KR20010023313A - Substituted 4-oxo-napthyridine-3-carboxamides as gaba brain receptor ligands - Google Patents

Abstract

The present invention includes a compound of formula (I) or a pharmaceutically acceptable non-toxic salt thereof, which compound is highly selective agonist, antagonist or inverse agonist for GABAa brain receptor, or GABAa brain receptor Prodrugs of agonists, antagonists or inverse agonists for:

(I)

In the above formula,

X is hydrogen, halogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkoxy or amino,

Y is unsubstituted or substituted alkyl, aryl, or heteroaryl.

These compounds are useful for diagnosing and treating anxiety, Down syndrome, sleep disorders, cognitive disorders and seizure disorders, and overdose of benzodiazepines and for improving agility.

Description

SUBSTITUTED 4-OXO-NAPTHYRIDINE-3-CARBOXAMIDES AS GABA BRAIN RECEPTOR LIGANDS} Substituted 4-oxo-naphthyridine-3-carboxamide as a BAA brain receptor ligand

γ-aminobutyric acid (GABA) is considered as one of the major inhibitory amino acid transfer factors in the mammalian brain. More than 40 years have passed since it was discovered that γ-aminobutyric acid was present in the brain. Roberts & Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187: 65-69, 1950. Since its discovery, there has been a tremendous effort to relate GABA to the pathogenesis of seizure disease, sleep disorders, anxiety and cognitive impairment. Rev. Neuroscience 8: 21-44, 1985. Although widespread, GABA is believed to be a transfer factor at about 30% of synapses in the brain when distributed throughout the mammalian brain. GABAs mediate their various functions through complexes of proteins ubiquitous on the ends of cell bodies and nerves, which are called GABAa receptors. Post-synaptic responses to GABA, although not constant, are usually mediated through changes in chloride conduction that cause hyperpolarization of cells. Drugs that interact at the GABA receptors may have a spectrum of pharmacological activity depending on their ability to alter the action of GABA.

1,4-benzodiazepines, such as diazepam, are widely used drugs worldwide as anxiolytics, sedative hypnotics, muscle relaxants and anticonvulsants. Many of these compounds are very potential drugs, and these potentials represent sites of action with high affinity and specificity for individual receptors. Early electrophysiology studies have shown that the main action of benzodiazepines improves inhibition of GABA action. Currently, compounds having similar activity to benzodiazepines are called agonists. Compounds that have activity in contrast to benzodiazepines are called inverse agonists, and compounds that block these two types of activity are called antagonists.

GABAa receptor subunits are cloned from bovine and human cDNA libraries. Schoenfield et al., 1988; Duman et al., 1989]. Numerous individual cDNAs have been identified as subunits of the GABAa receptor by cloning and expression. These are classified as α, β, γ, δ, ε and provide a molecular basis for GABAa receptor heterogeneity and individual domains of pharmacology. Shivvers et al., 1980; Levitan et al., 1989]. The γ subunit seems to be able to alter the GABA response of benzodiazepine-type drugs (Pritchett et al., 1989). The low Hill coefficient in ligand binding to the GABAa receptor indicates a unique profile of pharmacological action specific to the subtype.

Depending on the discovery of "receptors" for benzodiazepines and then the characterization of the interaction between GABA and benzoidazepine, the functionally important interactions of benzoidazepine with different neurotransmitters are largely the ability of GABA itself to change the neurotransmitter system. This is because it increased. In addition, each modified neurotransmitter may be involved in the expression of action. Depending on the mode of interaction, these compounds may exhibit a variety of activities (calm, anxiety relief and spasm inhibition, or insomnia, seizures and anxiety).

Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxylic acids and esters are known. See, for example, the following references: Eur. J. Med. Chem.-Chim. Ther. (1977), 12 (6), 549-55.

Polish patent 125299 describes compounds of the formula

Wherein N is ring nitrogen at 5 or 6 values, and R is CO ₂ H or CO ₂ Et.

Various 1,4-dihydro-4-oxo-1,5-naphthyridine-3-carboxamide derivatives of various penicillins are known. For example, German patent DD 279887 describes compounds of the formula

Japanese Patent No. 72-45118 describes ampicillin derivatives of 1,4-dihydroxy-4-oxo-3-naphthyridine.

The present invention relates to substituted 4-oxo-naphthyridine-3-carboxamides, and more particularly to substituted 4-oxo-naphthyridine-3-carboxamides that selectively bind to GABAa receptors. The present invention also relates to pharmaceutical compositions comprising said compounds, and methods of using said compounds to increase agility and to treat anxiety, overdose of benzodiazepine type drugs, Down syndrome, sleep disorders, seizure disorders and cognitive disorders. .

Summary of the Invention

The present invention provides a novel compound of formula (I) which interacts with the benzodiazepine receptor, GABAa binding site.

The present invention provides a pharmaceutical composition comprising a compound of formula (I). The present invention also provides compounds useful for diagnosing and treating anxiety, Down syndrome, sleep disorders, cognitive disorders and seizure disorders, and overdose of benzoidazepine drugs and for improving agility. Accordingly, a broad embodiment of the invention relates to compounds of formula (I)

In the above formula,

X is hydrogen, halogen, -OR _1, from a non-substituted C ₁ -C ₆ alkyl or halogen, and hydroxy-substituted by up to three substituents independently selected C ₁ -C ₆ alkyl, or -NR ₂ R ₃ Or;

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, benzothienyl (each of which is unsubstituted or halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylthio With up to 3 substituents selected from hydroxy, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy Substituted);

X contains 3 to 7 elements, and 2 or less of these elements are a carbon ring group ("X carbon ring group") which is a hetero atom optionally selected from oxygen and nitrogen, wherein the X ring group is unsubstituted or Substituted with one or more substituents selected from halogen, alkoxy, monoalkylamino, dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, or a heterocyclic group;

Y is unsubstituted or halogen, alkoxy, monoalkylamino, dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, heterocyclic group, -OR ₄ , -NR ₅ R ₆ , SR ₇ Or lower alkyl of 1 to 8 carbon atoms substituted with up to 2 substituents selected from aryl;

Y contains 3 to 7 elements, and 3 or less of these elements are carbon ring groups ("Y carbocyclic groups") which are heteroatoms optionally selected from oxygen and nitrogen, wherein any of Y carbocyclic groups The element is unsubstituted or substituted with halogen, —OR ₄ , —NR ₅ R ₆ , SR ₇ , aryl or heterocyclic group;

R ₁ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, wherein each alkyl is unsubstituted or substituted with —OR ₄ or —NR ₅ R ₆ ;

R ₂ and R ₃ are the same or different,

Hydrogen,

Lower alkyl unsubstituted or mono- or di-substituted with alkoxy, aryl, halogen, mono lower alkyl, di lower alkyl,

Aryl or aryl (C ₁ -C ₆ ) alkyl, wherein each aryl is unsubstituted or halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono (C ₁ -C ₆ ) alkyl Substituted with up to 3 substituents selected from amino or di (C ₁ -C ₆ ) alkylamino),

Cycloalkyl having 3 to 7 carbon atoms, unsubstituted or mono- or di-substituted with halogen, alkoxy, mono lower alkyl or di lower alkyl, or

-SO ₂ R ₈ ;

R ₄ is as defined for R ₁ ;

R ₅ and R ₆ are as defined for R ₂ and R ₃ , respectively;

R ₇ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms;

R ₈ is lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, substituted phenyl or unsubstituted 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 for diagnosing and treating anxiety, Down syndrome, sleep disorders, cognitive disorders and seizure disorders, and overdose of benzodiazepines and for improving agility.

Detailed description of the invention

The novel compounds included in the present invention can be described by formula (I) above.

In the above formula (I), —NR ₂ R ₃ may also be a heterocyclic group such as piperidine, in which case R ₂ and R ₃ together form a C ₅ -alkylene group. In addition, R ₂ and R ₃ may together form an alkylene or alkenylene group with or without two heteroatoms selected from nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

Similarly, the group —NR ₅ R ₆ in formula (I) may also be a heterocyclic group such as piperidine, in which case R ₅ and R ₆ together form a C ₅ -alkylene group. In addition, R ₅ and R ₆ may together form an alkylene or alkenylene group with or without two heteroatoms selected from nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl and piperidinyl.

Preferred compounds of formula (I) are those wherein X is (C ₁ -C ₆ ) alkoxy, more preferably (C ₁ -C ₃ ) alkoxy. Particularly preferred compounds of formula (I) include methoxy or ethoxy as the X group.

Another preferred compound of formula (I) is a compound in which Y is lower alkyl, eg methyl or ethyl, substituted by phenyl, pyridyl or pyrimidinyl. More preferred Y groups are unsubstituted or substituted with halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, amino, mono (C ₁ -C ₆ ) alkyl or di (C ₁ -C ₆ ) alkyl Benzyl.

When R ₂ and R ₃ in formula (I) are unsubstituted or substituted aryl or aryl (C ₁ -C ₆ ) alkyl, the aryl group is preferably phenyl, pyridyl or pyrimidinyl, and the alkyl group is preferably methyl And ethyl. More preferred are benzyl and phenyl. Especially preferred is benzyl.

When X is unsubstituted or substituted C ₁ -C ₆ alkyl, the preferred alkyl group is unsubstituted or substituted methyl, ethyl or propyl. More preferred alkyl is perhalomethyl and trihaloethyl. Preferred halogen is fluorine. Particularly preferred alkyl is 2,2,2-trifluoroethyl.

