MXPA00005750A - Antiviral compounds - Google Patents

Abstract

The present invention relates to heterocyclic Compounds having antiviral activity. In particular, Compounds of formula (I), wherein B, W, X, Y, Q, R1, R2, R3, R4 and n are as defined herein, are useful in the therapy and prophylaxis of viral infection in mammals.

Description

ANTIVIRAL COMPOUNDS FIELD OF THE INVENTION The present invention relates to heterocyclic compounds, and more particularly to naphthyridine compounds and their use in therapy and prophylaxis against viral infections.

BACKGROUND OF THE INVENTION Of the DNA viruses, the herpes group is the source of the most common viral diseases in man. The group consists of herpes simplex virus (HSV) type I and II, varicella zoster (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). As with other herpes viruses, infection with CMV leads to an association of the host virus throughout life. After a primary infection, the virus can spread for many years. Infection in otherwise healthy individuals is often asymptomatic, with 80% of the adult population harboring the virus in a latent form. In immunocompromised individuals, such as chemotherapy patients, organ transplant patients and in particular those suffering from AIDS, latent CMV can REF.120788 reactivate resulting in microcephaly, hepatosplenomegaly, hictheritis, convulsive attacks which can cause mental retardation, mononucleosis, retinitis and even death. In patients with AIDS, CMV is a predominant cause of morbidity. Several 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 well as the nucleoside analogs cytosine-arabinoside, adenine-arabinoside, iodoxyuridine and acyclovir, which is currently the treatment of choice for infection by herpes eimplex type I. Unfortunately, medications such as acyclovir that have been shown to be effective in treating certain herpesvirus infections are not effective enough to treat CMV. In addition, drugs currently used to treat CMV infection, such as ganciclovir (9- [(1,3-dihydroxy-2-propoxy) methyl] guanine) and foscarnet (phosphonoformic acid), lack acceptable side effects and profiles of their Safety of approved medications for the treatment of other herpesviruses. In the case of treatment for AIDS, the combination of HIV therapy is now the standard for care of people with HIV. There are now 11 anti-HIV drugs available by prescription. These anti-HIV drugs fall into three categories: nucleoside analogs, which include AZT, ddl, ddC, d4T and 3TCMR; protease inhibitors which include indinavir, nelfinavir, saquinavir and ritonavir and non-nucleoside reverse transcriptase inhibitors (NN TI), which include nevirapine and delavirdine. In comparison with HIV, there is currently only one authorized therapy for chronic hepatitis B virus infection, which is interferon. Other drugs that are currently under clinical trials include lamivudine, famciclovir, lobucavir and adefovir. But many studies have shown that most patients relapse after completing therapy and develop resistance to medications. The development of resistance has recently become a major concern in the treatment of HIV and HBV infections. Resistance usually occurs when the medications that are used are not powerful enough to complete stopping the replication of the virus. If the virus can be completely reproduced in the presence of drugs, it is likely to make changes in its structure, called mutations, until it finds one allows it to reproduce despite the medications. Once the mutation occurs, then It grows out of control and quickly becomes the dominant strain of the virus in the individual. The drug progressively becomes weaker against the new strain. There is also a growing concern about cross-resistance. Cross resistance occurs when mutations that cause drug resistance also cause resistance to another. Several studies have shown that, combining two medications, delays the development of resistance to one or both medications, compared to if they had been used alone. Other studies suggest combinations of three medications which extends this benefit even more. As a result, many people believe that multiple drug combination therapies are the best way to prevent, or at least delay, resistance. The only treatment currently available for HCV infection is interferon a (IFN-a). However, according to different clinical studies, only 70% of treated patients normalize their levels of alanine aminotransferase (ALT) in serum and after the suspension of IFN, 35% to 45% of responders relapse. In general, only 20% to 25% of patients are those who have long-term responses to IFN. However, pilot studies have suggested that combination therapy with IFN plus ribavirin (RIBA) results in a sustained response in most patients. Different HCV genotyrespond in a different way Unlike IFN therapy, the lb genotype is the most resistant to IFN therapy compared to type 2 73. Therefore, there remains a need for effective non-nucleoside therapeutic and prophylactic agents to treat viral infection. Accordingly, an object of the present invention is to provide a method for inhibiting viral replication in a mammal. It is also an object of the present invention to provide compounds and pharmaceutical compositions useful for inhibiting viral replication in a mammal.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a method for inhibiting viral replication other than cytomegalovirus (CMV) in a mammal, which comprises administering to the mammal an antiviral amount of a compound of formula (I): wherein W is selected from CH, CR3, CH2, C = 0, CHR3, N and NRS; one of X, Y, and Z is N or NRS, while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is selected from CH, CR3, CH2, C = 0, CHR3, N, NR5, OO S; B is selected from the group consisting of: (II) (III) (IV) where A is O, N or S; j. is selected from: C ^ alkyl, C2_6 alkenyl or C3.7 cycloalkyl optionally substituted with OH, halogen, amino, carboxyl, or C3.10 saturated or unsaturated (carbocycle or heterocycle) optionally substituted with OH, halogen, amino, mercapto, carboxy (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of C ^ .4 optionally substituted with OH, halogen, amino or Cx.4 alkoxy; C3.7 cycloalkyl fused to C6.X0 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of C ^ optionally substituted with OH, halogen, amino or Alkoxy of G, _47 R2 and R'2 are independently selected from H or C ^ alkyl, or Rx and R2, together, form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to C6_10 aryl or heteroaryl; and (C10.10 carbocycle or heterocycle), saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of C ^ optionally substituted with OH, halogen , amino or alkoxy of ^; R3 and R4 are independently selected from H, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of CX.6 I C2.6 alkenyl optionally substituted with OH, halogen, amino, or alkoxy of C ^ ,,, and (carbocycle or heterocycle) of saturated or unsaturated C3.10 substituted with OH, halogen, amino, mercapto, alkylthio of C1? alkoxycarbonyl of C1.t, C, 4 alkyl substituted with halo or Cx.4 alkoxy substituted with halo, C1.4 alkyl, Cx.4 alkoxy or carboxy; Rs is H, C ^ alkyl, or C? S acyl optionally substituted with OH, halogen, amino or C ^, alkoxy; and n is 0, 1 or 2. In a further aspect of the invention, viral inhibitory compounds (including CMV) and pharmaceutically acceptable salts thereof are provided, according to formula (I) wherein Q is selected from S , 0, N and NR5.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, the present invention provides a method for inhibiting viral replication in a mammal, comprising administering to the mammal a replication inhibiting amount of a compound of formula (I): (I) where W, X, Y, Q, Z, B, Rx to R4 and n are as defined herein. In a further aspect of the invention, viral replication inhibitory compounds and pharmaceutically acceptable salts thereof are provided, according to formula (V) .- (V) where in B, W, R3 and R4 are as defined here. In a further aspect of the invention, viral replication inhibiting compounds and pharmaceutically acceptable salts thereof are provided, according to formula (VI) .- (SAW) (VII) where A,, R1 # R2, R3 and R4 are as defined here. In a further aspect of the invention, viral inhibitory compounds and pharmaceutically acceptable salts thereof are provided, according to formula (VIII): (VIII) where A, R¡_ and R2 are as defined below. 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 straight or branched carbon chain but incorporating unsaturated carbon atoms. However, for convenience, the terms "alkoxy," "alkylthio," "acyl," "acyloxy," and "alkoxycarbonyl" refer to chains that are saturated or unsaturated and which may also be linear or branched. The chains mentioned above may have several substituents It is understood that there may be one or more substituents, unless otherwise specified The term "carbocycle" refers to a cyclic carbon chain or a ring which is saturated or unsaturated .

A "heterocycle" is a ring that incorporates heteroatoms that are selected from N, O and S, instead of carbon. The carbocycles and unsaturated heterocycles can be aromatic, i.e., aryl such as phenyl or naphthyl, or heteroaryl such as pyridine or quinoline. When indicated, any of the rings mentioned above may have several substitutions. It is understood that there may be one or more substituents, unless otherwise specified. The term "aryl" is a saturated carbocycle ring or rings of 6 to 16 carbon atoms. A "heteroaryl" is a carbocyclic unsaturated ring or rings of 6 to 16 carbon atoms that incorporate at least one heteroatom selected from N, O and S instead of carbon. The term "amino" includes primary amines, ie, NH 2, secondary amines, ie, NHR or tertiary amines, ie N (R) 2, wherein R is C 1, alkyl.

