MXPA98007482A - Naftiridine derivatives and their analogues that inhibit the citomegalovi - Google Patents

Abstract

The present invention relates to heterocyclic compounds, more particularly to naphthyridine compounds having antiviral activity. In particular, the compounds of the formula (I) wherein B, W, X, Y, R 1, R 2, R 3, R 4 and n are as defined herein, are useful in the therapy and prophylaxis of cytomegalovirus infections ( CMV) in mammals

Description

DERIVATIVES OF NAFTIRIDINA AND ITS ANALOGS THAT INHIBIT THE CITOMEGALOVIRUS FIELD D? THE G V? NTION The present invention relates to the heterocyclic compounds, and more particularly, to the naphthyridine compounds and to their use in therapy and prophylaxis of cytomegalovirus (CMV) infection.

BACKGROUND OF THE INVENTION Of the DNA viruses, the herpes group is the source of the most common viral disease in man. The group consists of herpes simplex virus (HSV) type I and II, varicella zoster (VZV), Epsteih-Barr virus (EBV) and cytomegalovirus (CMV). As with other herpesviruses, infection with CMV leads to a long-term association of the virus and the host. After a primary infection, the virus can be spread for a number of years. Infection in otherwise healthy individuals is often asymptomatic, since 80% of the adult population harbor viruses in the form REF. 28342 latent. In immunocompromised individuals, such as chemotherapy patients, organ transplant patients and in particular, people suffering from AIDS, latent CMV can be reactivated resulting in microcephaly, hepatosplenomegaly, jaundice, seizure access which can cause mental retardation, ononucleosis , retinitis and even death. In patients with AIDS, CMV is a predominant cause of morbidity. A variety of drugs have been developed to treat herpesvirus infection, including naturally occurring proteins and synthetic nucleoside analogues. For example, the natural antiviral protein, interferon, has been used in the treatment of herpesvirus infections, as they have been - the nucleoside analogues, the cytosine arabinoside, adenine arabinoside, iodoxyuridine and acyclovir, which is currently the treatment of choice for herpes simplex type I infection. Unfortunately, drugs such as acyclovir that have proven effective in treating certain herpesvirus infections are not effective enough to treat CMV. And the drugs currently used to treat CMV infection, such as ganciclovir infection (9 - [(1,3-dihydroxy-2-propoxy) ethyl] guanine) and foscarnet (phosphonoformic acid), lack acceptable side effects and profiles, insurance of approved drugs for the treatment of other herpesviruses. Thus, a need remains for non-nucleoside, therapeutic and prophylactic agents effective to treat CMV infection. Accordingly, an object of the present invention is to provide a method for inhibiting the replication of CMV in a mammal. An object of the present invention is also to provide the compounds and pharmaceutical compositions useful for inhibiting the replication of CMV in a mammal.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a method for inhibiting the replication of cytomegalovirus in a mammal, comprising administering to said mammal an anti-cytomegaloviral amount of a compound of the formula (I): wherein W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; B is selected from the group consisting of: where; A is Oxygen or Sulfur; Ri is selected from: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of 3 to 10 unsaturated carbon atoms, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms, optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and cycloalkyl of 3 to 7 carbon atoms fused to the aryl of 6 to 10 carbon atoms optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 atoms of carbon optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; R2 and R'2 are independently hydrogen, alkyl of 1 to 4 carbon atoms or Ri and R together form a saturated or unsaturated heterocycle of 5 or 6 members optionally fused to the aryl of 6 to 10 carbon atoms or to the heteroaryl; R3 and R4 are independently selected from hydrogen, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of 1 to 6 carbon atoms, optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms, and (carbocycle or heterocycle) of 3 to 10 carbon atoms saturated or unsaturated, optionally substituted by OH, halogen, amino, mercapto, alkylthio of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms carbon, alkyl of 1 to 4 carbon atoms substituted with halo, or alkoxy of 1 to 4 carbon atoms substituted with halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or carboxyl; R5 is hydrogen, alkyl of 1 to 6 carbon atoms or acyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and n is O, 1 or 2. In yet another aspect of the invention, cytomegalovirus inhibitor compounds and pharmaceutically acceptable salts thereof are provided according to formula (I), with the proviso that "2 when A is ° (II) when W and Y are both N or NR5, then Rx is different from allyl or 2-methoxybenzyl; ii) when A is either when X or Z is N or NR5, then W is N or NR5; Y F' iii) when A is ('when Z and N or NR5, then Rx is different from methyl.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a method for inhibiting the replication of cytomegalovirus in a mammal, which comprises administering to said mammal an anti-ganglionic amount of a compound of the formula (V): where it is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Ri is selected from: alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of from 3 to 10 unsaturated carbon atoms, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms, optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and cycloalkyl of 3 to 7 carbon atoms fused to the aryl of 6 to 1-Q carbon atoms optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) from 1 to 4 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; R2 is hydrogen, alkyl of 1 to 4 carbon atoms or Ri and R2 together form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to the heteroaryl or aryl of 6 to 10 carbon atoms; R3 and R4 are independently selected from hydrogen, OH, halogen, amino, cyano and (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of the β carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms carbon; R5 is hydrogen, alkyl of 1 to 6 carbon atoms or acyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and n is 0, 1 6 2. In yet another aspect of the invention, there is provided a method for inhibiting the replication of cytomegalovirus in a mammal, comprising administering to said mammal an anti-ganglionic amount of a compound of the formula (VI) : where W, X, Y, Z, Ri to R4 and n are as defined herein. In still another aspect of the invention, there is provided a method for inhibiting the replication of cytomegalovirus in a mammal, which comprises administering to said mammal an anti-ganglionic amount of a compound of the formula (VII): VII) where A is Oxygen or Sulfur, W, X, Y, Z, R? to R4 and n are as defined herein. In yet another aspect of the invention, cytomegalovirus inhibitor compounds and salts are provided. pharmaceutically acceptable thereof according to formula (I); (SAW); (VI) or (VII). In yet another aspect of the invention, there are provided the anti-cytomegalovirus compositions comprising a pharmaceutically acceptable carrier, diluent or adjuvant and a compound of the formula (I); (SAW); (VI) or (VII) or a pharmaceutically acceptable salt thereof. The present invention relates to compounds that inhibit CMV replication. These compounds are characterized by a heterobicyclic moiety as illustrated in formula (I), (V), (VI) or (VII): : i) Y where A, B, W, X, Y, Z, Rx to R4 and n are as defined herein. The term "alkyl" as used throughout the specification refers to a saturated carbon chain which may be linear or branched. Similarly, the term "alkenyl" is a linear or branched carbon chain but incorporates unsaturated carbon atoms. For convenience, however, the terms "alkoxy", "alkylthio", "acyl", "acyloxy" and "alkoxycarbonyl" refer to chains that are either saturated or unsaturated and can also be linear or branched. Where indicated, any of the above mentioned chains may have various substituents. It is understood that one or more substituents may exist, unless otherwise specified. The term "carbocycle" refers to a cyclic carbon ring or chain which is saturated or unsaturated. A "heterocycle" is a ring that incorporates heteroatoms selected from nitrogen, oxygen and sulfur instead of carbon. The unsaturated carbocycles and unsaturated heterocycles can be aromatic, for example, aryl such as phenyl or naphthyl, or heteroaryl such as pyridine or quinoline. Where indicated, any of the aforementioned rings may have various substitutions. It is understood that one or more substituents may exist unless otherwise specified. The term "amino" includes primary amines, for example NH2, secondary amines for example NHR, or tertiary amines for example N (R) 2 where R is alkyl of 1 to 4 carbon atoms. Also encompassed by the term are quaternary amines such as NH3 +. In the methods of the present invention, the replication of cytomegalovirus is inhibited by the administration of compounds of the formulas (I), (V), (VI), and (VII) as shown above, wherein: CH is selected , CR3, CH2, C = 0, CHR3, N and NR5; and one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4. It will be appreciated that the heterocyclic compounds of the invention can be saturated, unsaturated or partially unsaturated, and that X, Y and Z will have the appropriate valence for each condition. For example, when the rings are unsaturated, W may be N, CH or CR3. And on the contrary, when the rings are saturated it can be CH2, C = 0, CHR3, NH or NR5. The same principle applies to X, Y and Z. In a preferred embodiment n is 1. In a preferred embodiment it is N or NR5; In a preferred embodiment X is nitrogen or NR5, while Y and Z are independently CH, CR4, CH2, C = 0 or CHR4. In a preferred embodiment Y is Nitrogen or NR5, while X and Z are independently CH, CR4, CH2, C = 0 or CHR4. In a preferred embodiment Z is Nitrogen or NR5, while X and Y are independently CH, CR ,, CH2, C = 0 or CHR4. In a preferred embodiment the heterabicyclic ring incorporating W, X, Y and Z is unsaturated. In a particularly preferred embodiment, and Y are independently nitrogen or NR5, while X and Z are independently CH, CR, CH2, C = 0 or CHR4. In a particularly preferred embodiment, W and Y are both nitrogen, while X and Z are CH or CR4, and the heterobicyclic ring is unsaturated. In an even more preferred mode, W e And they are nitrogen, while X and Z are CH or CR4, the heterobicyclic ring is unsaturated and n is 1, whereby a 1, 6-naphthyridine ring is formed. In a preferred embodiment, A is O. Ri is selected from: Ri is selected from: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of 3 to 10 unsaturated carbon atoms, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms, optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and cycloalkyl of 3 to 7 carbon atoms fused to the aryl of 6 to 10 carbon atoms optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) 1 to 4 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; In a preferred embodiment, Rx is alkenyl of 2 to 6 carbon atoms; alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms substituted with a heteroaryl or 6-membered aryl or cycloalkyl ring of 3 to 7 carbon atoms optionally substituted with halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with halo, or alkoxy of 1 to 4 carbon atoms substituted with halo; cycloalkyl of 3 to 7 carbon atoms fused to a 6-membered heteroaryl or aryl ring optionally substituted with halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms substituted with halo. In a particularly preferred embodiment, Ri is benzyl, pyridinylmethyl or cyclohexyl ethyl optionally substituted with one or two substituents selected from hydroxyl; amino, in particular NH2 or NH3 *; alkyl of 1 to 4 carbon atoms, in particular, methyl; halogen, in particular fluoro, chloro or bromo; alkoxy of 1 to 4 carbon atoms, in particular methoxy or ethoxy; alkoxycarbonyl of 1 to 4 carbon atoms, in particular methoxycarbonyl; alkylthio having 1 to 4 carbon atoms, in particular methylthio; alkyl substituted with -halo of 1 4 carbon atoms, in particular trifluoromethyl. More particularly preferred Ri is benzyl optionally mono- or di-sus ti tuido in positions 2, 3, 5 or 6 of the ring, and more preferably in positions 2 and / or 6 with methyl ,. methoxy, ethoxy, hydroxyl, fluoro, bromo, chloro, methoxycarbonyl, methylthio, trifluoromethyl, trifluoromethoxy, NH2 or NH3 + C1 ~. In a still more preferred embodiment, Ri is benzyl optionally substituted in the 2-position with fluoro, chloro, bromo, methyl, methoxy, ethoxy, methoxycarbonyl, trifluoromethyl or NH + C1 ~. In another particularly preferred embodiment, Ri is cycloalkyl of 3 to 7 carbon atoms substituted with phenyl, which is optionally substituted with one or two substituents selected from hdroxyl, amino, alkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4"carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl substituted with halo of 1 to 4 carbon atoms More particularly preferred, cycloalkyl of 3 to 7 carbon atoms is cyclopropyl In another particularly preferred embodiment, Ri is cycloalkyl of 3 to 7 carbon atoms fused to phenyl, which is optionally substituted with one or two substituents selected from hydroxyl, amino, alkyl of 1 to 4 carbon atoms, halogen, alkoxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, or alkyl substituted with halo of 1 to 4 carbon atoms, more particularly preferred, is cycloalkyl of 3 to 7 carbon atoms, such as cyclopentyl or cyclohexyl, R2 and R'2 are indep hydrogen, alkyl of 1 to 4 carbon atoms, or Rx and R2 together form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to the heteroaryl or aryl of 6 to 10 carbon atoms. In a preferred embodiment, R 2 is hydrogen or methyl and more preferably hydrogen. R'2 is hydrogen or methyl and more preferably hydrogen. In another preferred embodiment, R together with Rx form a saturated heterocycle of 5 or 6"members optionally fused to the heteroaryl or aryl of 6 to 10 carbon atoms Suitable heterocycles of 5 or 6 members include piperidine; piperazine, morpholine, pyrrole, pyrazole and imidazole. These can be fused to a heteroaryl to aryl of 6 to 10 carbon atoms to give the appropriate bicyclic rings such as indole, purine, benzimidazole, quinoline or isoquinoline. R3 and R4 are independently selected from hydrogen, OH, halogen, amino, cyano and (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of 1 to 6 carbon atoms, optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms.