X in formula (I) is unsubstituted or substituted phenyl, naphthyl, 1- (5,6,7,8-tetrahydro) naphthyl, 4- (1,2-dihydro) indenyl, pyridinyl, Pyrimidyl, isoquinolinyl, benzofuranyl or benzothienyl groups, or preferably 1,2,3,4-tetrahydroisoquinolinyl groups.

In addition to compounds of formula (I), the present invention includes compounds of formula (IA):

In the above formula,

X is (i) hydrogen, halogen, monoalkylamino, dialkylamino, alkoxy,

(ii) groups of the formula

(In the above formula,

G is lower alkylene having 1 to 6 carbon atoms, or Wherein n is 0, 1 or 2, m is an integer from 1 to 5, provided that the sum of n + m is 1 to 5,

R ₁ is unsubstituted or hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is halogen, lower alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C _1- C ₆ ) alkylamino);

(iii) a group of formula:

(In the above formula,

G is as defined in (ii) above,

R ₂ and R ₃ are independently hydrogen, lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, -SO ₂ R ₈ (wherein R ₈ is (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₇ ) cycloalkyl, unsubstituted phenyl or substituted phenyl), or

R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl);

(iv) groups of the formula

(In the above formula,

R ₂ is as defined in (iii) above,

R ₄ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or substituted with one or more (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino or May be substituted with a di (C ₁ -C ₆ ) alkylamino group,

G is as defined in (ii) above);

(v) groups of the formula:

(In the above formula,

R ₂ and G are as defined above in (iv) and (ii),

R ₅ and R ₆ are independently hydrogen, lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, —SO ₂ R ₈ (wherein R ₈ is (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₇ ) cycloalkyl, unsubstituted phenyl or substituted phenyl), or

R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl);

(vi) groups of the formula:

(Wherein G is as defined in (ii) above); or

(vii) groups of the formula:

(Wherein G is as defined in (ii) above);

Y is (viii) lower alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, either of which is unsubstituted or at least one of hydroxy, halogen, (C ₁ -C ₆ ) alkoxy, alkoxyalkoxy ( Wherein each alkoxy is unsubstituted or is (C ₁ -C ₆ ) alkoxy), (C ₁ -C ₆ ) alkylthio, (C ₃ -C ₇ ) cycloalkylthio, aryl, heteroaryl, mono (C May be substituted with a _1- C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino group);

(ix) groups of the formula:

(In the above formula,

K is lower alkylene having 1 to 6 carbon atoms, unsubstituted or substituted with (C ₁ -C ₆ ) alkyl or alkylene, or In which K 'is independently hydrogen, (C ₁ -C ₆ ) alkyl or alkylene, n is 0, 1 or 2, m is an integer from 1 to 5, provided that n + m is The sum is 1 or more and 5 or less),

R ₉ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or substituted with halogen, lower alkoxy, monoalkylamino or dialkylamino);

(x) groups of the formula

(Wherein K is as defined in (ix) above);

(xi) groups of the formula:

(In the above formula,

K is as defined in (ix) above,

R ₁₃ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, wherein the alkyl and cycloalkyl groups are unsubstituted or include one or more (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino group);

(xii) groups of the formula:

(In the above formula,

K is as defined in (ix) above, respectively,

R ₇ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms);

(xiii) groups of the formula:

(In the above formula,

K is as defined in (ix) above, respectively,

R ₁₄ and R ₁₅ are independently hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ₂ R ₈ , wherein R ₈ is as defined above, or

R ₁₄ and R ₁₅ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl or piperidinyl);

(xiv) groups of the formula:

(Wherein K and R ₁₅ are as defined above in (ix) and (xii), respectively);

(xv) groups of the formula:

(Wherein K is as defined in (ix) above,

R ₁₀ and R ₁₀ ′ are the same or different and are selected from hydrogen, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, lower alkoxy having 1 to 6 carbon atoms, or cycloalkoxy having 3 to 7 carbon atoms,

R ₁₁ , R ₁₁ ′ and R ₁₂ are the same or different and are hydrogen, C ₁ -C ₆ alkyl, halogen, hydroxy, -OR ₄ , -CR ₇ (R ₉ ) NR ₅ R ₆ , -CR ₉ (R ₁₆ ) OR ₄ selected from OR

R ₁₁ and R ₁₂ together with the atoms to which they are attached form a (hetero) ring,

R ₁₆ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms);

(xvi) a group of formula

(Wherein K is each as defined in (ix) above and W is heteroaryl);

(xvii) groups of the formula

(Wherein K is as defined in (ix) above, R ₁₀ and R ₁₁ are as defined in (xv) above,

R ₁₇ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or halogen, lower alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C _1- C ₆ ) alkylamido);

(xviii) groups of the formula

(Wherein K, R ₁₀ , R ₁₂ and R ₁₇ are as defined above);

(xix) groups of the formula

(Wherein K is independently as defined in (ix) above and R ₁₀ is as defined above);

(xx) groups of the formula:

(Wherein K, R ₁₀ , R ₁₁ , R ₁₄ and R ₁₅ are as defined above);

(xxi) groups of the formula

(Wherein K, R ₁₀ , R ₁₂ , R ₁₄ and R ₁₅ are as defined above);

(xxii) pyrimidinyl (C ₁ -C ₆ ) alkyl or pyridyl (C ₁ -C ₆ ) alkyl; or

(xxiii) groups of the formula

(In the above formula,

R ₁₈ is hydrogen, amino, mono (C ₁ -C ₆₎ alkylamino, di (C ₁ -C ₆₎ alkylamino or the R ₁₉ unsubstituted or substituted (C ₁ -C ₆₎ alkyl, R ₁₉ is Wherein V and V 'are independently CH or nitrogen, A "is (C ₁ -C ₆ ) alkylene, R ₂₀ is phenyl, pyridyl or pyrimidinyl, each of which is independently substituted Or halogen, hydroxy (C ₁ -C ₆ ) alkoxy, amino, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino mono-, di- or tri-substituted)) .

Preferred pyrimidinyl (C ₁ -C ₆ ) alkyl as the Y group are 2- and 4-pyrimidinylmethyl. Preferred pyridyl (C ₁ -C ₆ ) alkyl as Y group are 2- and 4-pyridylmethyl.

Preferred benzyl Y groups are R ₁₈ is amino, or substituted methyl or ethyl groups. More preferred R ₁₈ substituents are piperazin-1-yl or piperidin-1-yl substituted with a halogenated benzyl group at the 4 position. Particularly preferred benzyl Y groups are 4- [1- [4- (4-fluorobenzyl) piperazinyl] methyl] benzyl and 4- [1- [4- (4-fluorobenzyl) piperidinyl] methyl] benzyl to be.

Preferred "X" groups in formula (IA) are various quinolinyl, isoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl groups, for example groups of the formula

The following formulas are preferred embodiments of the invention:

(Wherein Y is as defined above)

(Wherein Z is halogen and Y is as defined above.)

(Wherein R ₁ and Y are as defined above).

(Wherein R ₂ , R ₃ and Y are as defined above)

(Wherein R ₂ , R ₈ and Y are as defined above).

(Wherein R ₁ , G and Y are as defined above).

(Wherein R ₂ , R ₃ , G and Y are as defined above).

IX

(Wherein R ₂ , R ₄ , G and Y are as defined above).

(Wherein R ₂ , R ₅ , R ₆ , G and Y are as defined above.)

(Wherein G and Y are as defined above)

(Wherein R ₂ , G and Y are as defined above)

(Wherein X is as defined above and U is (C ₁ -C ₆ ) lower alkyl or (C ₁ -C ₆ ) cycloalkyl.)

(Wherein X, K and R ₁ are as defined above).

(Wherein X and K are as defined above)

(Wherein X, K and R ₄ are as defined above).

(Wherein X, K and R ₇ are as defined above).

(Wherein X, K, R ₁₄ and R ₁₅ are as defined above).

(Wherein X, K and R ₁₅ are as defined above).

(In the above formula,

R ₁₀ and R ₁₀ ′ are the same or different and may be selected from hydrogen, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, lower alkoxy having 1 to 6 carbon atoms, or cycloalkoxy having 3 to 7 carbon atoms. There is,

R ₁₁ , R ₁₁ ′ and R ₁₂ are the same or different and are hydrogen, (C ₁ -C ₆ ) alkyl, halogen, hydroxy, -OR ₄ , -CR ₇ (R ₉ ) NR ₅ R ₆ , -CR ₇ (R ₉ ) OR _4, or

R ₁₁ and R ₁₂ together with the atoms to which they are attached form a (hetero) ring,

R ₉ is as defined above.)

Wherein X and K are as defined above and W is heteroaryl.

(Wherein X, K, R ₁ , R ₁₀ and R ₁₁ are as defined above).

(Wherein X, K, R ₁ , R ₁₀ and R ₁₂ are as defined above.)

(Wherein X, K and R ₁₀ are as defined above).

(Wherein X, K, R ₁₄ , R ₁₅ , R ₁₀ and R ₁₁ are as defined above).

Preferred compounds of the present invention include the following formula (XXVII):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _a is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C ₁ -C ₆ alkylamino monophenyl, mono-, di- or tri-substituted phenyl,

R _b is lower alkyl or lower cycloalkyl.