They are also encompassed by the term quaternary amines such as NH3 +. In the methods of the present invention, viral replication is inhibited by administering compounds of formula (I), (V), (VI), (VII) and (VIII) as shown above, wherein: W is selected from CH , CR3, CH2, C = 0, CHR3, N and NR5; Y one of X, Y and Z is N or NRS while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4. It will be appreciated that the heterobicyclic compounds of the invention may be saturated, unsaturated or partially unsaturated and that W, X and Z will have the appropriate valence for each condition. For example, when the rings are unsaturated, it can be N, CH or CR3. Conversely, 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 NRS; In a preferred embodiment, X is N or NRS, while Y and Z are independently CH, CR4, CH2, C = 0 or CHR4. In a preferred embodiment, Y is N or NRS, while X and Z are independently CH, .CR4, CH2, C = 0 or CHR4. In a preferred embodiment Z is N or NR5, while X and Y are independently CH, CR4, CH2, C = 0 or CHR4. In a preferred embodiment Q is CH, CHRS. In a preferred embodiment Q is S, 0, N or NRS. In a preferred embodiment, the heterobicyclic ring incorporating a, X, Y and Z is unsaturated. In a particularly preferred embodiment, and Y are independently N or NRS while X and Z are independently CH, CR4, CH2, C = 0 or CHR4.

In a particularly preferred embodiment, W and Y are both N while X and Z are CH or CR4 and the heterobicyclic ring is unsaturated. In a more preferred embodiment, and Y are both N while X and Z are CH or CR4, the heterobicyclic ring is unsaturated and n is 1, thus forming a 1,6-naphthyridine ring. In a particularly preferred embodiment, Y is N or NRS, is CH or CR4, while X and Z are independently CH, CR4, CH2, C = 0 or CHR4. In a particularly preferred embodiment, Y is N, and W is CH or CHR4, while X and Z are CH or CR4 and the heterobicyclic ring is unsaturated. In a more preferred embodiment, Y is N, W is CH2 while X and Z are CH or CR4, the left heterocyclic ring containing X, Y and Z is unsaturated, Q is CH2 and n is 1, so they form a Dihydroisoquinoline ring. In another more preferred embodiment, W and Y are both N or NR5, while X and Z are CH or CR4, the left heterocyclic ring containing X, Y and Z is unsaturated, Q is S and n is 0, so that forms a thiazolo [5, 4-c] pyridine ring. In a preferred embodiment, A is O.R is selected from: C2_6 alkenyl C2.6 alkenyl or C3.7 cycloalkyl optionally substituted with OH, halogen, amino, carboxyl or (saturated cyclic or heterocycle) of C3.10 saturated or unsaturated optionally substituted by OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) ^ optionally substituted with OH, halogen, amino, or C ^ alkoxy; C3.7 cycloalkyl fused with C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of C1? optionally substituted with OH, halogen, amino, or alkoxy of G, _4; and (C3. X0 carbocycle or heterocycle), saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of ^ optionally substituted with OH, halogen, amino or C ^ alkoxy; In a preferred embodiment, Rx is C2.6 alkenyl; Cx.6 alkyl or C3.7 cycloalkyl substituted with a 6-membered aryl or heteroaryl, or a cycloalkyl ring optionally substituted with halogen, hydroxy, Cx.sub.4 alkyl, C.sub.4 alkoxy, C 3-4 alkylthio, C ^ alkoxycarbonyl, C ^ alkyl substituted with halo or C1-alkoxy? replaced with halo; and C3.7 cycloalkyl fused to an aryl or 6-membered heteroaryl ring optionally substituted with halogen, hydroxy, C4_4 alkyl / C4 alkoxy, alkylthio Cx_4, Cx_4 alkoxycarbonyl or Cx_4 alkyl substituted with halo. In an alternative embodiment, Rx is an unsubstituted C3.10 (carbocycle or heterocycle) optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted with OH , halogen, amino or alkoxy In a particularly preferred embodiment, Rx is benzyl, pyridinylmethyl or cyclohexylmethyl optionally substituted with one or two substituents that are selected from hydroxy; amino, in particular NH2 or NH3 +; Cx_4 alkyl, in particular methyl; halogen, in particular fluoro, chloro or bromo; Cx.4 alkoxy, in particular methoxy or ethoxy; Cx_4 alkoxycarbonyl, in particular methoxycarbonyl; alkylthio of Cx_4, in particular methylthio; Cx_4 alkyl substituted with halo, in particular, trifluoromethyl. More preferably, R x is optionally mono or disubstituted benzyl at the 2, 3, 5 or 6 positions of the ring and more preferably at the 2 and / or 6 positions, with methyl, methoxy, ethoxy, hydroxy, fluoro, bromine, chlorine, methoxycarbonyl, methylthio, trifluoromethyl, trifluoromethoxy, NH2 or NH3 + C1. "In a further preferred embodiment, Rx is benzyl optionally substituted at the 2-position with fluoro, chloro, bromo, methyl, methoxy, ethoxy, methoxycarbonyl, trifluoromethyl or NH3 + C1. "In another particularly preferred embodiment, Rx is C3.7 cycloalkyl substituted with phenyl which is optionally substituted with one or two substituents which are selected of hydroxyl, amino, Cx.sub.4 alkyl, halogen, Cx.sub.4 alkoxy, Cx.sub.4 alkoxycarbon, Cx.sub.4 alkylthio or C.sub.4.sub.4 alkyl substituted with halo .. More preferably, C3.7 cycloalkyl is cyclopropyl In another particularly preferred embodiment, Rx is C3.7 cycloalkyl fused to phenyl which is optionally substituted with one or two substituents which are selected from hydroxy, amino, Cx_4 alkyl, halogen, Cx.4 alkoxy, Cx_4 alkoxycarbonyl. , CX_4 alkylthio or Cx_4 alkyl substituted with halo, More preferably, the cycloalkyl of C3.7 is cyclopentyl or cyclohexyl, R2 and R'2 are independently H, Cx_4 alkyl, or R? and Ra together form a heter 5 or 6 membered saturated or unsaturated optionally fused to aryl or heteroaryl -6-10 'In a preferred embodiment, R2 is H or methyl and more preferably H. R'2 is H or methyl and more preferably H. In another preferred embodiment, R2 together with Rx form a heterocycle of 5 or 6 saturated or unsaturated member optionally fused to aryl or heteroaryl of C6.x0. The Suitable 5 or 6 membered heterocycles include piperidine, piperazine, morpholine, pyrrole, pyrazole and imidazole. These may be fused to an aryl or heteroaryl of C6.x0 to provide suitable bicyclic rings such as indole, purine, benzimidazole, quinoline or isoquinoline. Preferably, R * are independently selected from H, OH, halogen, amino, cyano, (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl) of Cx_6, optionally substituted by OH, halogen, amino or Cx_4 alkoxy, and (carbocycle or heterocycle) ) of saturated or unsaturated C3.X0, optionally substituted with OH, halogen, amino, mercapto, Cx_4 alkylthio, Cx_4 alkoxycarbonyl, Cx.4 alkyl substituted with halo or Cx.4 alkoxy substituted with halo, Cx alkyl. 4, Cx.4 alkoxy or carboxy; R3 and R4 are independently selected from H, OH, halogen, amino, cyano and (alkyl, alkoxy, acyl, acyloxy and alkoxycarbonyl) of Cx_6, C2.6 alkenyl optionally substituted with OH, halogen, amino or Cx4 alkoxy . It is appreciated that the ring incorporating X, Y and Z may be substituted with 1 to 4 substituents R4, while the ring incorporating a may be substituted with 1 to 3 substituents R3. Preferably R3 and R4 are independently selected from H, OH, halogen, amino, cyano and (alkyl, alkoxy, acyl, acyloxy and alkoxycarbonyl) of Cx_6 optionally substituted with OH, halogen, amino or Cx_4 alkoxy.

R3 and R4 are independently (carbocycle or heterocycle) of saturated or unsaturated C3.x0 optionally substituted with OH, halogen, amino, mercapto, Cx.4 alkyl, Cx_4 alkoxy or carboxy; In an alternative embodiment, R4 are independently aryl or heteroaryl or a 6-membered cycloalkyl ring optionally substituted with halogen, hydroxy, Cx_4alkyl and Cx_4alkoxy. In an alternative embodiment, R 4 is an aryl or heteroaryl or a 6-membered cycloalkyl ring optionally substituted with halogen, hydroxy, C x 4 alkyl, C x 4 alkoxy. In a further embodiment, R 4 is a 6-membered heteroaryl. In a further embodiment, R 4 is pyridyl. In a preferred embodiment, there is a substituent R3 which is selected from H; OH; halogen, in particular fluoro or chloro; and Cx.4 alkoxy, in particular methoxy or ethoxy. More preferably, R3 is H, chloro, hydroxy or methoxy, and most preferably H. In a preferred embodiment, R4 is selected from H, halogen, amino, OH, (alkyl, alkoxy, acyl, acyloxy and alkoxycarbonyl) of Cx_6 optionally substituted with OH, halogen or amino. Preferably, one or two R4 substituents exist, and most preferably there is a R4 substituent thereof. In a more preferred embodiment, R 4 is amino.