It is appreciated that the ring incorporating X, Y and Z may be substituted with one to four substituents R4 while the ring incorporating W may be substituted with one to three substituents R3. R3 and R4 are independently (carbocycle or heterocycle) of 3 to 10 carbon atoms saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or carboxyl; In an alternative embodiment, R3 and R4 are independently an aryl or heteroaryl ring or 6-membered cycloalkyl optionally substituted by halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms. In an alternative embodiment, R4 is a 6-membered aryl or heteroaryl ring or cycloalkyl optionally substituted with a halogen, hydroxyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms. In a further embodiment, R is a β-membered heteroaryl. In a further embodiment, R 4 is pyridyl. In a preferred embodiment, there is a substituent R3 which is selected from hydrogen; OH; halogen, in particular fluoro or chloro; and alkoxy of 1 to 4 carbon atoms, in particular methoxy or ethoxy. More preferably, R3 is hydrogen, chloro, hydroxyl or methoxy and more preferably hydrogen. In a preferred embodiment, R 4 is selected from hydrogen, halogen, amino, OH, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) from 1 to β carbon atoms, optionally substituted with OH, halogen or amino. Preferably, there are one or two substituents R and more preferably there is a substituent R. In a more preferred embodiment R4 is amino. In a more preferred embodiment R is aminoalkyl of 1 to 4 carbon atoms. In a more preferred embodiment R4 is OH. In a more preferred embodiment R4 is halogen. In a more preferred embodiment R 4 is methoxy.

In a more preferred embodiment R is hydrogen. R5 is hydrogen, alkyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms. In a preferred embodiment R5 is hydrogen. In a preferred embodiment R5 is alkyl of 1 to 4 carbon atoms and more preferably methyl. In a preferred embodiment, R5 is alkyl of 1 to 4 carbon atoms substituted with amino, and more preferably methyl or ethyl substituted with NH2. In a preferred embodiment, R5 is acyl of 1 to 4 carbon atoms and more preferably ethanoyl. In a preferred embodiment, R5 is acyl of 1 to 4 carbon atoms substituted with amine and more preferably ethanoyl substituted with NH2. Preferred compounds "of the invention include: compound # 1 N- (2-methylbenzyl) -2- (1, 6) aftiridinecarboxamide; compound # 2 N-benzyl-2- (1,6) naphthyridinecarboxamide; Compound # 3 N- (2-bromobenzyl) -2- [1, β] naphyridinecarboxamide; compound # 4 N- (2-chlorobenzyl-2- (1,6) naphthyridinecarboxamide; compound # 5 N- (2-bromobenzyl) -2- (1,6) naphthyridinecarboxamide; compound # 6 N- (3-bromobenzyl) - 2- (1,6) naphthyridinecarboxamide; compound # 7 N- (2-fluorobenzyl) -2- (1,6) naphthyridinecaboxamide; compound # 8 N- (4-chlorobenzyl) -2- [1,6] naphthyridinecarboxamide; compound # 9 N- (2-ethyloxybenzyl) -2- (1,6) naphthyridinecarboxamide; compound # 10 indan-1-ylamide of [1, 6] naphyridin-2-carboxylic acid; Naphthyridine-2-carboxylic acid compound # 11 (1, 2, 3, 4-tetrahydro-naphthalene-1-yl) -amide of [1, 6] naphthyridine-2-carboxylic acid; compound # 12 N- (3-? t? ethoxybenzyl) -2- (1,6) aftiridinecarboxamide; compound # 13 N- (2-trifluoromethylbenzyl) -2- (1, ß) naphthyridinecarboxamide; Compound # 14 N- (2,6-dimethoxybenzyl) -2- (1,6) aftiridinecarboxamide; Compound # 15 ([1-6] naphthyridine-2-carboxylic acid trans-2-phenyl-cyclopropyl) -amide; compound # 16 N- (2-amino-6-fluorobenzyl) -2- [1,6] naphthyridinecarboxamide; [1-6] naphthyridine-2-carboxylic acid compound # 17 (l-phenylethyl) -amide; # 1 (6,6-naphthyridine-2-carboxylic acid) # 18 (pyridin-2-ylmethyl) -amide; Compound # 19 [1, 6] naphthyridine-2-carboxylic acid cyclohexyl-methylamide; compound # 20 (3,4-dihydro-lh-isoquinolin-2-yl) - [1,6] naphthyridin-2-yl-methanone; compound # 21 N- (2-met ilthiobenzyl) -2- [1,6] naphthyridinecarboxamide; compound # 22 N- (2-hydroxybenzyl) -2- (1,6) naphthyridinecarboxamide; compound # 23 N- (2-methoxycarbonylbenzyl-2- (1,6) naphthyridinecarboxamide; compound # 24 allylamide (PFC-029) of (1,6) naphthyridine-2-carboxylic acid; compound # 25 N- (2- methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; compound # 26 N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; Compound # 27 (2- {[[[[1, 6] naphthyridine-2-carbonyl) -amino] -methyl} -phenyl) -carboxylic acid ester; Compound # 28 (2, 3, 4, 5-tetrahydrobenzo [b] oxepin-5-yl) amide of [1, β] naphthyridine-2-carboxylic acid; compound # 29 (chroman-4-yl) - [1, β] naphthyridine-2-carboxylic acid amide; Compound # 30 N- (2'-methoxybenzyl) -5-amino-2- [1, 6] naphthyrifidinecarboxa ida; Compound # 31 2, [1, 6] naphthyridine-2-carboxylic acid 3- (methylenedioxy) -benzylamide; Compound # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; Compound # 33 (2-N-ylaminobenzylamine) of 8-bromo- [l, 6] naphthyridine-2-carboxylic acid; Compound # 34 (2, isopropoxybenzylamine of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid; Compound # 35 (2-methoxybenzylamine) of β-bromo- [l-6] naphthyridin-2-carboxylic acid; # 36 (2-isopropoxybenzylamine) compound of 8-chloro- [1, 6] naphthyridin-2-carboxylic acid; Compound # 37 (2-N-ethylaminobenzylamine) of 8-chloro- [1, 6] naphthyridin-2-carboxylic acid; # 38 (2-isopropoxybenzylamine) compound of 8- (2-pyridyl- [1, 6] naphthyridine-2-carboxylic acid; compound # 39 2-trifluoromethylbenzylamine of [1, β] naphthyridin-2-thiocarboxylic acid; # 40 2-isopropoxybenzylamine of [1, 6] naphthyridine-2-thiocarboxylic acid; # 41 3-methoxybenzylamine compound of [1, 6] naphthyridin-2-thiocarboxylic acid; # 42 compound 2-isopropoxybenzylamine of 8-bro? o- [1, 6] naft iridin-2-thiocarboxylic acid; Aompuefto # 43 [l, 6] naphthyridin-2-thiocarboxylic acid 2-methoxybenzylamide; # 44 # [2,6] naphthyridine-2-thiocarboxylic acid 2-ethoxy-benzylamide; # 45 2-methoxy-cyclohexyl-methylamide of [1, 6] naft iridin-2-t-iocarboxylic acid; # 46 1- (2-iso-propoxy-phenyl) -3- [1, ß] naphthyridin-2-yl-urea; # 47 1- (2-iso-propoxybenzyl) -3- [1, β] naphyridin-2-yl-urea; # 48 1- (N-boc-4-aminobutyl-3- [1, 6] naphthyridin-2-yl-urea; # 49 hydrochloride 1- (4-aminobutyl) -3- [1, 6] naphthyridin-2-yl urea; compound # 50 l- [(S) -a-methybenzyl] -3- [1, 6] naphyridin-2-yl-urea; # 51 l- [(R) -a-methybenzyl] -3- [1, 6] naphyridin-2-yl-urea; Compound # 52 1- (2-methoxy-f-enyl) -3- [1, 6] napht-iridin-2-yl-urea; compound # 53 l-butyl-3- [1, 6] riaf tiridin-2-yl-urea; aompuesto # 54 1- (2-methoxybenzyl) -3- [1, 6] naf tir idin-2-yl-urea aompuesto # 55 1- (2-ethoxy-f-enyl) -3- [1, 6] naf t iridin-2-yl-urea somatic # 56 1- (2-methyl-f-enyl) -3- [1, 6 ] naf t iridin-2-yl-urea; Y # 57 (2-isopropoxybenzylamine) of 8- (2-pyridyl) -1- [1,6] naphthyridine-2-carboxylic acid.