More preferred compounds of formula (XXVII) are compounds wherein A is methylene, R _a is unsubstituted or substituted phenyl with methyl or ethyl and R _b is lower alkyl. Particularly preferred compounds of formula (XXVII) are those wherein A is methylene, R _a is phenyl and R _b is C ₁ -C ₃ alkyl.

Preferred compounds of the present invention include the following formula (XXVIII):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _a and R _a ′ are independently unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower A phenyl group mono-, di- or tri-substituted with alkyl or di-C ₁ -C ₆ alkylamino lower alkyl,

R _c is hydrogen or lower alkyl.

More preferred compounds of formula (XXVIII) are compounds in which A is methylene, R _a and R _a ′ are independently unsubstituted or substituted with methyl or ethyl, and R _c is lower alkyl. Particularly preferred compounds of formula (XXVIII) are those wherein A is methylene, R _a is phenyl substituted with lower alkyl in the para position, R _a 'is phenyl and R _c is C ₁ -C ₃ alkyl.

Preferred compounds of the present invention include the following general formula (XXIX):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d and R _e are independently a lower alkyl group.

More preferred compounds of formula (XXIX) are those wherein A is C ₂ -C ₄ alkylene. Particularly preferred compounds of formula (XXIX) are those wherein A is C ₂ -C ₄ alkylene, R _d is C ₁ -C ₃ alkyl and R _e is C ₂ -C ₄ alkyl.

Preferred compounds of the present invention include the following formula (XXX):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d is a lower alkyl group,

R _f is a chemical formula Is a group wherein E is oxygen or nitrogen and M is C ₁ -C ₃ alkylene or nitrogen.

More preferred compounds of formula (XXX) are those wherein A is C ₁ -C ₃ alkylene. Another preferred compound of formula (XXX) is a compound wherein A is C ₂ -C ₄ alkylene, R _d is C ₁ -C ₃ alkyl and R _e is C ₂ -C ₄ alkyl. Particularly preferred compounds of formula (XXX) are those wherein A is C ₂ -C ₄ alkylene, R _d is C ₁ -C ₃ alkyl, R _e is C ₂ -C ₄ alkyl, E is nitrogen and M is methylene , E is oxygen and M is methylene or ethylene or E and M are both nitrogen.

Another preferred compound of formula (XXX) is a compound wherein R _f is furanyl, tetrahydrofuranyl or imidazolyl.

Preferred compounds of the present invention include the following formula (XXXI):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d is lower alkyl unsubstituted or substituted with amino, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino,

R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl group mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl.

More preferred compounds of formula (XXXI) are those wherein A is C ₁ -C ₃ alkylene, R _a ′ is phenyl unsubstituted or substituted with methyl or ethyl, and R _d is C ₁ -C ₃ alkyl. Another preferred compound of formula (XXXI) is a compound wherein A is methylene, R _a 'is phenyl unsubstituted or substituted with methyl or ethyl, and R _d is C ₃ -C ₆ alkyl. Particularly preferred compounds of formula (XXXI) are the sodium, potassium or ammonium salts of the corresponding parent compound.

Other preferred compounds of formula (XXXI) are those wherein R _a ′ is phenyl substituted with mono-C ₁ -C ₆ alkylamino lower alkyl, di-C ₁ -C ₆ alkylamino lower alkyl.

Preferred compounds of the present invention include the following formula (XXXIa):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d is lower alkyl,

R _a "is phenyl, pyridyl, imidazolyl, pyrimidinyl or pyrrolyl, each of which is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C _1- Substituted with up to 2 substituents selected from C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C ₁ -C ₆ alkylamino lower alkyl.

More preferred compounds of formula (XXXIa) are those wherein R _a "is imidazolyl and R _d is C ₁ -C ₃ alkyl. Another preferred compound of formula (XXXIa) is A is methylene and R _a " Imidazolyl and R _d is C ₃ -C ₆ alkyl.

Preferred compounds of the present invention include the following formula (XXXII):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d and R _e are independently a lower alkyl group.

More preferred compounds of formula (XXXII) are those wherein A is C ₁ -C ₃ alkylene. Particularly preferred compounds of formula (XXXII) are those wherein A is C ₁ -C ₃ alkylene, R _d is C ₁ -C ₃ alkyl and R _e is C ₁ -C ₃ alkyl.

Preferred compounds of the present invention include the following formula (XXXIII):

In the above formula,

D is nitrogen or CH,

D 'is nitrogen or oxygen,

A is C ₁ -C ₆ alkylene,

R _a ′ is phenyl, pyridyl or thiazolyl, each of which is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C Mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl or di-C ₁ -C ₆ alkylamino lower alkyl.

More preferred compounds of formula (XXXIII) are compounds wherein A is C ₁ -C ₃ alkylene, R _a ′ is phenyl unsubstituted or substituted with lower alkyl or halogen, and D is halogen. Another preferred compound of formula (XXXIII) is a compound wherein A is methylene, R _a 'is phenyl unsubstituted or substituted with lower alkyl or halogen, D is nitrogen and D' is oxygen.

Preferred compounds of the present invention include the following formula (XXXIV):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _a 'is hydrogen,

R _a ′ is trienyl or phenyl, each of which is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C _1- Mono-, di- or tri-substituted with C ₆ alkylamino lower alkyl or di-C ₁ -C ₆ alkylamino lower alkyl.

More preferred compounds of formula (XXXIV) are those wherein A is C ₁ -C ₃ alkylene and R _a ′ is phenyl unsubstituted or substituted with lower alkyl or halogen. Another preferred compound of formula (XXXIV) is A, wherein A is methylene and R _a ′ is phenyl unsubstituted or substituted with lower alkyl or halogen.

Preferred compounds of the present invention include the following formula (XXXV):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _d is lower alkyl,

A 'is oxygen or methylene,

r is an integer of 1-3.

More preferred compounds of formula (XXXV) are those wherein A is C ₁ -C ₃ alkylene. Particularly preferred compounds of formula (XXXV) are those wherein A is C ₁ -C ₃ alkylene and R _d is C ₁ -C ₃ alkyl.

Preferred compounds of the present invention include the following formula (XXXVa):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _h and R _h ′ are independently hydrogen or lower alkyl, wherein each alkyl is unsubstituted or substituted with lower alkoxy,

A 'is oxygen or methylene,

r is an integer of 1-3.

More preferred compounds of formula (XXXVa) are those wherein A is C ₁ -C ₃ alkylene. Particularly preferred compounds of formula (XXXVa) are those wherein A is C ₁ -C ₃ alkylene and R _h is C ₁ -C ₃ alkyl.

Preferred compounds of the present invention include the following formula (XXXVI):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _g is lower alkoxy lower alkyl,

R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl.

Preferred compounds of the present invention include the following formula (XXXVII):

In the above formula,

R _j is lower alkoxy lower alkyl,

R _k is lower alkyl or cycloalkyl unsubstituted or substituted with hydroxy, lower alkyl or lower alkoxy, or

R _k is a phenyl group unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di- C ₁ -C ₆ alkylamino phenyl (C ₁ -C ₆ ) alkyl mono-, di- or tri-substituted with lower alkyl.

Preferred compounds of the present invention include the following formula (XXXVIII):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _l is lower alkoxy, benzyloxy, lower alkoxy lower alkoxy,

R _m is pyranyl, dihydropyranyl, tetrahydropyranyl, hexahydropyranyl, pyridine, dihydropyridine, tetrahydropyridine or piperidine.

Preferred compounds of formula (XXXVIII) are those wherein R ₁ is lower alkoxy and R _m is tetrahydropyranyl.

Preferred compounds of the present invention include the following formula (XXXIX):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _n is lower alkoxy, lower alkoxy lower alkoxy, benzyl or Is a group wherein D is nitrogen or CH, and D 'is nitrogen or oxygen,

R _o is pyranyl, 2-thienyl or 3-thienyl, or

R _o is 2-, 4- or 5-thiazolyl or 2-, 4- or 5-imidazolyl, each of which is unsubstituted or substituted with lower alkyl

Preferred compounds of the present invention include the following formula (XXXX):

In the above formula,

A is C ₁ -C ₆ alkylene,

R _h and R _h ′ are independently hydrogen or lower alkyl, wherein each alkyl is unsubstituted or substituted with lower alkoxy,

R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl group mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl, or

R _a ′ is thienyl unsubstituted or substituted with lower alkyl.

Preferred compounds of the present invention include the following formula (XXXXI):

In the above formula,

A is C ₁ -C ₆ alkylene,

D is nitrogen or CH,

D 'is nitrogen or oxygen,

R _p is unsubstituted or lower alkyl, or lower alkyl substituted with lower alkoxy.

Preferred compounds of the present invention include the following formula (XXXXII):

In the above formula,

A is C ₁ -C ₆ alkylene,

X is as defined in formula (I),

R ₁₈ is

(i) amino, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino, or

(ii) unsubstituted or of formula Lower alkyl substituted with V and V 'are independently CH or nitrogen, A''is C ₁ -C ₆ alkylene and R ₂₀ is phenyl, pyridyl or pyrimidinyl (they are each unsubstituted or Mono-, di- or tri-substituted with halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, mono (C ₁ -C ₆ ) alkylamino, or di (C ₁ -C ₆ ) alkylamino).