In a more preferred embodiment, R 4 is aminoalkyl of 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, R4 is vinyl. In a more preferred embodiment, R4 is H. Rs is H, Cx_6 alkyl or acyl optionally substituted with OH, halogen, amino or Cx.4 alkoxy. In a preferred embodiment Rs is H. In a preferred embodiment, Rs is Cx_4 alkyl, and more preferably methyl. In a preferred embodiment, R5 is Cx.4 alkyl substituted with amino, and more preferably methyl or ethyl substituted with NH2. In a preferred embodiment, Rs is acyl of Cx.4, and more preferably ethanoyl. In a preferred embodiment, Rs is acyl of Cx.4 substituted with amino, and more preferably ethanoyl substituted with NH2. Preferred compounds of the invention include those in Table 1.

Table 1 # 5 N- (2-bromobenzyl) -2- (1,6) naphthyridinecarboxamide # 6 N- (3-bromobenzyl) -2- (1, 6) aftiridin- carboxamide # 7 N- (2-fluorobenzyl) -2- (1,6) naphthyridinecarboxamide # 8 N- (4-chlorobenzyl) -2 - (1,6) naphthyridin- carboxamide # 9 N- (2-ethyloxybenzyl) -2- (1,6) naphthyridinecarboxamide # 12 N- (3-methoxybenzyl) -2 - (1,6) naphthyridin- carboxamide # 13 N- (2-trifluoromethyl-benzyl) -2- (1,6) naphthyridin- carboxamide # 14 N- (2,6-dimethoxybenzyl) -2- (1,6) naphthyridinecarboxamide # 15 ([1, 6] naf iridin-2-carboxylic acid trans-2-phenyl-cyclopropyl) -amide # 16 N- (2-fluoro-5-aminobenzyl) -2 - (1, 6) naf iridin- carboxamide # 17 (1-6) naphthyridinecarboxylic acid (l-phenylethyl) -amide # 18 (1, 6) naphthyridin-2- (pyridin-2-ylmethyl) -amide carboxylic # 19 [1, 6] naphthyridinecarboxylic acid cyclohexylmethyl-amide # 20 (3, 4-dihydro-lH-isoquinolin-2-yl) - [1,6] naphthyridin-2-yl- methanone # 21 N- (2-methylthiobenzyl) -2 - (1,6) naphthyridinecarboxamide # 22 N- (2-Hydroxybenzyl) -2- (1,6) naphthyridinecarboxamide # 23 N- (2-methoxycarbonylbenzyl) -2- (1,6) naphthyridine- carboxamide # 24 allylamide of (1, 6) naphthyridine-2-carboxylic acid # 25 N- (2-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide # 26 N- (2-propoxybenzyl) -2- [1, 6] naf iridin-2-carboxamide # 32 2'-methoxybenzylamide of acid 7.8- dhydroisoquinoline-6-carboxylic acid # 61 (thiazolo [5,4- c] pyridine-2-carboxylic acid (1) (phenyl) -phenylethyl) -amide # 62 (thiazolo [5,4- c] pyridine-2-carboxylic acid (1) (phenylethyl) -amide) # 63 2-isopropoxybenzylamine of 8- (vinyl) - [1, 6] naftiridin-2- carboxylic # 64 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid # 65 2-sec-butoxy-benzylamide of (S) - (+) - 8-bromo- [1, 6] naftiridin-2- carboxylic 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 - m e t or x i b e n c i l) - 2 - (1, 6) naphyridinecarboxamide; compound # 14 N - (2, 6-d i m e t o x i b e n c i l) - 2 - (1, 6) naphyridinecarboxamide; Compound # 19 [1, 6] naphthyridine-2-carboxylic acid cyclohexylmethylamide; compound # 24 allylamide of (1, 6) naphthyridine-2-carboxylic acid (PFC-029); compound # 25 N - (2 - m e t o x i b e n c i l) - 2 - (1,6) naphthyridinecarboxamide; Compound # 26 N- (2 -propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; Compound # 28 ([1,6] naphthyridine-2-carboxylic acid 2, 3, 4, 5-tetrahydrobenzo [B] oxepin-5-yl) -amide, - compound # 31 2, 3- (methylenedioxy) -benzylamide of [l, 6] naphthyridine-2-carboxylic acid, - # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinolin-6-carboxylic acid; Compound # 33 (2-N-ethylaminobenzylamine) of 8-bromo- [1,6] naphyridin-2-carboxylic acid; Compound # 35 (2-methoxybenzylamine) of 8-bromo- [1,6] naphyridine-2-carboxylic acid; # 36 (2-isopropoxybenzylamine) compound of 8-bromo- [1,6] naphyridine-2-carboxylic acid; compound # 40 2 - i sopropoxybenzyl 1 [1, 6] naphyridin-2-thiocarboxylic acid amine; Compound # 43 2-methoxy-benzylamide of [1, 6] naphyridin-2-thiocarboxylic acid; compound # 46 1- (2-iso-propoxy-phenyl) -3- [1,6] naphthyridin-2-ylurea; compound # 47 1- (2-iso -propoxybenzyl) -3- [1,6] naphthyridin-2-ylurea; compound # 51 1- [(R) -a-methylbenzyl] -3- [1,6] naphthyridin-2-ylurea; compound # 59 2-methoxybenzylamide of thiazolo [5,4- c] pyridine-2-carboxylic acid; # 60 compound 2-isopropoxybenzylamide of thiazolo [5,4- c] pyridine-2-carboxylic acid; Thiazolo [5,4-c] pyridine-2-carboxylic acid compound # 61 (1 (R) -phenylethyl) -amide, thiazolo [5- (1-S) -phenylethyl) -amide [5,4- c] ] pyridine-2-carboxylic acid; compound # 63 2-isopropoxybenzylamine of 8- (vinyl) - [1,6] naphthyridine-2-carboxylic acid; compound # 64 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; compound # 65 2-sec-butoxy-benzylamide of (S) - (+) - 8-bromo- [1,6] naphthyridine-2-carboxylic acid; 8-bromo- [1,6] naphidin-2-carboxylic acid compound # 66 (1-phenylethyl) -amide; compound # 67 phenethylamide of 7,8-dihydro-isoquinoline-6-carboxylic acid; compound # 68 [7 - (l, l-indol-3-yl) ethyl] 2- (l-indol-3-yl) ethyl-amide of 7,8-dihydro-isoquinoline-6-carboxylic acid compound # 69 [2- (li-indol-3-yl) -ethyl] - [1, 6] naphthyridine-2-carboxylic acid amide The most preferred compounds of this invention include: compound # 26 N- (2-propoxybenzyl) r 2 - [1,6] naphthyridine-2-carboxamide; # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; Compound # 33 (2-N-ethylaminobenzylamine) of 8-bromo- [1,6] naphthyridine-2-carboxylic acid; # 36 (2-methoxybenzylamine) compound of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid; Compound # 40 2 - [1, 6] naphthyridin-2-thiocarboxylic acid isopropoxybenzylamine; Compound # 43 2-methoxy-benzylamide of [1, 6] naphyridin-2-thiocarboxylic acid; compound # 46 1- (2-iso-propoxy-phenyl) -3- [1,6] naphthyridin-2-ylurea; compound # 47 1- (2-iso-propoxybenzyl) -3- [1,6] naphyridin-2-ylurea; compound # 51 l- [(R) -a-methylbenzyl] -3- [1, 6] naphthyridin-2-ylurea; compound # 59 2-methoxybenzylamide of thiazolo [5,4- c] pyridine-2-carboxylic acid; # 60 compound 2-isopropoxybenzylamide of thiazolo [5,4- c] pyridine-2-carboxylic acid; Thiazolo [5,4- c] pyridine-2-carboxylic acid compound # 61 (1 (R) -phenylethyl) -amide; Thiazolo [5,4-c] pyridin-2-carboxylic acid compound (62 (1) S-phenylethyl) -amide; compound # 63 2-isopropoxybenzylamine of 8- (vinyl) - [1,6] naphthyridin-2-carboxylic acid; compound # 64 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; compound # 65 2-sec-butoxy-benzylamide of (S) - (+) - 8-bromo- [1,6] naphthyridine-2-carboxylic acid; 8-bromo- [1, 6] naphthyridin-2-carboxylic acid compound # 66 (1-phenylethyl) -amide; compound # 67 phenethylamide of 7,8-dihydro-isoquinoline-6-carboxylic acid; # 68 [2- (lH-indol-3-yl) ethyl-amide of 7,8-dihydro-isoquinoline-6-carboxylic acid; Compound # 69 [1-6] naphidin-2-carboxylic acid [2- (lJ? -indol-3-yl) -ethyl] -amide] In a further preferred embodiment, the compounds of this invention include: Compound # 26 N- (2 -propoxybenzyl) -2- [1,6] naphtyridin-2-carboxamide; Compound # 32 2'-methoxybenzylamide of 7,8-dihydroisoquinoline-6-carboxylic acid; compound # 46 1- (2-iso-propoxy-phenyl) -3- [1,6] naphthyridin-2-ylurea; compound # 59 2-thiazolo [5,4- c] pyridin-2-carboxylic acid methoxybenzylamide; # 60 compound 2-isopropoxybenzylamide of thiazolo [5,4- c] pyridin-2-carboxylic acid; Thiazolo [5,4-c] pyridin-2-carboxylic acid compound # 61 (1 (R) -phenylethyl) -amide; Thiazolo [5,4- c] pyridin-2-carboxylic acid compound (62 (1) S-phenylethyl) -amide; compound # 63 2-isopropoxybenzylamine of 8- (vinyl) - [1,6] naphthyridine-2-carboxylic acid; compound # 64 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; 8-bromo- [1, 6] naphthyridine-2-carboxylic acid compound # 66 (1-phenylethyl) -amide; compound # 67 phenethylamide of 7,8-dihydro-isoquinoline-6-carboxylic acid; compound # 68 [7 - (lH-indol-3-yl) ethyl-amide of 7,8-dihydro-isoquinoline-6-carboxylic acid, - 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 synthesis route for producing the compounds of formula (VI) wherein A is 0, involves coupling a carboxylic acid intermediate of formula a. with an amino intermediate of formula b_ of scheme 1. The reaction will be carried out under conditions suitable for the formation of the amide bond, ie, in the presence of a suitable coupling agent such as EDC or dCC, for provide a final compound of formula (VI). The reaction is illustrated in scheme 1. Compounds of formula (VI) with A as O can be converted to compounds of formula (VI) with A as S by reacting with thionation agents such as Lawesson's reagent. The use of Lawesson's reagent is well known in the art (for example, see Synthesis, 941 (1979); Tetrahedron, 35, 2433 (1979); and Tet. Lett., 21, 4061 (1980). A preferred synthetic route to produce bicyclic compounds of formula (VII) involves coupling a bicyclic amino intermediate of formula c_ with the amido moiety d_. This reaction is illustrated by scheme 2. The reaction will be under a suitable condition for the formation of the "urea" bond in a suitable solvent to provide the compounds of formula (VII). The introduction of a substituent R2 into the nitrogen can be carried out using methods known in the art. The urea binding of compounds (VII) can also be converted to a thiourea by reacting the compounds with thionation agents as mentioned above.