The most preferred compounds of this invention include: compound # 2 N-benzyl-2- (1,6) naphthyridinecarboxamide; compound # 4 N- (2-chlorobenzyl) -2- (1,6) -naphthyridinecarboxamide; compound # 12 N- (3-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; # 14 N- (2,6-dimethoxybenzyl) -2- (1,6) naphthyridinecarboxamide; can be # 19 cyclohexyl-methylamide of [1, 6] naft iridin-2-carboxylic acid; # 24 allylated compound (PFC-029) of (1, ß) naphthyridine-2-carboxylic acid; compound # 25 N- (2-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; compound # 26 N- (2-propoxybenzyl) -2- (1,6) naphthyridin-2-carboxamide; ## STR8 ## (2, 3, 4, 5-tetrahydrobenzo [B] oxepin-5-yl) -amide of [1, 6] naphthyridine-2-carboxylic acid; Compound # 31 2, [1, 6] naphthyridine-2-carboxylic acid 3- (methylenedioxy) -benzylamide; # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; # 33 (2-N-ethylaminobenzylamine) of 8-bromo- [1, 6] naft iridin-2-carboxylic acid; Compound # 35 (2-methoxybenzylamine) of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid # 36 (2-isopropoxybenzylamine) compound of 8-chloro- [1, 6] naphthyridine-2-carboxylic acid; compound # 40 2-isopropoxybenzylamine [1, 6] naphthyridin-2-thiocarboxylic acid; # 43 2-methoxy-benzylamide of [1, β] naphthyridine-2-thiocarboxylic acid; compound # 46 1- (2-iso-propoxy-phenyl) -3- [1,6] naphthyridin-2-yl-urea; # 47 1- (2-iso-propoxybenzyl) -3- [1, 6] napht-iridin-2-yl-urea; Y compound # 51 l- [(R) -a-methylbenzyl] 3- [1,6] naphthyridin-2-yl-urea.

The most preferred compounds of this invention include: # 26 N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; Compound # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; # 33 (2-N-ethylaminobenzylamine) of 8-bromo- [l, 6] naphthyridine-2-carboxylic acid; # 36 (2-isopropoxybenzylamine) of 8-chloro- [1,1,6] naphthyridine-2-carboxylic acid; # 40 2-isopropoxybenzylamine of [1, β] naphthyridin-2-thiocarboxylic acid; # 43 2-methoxy-benzylamide of [l, 6] naphthyridin-2-thiocarboxylic acid # 43; # 46 1- (2-iso-propoxy-phenyl) -3- [1, ß] naphthyridin-2-yl-urea; # 47 1- (2-iso-propoxybenzyl) -3- [1, 6] napht-iridin-2-yl-urea; Y # 51 l- [(R) -a-methylbenzyl] -3- [1, 6] naphthyridin-2-yl-urea.

In a further preferred embodiment, the compounds of this invention include: compound # 26 N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; Compound # 33 (2-N-ylaminobenzylamine) of 8-bromo- [l, 6] naphthyridine-2-carboxylic acid; compound # 40 2-isoproroxybenzylamine [1, 6] naphthyridin-2-thiocarboxylic acid; Y compound # 46 1- (2-iso-propoxy-phenyl) -3- [1,6] naphthyridin-2-yl-urea.

The compounds of the present invention can be synthesized using conventional preparative steps and recovery methods known to those skilled in the art of organic chemistry. A preferred synthetic route for the production of the compounds of the formula V involves the coupling of a carboxylic acid intermediate of the formula a. with an amino intermediate of the formula b. The reaction will be under conditions suitable for amide bond formation, for example in the presence of a suitable coupling agent such as EDC or dCC, to produce the final compound of formula V. The reaction is illustrated in Scheme I. The compounds of formula V can be converted to the compounds of formula VI by reacting them with cloning agents such as Lawesson's reagent. The use of Lawesson's reagent is well known in the art (for example, see Syn thesi s, 941 (1979), Te trah edron, 35, 2433 (1979), and Te t.lett., 21, 4061 (1980). A preferred synthetic route for the production of the bicyclic compounds of formula VI involved the coupling of the amino bicyclic intermediate of formula c with an amido d portion.This reaction is illustrated by scheme 2. The reaction will be under conditions suitable for formation of the bond "urea" in a suitable solvent to produce the compounds of the formula Vlla The introduction of a substituent R 2 on the nitrogen can be carried out using methods known in the art The urea link of the compounds Vlla and Vllb can also be converted to a thiourea by the reaction of the compounds with thionation agents as mentioned above SCHEME 1 (I) where X, Y, Z, Rx to R4 and n are as previously defined. Intermediates a_, b and c_ can be obtained from commercial sources, for example, 2-carboxy [1, 6] naft iridine (Peakdale Fine Chemicals, Glossop, Derbyshire UK, PFC-027); 6, 7-dibromo-4-hydroxy- [1, 5] naphthyridine-2-carboxylic acid (Pomorski et al Rocz, Chem., 1974, 48 (2); 321); 1, 2, 3, 4-tetrahydrodo-8-hydroxy- [1, 6] naphthyridine-2-carboxylic acid (Abe et al. Tet. Lett., 1977, 9: 735). 0, alternatively the intermediaries a_, b and c_ can be prepared according to the established synthetic techniques.