A more preferred compound of Formula (XXXXII) is a compound of V is nitrogen and X is an unsubstituted or substituted by up to three halogen atoms or C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl. Particularly preferred compounds of formula (XXXXII) are those in which V and V 'are nitrogen and X is unsubstituted or substituted with up to 3 halogen atoms and C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl and A ″ is methylene or ethylene And R ₂₀ is halogenated phenyl A preferred R ₂₀ is 4-fluorophenyl A particularly preferred compound of formula (XXXXII) is X is 2,2,2-trifluoroethyl and V and V ' Is nitrogen, R ₂₀ is halogenated phenyl, and A and A 'are methylene or ethylene.

In some cases, the compound of formula (I) may contain one or more asymmetric carbon atoms, such that the compounds may exist in different stereoisomeric forms. These compounds may be for example racemates or in optically active form. In this case, single enantiomers, ie optically active forms, can be obtained by asymmetric synthesis or resolution of racemates. The decomposition of the racemate can be carried out by conventional methods such as, for example, crystallization in the presence of a disintegrant, such as chromatography using a chiral HPLC column.

Representative compounds of the invention comprising Formula (I) include, but are not limited to, the compounds of Table 1, their pharmaceutically acceptable acid and base addition salts. In addition, when the compounds of the present invention are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the product is a free base, addition salts, in particular pharmaceutically acceptable salts, dissolve the free base in the presence of a suitable organic solvent and this solution, according to the conventional method for preparing acid addition salts from base compounds. Can be produced by treating with an acid.

Non-toxic pharmaceutical salts include hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfinic acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid such as acetic acid, HOOC- Salts of acids such as (CH ₂ ) _n -ACOOH, where n is 0-4. 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 recognize various non-toxic pharmaceutically acceptable addition salts.

The present invention includes acylated prodrugs of compounds of formula (I). Those skilled in the art will recognize various synthetic methods that can be used to prepare prodrugs of the compounds included in Formula (I) and nontoxic pharmaceutically acceptable addition salts.

In the present invention, the term "lower alkyl" refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, pentyl, 2-pentyl, iso Pentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.

In the present invention, the term "cycloalkyl" means cycloalkyl having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “aryl” means a single ring (eg phenyl), multiple rings (eg biphenyl), or one or more aromatics (eg 1,2,3,4-tetrahydronaphthyl, naph Yl, anthryl or phenanthryl), for example mono-, di- or tri-substituted, unsubstituted or substituted with halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl and hydroxy Aromatic carbocyclic group having a polycondensed ring.

In the present invention, the term "lower alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, secondary butoxy, tertiary butoxy , Pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

In the present invention, the term "cycloalkoxy" means a cycloalkylalkoxy group having 3 to 7 carbon atoms, where cycloalkyl is as defined above.

In the present invention, the term "halogen" means fluorine, bromine, chlorine and iodine.

In the present invention, the term "heteroaryl (aromatic heterocycle)" means one or more aromatic ring systems of 5 to 7 membered rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen or sulfur. Such heteroaryl groups are, for example, thienyl, furanyl, thiazolyl, imidazolyl, (iso) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl, naphthyridinyl, benzimidazolyl and Benzoxazolyl.

Specific examples of heteroaryl groups are as follows:

In the above,

Q is nitrogen or -CR ₉ ;

T is -NR ₇ , oxygen or sulfur;

R ₉ , R ₁₀ , R ₁₀ ′, R ₁₁ , R ₁₁ ′, and R ₁₂ are as defined above.

When Y is a carbocyclic group, Y is attached to the amide nitrogen by a single bond. The result is an amide of the formula:

Wherein Y is as defined above, Represents a Y carbon ring group.

When X is a carbocyclic group, such moieties or groups include both aromatic heterocycles (heteroaryls), unsaturated heterocyclic ring systems, and saturated heterocyclic ring systems. Examples of such groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. Preferred X carbocycle groups are bonded to the monafthyridine moiety by nitrogen atoms in the X carbocycle. As such, for example, when pyrrolidinyl is an X carbocyclic group, it is preferably a 1-pyrrolidinyl group of the formula:

When Y is a carbocyclic group, such moieties and groups include both aromatic heterocycles (heteroaryl groups), unsaturated heterocyclic ring systems, and saturated heterocyclic ring systems. Examples of such groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. Preferred Y carbocyclic groups are bonded to the monafthyridine moiety by the nitrogen atoms in the Y carbocyclic groups. As such, for example, when pyrrolidinyl is a Y carbocyclic group, it is preferably a 1-pyrrolidinyl group of the formula:

As used herein, the term “substituted or unsubstituted phenyl” is no more than three, unsubstituted or independently selected from halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, mono lower alkylamino or di lower alkylamino It means a phenyl group substituted with a substituent.

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

Table 1

Pharmaceutical use of the compounds of the invention is illustrated by the following assay for GABAa receptor activity.

The assays described in Thomas and Tallman's literature are performed [J. Bio. Chem. 156: 9838-9842, J. Neurosci. 3: 433-440, 1983. The outer shell tissue of the rat is excised and homogenized in 25 volumes (w / v) of 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C.). Homogenates of this tissue are cooled (4 ° C.) and centrifuged at 20,000 × g for 20 '. The supernatant is decanted and the pellet is re-homogenized in the same volume of buffer and centrifuged again at 20,000 × g. The supernatant is decanted and the pellet frozen at -20 ° C overnight. The pellet is then thawed and re-homogenized in 25 volumes (original wt / vol) buffer and the procedure is performed twice. Finally the pellet was resuspended in 50 volumes (w / vol) of 0.05M Tris HCl buffer (pH 7.4 at 4 ° C).

Incubation contains 100 ml of tissue homogenate, 100 ml of 0.5 nM radioligand ( ³ H-Ro15-1788 [ ³ H-Flumazenil] specific activity 80 Ci / mmol), drug or blocker and buffer (total volume 500 ml). Incubation is carried out at 4 ° C. for 30 minutes and then rapidly filtered through GFB to separate free and bound ligands. The filter was washed twice with clean 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C.) and measured on a liquid scintillation meter. 1.0 mM diazepam is added to several tubes to determine nonspecific binding. Data is collected at three determinations and averaged to calculate the percentage inhibition of total specific binding. Total specific binding is the total binding minus the nonspecific binding. In some cases, the amount of unlabeled drug is varied and the entire displacement curve of the binding is performed. Convert data to K _i 's. The compounds of the present invention have a K _i 's of only 1 μM | when tested in the assay described above.

In addition, when the compounds of the present invention are agonists, antagonists or inverse agonists, the following assays can be used to determine their specific pharmaceutical utility. The following assays can be used to determine specific GABAa receptor activity.

Assays and variations thereof described in White and Gurley, NeuroReport 6: 1313-1316, 1995 and White, Gurley, Hartnett, Stirling, and Gregory, Receptors and Channels 3: 1-5, 1995 Is performed. Xenopus Laevis oocytes are enzymatically isolated and injected with mixed nonpolyadenylation cRNA in a ratio of 4: 1: 4 for each of the human derived α, β and γ subunits do. For each subunit combination, a current amplitude exceeding 10 nA occurs when enough messages are injected to apply 1 μM GABA.

Electrophysiological readings are performed using a two electrode voltage-clamp technique on a film with a potential of -70 mV.

Compounds are evaluated for GABA currents that induce less than 10% of the maximum inducible GABA currents. Each oocyte is exposed to increased concentrations of the compound to assess the concentration / effect relationship. Compound potency is expressed as the rate of change of current amplitude [100 × ((IC / I) -1)], where Ic is the GABA induced current amplitude observed in the presence of the compound and I is observed in the absence of the compound GABA induced current amplitude.

The specificity of the compound for the Ro15-1788 site is determined by the completion of the concentration / effect curve. After sufficient washing of oocytes to remove previously applied compounds, oocytes are exposed to GABA + 1 μM Ro15-1788 and then to GABA + 1 μM Ro15-1788 + compounds. The rate of change due to the addition of the compound is calculated as described above. The rate of change observed in the presence of Ro15-1788 is subtracted from the rate of change of current amplitude observed in the absence of 1 μM Ro15-1788. Its net value is used in the calculation of mean potency and EC ₅₀ value.

To assess the average potency and EC ₅₀ values, concentration / effect data are averaged for the cells and substituted into the logarithmic equation. Record the mean value as mean ± standard error.

Substituted 4-oxo-naphthyridine-3-carboxamides of formula (I) and salts thereof are found in humans, non-human animals, pets, especially dogs and cats, and livestock such as sheep, pigs, and cattle It is suitable for the diagnosis and treatment of anxiety, Down syndrome, sleep disorders, cognitive disorders, seizure disorders and overdose of benzodiazepines, and for improving agility.

Compounds of formula (I) are administered rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles, orally, topically, or parenterally by inhalation or spraying. do. As used herein, the term “parenteral administration” includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. Also provided are pharmaceutical formulations comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. One or more compounds of formula (I) may be present with one or more nontoxic pharmaceutically acceptable carriers, diluents and / or adjuvants, and, if desired, other active ingredients. Pharmaceutical compositions containing a compound of formula (I) may be in a form suitable for oral use, such as tablets, pills, sugar-containing tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, It may exist in the form of syrup or elixir.