Scheme 1 to 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] naphthyridine (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-tetrahydro-8-hydroxy- [1,6] naphthyridine-2-carboxylic acid (Abe et al Tet. Lett., 1977, 9: 735). Or, alternatively, intermediaries a., Faith and c can be prepared according to the established synthesis techniques.

Scheme 2 Compounds according to formula (VIII) thiazolo [5, 4-c] pyridines can be synthesized using established organic chemistry techniques. For example, a Synthesis scheme is described in Katner et al (1990) J. Heterocycl. Chem. 27 (3): 563. It will be appreciated that certain substituents require protection during the course of subsequent synthesis and deprotection. For example, when R3 or R4 is hydroxyl, it may be necessary to protect it by conversion to an alkoxy or ester, and subsequently to deprotect it. Protective groups for other substituents are described in Protective Groups in Orcranic Synthesis. 2nd ed., Greene and Wuts, John Wiley & Sons, New York, 1991. It will be appreciated by those skilled in the art that the compounds of formula I, depending on the substituents, may contain one or more chiral centers and therefore may exist in the form of many different isomers, optical isomers. (ie, enantiomers) and mixtures thereof including racemic mixtures. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention. In accordance with the methods of the present invention, the compounds of formula (I) are administered to a mammal to inhibit replication or to reduce the cytopathic effects of the viruses. In particular, the HIV virus, which is known to be the causative agent of the acquired immunodeficiency syndrome (AIDS). Other viruses inhibited with compounds of formula (I) include, but are not limited to, HSV-1 (herpes simplex virus) type 1), HSV-2 (herpes simplex virus type 2), HBV (hepatitis B virus), HCV (hepatitis C virus), HPV (human papilloma virus), influenza A, influenza B, RSV ( respiratory syncytial virus), RV (rhinovirus), AV (adenovirus), parainfluenza virus and cytomegalovirus (CMV). In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of the HIV virus. In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of hepatitis B virus. In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit the replication or reduce the cytopathic effects of the hepatitis C virus. In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of HSV-1 (herpes virus). simplex type 1) or HSV-2 (herpes simplex virus type 2) . In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of influenza A.

In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit the replication or reduce the cytopathic effects of influenza B. In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of RSV (respiratory syncytial virus). In a preferred embodiment, the compounds of formula (I) 'are administered to a mammal to inhibit replication or reduce the cytopathic effects of RV (rhinovirus). In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of AV (adenovirus). In a preferred embodiment, the compounds of formula (I) are administered to a mammal to inhibit replication or reduce the cytopathic effects of parainfluenza virus. In addition, the compounds of formula (I) interact with the transduction pathway of the nuclear factor K B (NFKB) signal. Accordingly, the compounds of formula (I) can be used to treat conditions mediated by tumor necrosis factor (TNFa) or other cytosines under transcriptional control of NFKB. Conditions include diseases acute and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, Krohn's disease, colitis and septic shock. Additionally, the effective dose of the compounds of formula (I) and the pharmaceutically acceptable salts, capable of inhibiting viral replication, can be used in combination with a second antiviral agent that is selected from the group consisting of Lamivudine, hydroxymethyl-4- (cytosin-1 '-il) -1, 3-oxathiolane, FTC, AZT, d4T, nevirapine, DMP-2266, nelfinavir, indinavir, delavirdine, 9 - [(2-hydroxymethyl) -1, 3-dioxolan-4- il] guanine, 2-amino-9 - [(2-hydroxymethyl) -1, 3-dioxolan-4-ylkadenine, MKC-442, 1592U89 (abacavir), 141W94, MK-639, Indinavir, saquinavir, ritonavir, TIBO, HEPT, BHAP,, α-APA-TSAO, calanolides, L-697, 661, 2 ', 3' -dideoxycytidine (ddC), 2 ', 3' -dideoxydenosine, 2 ', 3' -dideoxyinosine (ddl), 3 '-deoxythymidine, 2', 3 '-dideoxy-2', 3'-dideshydrotimidine, and 2 ', 3'-dideoxy-2', 3'-dideshydrocytidine and ribavirin, acyclic nucleosides such as acyclovir, ganciclovir, interferons such as interferon alpha, beta and gamm to; glucuronidation inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; immunomodulators such as interleukin II (IL2) and colony stimulating factor of granulocyte macrophages (GM-CSF), erythropoietin, ampligen, thymomodulin, thymopentin, foscarnet, glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine, 1- deoxynojirmicin; and HIV inhibitors a CD4 receptors such as soluble CD4, fragments of CD4, hybrid CD4 molecules and inhibitors of HIV aspartyl protease such as L-735,524. The present invention also provides antiviral compositions which comprise a pharmaceutically acceptable carrier or adjuvant and an amount of a compound of formula (I), effective to inhibit viral replication in a mammal. The proportion of each carrier, diluent or adjuvant is determined by the solubility and chemical nature of the compound as well as the route of administration, in accordance with standard pharmaceutical practice. Viral replication inhibitory compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. Where appropriate, the formulations can be conveniently presented in discrete or separate dosage units and can be prepared by any of the methods well known in the pharmacy art. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then, if necessary, forming the product in the desired formulation.

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, tablets in the form of capsules, powders, granules, dragees, suppositories, reconstitutable powders or liquid preparations, such as sterile oral or parenteral solutions or suspensions. The compounds of the formula (VIII) wherein A is 0 can also be administered via an intraocular implant to treat retinitis, as a result of CMV infection.In particular, these compounds can be embedded in a polymer-based implant which will be released in The eye over an extended period of time In order to obtain consistency of administration, it is preferred that a composition of the invention be in the form of a unit dose The dosage unit presentation forms for oral administration can be tablets and capsules and they 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, tableting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or cellulose microcrystalline; or pharmaceutically acceptable wetting agents such as sodium laurisulfate. The compounds can be injected parenterally; that is, intramuscularly, intravenously or subcutaneously. For parenteral administration, the compound can be used in the form of sterile solutions containing other solutes, for example saline or glucose sufficient to render the solution isotonic. The amount of active ingredient administered parenterally will be from about 0.01 mg / kg / day 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 much more preferably 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 can 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 lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring and coloring agents, and then dehydrated enough to make the mixture suitable for pressing it into solid form. The amount of active ingredient administered orally will depend on the bioavailability of the specific compound. The solid oral compositions can be prepared by conventional methods of blanking, filling, tabletting or the like. Repeated combined operations can be used to distribute the active agent through those compositions that use large amounts of filler materials. Of course, such operations are 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 oral liquid 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, agents that improve the suspension may be included such as sorbitol, syrup, cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible 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 which are selected from the group consisting of glycerin, propylene glycol, ethylene glycol and ethyl alcohol; preservatives, for example, methyl para-hydroxybenzoate, para- ethyl hydroxybenzoate, n-propyl para-hydroxybenzoate or n-butyl para-hydroxybenzoate sorbic acid; and, if desired, conventional flavoring or coloring agents. For parenteral administration, fluid unit dosage forms can be prepared using the peptide and a sterile vehicle, and depending on the concentration used, it can be 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 subsequent sealing of the storage carrier or packaging. Adjuvants, such as local anesthetics, 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 a bottle and removing the water under vacuum (for example, by lyophilizing the composition). Parenteral suspensions can be prepared in a substantially similar manner, except that the peptide must be suspended in the vehicle instead of being dissolved, furthermore, the sterilization is not carried out by filtration. However, the compound can be sterilized by exposing it to ethylene oxide before suspending it in a sterile vehicle. Advantageously, a surfactant or wetting solution may be included in the composition to facilitate uniform distribution of the compound.