Scheme 2 r N It will be appreciated that certain substituents require protection during the course of synthesis and subsequent deprotection. For example, when R3 or R4 is hydroxyl, it may be necessary to protect it by conversion to an alkoxy or an ester and subsequently it is deprotected. Protective groups for other substituents are described in Protective Groups in Organic Synthesis, 2a. ed. , Greene and Wuts, John Wiley & Sons, New York, 1991. It may be appreciated by those of skill in the art that compounds of formula I, V, VI and VII, depending on the substituents, may contain one or more chiral centers and thus exist in the form of many different isomers, optical isomers (e.g. enantiomers) and mixtures thereof, including racemic mixtures. All other isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. The present invention also provides anti-cytomegalovirus compositions comprising a pharmaceutically acceptable carrier or adjuvant and an amount of a compound of formula I, V, VI and VII, effective to inhibit the replication of CMV in a mammal. The proportion of each carrier, diluent or adjuvant is determined with the solubility and the chemical nature of the compound and the route of administration in accordance with standard pharmaceutical practice. The therapeutic and prophylactic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions. Such compositions may be in the form of tablets, capsules, pills, powders, granules, troches, suppositories, reconstitutable powders, or liquid preparations, such as sterile or oral parenteral solutions or suspensions. The compounds of the invention can be administered via an intraocular implant for the treatment of retinitis as a result of CMV infection. In particular, the compounds can be embedded in an implant based on a polymer, which will be released to the eye over a prolonged period of time. In order to obtain administration consistency, it is preferred that a composition of the invention be in the form of a unit dose. The unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients. For example, binding agents, such as acacia, gelatin, sorbitol, or polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for the formation of tablets such as magnesium stearate; disintegrators, such as starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium laurisulfate. The compounds can be injected parenterally; being this - intramuscularly, intravenously or subcutaneously. For parenteral administration, the compound can be used in the form of sterile solutions containing other solutes, for example, enough saline or glucose to render the solution isotonic. The amount of active ingredient administered parenterally will be approximately 0.01 to 250 mg / kg / day, preferably from about 1 to 10 mg / kg / day, more preferably from about 0.5 to 30 mg / kg / day, and more preferably from about 1-20 mg / kg / day. The compounds can be administered orally in the form of tablets, capsules or granules containing suitable excipients such as starch, lactose, white sugar and the like. The compounds may be administered orally in the form of solutions which may contain coloring and / or flavoring agents. The compounds can also be administered sublingually in the form of troches or tablets in which each active ingredient is mixed with sugar or corn syrups, flavoring and coloring agents, and then dehydrated sufficiently to make the mixture suitable for pressing in solid form . The amount of active ingredient administered orally will depend on the availability of the specific compound. Oral solid compositions can be prepared by conventional mixing, filling, tabletting, or the like. Repeated mixing operations can be used to distribute the active agent throughout these compositions, using large amounts of fillers. Such operations are, of course, conventional in the art. The tablets can be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The liquid oral preparations may be in the form of emulsions, syrups, or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may or may not contain conventional additives. For example, suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or edible hydrogenated fats; emulsifying agents, such as sorbitan monooleate or acacia; non-aqueous vehicles, which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerin, propylene glycol, ethylene glycol, and ethyl alcohol; preservatives, for example methyl parahydroxybenzoate, ethyl para-hydroxybenzoate, n-propyl parahydroxybenzoate, or n-butyl para-hydroxybenzoate sorbic acid; and, if desired, conventional flavoring or coloring agents. For parenteral administration, fluid unit dose forms can be prepared by using the peptide and a sterile vehicle and, depending on the concentration employed, it can be either suspended or dissolved in the vehicle. Once in solution, the compound can be injected and sterilized by filtration before filling a suitable vial or ampoule and subsequently the carrier or storage package is sealed. Adjuvants such as a local anesthetic, a preservative or a buffering agent can be dissolved in the vehicle before use. The stability of the pharmaceutical composition can be improved by freezing the composition after filling the bottle and removing the water under vacuum (e.g., lyophilization of the composition). Parenteral suspensions may be prepared in substantially the same manner, except that the peptide must be suspended in the vehicle instead of being dissolved and, furthermore, sterilization by filtration is not feasible. The compound can be sterilized, for example, by exposing it to ethylene oxide prior to suspension thereof, in a sterile vehicle. A surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound. The pharmaceutical compositions of this invention comprise an inhibitory amount of the cytomegalovirus replication of one of the compounds of the formula I, V, • VI and VII and a pharmaceutically acceptable carrier, diluent or adjuvant. Typically, they contain from about 0.1% to about 99% by weight of the active compound, and preferably from about 10% to about 60% by weight, depending on which method of administration is employed.

An inhibitory amount of cytomegalovirus replication is that amount of active compound required to slow the progression of viral replication or reduce the viral load of that which might otherwise occur in the administration of said compound. 0, is also an amount of the active compound required to slow the progression or reduce the intensity of symptoms resulting from CMV infection or elimination thereof. The inhibitory activity of the cytomegalovirus, of the compounds of the invention, can be determined according to the plaque reduction assay described in detail in the examples. Under these particular conditions, a compound having such an activity will show an ICSO of about 50 μg / ml or less, preferably 25 μg / ml or less, more preferably 10 μg / ml or less, and more preferably less than 1 μg / ml. The doctors will determine the dosage of the present therapeutic agents that will be most suitable. The dose may vary with the mode of administration and the particular compound chosen. In addition, the dose may vary with the particular patient being treated. The dose of the compound used in the treatment will vary, depending on the viral load, the weight of the patient, the relative efficacy of the compound and the judgment of the treating physician. Such therapy can be extended for several weeks or months, in an intermittent or uninterrupted manner. To further assist in understanding the present invention, the following non-limiting examples are provided.

EXAMPLE 1 Synthesis # 1 N- (2-methylbenzyl) -2- (1, 6) naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), in anhydrous tetrahydrofuran (5 ml) at 0 ° C, triethylamine (44 ml, 0.316 mmol) was added. After 5 minutes, isopropyl chloroformate (0.316 ml, 1M solution in toluene, 0.316 mmol) was added. The mixture was stirred at 0 ° C for 20 minutes, then 2-methylbenzylamine (53.46 ml, 0.43 mmol) was added to the mixture at 0 ° C. The resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 5 hours and then diluted in methylene chloride (100 ml). The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give the crude mixture. Chromatography of the crude product (Hex: EtOAc = 1: 1 to pure EtOAc) gave the desired product as a white solid (29.8 mg, 37%): m.p. 120-121 ° C. compound # 2 N-benzyl-2- (1,6) naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), benziamine (45 mg, 0.42 mmol) in anhydrous tetrahydrofuran (5 ml) ) at 0 ° C l- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol) was added. The resulting mixture was allowed to stir at room temperature After 20 min, dimethylformamide (2 ml) was added to the reaction mixture, and the mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue redissolved in methylene chloride (100 ml) The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture. Chromatography of the crude product (Hex: EtOAc = 1: 1 to pure EtOAc) gave the desired product as a white solid (97 mg, 99%): mp 113-115 ° C. # 3 N- (2-bromobenzyl) -2- [1, 6] naphthyridine carboxamide To a stirred solution of 4-bromobenzylamine hydrochloride (97.8 mg, 98%, 0.431 mmol) in anhydrous dimethylformamide (5 mL) was added triethylamine (60.1 μL, 0.431 mmol). After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), hydrated 1-hydroxybenzotriazole (42.7 mg, 0.316 mmol) and 1- (3-dimethylamino-propyl) hydrochloride were added sequentially. 3-ethylcarbodiimide (60.6 mg0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (100 ml). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (100 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture. Chromatography of the crude product (Hex: EtOAc = 1: 1 to pure EtOAc) gave the desired product as a white solid (97 mg, 99%): m.p. 149-150 ° C. # 4 N- (2-chlorobenzyl) -2- (1,6) -naphthyridinecarboxamide To a stirring mixture of 2 - [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (5 ml) at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) was added sequentially. -chlorobenzylamine (54.7 μl, 95% ",, 0.43 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol) The resulting mixture was allowed to stir at room temperature overnight and The solvent was removed in vacuo and the resulting residue redissolved in methylene chloride (100 ml) The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue redissolved in methylene chloride (100 ml) The organic layer was washed with sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture. of the product cr udo (Hex: EtOAc = 1: 1 to neat EtOAc) gave the desired product as a white solid (83 mg, 97%): m.p. 120-121 ° C. # 5 N- (2-bromobenzyl) -2- (1,6) naphthyridinecarboxamide; To a stirring solution of 2-bromobenzylamine hydrochloride (80.7 mg, 95%, 0.345 mmol) in anhydrous dimethylformamide (5 ml) was added triethylamine (51.8 μl, 0.345 mmol.) After 5 minutes, 2- acid was added. [1, 6] naphthyridinecarboxylic (40 mg, 0.229 mmol), hydrated 1-hydroxybenzotriazole (34.2 mg, 0.253 mmol) and l- (3-dimethylaminopropyl) -3-ylcarbodii ida hydrochloride (48.5 mg, 0.253 mmol) sequentially. The resulting mixture was allowed to stir at room temperature for 4 hours and was found to be clear. The solvent was removed in vacuo and the resulting residue redissolved in methylene chloride (100 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture. Chromatography of the crude product (Hex: EtOAc = 1: 1 to EtOAc. Pure) gave the desired product as a white solid (70 mg, 89%): m.p. 129-130 ° C. # 6 N- (3-bromobenzyl) -2- (1,6) naphthyridinecarboxamide; To a stirred solution of 3-bromobenzylamine hydrochloride (77.5 mg, 0.345 mmol) in anhydrous dimethylformamide (5 ml) was added triethylamine (51.8 μl, 0.345 mmol). After 5 minutes, 2- [lm, β] naphthyridinecarboxylic acid (40 [mu] g, "0.229 mmol), hydrated 1-hydroxybenzotriazole (34.2 mg, 0.253 mmol) and g2 2 & 2 S2imid fS were added sequentially. The resulting mixture was allowed to stir at room temperature overnight and was found to be clear The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (100 ml) The organic layer was washed with acidic carbonate aqueous sodium, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture, chromatography of the crude product (Hex: EtOAc = 1: 1 to neat EtOAc) gave the desired product as a white solid (64 mg, 81%). %): mp 112-113 ° C. # 7 N- (2-fluorobenzyl) -2- (1,6) naphthyridine carboxamide; To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (6.3 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-fluorobenzylamine (51.0 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (100 ml). The organic layer was washed with carboparate, aqueous sodium acid, dried over anhydrous magnesium sulfate and concentrated to give the crude mixture. Flash column chromatography of the crude product (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (79.2 mg, 98%): m.p. 110-111 ° C. aompuesto # 8 N- (4-chlorobenzyl) -2- [1,6] naftiridine-carboxamide To a stirring mixture of 2- [1, 6] naft iridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (6.3 ml) at room temperature - hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) was added sequentially, chlorobenzylamine (53.5 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (50 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated to give the crude mixture. Flash column chromatography of the crude product (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (80.3 mg, 94%): m.p. 110-111 ° C. # 9 N- (2-ethoxybenzyl) -2- [1, 6] naphthyridine-carboxamide To a stirring mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (6.3 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2- fluorobenzylamine (64.9 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (50 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated to give the crude mixture. Flash column chromatography of the crude product (50% d-hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (85.0 mg, 96%): m.p. 79-80 ° C. # 10 indan-1-amide of [1, 6] naphyridine-carboxylic acid To a stirring mixture of 2- [1,6-naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (6.3 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-aminoindane (56.0 μl 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ylcarbodii ida hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (50 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated to give the crude mixture. Flash column chromatography of the crude product (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (80.1 mg, 96%): m.p. 156-157 ° C. # 11 (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -acid [1, 6] naphthyridine-2-carboxylic acid To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (6.3 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1, 2, 3, 4-tetrahydro-1-naphthylamine (63.0 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo and the resulting residue was redissolved in methylene chloride (50 ml). The organic layer was washed with aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated to give the crude mixture. Flash column chromatography of the crude product (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (87.0 mg, 100%): m.p. 164-165 ° C. aompuesto # 12 N- (3-methoxybenzyl) -2- [1,6] naphthyridine-carboxamide To a stirring mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at ambient temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 3 -methoxybenzylamine (56.6 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a clear oil (79.1 mg, 94%). compound # 13 N- (2-trifluoroethylbenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, β] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2- (trifluoromethyl) -benzylammir (61.6 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (90.9 mg, 96%): m.p. 125-127 ° C. compound # 14 N- (2,6-dimethoxybenzyl) -2- [1,6] naphthyridine carboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2, β-dimethoxybenzylamine (75.0 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (90.6 mg, 98%): m.p. 169-171 ° C.