Compositions intended for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, which compositions contain one or more agents selected from the group consisting of sweetening, flavoring, coloring and preservatives. It is possible to provide pharmaceutical preparations that are both nice and easy to eat. Tablets contain the active ingredient in combination with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Preparations for granulation and degradation such as cornstarch or alginic acid; Binders such as starch, gelatin or acacia; And lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay degradation and absorption in the gastrointestinal tract to provide long lasting action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be used.

Formulations for oral use also include hard gelatine capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient in an aqueous or oily medium such as peanut oil, liquid paraffin. Or as soft gelatin capsules mixed with olive oil.

Aqueous suspensions contain the active materials with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; Dispersants or wetting agents include natural phospholipid stearate, long chain aliphatic alcohols such as condensation products of heptadecaethyleneoxycetanol and ethylene oxide, hexitols such as polyoxyethylene sorbitol monooleate and partial esters derived from fatty acids and ethylene oxide Condensation products of ethylene oxide and partial esters derived from hexitol anhydrides and fatty acids such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. The oily suspension may contain thickening agents, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents set forth above may be added to provide an oral preparation that is easy to eat. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient with dispersants, wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

The pharmaceutical compositions of the present 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 a mixture thereof. Suitable emulsifiers are natural gums such as gum acacia or gum tragacanth, natural phospholipids such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides such as sorbitan monools Rate, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. The formulation may also contain analgesics, preservatives, flavors and coloring agents. The pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a parenterally acceptable non-toxic diluent or solvent, eg, 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 employed as a solvent or suspending medium. For this purpose, a low irritant fixed oil can be used including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient (solid at room temperature, but liquid at rectal temperature, which melts in the rectum to release the drug).

The compound of formula (I) may be administered parenterally in a sterile medium. Depending on the concentration and the vehicle used, the drug may be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffers may be dissolved in the vehicle.

Dosing levels of about 0.1 to 140 mg / kg body weight per day are useful for the treatment of the diseases presented above (dose of about 0.5 mg to 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the species of the host animal being treated, the particular mode of administration, and the weight of the host. Dosage unit forms will generally contain about 1 to about 500 mg of active ingredient.

However, the specific dosage level for a particular patient may vary depending on the activity, age, weight, general health, sex, diet, time of administration, mode of administration, rate of excretion, drug combination and treatment of the specific compound used. It will depend on various factors, including severity.

For administration to non-human animals, the composition may also be added to animal feed or drinking water. It would be convenient to formulate such compositions of animal feed and drinking water into a mullet-dose of the drug to allow the animal to take the composition in an appropriate amount according to the diet. It will also be convenient for the composition to be present as a premix for addition to feed or drinking water.

The process for preparing the compounds of the present invention is shown in Scheme (I):

Scheme I

In Scheme (I), the substituents X and Y are as shown in formula (I) above.

Those skilled in the art will appreciate that the starting materials may vary and additional steps may be used to prepare the compounds included in the present invention, as illustrated in the Examples below. In some cases, it may be necessary to protect some reactive functional groups to achieve some of the above modifications. In general, the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as those required to attach and separate these groups.

The invention is further illustrated by the following examples which do not limit the invention in terms of the scope or spirit of the specific processes described herein.

Example 1

Preparation of Starting Materials and Intermediates

Starting materials and various intermediates can be obtained from commercial sources, prepared from commercial organic compounds, or prepared using well known synthetic methods.

Examples of methods for making the intermediates of the invention are given below.

1. 2-benzylamino-5-nitropyridine

A solution of 2-chloro-5-nitropyridine (1.59 g, 10 mmol) and benzylamine (2.3 ml, 21 mmol) in ethanol (10 ml) was heated at reflux for 2 hours. The reaction mixture was brought to ambient temperature, 1.2N HCl was added, a precipitate was obtained, washed with water and dried to give 2.02 g of 2-benzylamino-5-nitropyridine as a yellow solid.

2. 2-benzylamino-5-aminopyridine

A mixture of 2-benzylamino-5-nitropyridine (2.02 g) and 10% Pd / C (202 mg) in ethanol (20 ml) was placed in a Parr bottle and shaken under hydrogen (50 PSI) for 3 hours. The mixture was filtered through celite with dichloromethane and concentrated in vacuo to yield 1.76 g of 2-benzylamino-5-aminopyridine as a burgundy oil.

3. Diethyl (2-benzylamino-5-pyridylaminomethylene) malonate

A mixture of 2-benzylamino-5-aminopyridine (1.76 g) and diethyl ethoxymethylenemalonate (1.78 ml, 8.82 mmol) was heated at 130 ° C. for 2 hours. The mixture was evaporated while warming. After cooling, the product was triturated with 2: 1 hexanes / ether and collected to yield 2.74 g of diethyl (2-benzylamino-5-pyridylaminomethylene) malonate as a gold solid.

4. Ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Diethyl (2-benzylamino-5-pyridylaminomethylene) malonate (2.23 g) was added to diphenyl ether (10 ml) preheated to 230 ° C. Then it was heated for 5 hours, the reaction flask was removed from the oil bath and the mixture was cooled to ambient temperature. The product was triturated with 1: 1 hexanes / ether, collected, washed with ether and dried to give ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3 as a brown solid. 1.47 g of carboxylate were obtained.

5. 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid

A mixture of ethyl 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (60 mg), 1N NaOH (2 ml) and ethanol (0.5 ml) was added at reflux temperature. Heated for 2 hours. The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride was added. The resulting precipitate was collected, washed with water and ether and dried to yield 35 mg 6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid as a brown solid. It was.

6. 2-ethoxy-5-nitropyridine

At ambient temperature 2-chloro-5-nitropyridine was added to a homogeneous solution of potassium hydroxide (3.93 g, 70 mmol) in ethanol (35 ml). 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, washed with water and dried to give 3.60 g of 2-ethoxy-5-nitropyridine as a beige solid.

7. 2-ethoxy-5-aminopyridine

A mixture of 2-ethoxy-5-nitropyridine (3.60 g) and 10% Pd / C (360 mg) in ethanol (40 ml) was placed in a Parr bottle and shaken under hydrogen (50 PSI) for 16 hours. The mixture was filtered through celite with dichloromethane and concentrated in vacuo to afford 2.892 g of 2-ethoxy-5-aminopyridine as a gold solid.

8. Diethyl (2-ethoxy-5-pyridylaminomethylene) malonate

A mixture of 2-ethoxy-5-aminopyridine (2.89 g, 20.9 ml) and diethyl ethoxymethylenemalonate (4.23 ml, 20.9 mmol) was heated at 130 ° C. for 4.5 hours. The mixture was evaporated while warming. After cooling, the product was triturated with 2: 1 hexanes / ether and collected to give 6.04 g of diethyl (2-ethoxy-5-pyridylaminomethylene) malonate as a beige solid.

9. Ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Diethyl (2-ethoxy-5-pyridylaminomethylene) malonate (6.04 g) was added to diphenyl ether (20 ml) preheated to 230 ° C. It was then heated for 0.5 h, the reaction flask was removed from the oil bath and the mixture was cooled to ambient temperature. The product was triturated with 1: 1 hexanes / ether, collected, washed with ether and dried to give ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3 as a tan solid. 2.98 g of carboxylate was obtained.

10. 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid

A mixture of ethyl 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (2.98 g), 1N NaOH (50 ml) and ethanol (10 ml) was added at reflux temperature. Heated for 2 hours. The reaction mixture was cooled in an ice bath, acidified and the resulting precipitate collected, washed with water and dried to give 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyl as a beige solid. 2.42 g of ridine-3-carboxylic acid were obtained.

11. 4-[(n-tert-butoxycarbonyl) -methylaminomethyl) benzylamine hydrochloride

a) A solution of [alpha] -bromo-p-tolunitrile (4.90 g, 25 mmol) in acetonitrile (50 ml) at 0 [deg.] C. was added dropwise to a solution of 40% aqueous methylamine (21.5 ml, 250 mmol) in It was added to the stirred solution. The reaction mixture was stirred for 0.5 h and then concentrated in vacuo. Water was added to the residue and extracted twice with dichloromethane. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to give 1.41 4- (methylaminomethyl) benzonitrile as a yellow oil containing about 30% N, N-bis (4-benzonitrile) methylamine. g was obtained. The pH of the aqueous layer was adjusted to greater than 8 and extracted twice with 9: 1 dichloromethane: methanol. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1.13 g of pure 4- (methylamino) benzonitrile as a colorless oil.

b) di-tert-butyl dicarbonate (1.77 g, 8.1 mmol) was added 4- (methylaminomethyl) -benzonitrile (1.13 g, 7.7 mmol) in 1,4-dioxane (15 ml) at ambient temperature; To a stirred mixture of 1N NaOH (15 ml) was added. The reaction mixture was stirred for 2 hours, poured into saturated aqueous sodium chloride and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield 1.81 g of crude 4- [N- (tert-butoxycarbonyl) -methylaminomethyl] benzonitrile. The crude material was filtered through a 1 "silica gel pad, eluted first with hexanes and then eluted with ether. The ether filtrate was concentrated to pure 4- [N- (tert-butoxycarbonyl)-as a colorless oil. Methylaminomethyl] benzonitrile was added, to which 10% Pd / C (170 mg) and ethanol in Parr .. The mixture was shaken under hydrogen (50 PSI) for 4.5 h, then filtered through celite and The residue was taken up in ethanol, 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 afford 4- [N as a light gray solid. 1.346 g of-(tert-butoxycarbonyl) -methylaminomethyl] benzylamine hydrochloride were obtained.