For topical administration to the epidermis, the compounds according to the present invention can be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. The lotions can be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspension improving agents, thickening agents or coloring agents. The pharmaceutical compositions of this invention comprise an inhibitory amount of viral replication of compounds of formula (I) and a pharmaceutically acceptable carrier, diluent or adjuvant. Typically, they contain from about 0.1% to about 99% by weight of active compound, and preferably from about 10% to about 60% by weight, depending on which method of administration is used. An inhibitory amount of viral replication is that amount of active compound necessary to slow the progress of viral replication or reduce the viral load of that which could otherwise occur without administration of the compound. Or, it is an amount of active compound needed to slow progress or reduce the intensity of the symptoms that result from the viral infection or the elimination of it. The viral inhibitory activity of the compounds of the invention can be determined in accordance with the plaque reduction assay for CMV or other standard assays for other viruses, which are described in detail in the examples.

Under these particular conditions, a compound having activity against CMV will exhibit an IC50 of about 50 ug / ml or less, preferably 25 ug / ml or less, much more preferably 10 ug / ml or less and so the preferred less than 1 μg / ml. The doctors will determine the dosage of the present therapeutic agents which will be the most appropriate.

The dosages may vary with the mode of administration and the particular compound chosen. In addition, the dosage may vary with the particular patient under treatment. The dosage 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 doctor performing the treatment. Such therapy may be prolonged for several weeks or months, intermittently or uninterrupted. To further assist in the understanding of the present invention, the following non-limiting examples are provided.

EXAMPLE 1 Synthesis Compound # 1 N- (2-methylbenzyl) -2- [1,6] naphthyridine-2-carboxamide To a stirred mixture of 2- [1, 6] naphthyridine-carboxylic acid (50 mg, 0.287 mmol) in 5 ml of anhydrous THF at 0 ° C is added triethylamine (44 ml, 0.316 mmol). After 5 minutes, isopropyl chlorformate (0.316 ml, 1M solution in toluene, 0.316 mmol) is added. The mixture is stirred at 0 ° C for 20 minutes, and then 2-methylbenzylamine (53.46 ml, 0.43 mmol) is added to the mixture at 0 ° C. The resulting mixture is allowed to warm to room temperature and is stirred at room temperature for 5 hours and then diluted in 100 ml in CH2C12. The organic layer is washed with water, dried over anhydrous MgSO 4 and concentrated to provide the crude mixture. Chromatography of the crude material (Hex: EtOAc = 1: 1 to pure EtOAc) gives 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-hydroxybenzo-triazole hydrate (42.7 mg, 0.316 mmol), benzylamine (45 mg, 0.42 mmol) in 5 ml of THF Anhydrous at 0 ° C is added 1- (3-dimethylaminopropyl) -3-ethylcabodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture is allowed to stir at RT (room temperature). After 20 minutes, 2 ml of DMF are added to the reaction mixture and the mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue is redissolved in 100 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous MgSO 4 and concentrated to provide the crude mixture. Chromatography of the crude mixture (Hex: EtOAc = 1: 1 to pure EtOAc) gives the desired product as a white solid (97 mg, 99%): m.p. 113-115 ° C.

Compound # 3 N- (2-bromobenzyl) -2- [1,6] naphthyridinecarboxamide To a stirring solution of 4-bromobenzylamine hydrochloride (97.8 mg, 98%, 0.431 mmol) in 5 ml of anhydrous DMF, triethylamine (60.1 μL, 0.431 mmol) is added. After 5 minutes, 2- acid is added sequentially [1, 6] naphthyridinecarboxylic (50 mg, 0.287 mmol), l-hydroxybenzyltriazole hydrate (42.7 mg, 0.316 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue is redissolved in 100 ml of CH2C12. The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue is redissolved in 100 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous MgSO 4 and concentrated to provide the crude mixture. Chromatography of the crude mixture (Hex: Et0Ac = 1: 1 to pure EtOAc) gives the desired product as a white solid (97 mg, 99%): m.p. 149-150 ° C.

Compound # 4 N- (2-chlorobenzyl) -2- [1,6] naphthyridine-carboxamide To a stirred mixture of 2- [1,6-naphthyridine-carboxylic acid (50 mg, 0.287 mmol) in 5 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) is added sequentially. 2-chlorobenzylamine (54.7 μl, 95%, 0.43 mmol) and 1- (3-dimethylaminopropyl) -3-carbodiimide hydrochloride (60.6 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue is redissolved in 100 ml of CH2C12. The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 100 ml of CH2C13. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous MgSO 4 and concentrated to provide the crude mixture. Chromatography of the crude mixture (Hex: EtOAc = 1: 1 to pure EtOAc) gives the desired product as a white solid (83 mg, 97%): m.p. 120-121 ° C.

Compound # 5 N- (2-bromobenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred solution of 2-bromobenzylamine hydrochloride (80.7 mg, 95%, 0.345 mmol) in 5 ml of anhydrous DMF, triethylamine (51.8 μl, 0.345 mmol) is added.

After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (40 mg, 0.229 mmolee), 1-hydroxybenzotriazole hydrate (34.2 mg, 0.253 mmole) and hydrochloride are added sequentially. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (48.5 mg, 0.253 mmol). The resulting mixture is allowed to stir at room temperature for 4 hours and is found to be clear. The solvent is removed under vacuum and the resulting residue is redissolved in 100 ml of CH2C12. The organic layer is washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to provide the crude mixture. Chromatography of the crude mixture (Hex: EtOAc = 1: 1 to pure EtOAc) gives the desired product as a white solid (70 mg, 89%): m.p. 129-130 ° C.

Compound # 6 N- (3-bromobenzyl) -2- [1,6] naphthyridine carboxamide To a stirring solution of 3-bromobenzylamine hydrochloride (77.5 mg, 0.345 mmol) in 5 ml of anhydrous DMF, triethylamine (51.8 μl, 0.345 mmol) is added. After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (40 mg, 0.229 mmol), 1-hydroxybenzotriazole hydrate (34.2 mg, 0.253 mmol) and 1- (3-dimethylaminopropyl) -3- hydrochloride are sequentially added. ethylcarbodiimide (48.5 mg, 0.253 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the residue The resulting solution is redissolved in 100 ml of CH2C12. The organic layer is washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to provide the crude mixture. Chromatography of the crude mixture (Hex: EtOAc = 1: 1 to pure EtOAc) gives the desired product as a white solid (64 mg, 81%): m.p. 112-113 ° C.

Compound # 7 N- (2-fluorobenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 6.3 ml of DMF anhydrous at room temperature, 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 mmoles). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 50 ml of CH2C12. The organic layer is washed with aqueous NaHCO3, dried over anhydrous MgSO4, and concentrated to provide the crude mixture. Flash column chromatography of the crude mixture (hexane / ethyl acetate to 100% ethyl acetate) provides the desired product as a white solid (79.2 mg, 98%): m.p. 110-111 ° C.

Compound # 8 N- (4-chlorobenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 6.3 ml of anhydrous DMF at room temperature, hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 4-chlorobenzylamine ( 53.5 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 50 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous Na 2 SO 4, and concentrated to provide the crude mixture. Flash column chromatography of the crude mixture (hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (80.3 mg, 94%): m.p. 110-111 ° C.

Compound # 9 N- (2-ethoxybenzyl) -2- [1,6] naphthyridine carboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 6.3 ml of DMF anhydrous at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-ethoxybenzylamine (64.9 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmoles). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 50 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous Na 2 SO 4, and concentrated to provide the crude mixture. Instant column chromatography of the crude mixture (hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (85.0 mg, 96%): m.p. 79-80 ° C.

Compound # 10 Indan 1-6-naphthyridine-2-carboxylic acid 1-ylamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 6.3 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) is added sequentially. aminoindan (56.0 μl, 0.431 mmol) and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 50 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous Na 2 SO 4, and concentrated to provide the crude mixture. Flash column chromatography of the crude mixture (hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (80.1 mg, 96%): m.p. 156-157 ° C.

Compound # 11 (1, 6) naphthyridine-2-carboxylic acid (1, 2, 3,4-tetrahydro-naphthalene-1-yl) -amide) To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 6.3 ml of DMF anhydrous at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) is added sequentially, 1,2,3,4-tetrahydro-1-naphthalenamine (63.0 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum and the resulting residue redissolved in 50 ml of CH2C12. The organic layer is washed with aqueous NaHCO 3, dried over anhydrous Na 2 SO 4, and concentrated to provide the crude mixture. Flash column chromatography of the crude mixture (50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (87.0 mg, 100%): m.p. 164-165 ° C.