Compound # 15 ([1, 6] naphthyridine-2-carboxylic acid trans-2-phenyl-cyclopropyl) -amide To a stirring mixture of trans-2-phenylcyclopropylamine hydrochloride (75.3 mg, 0.431 mmol) in anhydrous dimethylformamide (1.0 mL) was added triethylamine (60.0 μL, 0.431 mmol). After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), 1-hydroxybenzotriazole hydrate (42 * 7 mg, 0.316 mmol), and 1- (3-dimethylaminopropyl) hydrochloride were sequentially added. 3-ethylcarbodiimide (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash chromatography -, column residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (79.2 mg, 95%): m.p. 123-124 ° C. compound # 16 N- (2-amino-6-fluorobenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-amino 6-fluorobenzylamine (60.0 μl) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a white solid (80.0 mg, 94%): m.p. 165 (decomposes). [1-6] naphthyridine-2-carboxylic acid compound # 17 (l-phenylethyl) -amide To a stirred mixture of 2- [1, 6] np.phthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was added sequentially, hydrated 1-hydroxybenzotriazole (42.7 mg, 0.31.6 mmol), 1-fenflet-ilamine (56.1 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, Q.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a clear oil (78.7 mg, 99%). # 1 - (1, 6) naphthyridine-2-carboxylic acid compound # 18 (pyridin-2-ylmethyl) -amide To a stirred mixture of 2- [1,6-naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2- ( aminomethyl) pyridine (45.3 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 5% methanol / ethyl acetate) gave the desired product as a light brown solid (78.7 mg, 99%): m.p. 123-125 ° C. sompues | to # 19 [1, 6] naft iridin-2-carboxylic acid cyclohexyl-methylamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), cyclohexanemethylamine ( 57.2 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (100% ethyl acetate) gave the desired product as a white solid (74.9 mg, 97%): m.p. 62-63 ° C.

Compound # 20 (3, 4-dihydro-lH-isoquinolin-2-yl) - [1,6] naphthyridin-2-yl-methanone To a stirred mixture of 2- [1,6-naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous dimethylformamide (1.0 ml) at room temperature was sequentially added 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1.2 , 3,4-tetrahydroisoquinoline (55.6 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir. at room temperature overnight and it was found to be clear. The solvent was removed in vacuo. Flash column chromatography of the residue (100% ethyl acetate) gave the desired product as a white solid (79.1 mg, 95%): m.p. 98-100 ° C.

Aompuesto # 21 N- (2-me t il thiobencil) -2- [1, 6] naftiridin-carboxamide To a stirring mixture of 2-methylsulfanylbenzylamine chloride (81.7 mg, 0.431 mmol) in. Anhydrous dimethylformamide (1.0 ml) was added triethylamine (60.0 μl, 0.431 mmol). After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), hydrated 1-hydroxybenzotriazole (42.7 mg, 0.316 mmol), and 1- (3-dimethylaminopropyl) hydrochloride were added sequentially. 3-ethylcarbodiimide (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight. The solvent was removed in vacuo. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gave the desired product as a light brown solid (88.2 mg, 99%): m.p. 102-103 ° C. # 32 2'-methoxy-benzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid step 1 Chromium trioxide (15.50, 173.1 mmol) in one portion was added to a solution of pyridine (28 mL, 346.20 mmol) in dichloromethane (175 mL) at 0 ° C. The cooling bath was removed and the mixture was allowed to stir for 30 min. To that solution was then added a solution of the alcohol (Cheng, C.Y, Hsin, L.W., Liou, J.P. Tetrahedron, 1996, 52, 10935). (3.851 g, 25.85 mmol) in dichloromethane (15 ml). The mixture was then allowed to stir at room temperature for 2 hours and the solution was decanted, the solvent was then removed and the reactant was removed. purified by chromatography eluting with 2% methanol in methylene chloride. The desired compound was obtained as a pale yellow solid (2662 g, 70%).

XH NMR (400 MHz, CDC13) d: 8.69 (s, 1H, H-1), 8.64 (d, 1H, H-2, J = 7.1 Hz), 7.78 (d, 1H, H-4, J = 7.1 Hz), 2.99 (t, 2H, H-6, J = 6.2 Hz), 2.73 (t, 2H, H-8, J = 6.3 Hz), 2.21 (t, 2H, H-7, J = 6.2 Hz).

Step 2 LiHMDS in tetrahydrofuran (1 M, 11. 0 ml, 1 mmol) was added to a solution (lithium 1,1,1,3,3,3-hexamethyldisilazane) of setone (115 mg, 0.78 mmol) in tetrahydrofuran (3 ml) at -78 ° C. After min. at this temperature methyl cyanoformate (0.3 ml, 3.9 mmol) was added and the mixture was allowed to stir overnight. The reaction was then quenched with saturated ammonium chloride and extracted with ethyl acetate. Then it was dried with sodium sulfate. The residue was triturated with cold ethyl acetate yielding the desired compound. (75 mg, 47%) 1 H NMR (400 MHz, CDCl 3) d: 11.81 (s, 1 H, OH), 8.63 (d, 1H, H-3, J = 5.9 Hz),), 8.58 (s, 1H, H-1), 8.16 (d, 1H, H-4, J = 5.9 Hz), 3.93 (s, 3H, OCH3), 3.05 (t, 2H, H-8, J = 7.8 Hz), 2.74 (t, 2H, H-7, J = 8.5 Hz). step 3 To a solution of enol from step 2 (350 mg, 1.71 mmol) in methanol (10 ml) was stirred in the presence of palladium on carbon (10%, 350 mg) under an atmosphere of hydrogen per lh. The catalyst was then removed by filtration through celite and the filtrate was concentrated to dryness to give the desired compound as a white solid (350 g, 100%) 1 H NMR (400 MHz, DMSO) d: 8.72 (2, 1H, Hl), 8.67 (d, 1H, H-3, J = 5.8 Hz),),, 7.90 (d, 1H, H-4, J = 5.8 Hz), 6.6 (broad, 1H, OH), 5.02 (d , 1H, H-5, J = 4.3 Hz), 3.63 (s, 3H, OCH3), 3.0 (, 2H), 2.8 (i, 1H), 2.0 (m 1H), 1.9 (m, 1H).