Example 2

1.N-n-butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (59 mg, 0.2 mmol) and tri at 0 ° C. in N, N-dimethylformamide (1 ml) To a solution of ethylamine (59 ml, 0.42 mmol) was added ethyl chloroformate (39 ml, 0.41 mmol). After stirring for 1 hour at 0 ° C., n-butylamine (99 ml, 1.0 mmol) was added. The reaction mixture was stirred for additional 2 h at 0 ° C. and then poured into saturated aqueous sodium chloride. The mixture is cooled in an ice bath, the precipitate is collected, washed with water and ether and dried to give Nn-butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphti as a brown solid. 49 mg of ridine-3-carboxamide were obtained. Compound 1. Another name for this compound is N-butyl (4-oxo-6- (benzylamino) (3-hydro-5-azaquinolyl)) formamide.

2. N- [2- (ethylthio) ethyl] 6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (55 mg, 0.25 mmol) and tree in N, N-dimethylformamide (2 ml) at 0 ° C To a solution of ethylamine (73 ml, 0.53 mmol) was added ethyl chloroformate (49 ml, 0.52 mmol). After stirring for 0.5 h at 0 ° C., 2- (ethylthio) ethylamine hydrochloride (172 ml, 1 mmol) and triethylamine (139 ml, 1 mmol) were added. The reaction mixture was stirred at 0 ° C. for 0.5 h, then poured into 1.2 N HCl, cooled in an ice bath, the resulting precipitate collected, washed with water and dried to give N- [2- (ethylthio) as a beige solid. ) Ethyl] 57 mg of 6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide were obtained; m.p 257-259 ° C. (d). Compound 5.

3. N- [4- (methylaminomethyl) benzyl] 6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide hydrochloride

6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine in 4: 1 tetrahydrofuran: N, N-dimethylformamide (2 ml) at 0 ° C. To a solution of -3-carboxylic acid (106 mg, 0.4 mmol) and triethylamine (117 ml, 0.84 mmol) was added ethyl chloroformate (66 ml, 0.82 mmol). After stirring at 0 ° C. for 1.25 h, 4-[(N-tert-butoxycarbonyl) -methylaminomethyl) benzylamine hydrochloride (120 ml, 0.42 mmol) and triethylamine (59 ml, 0.42 mmol) Added. The reaction mixture was stirred at 0 ° C. for 0.75 hours, then brought to ambient temperature and stirred for 20 hours. N, N-dimethylethylenediamine (132 ml, 1.2 mmol) was added and the reaction mixture was stirred for 1 h and then concentrated in vacuo. The residue was cooled in an ice bath, saturated aqueous sodium chloride was added and the mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated to afford crude N- [4- (N-tert-butoxycarbonyl) -methylaminomethyl) benzyl] 6- (2- 177 mg of methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide were obtained.

Crude N- [4- (N-tert-butoxycarbonyl) -methylaminomethyl) benzyl] 6- (2-methoxyethoxy) -4-oxo-1, in dichloromethane (1 ml) at ambient temperature To 4-dihydro-1,5-naphthyridine-3-carboxamide was added dropwise 1: 1 trifluoroacetic acid: dichloromethane (2 ml). The reaction mixture was stirred for 1 h, concentrated in vacuo, the residue dissolved in ethanol and 1.0 M HCl in ether (0.8 ml) added. The precipitate was collected by N- [4- (methylaminomethyl) benzyl] 6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide 68 mg of hydrochloride were obtained. Compound 10.

4. N- [4- (methoxy) benzyl] 6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide

6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxyl in 5: 1 tetrahydrofuran: N, N-dimethylformamide (6 ml) at 0 ° C. To a solution of acid (80 mg, 0.3 mmol) and triethylamine (0.11 ml, 0.8 mmol) was added ethyl chloroformate (0.09 ml, 0.9 mmol). After stirring for 0.5 h at 0 ° C., 4-methoxybenzylamine (0.1 ml, 0.8 mmol) was added. The reaction mixture was brought to ambient temperature and stirred for 0.5 h. Water was added and the resulting precipitate was collected, washed with water and ether and dried. The solid was combined with 1N 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 bring the pH to 8, the precipitate collected, washed with water and ether and dried to give N- [4- (methoxy) benzyl] 6-pyrrolidino 69 mg of 4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide were obtained; m.p. 270-272 ° C. Compound 8.

5a. N-benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide, sodium salt

N-benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (914 mg, 2.83 mmol) was suspended in ethyl alcohol (9 ml) and 10N NaOH (0.27). ml) was added. The mixture was heated to homogeneity, then cooled and concentrated. The resulting solid was treated with ethyl acetate (5 ml) and ethyl alcohol (250 ml) and the resulting mixture was stirred for 22 hours. The precipitate was collected, washed with ethyl acetate and dried to give the sodium salt of N-benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide as a tan solid ( Compound 12) 960 mg was obtained.

5b. N-benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide, potassium salt; (Compound 13) m.p. 286-288 ° C.

Example 3

The following compounds were prepared essentially according to the process described in Examples 1 and 2:

(a) N-n-butyl 6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 14) m.p. 330 ° C. (d).

(b) N-propan-3-ol 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 15) m.p. 271-272 ° C.

(c) N-n-butyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 16) m.p. 274-276 ° C.

(d) N- (2-ethylthio) ethyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 17) m.p. 257-259 ° C.

(e) N-n-butyl 6- (N-benzylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 18).

(f) N-n-pentyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 19) m.p. 265-265 ° C.

(g) N- (3-isopropoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 20).

(h) N-benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 21) m.p. 275-278 ° C.

(i) N-2-pentyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 22).

(j) N- (2-tetrahydrofuranyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 4) m.p. 235-237 ° C.

(k) N- (3-methoxy) propan-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 23).

(l) N- (3-methoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 24).

(m) N- (2-methoxy) ethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 25).

(n) N-isoamyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 26) m.p. 279-281 ° C.

(o) N- (2-furanyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 27) m.p. 245 ° C. (d).

(p) N- (3-methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 11) m.p. 250-253 ° C. (d).

(q) N- (3-ethoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 28) m.p. 224-225 ° C.

(r) N-2- (2-methyl) butyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 29) m.p. 282-283 ° C. (d).

(s) N-2-pentan-1-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 30) m.p. 232-234 ° C.

(t) N-5-pentanol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 31) m.p. 223-224 ° C.

(u) N-1-cyclohexane-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 32) m.p. 268-270 ° C.

(v) N-benzyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 33) m.p. 273-274 ° C.

(w) N- (2-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 34) m.p. 266-271 ° C.

(x) N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 35) m.p. 281 ° C.

(y) N- (4-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 36) m.p. 283-286 ° C.

(z) N- (imidazol-4-ylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 6). [Other name: (6-ethoxy-4-oxo (3-hydro-5-azaquinolyl))-N- (imidazol-4-ylmethyl) formamide].

(aa) N-4-tetrahydropyranyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 37) m.p. 303-305 ° C.

(bb) N- (3-thienyl) methyl 6-ethoxy-4-oxo-1,4-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-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 39) m.p. 281 ° C.

(dd) N- (2-tetrahydropyranyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 40) m.p. 204-206 ° C.

(ee) N- (2-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 41) m.p. 157-162 ° C.

(ff) N- (3-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 42) m.p. 297-302 ° C.

(gg) N- (4-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 43).

(hh) N- (4-methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 44) m.p. 186 ° C.

(ii) N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 45) m.p. 301 ° C.

(jj) N-benzyl 6- (N-methyl, N-toluenesulfonyl-amino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 2). [Other name: (6- (methyl ((4-methylphenyl) sulfonyl) amino) -4-oxo (3-hydro-5-azaquinolyl))-N-benzylformamide].

(kk) N-benzyl 6- (methylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 46).

(ll) N-piperonyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 9) m.p. 190 ° C.

(mm) N-piperonyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 47) m.p. 186 ° C.

(nn) N-2- (imidazol-4-ylethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 48) m.p. 268 ° C.

(oo) N- (4-methylbenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 49) m.p. 270-271 ° C.

(pp) N-benzyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 50) m.p.> 300 ° C.

(qq) N-benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 51) m.p. 246-249 ° C.

(rr) N-isoamyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 52) m.p. 295-298 ° C.

(ss) N-benzyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 53) m.p. 88-90 ° C.

(tt) N- (2-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 7) m.p. 137-139 ° C.

(uu) N- (3-ethoxy) propyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 54) m.p. 150-152 ° C.

(vv) N-n-butyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 55) m.p. 275-277 ° C.

(ww) N- (2-pyridyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 56) m.p. 125-127 ° C.

(xx) N- (2-thienyl) methyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 57) m.p. 235-236 ° C.

(yy) N-isoamyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 58) m.p. 254-256 ° C.

(zz) N- (2-thienyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 59) m.p. 277-279 ° C.

(aaa) N- (2-thienyl) methyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 60) m.p. 240 ° C.

(bbb) N- (2-thiazolyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 61) m.p. 270-272 ° C.

(ccc) N- (4-methylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 62).

(ddd) N- [4- (1-methylamino) ethyl] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 63) m.p. 259-262 ° C.

(eee) N- (2-tetrahydrofuranyl) methyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 64) m.p. 285-288 ° C.