Compound # 12 N- (3-methoxybenzyl) -2- [1,6] naphthyridine carboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 3- are added sequentially. methoxybenzylamine (56.6 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be - 3 - transparent. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a clear oil (79.1 mg, 94%).

Compound # 13 N- (2-trifluoromethylbenzyl) -2- [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2- are added sequentially. trifluoromethylbenzylamine (61.6 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives 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 1.0 ml of DMF anhydrous at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2,6-dimethoxybenzylamine (75.0 g, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg) are added sequentially. mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives 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-phenyl-cyclopropylamine hydrochloride (75.3 mg, 0.431 mmol) in 1.0 ml DMF Anhydrous triethylamine (60.0 μL, 0.431 mmol) is added. 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) -3 hydrochloride are sequentially added. ethylcarbodiimide (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (79.2 mg, 95%): m.p. 123-124 ° C.

Compound # 16 N- (2-amino-6-f-luorobenzyl) [1,6] naphthyridinecarboxamide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.315 mmol), 60.0 μl is sequentially added. of 2-amino-6-fluorobenzylamine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). Allow the resulting mixture to stir at room temperature atmosphere during the night and you find that it is transparent. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a white solid (80.0 mg, 94%): m.p. 165 (decomposition).

Compound # 17 [1, 6] naphthyridine-2-carboxylic acid (1-phenylethyl) -amide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of DMF anhydrous at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 1-phenylethylamine (56.1 μl, 0.431 mmol) and l- (3-dimethylaminopropyl) -3-ethylcabodiimide hydrochloride (61.8 mg, 0.316 mmoles). The resulting mixture allows it to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a clear oil (78 mg, 99%).

Compound # 18 [1, 6] naphthyridine-2-carboxylic acid (Pyridin-2-ylmethyl) -amide To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of DMF is anhydrous at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2- (aminomethyl) pyridine (45.3 μl, 0.431 mmol) and hydrochloride are added sequentially. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (hexane 50% / ethyl acetate to 5% methanol / ethyl acetate) gives the desired product as a light brown solid (78.7 mg, 99%): m.p. 123-125 ° C.

Compound # 19 [1, 6] naphthyridine-2-carboxylic acid cyclohexyl-methylamide - 6§ - To a stirred mixture of 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in 1.0 ml of anhydrous DMF at room temperature, 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316) is added sequentially. mmoles), cyclohexanomethylamine (57.2 μl, 0.431 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight and is found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) gives 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 1.0 ml of anhydrous DMF at room temperature is 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). It allows the The resulting mixture is stirred at room temperature overnight and found to be clear. The solvent is removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) gives the desired product as a white solid (79.1 mg, 95%): m.p. 98-100 ° C.

Compound # 21 N- (2-methylthiobenzyl) - [1,6] naphthyridinecarboxamide To a stirring mixture of 2-methylsulfanylbenzylamine hydrochloride (81.7 mg, 0.431 mmol) in 1.0 ml of anhydrous DMF is added triethylamine (60.0 μl, 0.431 mmol). After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (50 mg, 0.287 mmol), l-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol) and 1- (3-dimethylaminopropyl) -3- hydrochloride are added sequentially. ethylcarbodiimide (61.8 mg, 0.316 mmol). The resulting mixture is allowed to stir at room temperature overnight. The solvent is removed under vacuum. Flash column chromatography of the residue. { 50% hexane / ethyl acetate to 100% ethyl acetate) gives the desired product as a light brown solid (88.2 mg, 99%): m.p. 102-103 ° C.

Compound # 32 7,8-dihydroisoquinoline-6-carboxylic acid-7-methoxybenzylamide Eta a i Bromine trioxide (15.50, 173.10 mmol) is added in one portion in a pyridine solution (28 ml, 346.20 mmol) in 175 ml of dichloromethane at 0 ° C. The cooling bath is removed and the mixture is allowed to stir for 30 minutes. To this solution is added an alcohol solution (Cheng, C.Y, Hsin, L.W., Liou, J.P. Tetrahedron, 1996, 52, 10935). (385.1 g, 25.85 mmoles) in 15 ml of dichloromethane. The mixture is then stirred at room temperature for 2 hours and the solution is decanted, the solvent is then removed and the residue is purified by chromatography eluting with 2% MeOH in CH2C12. The desired compound is obtained as a light yellow solid (2662 g, 70%).

XK NMR (400 MHZ, CDC13) d: 8.69 (s, 1H, Hl), 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).

Stage 2 LiHMDS in THF (1M, 11.0 mL, 1 mmol) is added to a solution of ketone (Lithrium 1, 1, 3, 3, 3-hexamethyldisilazane) (115 mg, 0.78 mmol) in 3 mL of THF a - 78 ° C. After 15 minutes at this temperature, methyl cyanoformate (0.3 ml, 3.9 mmol) is added and the mixture is allowed to stir overnight. The reaction is then suspended with saturated ammonium chloride and extracted with ethyl acetate. Then it is dried (Na2SO4). The residue is triturated with cold ethyl acetate, which gives the desired product (75 mg, 47%) H NMR (400 MHz, CDC13) d: 11.81 (s, 1H, OH), 8.63 (d, 1H, H- 3, J = 5.9 Hz), 8.58 (s, 1H, Hl), 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 = 8.5Hz).

Stage 3 A solution of enol from step 2 (350 mg, 1.71 mmol) in 10 ml of methanol is stirred in the presence of palladium in carbon (10%, 350 mg) under an atmosphere of hydrogen for 1 hour. The catalyst is then removed by filtration through Celite and the filtrate is concentrated to dryness to provide the desired compound as a white solid (350 mg, 100%). * H NMR (400 MHz, DMSO) d: 8.72 (s, 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 (m, 2H), 2.8 (m, 1H), 2.0 (m, 1H), 1.9 (m, 1H).

Stage 4 Methanesulfonyl chloride (0.18 ml, 2.37 mmol) is added to a solution of alcohol from step 3 (350 mg, 1.69 mmol) and triethylamine (0.35 ml, 2.54 mmol) in 10 ml of dichloromethane, at 0 ° C. The mixture is then stirred at room temperature for 2 hours and the solution is then washed with water, NaHCO 3 and dried using Na 2 SO 4. The solvent is then removed and the residue is taken up in 5 ml of dichloroethane and treated with DBU (1,8-diazabicyclo [5.4.0] undec-7-ene) (0.5 ml). The solution is stirred for 2 hours at room temperature and the solvent is removed under vacuum and the residue is purified by chromatography (1% MeOH in CH2C12) to give the desired compound (159 mg, 50% from alcohol). XH 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, 0CH3), 2.87 ( t, 2H, H-8, J = 8.0 Hz), 2.69 (t, 2H, H-7, J = 8.0 Hz).

Stage 5 NaOH (IN, 1.3 ml, 1.3 mmol) is added to a solution of the ester from step 4 (159 mg, 0.84 mmol) in 3 ml of dioxane at rt (room temperature). After 3 hours, the mixture is concentrated to approximately 1 ml and HCl (6N) is cautiously added to an ice-cooled solution, until a pH of 5 is reached. The resulting precipitate is collected, washed with water and dried under vacuum (92 mg, 62%). X H NMR (400 MHz, DMSO) 6: 8.42 (m, 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 = 7.5Hz). fitapa 6 A solution of the acid from step 5 (60 mg, 0.34 mmol), 1- (3-methylaminopropyl) -3-carbodiimide hydrochloride (79 mg, 0.41 mmol) and HOBT (1-hedroxybenzotriazole hydrate) (55 mg, 0.41 mmol), 2-methoxybenzylamine (54 μl, 0.41 mmol) in 1 ml of DMF is stirred at room temperature for 24 hours. The solvent is then removed under vacuum and the residue purified by chromatography eluting with 50-100 EtAC in hexanes. The desired compound is obtained as a white solid (80 mg, 79%). XH NMR (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, 0CH3), 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 acid of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid Stage 1 2-N-ethyl-2-aminobenzonitrile A solution of lithium bis (trimethylsilyl) amide (7.6 ml, 1M in tetrahydrofuran) is added to a cold solution (0 ° C) of 2-aminobenzonitrile (1 g, 8.5 mmol) in 10 ml of tetrahydrofuran and 2 ml of DMF. The resulting solution is stirred for 30 minutes, and then iodoethane (0.68 ml, 8.5 mmol) is added dropwise. The solution is allowed to reach room temperature and is stirred overnight. After the reaction mixture is suspended with saturated NH4C1 evaporated and diluted with CH2C12, washed with water, brine and the combined organic extracts are dried with Na2SO4 and concentrated. The resulting liquid is subjected to chromatography on silica gel (30% EtOAc-Hex), which provides the title compound in a 9 to 1 ratio of the non-separable mono- and bis-alkylated compounds.