Step 4 Methanesulfonyl chloride (0.18 ml, 2.37 mmol) was added to a solution of the alcohol from step 3 (350 mg, 1.69 mmol) and triethylamine (0.35 ml, 2.54 mmol) in dichloromethane (10 ml) at 0 ° C. The mixture was then stirred at room temperature for 2 h and the solution was then washed with water, sodium hydrogen carbonate, and dried using sodium sulfate. The solvent was then removed and the residue taken up in dichloromethane (5 ml) and treated with DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) (0.5 ml). The solution was stirred for 2 h at room temperature and the solvent was removed in vacuo and the residue was purified by chromatography (1% methanol in methylene chloride) to give the desired compound (159 mg, 50% alcohol). 1 H NMR (300 MHz, CDC13) d: 8.46 (d, 1H, H-3, J = 4.4 Hz), 8.44 (s, 1H, Hl), 7.44 (s, 1H, H-5), 7.06 (d, 1H, H-4 J = 4.4 Hz), 3.83 (s, 3H, OCH3), 2.87 (t, 2H, H-8, J = 8.0 Hz), 2.69 (t, 2H, H-7, J = 8.0 Hz ).

Step 5 Sodium hydroxide (IN, 1.3 ml, 1. 3 mmol) was added to an ester solution from step 4 (159 mg, 0.84 mmol) in dioxane (3 ml) at room temperature. After 3 h, the mixture was concentrated to approximately 1 ml and HCl (6N) was carefully added to the cooled solution on ice until an equal pH was reached. The resulting precipitate was collected, washed with water and dried at room temperature. empty. (92 mg, 62%). 1 H NMR (400 MHz, DMSO) d: 8.42 (, 2H, Hl and H-3), 7.45 (s, 1H, H-5), 7.31 (d, 1H, H-4, J = 4.9 Hz), 2.82 (t, 2H, H-8, J = 8.2, Hz), 2.53 (t, 2H, H-7, J = 7.5 Hz).

Step 6 To a solution of the acid from step 5 (60 mg, 0. 34 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), and HOBT (1-hydroxybenzotriazole hydrate) (55 mg, 0.41 mmol), 2-methoxybenzylamine (54 μL, 0.41 mmol ) in dimethylformamide (1 ml) was stirred at room temperature for 24 h. The solvent was then removed in vacuo and the residue was purified by chromatography eluting with 50-100 ethyl acetate in hexanes. The desired compound was obtained as a white solid. (80 mg, 79%). 1H (300 MHz, CDC13) d: 8.45 (d, 1H, J = 4.8 Hz), 8.41 (s, 1H, Hl), 7.31 (m, 2H), 7.10 (s, 1H, H-5), 7.03 ( d, 1H, H-4, J = 4.8 Hz), 6.94 (broad, 1H, NH), 4.59 (d, 2H, CH2, J = 5.8 Hz), 3.91 (s, 3H, OCH3), 2.88 (t, 2H, H-8, J = 8.0 Hz), 2.64 (t, 2H, H-7, J * = 8.3 Hz). compound # 33 2-N-ethylaminobenzylamine of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid step 1 N-ethyl-2-aminobenzonitrile A solution of lithium bis (trimethylsilyl) amide (7.6 ml, 1M in tetrahydrofuran) is added to a cold (0 ° C) solution of 2-aminobenzonitrile (1 g, 8.5 mmol) in tetrahydrofuran (10 ml) and dimethylformamide ( 2 ml). The resulting solution is stirred for 30 minutes, then iodoethane (0.68 ml, 8.5 mmol) is added dropwise. The solution is allowed to reach room temperature and stirred overnight. The reaction mixture was then quenched with saturated ammonium chloride, evaporated, diluted with methylene chloride, washed with water, brine and the combined organic extracts were dried with sodium sulfate and concentrated. The resulting liquid was chromatographed on silica gel (30% ethyl acetate-hexane) to give the title compound in a 9 to 1 ratio of the non-separable mono- and bis-alkylated compounds.

N-et i -2-aminobenzoni trilo: 1 H NMR (400 MHz) (CDC13) d: 7.41-7.33 (m, 2 H, Ph), 6.68 - 6.65 (, 2 H, Ph), 4.5 (s, 1 H, NH) , 3.29-3.22 (, 2H, CH-2N), 1.32 (t, J = 7 Hz, eH, CH3CH2) N-diethyl-2-aminobenzonyl trile: 1 H NMR (400 MHz) (CDC13) d: 7.41-7.33 (m, 2 H, Ph), 6.68-6.65 (m, 2 H, Ph), 4.5 (s, 1 H, NH) , 3.41 (q, 4H, CH2N), 1.20 (t, J = 7 Hz, 6H, CH3CH2) step 2 N-Ethyl-2-aminobenzylamine dihydrochloride N-diethyl-2-aminobenzamine dihydrochloride N-Ethyl-2-aminobenzoni tryl (0.4 g, 2.7 mmol), 10% Pd / C (100 mg) is added in a dry flask followed by ethanol (15 ml). Hydrochloric acid (2.7 ml, 4M in dioxane) was added to this solution. The resulting reaction was placed under an atmosphere of H2 (gaseous). The resulting solution was filtered over celite, evaporated, triturated with ether, and the solvent was evaporated to yield the above intermediate.

N-ethyl-2-aminobenzylamine 1H NMR dichloride (400 MHz) (DMSO) d: 8.5-8.2 (m, 3H, NH3), 7. 35-7.25 (1, 2H, Ph), 7.34 (t, J = 7.5 Hz, 1H, Ph) 7.1-6.9 (m, 2H, Ph), 4.07 (s, 2H, CH2N), 3.19 (1, 2H, J = 7 Hz, CH3CH2), 1.27 (t, J = 7 Hz, 3H, CH3CH2) N-Diethyl-2-aminobenzamine dihydrochloride: 1 H NMR (400 MHz) (DMSO) d: 8.5-8-.2 (m, 3H, NH 3), 7.35-7.25 (1, 2H, Ph), 7.34 (t, J = 7.5 Hz, 1H, Ph) 7.1-6.9 (, 2H, Ph), 4.07 (s, 2H, CH2N), 3.33 (1, 2H, J = 7 Hz, CH3CH2), 1.07 (t, J = 7 Hz , 3H, CH3CH2) step 3 8-bromo- [1, 6] naphyridin-2-carboxylic acid Br2 is added in 40 minutes to a suspension of [1, 6] naphthyrin-2-carboxylic acid (3 q 17.25 mmol) in acetic acid (150 ml) at room temperature (18.96 mmol). The solution was stirred overnight at room temperature and then the mixture was quenched with ice and stirred for 1 hour. The solution was evaporated to dryness and then triturated, filtered and washed with a minimum of cold water. The resulting composition was dried under vacuum overnight to yield the title compound in 59% yield. 1 H NMR (400 MHz) (DMSO) d: 14.1-13.8 (M, 1H, COOH), 9.49 (s, 1H, H5), 9.10 (a, 1H, H7), 8.83 (d, 1H, J = 8.5 Hz , H4), 8.31 (d, 1H, J = 8.5 Hz, H3) Step 4 2-N-ethylamino-benzylamine of β-bromo- [1, 6] naphthyridine-2-carboxylic acid Triethylamine (0.095 mL, 0.68 mmol) was added to a solution of the salt (57 mg, 0.255 mmol) in dimethylformamide (1.5 mL) at room temperature. The solution was stirred for five minutes. Simultaneously, the acid (30 mg, 0.12 mmol), HOBT (25 mg, 0.19 mmol) and EDCI (36 mg, 0.19 mmol) were added. The reaction was allowed to stir overnight at room temperature. The solution was evaporated to dryness and the residue was dissolved in a minimum of methylene chloride and purified using flash chromatography (50% AcOEt / hexane to 100% AcOEt) to yield the title compound in 61% yield. 1 H NMR (400 MHz) (CDC13) d: 9.27 (s, 1H, H5), 9.05 (s, 1H, H /), 8.65-8.55 (s, 1H, NH), 8.55-8.45 (m, 2H, J4 and H3), 7.3-7.2 (m, 2H, Ph), 7.85-7.65 (m, 2H, Ph), 4.67 (d, 2H, J = 6.5, Hz, CH2), 3.25-3.15 (m, 2H, CH2CH3 ), 1.4-1.3 (, 3H, CH3CH2) step 5 8-bromo- [l, b] naphthyridine-2-carboxylic acid 2-N-ethylaminobenzylamine hydrochloride salt Hydrochloric acid was added to a solution of the amide (28.4 mg, 0.06 mmol) in methylene chloride (0.5 ml) at room temperature (1 ml, 4M in dioxane). The solution was stirred for 20 minutes at room temperature. The suspension was evaporated to a point and then triturated in ether to yield the title compound in quantitative yield. 1 H NMR (400 MHz) (CDC13) d: 9.27 (s, -1 H, H5), 9.5 (s, 1 H, H7), 8.65-8.55 (s, 1 H-, NH), 8.55-8.45 (m, 2H, H4 and H3), 7.3-7.2 (m, 2H, Ph), 7.85-7.65 (m, 2H, pH), 4.67 (d, 2H, J = 6.5 Hz, CH2), 3.25-3.15 (m, 2H, CH2CH3 ), 1.4-1.3 (, 3H, CH3CH2) compound # 39 2-trifluoromethylbenzylamine [1, 6] naft iridin-2-thiocarboxylic acid Lawesson's reagent was added to a stirred solution of BCH-5024 (30 mg, 0.09 mmol) in toluene (1.5 mL) (38 mg, 0.09 mmol). The solution was then heated to 90 ° C for 1 h. The solvent was evaporated and the product was purified by flash chromatography (50% AcOEt / He up to 100% AcOEt) to produce 25.8 mg of the thioamide derivative. 1 H NMR (400 MHz, CDC13); 10.55 (s broad, 1H), 9.3 (s, 1H), 9.0 (d, J = 8.5 Hz, 1H), 8..81 (d, J = 6 Hz, 1H), 8.44 (d, J = 8.5 Hz *. 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 5.37 (d, J = 6 Hz, 2H). compound # 46 1 - (2-iso-propoxyfyl) -3- [1, 6] naf: tir idin-2 - i l -urea CH2C12 A solution of 2-isopropoxyphenylamine (400 mg, 2.64 mmol) and N, N-diisopropylethylamine (1.02, 5.82 mmol) in dichloromethane (10.0 ml) was added dropwise via a cannula to a solution of triphosgene (274.7 mg, 0.93 mmol) in dichloromethane (6.0 ml) at -78 ° C. The solution was stirred at -78 ° C for 1 hour, then at 0 ° C for 1 hour, and then at room temperature for 1 hour. The mixture was concentrated, triturated with pentane, and then filtered. The desired isocyanate was isolated co or "a brown oil (449.7 mg, 96%): XH NMR (400 MHz, CDC13) d: 7.12 (lh, pH), 6.99 (1H, pH), 6.90 (1H, pH), 6.86 (1H, pH), 4.65 ( septete, 1H, CH, J 6.5 Hz), 1.42 (d, 6H, CH3, J 6.5 Hz) ppm. A mixture of the isocyanate (45.8 mg, 0.258) and the amine (25 mg, 0.172) in acetonitrile (1 ml) was heated to reflux for 3 hours. The solvent was removed using a rotary evaporator. The residue was then triturated with diethyl ether, filtered, and washed with diethyl ether. The solid was washed again with ethanol and then with diethyl ether repeatedly. The desired product was isolated as a light brown solid (34.4 mg, 62%), m.p. > 200 ° C; 1 B. NMR (400 MHz, DMSO) d 11.33 (broad s, 1H, NH), 10.56 (s broad, 1H, NH), 9.17 (s, 1H, H-5), 8.68 (d, 1H, H-7, J 5.8 Hz), 8.43 (d, 1H, H-5, J 8.9 Hz), 8.16 (1H, Ph), 7.68 (d, 1H, H-8, J 5.8 Hz), 7.50 (d, 1H, H-3, J 8.9 Hz), 7.12 (1H, Ph), 7.03 (1H, Ph), 6.93 (1H, Ph), 4.70 (septet, 1H, CH, J 6.0 Hz), 1.34 (d, 6H, CH, J 6.0 Hz) ppm.