(fff) N-n-pentyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 65) m.p. 278-280 ° C.

(ggg) N- (3-methoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 66) m.p. 204-205 ° C.

(hhh) N- (3-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 67) m.p. 263-265 ° C.

(iii) N- (4-methylaminomethyl) benzyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 68) m.p. 275-277 ° C.

(jjj) N-n-butyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 69) m.p. 57-58 ° C.

(kkk) N- (4-methoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 70) m.p. 270-272 ° C.

(lll) N- (2-thienyl) methyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 71) m.p. 265-267 ° C.

(mmm) N- [4- (1-methylamino) ethyl] benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 72).

(nnn) N- (4-methylaminomethyl) benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 73) m.p. 270-271 ° C.

(ooo) N- [4- (1-methylamino) ethyl] benzyl 6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 74) m.p. 260-263 ° C.

(ppp) N- [4- (1-methylamino) ethyl] benzyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 75) m.p. 298-302 ° C.

(qqq) N- (4-ethoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 76) m.p. 278-281 ° C.

(rrr) N- (4-ethoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 77) m.p. 265-267 ° C.

(sss) N- (4-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 78) m.p. 295-297 ° C.

(ttt) N- (3-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 79) m.p. 276-278 ° C.

(uuu) N-piperonyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 80) m.p. 246-247 ° C.

(vvv) N-benzyl 6- (2-methylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 81).

(www) N-benzyl 6- (2-dimethylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 82) m.p. 194-198 ° C.

(xxx) N- (4-ethylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 83) m.p. 194 ° C. (d).

(yyy) N-benzyl 6- (2-methoxy) ethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 84) m.p. 254-257 ° C.

(zzz) N- (3-methylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 85) m.p. 187 ° C. (d).

(aaaa) N- (4-dimethylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 86) m.p. 200 ° C. (d).

(bbbb) N- (3-methylaminomethyl) benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 87) m.p. 184 ° C. (d).

(cccc) N- [4- (1-imidazolylmethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 88) m.p. 143-145 ° C.

(dddd) N- [4- (1-morpholinomethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride; (Compound 89) m.p. 215-218 ° C.

(eeee) N- [3- (1-morpholinomethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide; (Compound 90) m.p. 195-198 ° C.

(ffff) N- {4- [1- (4-methylpiperazinomethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 91).

(gggg) N- [4- (1,2,4-triazol-1-ylmethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3- Carboxamide hydrochloride; (Compound 92) m.p. 195-200 ° C.

(hhhh) N-benzyl 6-benzylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 93).

(iiii) N-cyclohexyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 94).

(jjjj) N-cyclohexylmethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 95).

(kkkk) N- (4-aminobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 96).

(llll) N- (4-pyridylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 97).

(mmmm) N-benzyl 6-tetrahydroisoquinolinyl-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 98).

(nnnn) N- {4- [1- [4- (4-fluorobenzyl) piperazinyl] methyl] benzyl} 6- (2,2,2-trifluoroethyl) -4-oxo-1, 4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 99) mp 234-236 ° C.

(oooo) N- (3-isopropoxypropyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide (Compound 3) [other name: ( 6-ethoxy-4-oxohydropyridino [3,2-b] pyridin-3-yl) -N- [3- (methylethoxy) propyl] carboxamide].

The compounds of the present invention, methods and processes for making and using the same, have been described in complete, clear, concise and accurate terms so that those skilled in the art can make and use them. It is to be understood that what has been described above describes preferred embodiments of the invention and modifications may be made within the spirit and scope of the invention as set forth in the claims below. In particular, the following claims are intended to conclude the present specification in order to express and clearly claim the subject matter to be protected in the present invention.

Claims (106)