N-ethyl-2-aminobenzonitrile: XH NMR (400 MHz) (CDC13) d: 7.41-7.33 (m, 2H, Ph). 6.68-6.65 (m, 2H, Ph), 4.5 (s, 1H, NH), 3.29-3.22 (m, 2H, CHjN), 1.32 (t, J = 7 Hz, 3H, CH ^ CH ^, N-diethyl-2-aminobenzonitrile: XH NMR (400 MHz) (CDC13) d: 7.41-7.33 (m, 2H, Ph), 6.68-6.65 (m, 2H, £ h.), 4.5 (s, 1H, NH.), 3.41 (c, 4H , CH2N), 1.20 (t, J = 7 Hz, 6H, CfísCH, Stage 2 N-ethyl-2-aminobenzylamine dihydrochloride and N-diethyl-2-aminobenzamine dihydrochloride N-Ethyl-2-aminobenzonitrile (0.4 g, 2.7 mmol) is added to 100 mg of 10% Pd / C in a dry flask, followed by 15 ml of ethanol. To this solution is added HCl (2.7 ml, 4M in dioxane). The resulting reaction is placed under an atmosphere of H2 (g). The resulting solution is filtered over Celite and evaporated, triturated with ether and the solvent is evaporated to provide the above intermediate.

N-ethyl-2-aminobenzylamine dihydrochloride: X H NMR (400 MHz) (DMSO) d: 8.5-8.2 (m, 3 H, NH 3), 7.35- 7.25 (1.2 H, Ph), 7.34 (t, J = 7.5 Hz, 1 H, Ph), 7.1-6.9 (m, 2H, Ph), 4.07 (s, 2H, CüjN), 3.19 (c, 2H, J = 7 Hz, CH3CH2), 1.27 (t, J = 7 Hz, 3H, CE ^ CTLj).

N-Diethyl-2-aminobenzamine dihydrochloride: X H NMR (400 MHz) (DMSO) d: 8.5-8.2 (m, 3 H, NH, 7.35- 7.25 (1.2 H, Ph.), 7.34 (t, J = 7.5 Hz, 1 H, Ph), 7.1-6.9 (m, 2H, Ph), 4.07 (s, 2H, C &N), 3.33 (c, 2H, J = 7 Hz, ^ CH, 1.07 (t, J = 7 Hz, 3H, CifcCHa).

Stage 3 8-bromo- [1, 6] naf iridin-2-carboxylic acid Br2 is added over 40 minutes to a suspension of [1, 6] naphthyridine-2-carboxylic acid (3 g, 17.25 mmol) in acetic acid (150 ml) at room temperature (18.96 mmol). The solution is stirred overnight at room temperature and then the mixture is suspended with ice and stirred for 1 hour. The suspension is evaporated to dryness and then ground, filtered and washed with a minimum of cold water. The The resulting composition is dried under vacuum overnight to provide the title compound in 59% yield. X H NMR (400 MHz) (DMSO) d: 14.1-13.8 (M, 1H, COOH), 9.49 (s, 1H, H5), 9.10 (s, 1H, H7), 8.83 (d, 1H, J = 8.5 Hz , H4), 8.31 (d, 1H, J = 8.5 Hz, H3).

Stage 4 8-Bromo- [1, 6] naphthyridine-2-carboxylic acid 2-N-ethylamino-benzylamine .Cl N ' Triethylamine (0.095 ml, 0.68 mmol) is added to a solution of the salt (57 mg, 0.255 mmol) in 1.5 ml of DMF, at room temperature. The solution is stirred for 5 minutes. Simultaneously, the acid (30 mg, 0.12 mmol), HOBT (25 mg, 0.19 mmol) and EDC1 (36 mg, 0.19 mmol) are added. The reaction is allowed to stir overnight at room temperature. The solution is evaporated to dryness and the residue is dissolved in a minimum of CH2C12 and purified using flash chromatography (AcOEt 50% / Hexane to AcOEt 100%) to give the title compound in a yield of 61%. XH NMR (400 MHz) (CDC13) d: 9.27 (s, 1H, H5), 9.05 (s, 1H, H7), 8.65-8.55 (s, 1H, 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 (m, 3H, CH3CH2).

Stage 5 Salt of 2-N-ethylaminobenzylamine hydrochloride of 8-bromo [1, 6] naphthyridine-2-carboxylic acid HCl in dioxane Cl is added to a solution of the amide (28.4 mg, 0.06 mmol) in 0.5 mL of CH2C12 at room temperature (1 mL, 4M in dioxane). The solution is stirred for 20 minutes at room temperature. The suspension is evaporated to dryness and then trituted in ether to provide the title compound in quantitative yield. XH NMR (400 MHz) (CDC13) d: 9.27 (s, 1H, H5), 9.05 (s, 1H, H7), 8.65-8.55 (s, 1H, 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 (m, 3H, CH3CH2).

Compound # 39 2 - . 2 - tri f luorome t i lbenc il acid amine [1, 6] naphthyridin-2-thiocarboxylic Reagent by Lawesson Tolueno 9o ° C Lawesson's reagent is added to a stirred solution of BCH-5024 (30 mg, 0.09 mmol) in 1.5 ml of toluene (38 mg, 0.09 mmol). The solution is then heated at 90 ° C for 1 hour. The solvent is evaporated and the product is purified by flash chromatography (50% AcEt / He up to 100% AcOEt) to provide 25.8 mg of the thioamide derivative. lHR N (400 MHz, CDC13): 10.55 (broad s, 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-propoxy-phenyl) -3- [1,6] naphthyridin-2-yl-urea; A solution of 2-isopropoxyphenylamine (400 mg, 2.64 mmol) and N, N-diisopropylethylamine (1.02 mg, 5.82 mmol) in 10.0 ml of dichloromethane is added dropwise via a cannula to a solution of trisofogen (274.7 mg, 0.93 mmol) in 6.0 ml of dichloromethane at -78 ° C. The solution is stirred at -78 ° C for 1 hour, and then at 0 ° C for 1 hour, subsequently at room temperature for 1 hour. The mixture is concentrated, triturated with pentane and then filtered. The desired isocyanate is isolated as a brown oil (449.7 mg, 96%): X H NMR (400 MHz, CDC13) 5: 7.12 (1H, Ph), 6.99 (1H, Ph), 6.90 (1H, Ph), 6.86 (1H, Ph), 4.65 (septet, 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 mmol) and the amine (25 mg, 0.172 mmol) in 1 mL of acetonitrile is refluxed for 3 hours. The solvent is removed using a rotary evaporator. The residue is then triturated with diethyl ether, filtered and washed with diethyl ether. The solid is washed again with ethanol and then with diethyl ether, repeatedly. The desired product is isolated as a light brown solid (34.4 mg, 62%): m.p. > 200 ° C. H NMR (400 MHz, DMSO) d: 11.33 (broad s, 1H, NH), 10.56 (broad s, 1H, NH), 9.17 (s, 1H, H-5), 8.68 (d, 1H, H-7) , J = 5.8 Hz), 8.43 (d, 1H, H-4, 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, CH3, J = 6.0 Hz) ppm.

Compound # 63 8- (vinyl) [1, 6] naphthyridine-2-carboxylic acid 2-isopropoxybenzylamine # 63 To a mixture of bromide (0.05 mg, 0.125 mmol), year-old vinyltributyl (0.047 ml, 0.1625 mmol), bis (triphenylphosphine) dd (II) dichloride (7 mg, 0.01 mmol) is added 1 ml of DMF and acylated at 120 ° C for 1 hour. The solution is evaporated to dryness and the residue is dissolved in a minimum of CH2C12 and purified using flash chromatography (He 100% AcOEt 100%). X H NMR (400 MHz), (DMSO) d: 9.25 (s, 1 H), 9.00 (s, 1 H), 8.73 (m, 1 H), 8.48 (d, J = 8.5 Hz, 1 H), 8.44 (d, J = 8.5 Hz, 1H), 7.80 (dd, J = 11.5 Hz, 1H), 7.40 (d, 1H, J = 7.5 Hz), 7.3-7.2 (m, 1H), 6.95-6.91 (m, 2H), 6.12 (d, 1H, J = 17.5 Hz), . 59 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 6.5 Hz, 1H), 4.74-4.68 (m, 1H), 1.46 (d, J = 6 Hz, 1H).

Compound # 64 2-isopropoxybenzylamine of 8- (methyl) [1, 6] naphthyridine-2-carboxylic acid DMF # 64 To a mixture of bromide (156.8 mg, 0.39 mmol), tetramethyltin (0.22 ml, 1.56 mmol), bis (triphenylphosphine) dd (II) dichloride (42 mg, 0.06 mmol) are added. 3 ml of DMF and the flask is sealed with a glass stopper and heated at 80 ° C for 24 hours. The solution is evaporated to dryness and the residue is dissolved in a minimum of CH2C12 and purified using flash chromatography (AcOEt 50% / He up to AcOEt 100%). XR NMR (400 MHz) (DMSO) d: 9.20 (s, 1H), 8.71 (m, 1H), 8.67 (s, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 7.41 (d, 1H, J = 7 Hz), 7.28-7.25 (m, 1H), 6.94-6.90 (m, 2H), 4.74 (d, J = 6.5 Hz, 1H), 4.72- 4.66 (m, 1H), 2.77 (s, 3H), 1.44 (d, J = 6 Hz, 1H).