In a similar manner, the following compounds were prepared: aompuesto # 22 N- (2-hidroxibencii) -2- (1,6) naftiridin-carboxamide # 23 N- (2-methoxycarbonylbenzyl-2- (1,6) naphthyridinecarboxamide compound # 26 N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide somatic # 27 (2- {2- [{[[[[6]] naphthyridin- tert-butyl ester 2- carbonyl) -amino] -methyl.} - phenyl) carbon ################################################################################################ # 29 (chroman-4-yl) - [1, 6] naphthyridine-2-carboxylic acid amide compound # 30 N- (2 '-methoxybenzyl) -5-amino-2- [1, β] naphthyrifidinecarboxamide compound # 31 2, 3- (methylenedioxy) -benzylamide of [1, 6] naphthyridine-2-carboxylic acid compound # 33 (2-N-ethylaminobenzylamine) of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid compound # 34 (2, isopropoxybenzylamine of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid # 35 (2-methoxybenzylamine) of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid # 36 (2-isopropoxybenzylamine) of 8-chloro- [1, 6] naphthyridine-2-carboxylic acid Compound # 37 (2-N-ethylaminobenzylamine) of 8-chloro- [1, 6] naphthyridine-2-carboxylic acid # 38 (2-isopropoxybenzylamine) compound of 8- (2-pyridyl) - [1, 6] naphthyridin-2-carboxylic acid # 40 isopropoxybenzylamine compound of [1, 6] naphthyridin-2-thiocarboxylic acid sompuesjto # 41 3-methoxybenzylamine [1, 6] naphthyridin-2-thiocarboxylic acid # 42 2-isopropoxybenzylamine of 8-bromo- [1, 6] naphthyridin-2-thiocarboxylic acid # 43 2-methoxybenzylamide [1, 6] naphthyridine-2-thiocarboxylic acid # 44 2-ethoxy-benzylamine [1, 6] naphthyridine-2-thiocarboxylic acid compound # 45 2-methoxy-cyclohexylmethyl-amide of [1, β] naphthyridin-2-thiocarboxylic acid compound # 47 1- (2-iso-propoxybenzyl) -3- [1,6] naphthyridin-2-yl-urea compound # 48 1- (N-boc-4-aminobutyl-3- [1, 6] napht-iridin-2-yl-urea) # 49 hydrochloride 1- (4-aminobutyl) -3- [1, 6] naf t iridin-2-yl-urea somatic # 50 l- [(S) -a-methylbenzyl] -3- [1, 6] naphyridin-2-yl-urea somatic # 51 l- [(R) -a -met-ilbenzyl] -3- [1, ß] naf tiridin-2-yl-urea compound # 52 1- (2-methoxy-fyl) -3- [1, 6] naphyridin-2-yl-urea # 53 l-butyl-3- [1, 6] naphyridin-2-yl-urea compound # 54 1- (2-methoxybenzyl) -3- [1, 6] naphyridin-2-yl-urea compound # 55 1- (2-ethoxy-f-enyl) -3- [1,6] naphyridin-2-yl-urea compound # 56 1- (2-methyl-f-enyl) -3- [1, 6] naphyridin- 2-yl urea; Compound # 57 (2-isopropoxybenzylamine) of 8- (2-pyridyl) -1- [1, 6] naft iridin-2-carboxylic acid The following compounds were obtained commercially (Peakdale Fine Chemicals Limited, Glossop Derbyshire, UK): compound # 24 (1-6) naphthyridine-2-carboxylic acid (PFC-0-29) compound # 25 N- (2-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide (PFC-032) EXAMPLE 2 CMV Plate Reduction Assay The anti-CMV activity of the test compounds was evaluated in a plaque reduction assay as follows: In 12-well tissue culture plates, 1.5 x 105 or Hs68 cells (human fibroblast cell line) were seeded onto plates. lung) per well with 2 ml of DMEM with 10% fetal bovine serum and incubated in 5% C02 / air at 37 ° C overnight or until the cells were ready. The medium was then removed - and the cells were inoculated with 0.5 ml (containing 200 pfu / ml diluted in DMEM with 2% FBS) of HCMV virus in each well. After absorption at 37 ° C for 2 hours, the vipus was removed and the cell monolayers were flooded (1 ml) with 2% DMEM of FBS containing the test compounds at various concentrations.

The cells were then incubated at 37 ° C for 8 days, and then fixed with one volume (1 ml) of 8% formaldehyde / water or 1 x PBS for 30 minutes. The formaldehyde solution was removed and the cell monolayers were stained with 2% crystal violet / 20% EtOH for a few seconds and then rinsed with water. The monolayers were examined for the presence of plates under a microscope, the percentage reduction of plaque for each compound was determined by comparison with untreated cells (without test compound) and the 50% inhibitory concentration (IC50) was established. It was used in ganciclovir as a positive control.

Note: the DMEM medium contained 1% glutamine and 1% pen / strep.

EXAMPLE 3 Cytotoxicity assay The cytotoxicity of the test compounds was evaluated according to the following procedure: 96 well flat bottom plates were seeded with 5 x 103 Vero-34 cells / well and 1 x 104 f? S-68 or i-38 cells / well respectively, and were incubated overnight at 37 ° C and 5% C02 / air.

After incubation, the supernatant medium was removed and replaced with dilutions of the test compound in 2% DMEM (150 μl). The cells were then incubated for 48 hours in a 5% C02 incubator at 37 ° C. 50 μl / well of a 10 μCi / ml solution of tritiated methyltidine (specific activity of approximately 2 Ci / mmol) were added to the culture medium and incubated overnight (18 hours) in a 5% CO 2 incubator. 37 ° C The cells were then harvested on a glass fiber filter (Printed Filtermat A 1450-421 Wallac) with a Tomtec cell harvester. The suspended cells were harvested directly on the filter while for the adherent cells, the medium was first removed, then the cells were washed with PBS and "trypsinized for 2-3 minutes (50 μl trypsin / well) before harvesting." The filters were dried for 1 hour at 37-40 ° C and then dried. , go were placed in bags (1450-microbeta # 1450-432 Wallac) with 4.5 ml of Betascint and the beads obtained with Microbeta 1450 Wallac (protocol 1).

The percentage of cell proliferation was determined by comparison to the control (without test compound) and with this the 50% inhibitory concentration was established. It was found that the compounds according to the invention inhibited CMV according to the plaque reduction assay and were compared favorably to ganciclovir. The results are summarized in Table 1. The compounds were tested in tandem with ganciclovir which consistently showed an IC50 of > 0.1 < 0.5 μg / ml and a CC5o that ranged from ~ 10 to 200 μg / ml.

