -R 12 together with the atoms to which they are attached form a (hetero) cyclic ring; and R 16 is hydrogen, lower alkyl of 1-6 carbon atoms, or cycloalkyl of 3-7 carbon atoms (xvi) a group of the formula: w wherein K is as defined above for ix; and W is heteroaryl; (xvii) a group with the formula: where K is as previously defined for the ix case; R00 and Rn are as previously defined for xv, and 6R17 is hydrogen, lower alkyl or (C3-C7) cycloalkyl, where alkyl or cycloalkyl is optionally substituted with halogen, lower alkoxy, or mono- or di (C1-6). -C6) alkylamino; (xviii) a group of the formula: R 1 n wherein K, R 10, R 12 and R 7 are as defined above; (xix) group with formula: wherein each K is independently defined as above for ix and R10 is defined above; (xx) Group with formula: NR14R15 wherein K, R10, R11, Ru and R15 are as defined above; and (xxi) a group of formula: wherein K, R10, R12, Ru and R15 are as defined above. 3. A compound according to claim 1 which is 7 LV 12539 N · H. wherein A is C1-C6 alkylene; R a is phenyl optionally mono-, di- or tri-substituted with halogen, lower alkyl, or mono- or di-C 1 -C 6 alkylamino, or mono- or di-C 1 -C 6 alkylamino lower alkyl; and Rb is lower alkyl or lower cycloalkyl. 4. A compound according to claim 1 which is R N H Ra 'wherein A is C 1 -C 6 alkylene; Ra and Ra 'are independently phenyl, optionally mono-, di-, or tri-substituted by halogen, lower alkyl, lower alkoxy, or mono- or di-C 1 -C 6 alkylamino, or lower mono- or di-C 1 -C 6 alkylamino. ; and Rc is hydrogen or lower alkyl. 5. The compound of claim 1, which is o o H N 1 -C 4 O R H wherein A is C 1 -C 6 alkylene; Rd and Re are independently lower alkyl. A compound according to claim 1 which is -O-N H R, N H 8 wherein A is C 1 -C 6 alkylene; Rd is the lower alkyl; and Rf is a group with the formula: wherein E is oxygen or nitrogen; and M is C1-C3 alkylene or nitrogen. A compound according to claim 1 which is H wherein A is C 1 -C 6 alkylene; Rd is the lower alkyl; and R a 'is phenyl optionally mono-, di-, or tri-substituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C 1 -C 6 alkylamino, or lower alkyl or di-C 1 -C 6 alkylamino. 8. The compound of claim 1, which is H where A is C 1 -C 6 alkylene; and Rd and Re are independently lower alkyl. 9. The compound of claim 1 which is H 9 EN 12539 wherein D is nitrogen or CH; D 'is nitrogen or oxygen; A is C1-C6 alkylene; and R a 'is phenyl optionally mono-, di- or tri-substituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C 1 -C 6 alkylamino, or lower alkyl or di-C 1 -C 6 alkylamino. 10. The compound of claim 1, which is N ^ H A. R.! wherein A is C1-C6 alkylene; and R a 'is phenyl optionally mono-, di-, or tri-substituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C 1 -C 6 alkylamino, or mono- or di-C 1 -C 6 alkylamino lower alkyl. 11. A compound according to claim 1 which is H where A is C 1 -C 6 alkylene; and Rd is the lower alkyl; A 'is oxygen or methylene; and r is an integer from 1 to 3. A compound according to claim 1 which is wherein A is C1-C6 alkylene; R8 is lower alkoxy lower alkyl; and Ra' and phenyl are optionally mono-, di- or tri-substituted with halogen, lower alkyl, lower alkoxy, or mono- or di-CrCe alkylamino, or mono- or di-C1-C6 alkylamino lower alkyl. 10 A compound according to claim 1 which is N-n-Butyl 6-benzylamino-4-oxy-1,4-dihydro-1,5-naphthyrid-3-carboxamide. A compound according to claim 1 which is N- [2- (Ethylthio) ethyl] 6-methoxy-4-oxy-1,4-dihydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- [4- (Methylaminomethyl) benzyl] 6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (4-Methoxybenzyl) 6-pyrrolidino-4-oxy-1,4-dihydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-Butyl 6-chloro-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-Propan-3-ol 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-Butyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-Ethylthio) ethyl 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-Butyl 6- (N-benzylamino) -4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-n-Pentyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-isopropoxy) propyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-Benzyl-6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 25. The compound of claim 1, which is Ν-2-Pent! 6-Ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-Tetrahydrofuranyl) methyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (3-Methoxy) propan-2-ol 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-Methoxy) propyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (2-Methoxy) ethyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 11 LV 12539 A compound according to claim 1 which is N-benzamyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-Furanyl) methyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (3-Methoxybenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-Ethoxy) propyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-2- (2-Methyl) butyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyrine-3-carboxamide. A compound according to claim 1 which is N-2-Pentan-1-ol 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-5-Pentanol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 37. The compound of claim 1 which is N-1-Cyclohexan-2-ol 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-Benzyl 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-Fluorobenzyl) 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-Fluorobenzyl) 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-Fluorobenzyl) 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 42. The compound of claim 1 which is N- (4H-Imidazolyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is Ν-4-Tetrahydropyranyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (3-Thienyl) methyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-2- (6-Methyl) heptan-6-ol 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-Tetrahydropyranyl) methyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 12 A compound according to claim 1 which is N- (2-Fluorobenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (3-Fluorobenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-Fluorobenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (4-Methoxybenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N- (3-Fluorobenzyl) 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-Benzyl 6- (N-methyl, N-toluenesulfonylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 53. The compound of claim 1 which is N-Benzyl 6- (methylethyl) -4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 54. The compound of claim 1 which is N-Piperonyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1 which is N-Piperonyl 6-methoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1, which is N-2- (4H-Imidazolyl) ethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 57. The compound of claim 1 which is N- (4-Methylbenzyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide C. The compound of claim 1 which is N-Benzyl 6- (2-methoxyethoxy) -4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 59. The compound of claim 1 which is N-Benzyl 6-dimethylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 60. A compound according to claim 1 which is N-benzamyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamate. 