Compounds of the formula: or pharmaceutically acceptable salts thereof In the above formula, X is hydrogen, halogen, -OR ₁ , C ₁ -C ₆ alkyl unsubstituted or substituted with up to 3 substituents independently selected from halogen and hydroxy, 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 unsubstituted or halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkylthio With up to 3 substituents selected from hydroxy, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy Substituted); X contains 3 to 7 elements, and 2 or less of these elements are carbon ring groups ("X carbocyclic groups") which are optionally heteroatoms selected from oxygen and nitrogen, wherein X carbocyclic groups are substituted Unsubstituted or halogen, (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, sulfonamide, aza (C ₃ -C ₇ ) cycloalkyl, ( Substituted with one or more substituents selected from C ₃ -C ₇ ) cycloalkylthio, (C ₁ -C ₆ ) alkylthio, phenylthio or heterocyclic groups; Y is unsubstituted or halogen, (C ₃ -C ₇ ) cycloalkyl, (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, sulfonamide , Aza (C ₃ -C ₇ ) cycloalkyl, (C ₃ -C ₇ ) cycloalkylthio, (C ₁ -C ₆ ) alkylthio, phenylthio, heterocyclic group, -OR ₄ , -NR ₅ R ₆ , Lower alkyl having 1 to 8 carbon atoms, substituted with up to 2 substituents selected from SR ₇ , unsubstituted aryl or substituted aryl; Y contains 3 to 7 elements, and 3 or less of these elements are carbon ring groups ("Y carbocyclic groups") which are heteroatoms optionally selected from oxygen and nitrogen, wherein any of Y carbocyclic groups The element is unsubstituted or substituted with halogen, —OR ₄ , —NR ₅ R ₆ , SR ₇ , aryl or heterocyclic group; R ₁ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, wherein each alkyl is unsubstituted or substituted with —OR ₄ or —NR ₅ R ₆ ; R ₂ and R ₃ are the same or different, Hydrogen, Lower alkyl unsubstituted or mono- or di-substituted with alkoxy, aryl, halogen, mono lower alkyl or di lower alkyl, Aryl or aryl (C ₁ -C ₆ ) alkyl, wherein each aryl is unsubstituted or halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, mono (C ₁ -C ₆ ) alkyl Substituted with up to 3 substituents selected from amino or di (C ₁ -C ₆ ) alkylamino), Cycloalkyl having 3 to 7 carbon atoms, unsubstituted or mono- or di-substituted with halogen, alkoxy, mono lower alkyl or di lower alkyl, or -SO ₂ R ₈ ; R ₄ is as defined for R ₁ ; R ₅ and R ₆ are as defined for R ₂ and R ₃ , respectively; R ₇ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms; R ₈ is lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, unsubstituted phenyl or substituted phenyl. Compounds of the formula: or pharmaceutically acceptable salts thereof In the above formula, X is (i) hydrogen, halogen, monoalkylamino, dialkylamino, alkoxy, (ii) groups of the formula (In the above formula, G is lower alkylene having 1 to 6 carbon atoms, or Wherein n is 0, 1 or 2, m is an integer from 1 to 5, provided that the sum of n + m is 1 to 5, R ₁ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or halogen, lower alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C _1- C ₆ ) alkylamino); (iii) a group of formula: (In the above formula, G is as defined in (ii) above, R ₂ and R ₃ are independently hydrogen, lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, -SO ₂ R ₈ (wherein R ₈ is (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₇ ) cycloalkyl, unsubstituted phenyl or substituted phenyl), or R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclic moiety such as imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl); (iv) groups of the formula (In the above formula, R ₂ is as defined in (iii) above, R ₄ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms, which is unsubstituted or substituted with one or more (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino or May be substituted with a di (C ₁ -C ₆ ) alkylamino group, G is as defined in (ii) above); (v) groups of the formula: (In the above formula, R ₂ and G are as defined above in (iv) and (ii), R ₅ and R ₆ are independently hydrogen, lower alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, —SO ₂ R ₈ (wherein R ₈ is (C ₁ -C ₆ ) alkyl, ( C ₃ -C ₇ ) cycloalkyl, unsubstituted phenyl or substituted phenyl), or R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic moiety; (vi) groups of the formula: (Wherein G is as defined in (ii) above); or (vii) groups of the formula: (Wherein G is as defined in (ii) above); Y is (viii) lower alkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 7 carbon atoms, either of which is unsubstituted or at least one halogen, (C ₁ -C ₆ ) alkoxy, alkoxyalkoxy, Each alkoxy is (C ₁ -C ₆ ) alkoxy), (C ₁ -C ₆ ) alkylthio, (C ₃ -C ₇ ) cycloalkylthio, aryl, heteroaryl, mono (C ₁ -C ₆ ) alkyl May be substituted with an amino or di (C ₁ -C ₆ ) alkylamino group); (ix) groups of the formula: (In the above formula, K is lower alkylene having 1 to 6 carbon atoms, unsubstituted or substituted with (C ₁ -C ₆ ) alkyl or alkylene, or In which K 'is independently hydrogen, (C ₁ -C ₆ ) alkyl or alkylene, n is 0, 1 or 2, m is an integer from 1 to 5, provided that n + m is The sum is 1 or more and 5 or less), R ₉ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or substituted with halogen, lower alkoxy, monoalkylamino or dialkylamino); (x) groups of the formula (Wherein K is as defined in (ix) above); (xi) groups of the formula: (In the above formula, K is as defined in (ix) above, R ₁₃ is hydrogen, lower alkyl of 1 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, wherein the alkyl and cycloalkyl groups are unsubstituted or include one or more (C ₁ -C ₆ ) alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino group); (xii) groups of the formula: (In the above formula, K is as defined in (ix) above, respectively, R ₇ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms); (xiii) groups of the formula: (In the above formula, K is as defined in (ix) above, respectively, R ₁₄ and R ₁₅ are independently hydrogen, lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, -SO ₂ R ₈ , wherein R ₈ is as defined above, or R ₁₄ and R ₁₅ together with the nitrogen atom to which they are attached form a heterocyclic moiety); (xiv) groups of the formula: (Wherein K and R ₁₅ are as defined above in (ix) and (xii), respectively); (xv) groups of the formula: (Wherein K is as defined in (ix) above, R ₁₀ and R ₁₀ ′ are the same or different and are selected from hydrogen, halogen, hydroxy, lower alkoxy having 1 to 6 carbon atoms, or cycloalkoxy having 3 to 7 carbon atoms, R ₁₁ , R ₁₁ ′ and R ₁₂ are the same or different and are selected from hydrogen, halogen, hydroxy, —OR ₄ , —CR ₇ (R ₉ ) NR ₅ R ₆ or —CR ₇ (R ₁₆ ) OR ₄ , R ₁₁ and R ₁₂ together with the atoms to which they are attached form a (hetero) ring, R ₁₆ is hydrogen, lower alkyl having 1 to 6 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms); (xvi) a group of formula (Wherein K is each as defined in (ix) above and W is heteroaryl); (xvii) groups of the formula (Wherein K is as defined in (ix) above, R ₁₀ and R ₁₁ are as defined in (xv) above, R ₁₇ is hydrogen, lower alkyl or (C ₃ -C ₇ ) cycloalkyl, wherein alkyl or cycloalkyl is unsubstituted or halogen, lower alkoxy, mono (C ₁ -C ₆ ) alkylamino or di (C _1- C ₆ ) alkylamido); (xviii) groups of the formula (Wherein K, R ₁₀ , R ₁₂ and R ₁₇ are as defined above); (xix) groups of the formula (Wherein K is independently as defined in (ix) above and R ₁₀ is as defined above); (xx) groups of the formula: (Wherein K, R ₁₀ , R ₁₁ , R ₁₄ and R ₁₅ are as defined above); And (xxi) groups of the formula (Wherein K, R ₁₀ , R ₁₂ , R ₁₄ and R ₁₅ are as defined above). A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _a is halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C ₁ -C ₆ Phenyl unsubstituted, di- or tri-substituted or substituted with alkylamino lower alkyl, R _b is lower alkyl or lower cycloalkyl. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _a and R _a ′ are independently unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower A phenyl group mono-, di- or tri-substituted with alkyl or di-C ₁ -C ₆ alkylamino lower alkyl, R _c is hydrogen or lower alkyl. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _d and R _e are independently a lower alkyl group. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _d is a lower alkyl group, R _f is a chemical formula Is a group wherein E is oxygen or nitrogen and M is C ₁ -C ₃ alkylene or nitrogen. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _d is lower alkyl, R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _d and R _e are independently a lower alkyl group. A compound according to claim 1 having the formula: In the above formula, D is nitrogen or CH, D 'is nitrogen or oxygen, A is C ₁ -C ₆ alkylene, R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _d is lower alkyl, A 'is oxygen or methylene, r is an integer of 1-3. A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, R _g is lower alkoxy lower alkyl, R _a ′ is unsubstituted or halogen, lower alkyl, lower alkoxy, mono-C ₁ -C ₆ alkylamino, di-C ₁ -C ₆ alkylamino, mono-C ₁ -C ₆ alkylamino lower alkyl or di-C Phenyl mono-, di- or tri-substituted with _1- C ₆ alkylamino lower alkyl. A compound according to claim 1, which is N-n-butyl-6-benzylamino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- [2- (ethylthio) ethyl] 6-methoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. . The compound of claim 1, wherein N- [4- (methylaminomethyl) benzyl] 6- (2-methoxyethoxy) -4-oxo-1,4-dihydro-1,5-naphthyridine-3-car Compound characterized in that it is a boxamide. 2. A compound according to claim 1, characterized in that it is N- [4- (methoxy) benzyl] 6-pyrrolidino-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide. compound. A compound according to claim 1, which is N-n-butyl 6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-propan-3-ol 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-n-butyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-ethylthio) ethyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-n-butyl 6- (N-benzylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-n-pentyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-isopropoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl-6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-2-pentyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-tetrahydrofuranyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. . The compound according to claim 1, which is N- (3-methoxy) propan-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. Compound. A compound according to claim 1, which is N- (3-methoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-methoxy) ethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-isoamyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-furanyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-ethoxy) propyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-2- (2-methyl) butyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound according to claim 1, which is N-2-pentan-1-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-5-pentanol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-1-cyclohexane-2-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound according to claim 1, which is N- (4 / 5-imidazolylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. compound. A compound according to claim 1, which is N-4-tetrahydropyranyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-thienyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound according to claim 1, which is N-2- (6-methyl) heptan-6-ol 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. Compound made into. A compound according to claim 1, which is N- (2-tetrahydropyranyl) methyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. . A compound according to claim 1, which is N- (2-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-fluorobenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-methoxybenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-fluorobenzyl) 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The 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 Compound made into. A compound according to claim 1, which is N-benzyl 6- (methylamino) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-piperonyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-piperonyl 6-methoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1, which is N-2- (4 / 5-imidazolyl) ethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. Compound made into. A compound according to claim 1, which is N- (4-methylbenzyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-isoamyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-ethoxy) propyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-n-butyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-pyridyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-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. Characterized by a compound. A compound according to claim 1, which is N-isoamyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-thienyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-thienyl) methyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-thiazolyl) methyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-methylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound according to claim 1, which is N- [4- (1-methylamino) ethyl] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide Compound made into. A compound according to claim 1, which is N- (2-tetrahydrofuranyl) methyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. . A compound according to claim 1, which is N-n-pentyl 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-methoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-fluorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1, wherein N- (4-methylaminomethyl) benzyl 6- (2-methoxyethoxy) -4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide Compound characterized in that. A compound according to claim 1, which is N-n-butyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-methoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (2-thienyl) methyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound according to claim 1, which is N- [4- (1-methylamino) ethyl] benzyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide Compound made into. The compound of claim 1, which is N- (4-methylaminomethyl) benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride Compound made into. The compound according to claim 1, which is N- [4- (1-methylamino) ethyl] benzyl 6-chloro-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. Compound. The compound of claim 1, wherein N- [4- (1-methylamino) ethyl] benzyl 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydro Compound characterized in that the chloride. A compound according to claim 1, which is N- (4-ethoxybenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-ethoxybenzyl) 6-pyrrolidino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (3-chlorobenzyl) 6-morpholino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-piperonyl 6-dimethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. A compound according to claim 1, which is N-benzyl 6- (2-methylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6- (2-dimethylamino) ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-ethylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6- (2-methoxy) ethylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. 2. A compound according to claim 1, characterized in that it is N- (3-methylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. compound. 2. A compound according to claim 1, characterized in that it is N- (4-dimethylaminomethyl) benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride. compound. 2. A compound according to claim 1 which is N- (3-methylaminomethyl) benzyl 6-n-propoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide hydrochloride Compound made into. The compound of claim 1, which is N- [4- (1-imidazolylmethyl)] benzyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide Characterized by a compound. The compound of claim 1, wherein Y is pyrimidinylmethyl, pyridylmethyl, or a group of formula: In the above formula, R ₁₈ is hydrogen, amino, mono (C ₁ -C ₆₎ alkylamino, di (C ₁ -C ₆₎ alkylamino, or R ₁₉ is optionally substituted (C ₁ -C ₆₎ alkyl, R ₁₉ is Wherein V and V 'are independently CH or nitrogen, A "is (C ₁ -C ₆ ) alkylene, and R ₂₀ is each unsubstituted or halogen, hydroxy (C ₁ -C ₆ ) alkoxy, Phenyl, pyridyl or pyrimidinyl mono-, di- or trisubstituted with amino, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino). A compound according to claim 1 having the formula: In the above formula, A is C ₁ -C ₆ alkylene, X is as defined in formula (I), R ₁₈ is (i) amino, mono (C ₁ -C ₆ ) alkylamino or di (C ₁ -C ₆ ) alkylamino, or (ii) unsubstituted or of formula Lower alkyl substituted with V and V 'are independently CH or nitrogen, A''is C ₁ -C ₆ alkylene and R ₂₀ is unsubstituted or halogen, hydroxy, C ₁ -C _{6, respectively} Phenyl, pyridyl or pyrimidinyl mono-, di- or tri-substituted with alkoxy, amino, mono (C ₁ -C ₆ ) alkylamino, or di (C ₁ -C ₆ ) alkylamino. A compound according to claim 1, which is N-benzyl 6-benzylamino-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-cyclohexyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-cyclohexylmethyl 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-aminobenzyl) -6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N- (4-pyridylmethyl) 6-ethoxy-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. A compound according to claim 1, which is N-benzyl 6-tetrahydroisoquinolinyl-4-oxo-1,4-tetrahydro-1,5-naphthyridine-3-carboxamide. The compound of claim 1, wherein N- {4- [1- [4- (4-fluorobenzyl) piperazinyl] methyl] benzyl} 6- (2,2,2-trifluoroethyl) -4-oxo -1,4-tetrahydro-1,5-naphthyridine-3-carboxamide.