Table 1 Cl- C50 (μg / ml) (μg / ml) # 2 N-benzyl-2-50 (1, 6) naphthyridinecarboxamide; # 3 N- (-bromobenzyl.} -2-> 10 <5O-> 10 <0 [1, 6] naphthyridinecarboximide # 4 N- (2-chlorobenzyl-2 > 0.5 < 1 -100 (1.6) naphthyridinecarboxamide; # 5 N- (2-feromobenzyl) -2- 1 > 0.5 < 1-100 (1.6) naphthyridinecarboxamide; IC50 CC50 (μg / ml) (μg / ml) # 6 N- (3-bromobenzyl) -2- > 1 < 5-50 (1,6) naphthyridine-r-oxamide; # 7 N- (2-fluorobenzyl) - - < 5 ~ 10β and 2- (1, 6) naphthyridinecarboxamide; # 8 N- (4-chlorobenzyl) -2- > 1 < 10 > 6.25 < 1 [1, 6] naphthyridinecarboxamide; # 9 N- (2-ethyloxybenzyl- -0.1 ~ &.25 2- (1, 6) naphthyridinecarboxamide; C? 50 CC50 (μg / ml) (μg / ml) # 20 (3, 4-dihydro-lH-> 5 <25> 100 isoquinolin-2-yl) - [1, 6-naphthyridin-2-yl-methanone; # 2 1 N- (2-methylthiobenzyl) - > 1 < 10 -50 2- [1, 6] naf tiridincarboxamide; # 22 N- (2- <5> 25 <100 hydroxybenzyl) -2- (1, 6) naphthyridine carboxamide; # 23 N- (2- <5 > 100 methoxycarbonyl-benzyl-2- (1,6) naphthyridine carboxamide; CIso CC50 (μg / ml) (μg / ml) # 24 acid allylamide > 5 < 10 > 10 < 100 (1.6) naphyridin-2-carboxylic acid; # 25 N-. { 2- m-ethoxybenzyl) - > G.3 > 12-0 2- (1, 6) naphthyridone- < 1.5 < l-5-0 carboxamide; # 26 N- (2-> 0.005 -1.5 propoxybenzyl) -2- < 0.01 [1, ßlnaf tiridin-2-carboxamide; # 32 2 '-methoxybenzyl a > 0.1 > 50 of acid 7.8- < 1 < 100 dihydroisoquinoline-6-carboxylic acid; CI5o CC50 (μg / ml) (μg / ml) # 33 (2-N- <0.01> 6.25 ethylaminobenzyl ina) < 12.5 of 8-bromo- [1, 6] naphyridine-2-carboxylic acid; # 34 (2-> 0.1 -12.5 isopropoxybenzylamine <1-8-bromo-1,6-naphthyridine-2-carboxylic acid; # 35 -0.01 -12.5 methoxybenzylamine) of 8-bromo- [1, 6] naphyridine-2-carboxylic acid; It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (20)

1. Use of a compound of the formula (I) for the manufacture of a medicament for inhibiting the replication of the cytomegalovirus in a mammal by administering to itself an anti-cytomegalovirus amount of said compound: where; W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; B is selected from the group consisting of: where; A is Oxygen or Sulfur; R; is selected from: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of 3 to 10 unsaturated carbon atoms, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy from 1 to 4 carbon atoms; and cycloalkyl of 3 to 7 carbon atoms fused to the aryl of 6 to 10 carbon atoms optionally substituted with OH, halogen, amine, mercapto, carboxyl, - (alkyl, alkoxy, alkylthio, acyl, acyloxy or "alkoxycarbonyl) of 1 to 4 carbon atoms optionally substituted by OH, halogen, amino or alkoxy of 1 to 4 carbon atoms: R2 and R'2 are independently hydrogen, 1 to 4 carbon atoms or Ri and R2 together form a saturated or unsaturated heterocycle of 5 or 6 members optionally fused to the aryl of 6 to 10 carbon atoms or to the heteroaryl; P-3 and R4 are independently selected from hydrogen, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) from 1 to 6 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms, and (carbocycle or heterocycle) of 3 to 10 carbon atoms saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, alkylthio of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with halo, or C 1 -C 4 -alkoxy substituted with halo, C 1-4 -alkyl, C 1-4 -alkoxy, or carboxyl; R5 is hydrogen, alkyl of 1 to 6"carbon atoms or acyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 - to 4 carbon atoms; and n is 0, 1 or 2.

2. The use according to claim 1, characterized in that W is N or NR5.

3. The use according to claim 1, characterized in that Y is N or NR5 and X and Y are independently selected from CH, CR4 CH :, C = 0 and CHR.,.

4. The use according to claim 1, characterized in that Rx is benzyl optionally substituted with one or two substituents selected from hydroxyl, amino, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with halo »

5. The use according to claim 1, characterized in that R2 and R'2 is hydrogen.

6. The use according to any of claims 1 to 4, characterized in that R is hydrogen.

7. The use according to any of claims 1 to 4, characterized in that R4 is hydrogen.

8. An anti-cytomegalovirus composition, characterized in that it comprises a pharmaceutically acceptable carrier, diluent or adjuvant, and a compound of the formula (I) or a pharmaceutically acceptable salt thereof: W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; B is selected from the group consisting of: where; A is Oxygen or Sulfur; Ri is selected from: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of 3 at 10 unsaturated carbon atoms, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and cycloalkyl of 3 to 7 carbon atoms fused to the aryl of 6 to 10 carbon atoms optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 atoms carbon optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; R'2 are independently hydrogen, alkyl of 1 to 4 carbon atoms or Ri and R2 together form a saturated or unsaturated heterocycle of 5 or 6 members optionally fused to the aryl of 6 to 10 carbon atoms or to the heteroaryl; R3 and R are independently selected from hydrogen, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of 1 to 6 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms, and (carbocycle or heterocycle) of 3 to 10 carbon atoms saturated or unsaturated, optionally substituted by OH, halogen, amino, mercapto, alkylthio of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with halo, or alkoxy of 1 to 4 carbon atoms substituted with halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or carboxyl; R5 is hydrogen, alkyl of 1 to 6 carbon atoms or acyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and n is 0, 1 or 2.

9. A composition according to claim 8, characterized in that W is N or NR5.

10. A composition according to claim 8, characterized in that Y is N or NR5 and X and Z are independently selected from CH, CR4, CH2, C = 0 and CHR4.

11. A composition according to claim 8, characterized in that Rx is benzyl optionally substituted with one or two substituents selected from hydroxyl, amino, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, and alkyl of 1 to 4 carbon atoms substituted with halo.

12. A composition according to claim 8, characterized in that R2 and R '2 is hydrogen.

13. A composition according to any of claims 8 to 12, characterized in that R3 is hydrogen.

14. A composition according to any of claims 8 to 13, characterized in that R4 is hydrogen.

15. A compound of the formula (I) and the pharmaceutically acceptable salts thereof: characterized in that W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y and Z is Nitrogen or NR5 while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; B is selected from the group consisting of: where; A is Oxygen or Sulfur; Ri is selected from: alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, optionally substituted with hydroxyl, halogen, amino, carboxyl or (carbocycle or heterocycle) of 3 to 10 atoms -j --- l-a --- sab-ca- ------ abra-b, optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of "1 to 4 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms, and cycloalkyl of 3 to 7 carbon atoms. carbon fused to the aryl of 6 to 10 carbon atoms optionally substituted with OH, halogen, amino, mercapto, carboxyl, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of 1 to 4 carbon atoms optionally substituted with OH, halogen , amino or alkoxy of 1 to 4 carbon atoms, R2 and R'2 are independently hydrogen, alkyl, 1 to 4 carbon atoms or Ri and R2 together form a saturated or unsaturated heterocycle of 5 or 6 members optionally fused to the aryl of 6 to 10 carbon atoms or to the heteroaryl; R and R4 are independently selected from hydrogen, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of 1 to 6 carbon atoms, optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms, and (carbocycle or heterocycle) of 3 to 10 carbon atoms, saturated or unsaturated, optionally substituted by OH, halogen, amino, mercapto, alkylamide of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms. carbon, alkyl of 1 to 4 carbon atoms substituted with halo, or alkoxy of 1 to 4 carbon atoms substituted with halo, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or carboxyl; R5 is hydrogen, alkyl of 1 to 6 carbon atoms or acyl of 1 to 6 carbon atoms optionally substituted with OH, halogen, amino or alkoxy of 1 to 4 carbon atoms; and n is 0, 1 or 2 where; i) when A is •; and when W and Y are both N or NR5, then Ri is different from allyl or 2-methoxybenzyl; ? , li) when A is either when X or Z is N or NR5, then W is N or NR5; Y , N: iii) when A is O (II) when Z is N or NR5, then R. is different from methyl

16. A compound according to claim 15, characterized in that W is N or NR5.

17. A compound according to claim 15, characterized in that Y is N or NR5 and X and Z are independently selected from CH, CR4, Cff2, C = 0 and CHR.

18. A compound according to claim 15, characterized in that Ri is benzyl, optionally substituted with one or two substituents selected from hydroxyl, amino, halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxycarbonyl of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 carbon atoms substituted with halo.

19. A compound according to claim 15, characterized in that R2, R'2, R3 and R are each hydrogen.

20. A compound according to claim 15, characterized in that it has cytomegalovirus inhibitory activity.