61. The compound of claim 1 which is N-Benzyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 62. The compound of claim 1 which is N- (2-Fluorobenzyl) 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 63. The compound of claim 1 which is N- (3-Ethoxy) propyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 13 LV 12539 64. A compound according to claim 1 which is Ν-π-Butyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 65. The compound of claim 1 which is N- (2-pyridyl) methyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyrine-3-carboxamide. The compound of claim 1 which is N- (2-Thienyl) methyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 67. The compound of claim 1 which is N-benzamyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 67. The compound of claim 1 which is N- (2-Thienyl) methyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (2-Thienyl) methyl 6-dimethylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 69. A compound according to claim 1 which is N- (2-Thiazolyl) methyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 70. The compound of claim 1 which is N- (4-Methylaminomethyl) benzyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 71. The compound of claim 1 which is N- [4- (1-Methylamino) ethyl] benzyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 72. The compound of claim 1 which is N- (2-Tetrahydrofuranyl) methyl 6-dimethylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 73. The compound of claim 1 which is N-n-Pentyl 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 74. A compound according to claim 1 which is N- (3-Methoxybenzyl) 6-morphol-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 75. The compound of claim 1 which is N- (3-Fluorobenzyl) 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 76. The compound of claim 1 which is N- (4-Methylaminomethyl) benzyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N-n-Butyl 6-pyrrolidino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-Methoxybenzyl) 6-pyrrolidino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 79. The compound of claim 1 which is N- (2-Thienyl) methyl 6-pyrrolidino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 14 80. The compound of claim 1 which is N- [4- (1-Methylamino) ethyl] benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-Methylamino) benzyl 6-n-propoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. A compound according to claim 1 which is N- [4- (1-Methylaminomethyl) ethyl] benzyl 6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 83. The compound of claim 1 which is N- [4- (1-Methylamino) ethyl] benzyl 6-pyrrolidino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 84. The compound of claim 1 which is N- (4-Ethoxybenzyl) 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1 which is N- (4-Ethoxybenzyl) 6-pyrrolidino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 86. The compound of claim 1 which is N- (4-Chlorobenzyl) 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 87. The compound of claim 1 which is N- (3-Chlorobenzyl) 6-morpholino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 88. The compound of claim 1 which is N-Piperonyl 6-dimethylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 89. The compound of claim 1 which is N-Benzyl 6- (2-methylamino) ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 90. The compound of claim 1 which is N-Benzyl 6- (2-dimethylamino) ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 91. The compound of claim 1, which is N- (4-Ethylaminomethyl) benzyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 92. The compound of claim 1 which is N-Benzyl 6- (2-methoxy) ethylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 93. The compound of claim 1 which is N- (3-Methylaminomethyl) benzyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 94. The compound of claim 1 which is N- (4-Dimethylaminomethyl) benzyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 95. The compound of claim 1 which is N- (3-Methylaminomethyl) benzyl 6-n-propoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. 96. A compound according to claim 1 which is N- [4- (1-lidazolylmethyl) benzyl] 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 15 LV 12539 97. The compound of claim 1, wherein Y is pyrimidinylmethyl, pyridylmethyl, or a group of the formula: wherein R18 is hydrogen, amino, mono-, or di (ι-ι-Οβ) alkylamino, or C1-C6 alkyl optionally substituted with Rig wherein Ris is: wherein V and V are independently CH or nitrogen; A 1 'is C 1 -C 6 alkylene; and R20 is phenyl, pyridyl, or pyrimidinyl, each of which is optionally mono-, di- or tri-substituted independently with halogen, hydroxy, C1-C6 alkoxy, amino, or mono- or di (C1-C6); ) an alkylamino group. 98. The compound of claim 1, which is H wherein A is C 1 -C 6 alkylene; X is as defined above for formula I; and Ris is (i) an amino group or a mono- or di (C 1 -C 6) alkylamino group; or (ii) the lower alkyl optionally substituted with wherein V and V are independently CH or nitrogen; A 1 'is C 1 -C 6 alkylene; and 16 R 20 is phenyl, pyridyl or pyrimidinyl, each of which is optionally mono-, di-, or tri-substituted independently with halogen, hydroxy, C 1 -C 6 alkoxy, amino or mono- or di (C 1 -C 6) alkylamino. A compound according to claim 1 which is N-Benzyl 6-benzylamino-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 100. The compound of claim 1 which is N-Cyclohexyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 101. The compound of claim 1 which is N-Cyclohexylmethyl 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 102. The compound of claim 1 which is N- (4-Aminobenzyl) -6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 103. The compound of claim 1 which is N- (4-pyridylmethyl) 6-ethoxy-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 104. The compound of claim 1 which is N-Benzyl 6-tetrahydroisoquinolinyl-4-oxy-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 105. The compound of claim 1, which is N- {4- [1- [4- (4-fluorobenzyl) piperazinyl] methyl] benzyl} 6- (2,3,2-trifluoroethyl) -4-oxy-1 4-Tetrahydro-1,5-naphthyridine-3-carboxamide.