Compound # 65 (S) - (+) - 8-bromo- [1, 6] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide # 65 To an agitated solution of the hydrochloride salt (74.7 mg, 0.346 mmol) in 1.0 anhydrous DMF, triethylamine (48.2 μl, 0.346 mmol) is added. After 5 minutes, 2- [1, 6] naphthyridinecarboxylic acid (73.0 mg, 0.288 mmol), 1-hydroxybenzotriazole hydrate (42.9 mg, 0.317 mmol) and 1- (3-dimethylaminopropyl) -3 hydrochloride are sequentially added. -ethylcarbodiimide (62.0 g, 0.317 mmol). The resulting mixture is allowed to stir at rt overnight. The solvent is removed under vacuum. Flash column chromatography of the residue (hexane / ethyl acetate) gives the desired product as a white solid (106.6 mg, 89%): m.p. 78-80 ° C.

Compound # 66 8-Bromo- [1, 6] naphyridin-2-carboxylic acid (1-f-enyl-ethyl) -amide # 66 This compound is prepared following the scheme described for the synthesis of compound # 33. XH NMR (400 MHz, CDC13): 9.27 (s, 1H), 9.06 (s, 1H), 8.64 (d, J = 6.6 Hz, 1H), 8.50 (2d, J = 8.5 Hz, 2H), 7.40 (m , 5H), 5.38 (m, 1H), 1.71 (d, J = 6.9 Hz, 3H).

Compound # 67 7,8-Dihydro-isoquinoline-6-carboxylic acid phenetylamide # 67 To an agitated mixture of the acid (40 mg, 0.228 mmol) in 1.0 ml of anhydrous DMF at RT, 1-hydroxybenzotriazole hydrate (33.9 mg, 0.251 mmol), the amine (43.4 μl, 0.342 mmol) and hydrochloride are added sequentially. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (49.1 mg, 0.251 mmol). The resulting mixture is allowed to cool to RT overnight. The solvent is removed under vacuum. Flash column chromatography of the residue (100% ethyl acetate) gives the desired product as a white solid (50.5 mg, 80%).

Compound # 68 [2- (lH-indol-3-yl) -ethyl-amide of 7,8-dihydro-isoquinoline-6-carboxylic acid To a suspension of 7,8-dihydro-isoquinoline-6-carboxylic acid (50 mg, 0.29 mmol) in 2 ml of THF at 0 ° C is added N-methyl morpholine (96 μl, 0.87 mmol) followed by chloroformate from isopropyl (1M in toluene, 0.29 ml, 0.29 mmol). After 1 hour at RT, for example, tryptamine rhloride (62 mg, 0.31 mmol), and then allow the mixture to warm to room temperature and stir at 2 hours.

NaOH (IN, 1 ml) is added and the product is extracted into methylene chloride. After drying the solution (Na 2 SO 4) and removing the solvent, the resulting solid is triturated with ether. The solid is then dissolved in 5 ml of methylene chloride and HCl (4N in dioxane, 1 ml) is added. Volatile fractions are removed and the solid is triturated with ether and dried under vacuum (69 mg, 68%). X H NMR (400 MHz, DMSO) d: 10.84 (s, 1 H, H-5), 8.70 (m, 2H), 8.56 (t, 1H, NH), 7.79 (d, 1H, J = 5.7 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.34 (m, 2H), 7.19 (s, 1H), 7.06 (t, 1H, J = 7. 6 Hz), 6.98 (t, 1H, J = 7.6 Hz), 3.44 (m, 2H), 2.99 (t, 2H, J = 8.3 Hz), 2.91 (t, 2H, J = 7.6 Hz), 2.64 (t, 2H, J = 8.2 Hz).

In a similar manner, the following compounds are prepared: Compound # 22 N- (2-hydroxybenzyl) -2- (1,6) naphthyridinecarboxamide; Compound # 23 N- (2-methoxycarbonylbenzyl) -2- (1, 6) naphyridin-2-carboxamide; Compound # 26 N- (2-propoxybenzyl) -2 - [1,6] naphryldidinecarboxamide; Compound # 27 (2. {[[([1, 6] naphthyridine-carbonyl) -amino] -methyl} -phenyl) -carbonyl ester; Compound # 28 (1, 6) naphthyridine-2-carboxylic acid (2,3,4,5-tetrahydrobenzo [B] oxepin-5-yl) -amide; Compound # 29 (chromium-4-yl) -amide of [1, 6] naphyridin-2-carboxylic acid; Compound # 30 N- (2'-methoxybenzyl) -5-amino-2- [1,6] naphyridinecarboxamide; Compound # 31 2, 3- (methylenedioxy) -benzylamide of [1, 6] naphyridin-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; Compound # 35 (2-methoxybenzylamine) of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid; Compound # 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; Compound # 38 (2-isopropoxybenzylamine) of 8- (2-pyridyl) - [1,6] naphthyridine-2-carboxylic acid; Compound # 40 2-isopropoxybenzylamine) of [1, 6] naphthyridin-2-thiocarboxylic acid; Compound # 41 3 -methylbenzylamine) of [1, 6] naphyridin-2-thiocarboxylic acid, - Compound # 42 2-isopropoxybenzylamine of 8-bromo- [1, 6] naphyridin-2-thiocarboxylic acid; Compound # 43 2-methyl [1, 6] naphthyridin-2-thiocarboxylic acid t-oxybenzyl amine; Compound # 44 2 - e t oxib in 1 i amide of [1, 6] naphthyridine-2-thiocarboxylic acid; Compound # 45 2-methoxy-cyclohexylmethyl-amide [1, 6] naphyridin-2-thiocarboxylic acid, - Compound # 47 l- (2-iso-propoxybenzyl) -3- [1,6] naphthyridin-2-yl urea; Compound # 48 1- (N-Boc-4-aminobutyl) -3- [1,6] naphthyridin-2-yl urea; Compound # 49 1- (4-aminobutyl) -3 [1,6] naphthyridin-2-yl-urea hydrochloride; Compound # 50 1- [(S) -a-methylbenzyl] -3- [1, 6] naphthyridin-2-yl-urea; Compound # 51 1- [(R) -a-methylbenzyl] -3- [1,6] naphthyridin-2-yl-urea; Compound # 52 1- (2-methoxy-phenyl] -3- [1,6] naphthyridin-2-ylurea; Compound # 53 l-butyl-3- [1, 6] naphthyridin-2-yl-urea; Compound # 54 1- (2-methoxybenzyl] -3- [1,6] naphthyridin-2-ylurea; Compound # 55 1- (2-ethoxy-phenyl] -3- [1,6] naphthyridin-2-yl-urea; Compound # 56 1- (2-methyl-phenyl] -3- [1,6] naphthyridin-2-ylurea; Compound # 57 (2-isopropoxybenzylamine) of 8- (2-pyridyl) - [1,6] naphthyridine-2-carboxylic acid; Y Compound # 69 [[6,6] naphthyridine-2-carboxylic acid [2- (lh-indol-3-yl) -ethyl] -amyl] -amide.

The following compounds are obtained commercially (Peakdale Fine Chemicals Limited, Glossop Derbyshire, United Kingdom): Compound # 24 Allylamide of (1, 6) naphthyridine-2-carboxylic acid (PFC-029); Compound # 25 N- (2-methoxybenzyl) -2- (1,6) naphthyridine-2-carboxamide (PFC-032).

EXAMPLE 2 Preparation of tlazol [5,4- C] pyridine compounds Compounds # 58 and # 59 [5, 4-c] pyridin-2-carboxylic acid ethyl ester and thiazolo [5, 4-c] pyridine-2-carboxylic acid 2-methoxybenzylamide # 58 # 59 To a solution of the thiazolo [5, 4-c] pyridine-2-carboxylic acid ethyl ester (14 mg, 0.08 mmol) and 2-methoxybenzylamine (0.03 ml, 0.23 mmol) in 0.3 ml of dichloromethane is added a solution of trimethylaluminum in hexane (0.115 ml, 2.0M, 0.23 mmole). The solution is then stirred for 5 hours at room temperature. After the usual treatment, the product is purified by flash chromatography (CH2Cl2 / EtOAc 2: 1) to provide 14 mg of the thiazole derivative. ? NMR (400 MHz, CDC13): 9.32 (s, 1H), 8.72 (d, J = 6.0 Hz, 1H), 7.95 (d, J = 6.0 Hz, 2H), 7.35 (broad d, J = 7.6 Hz, 2H ), 7.35 (m, 2H), 6.95 (m, 2H), 4.71 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H).

Compound # 60 Thiazolo [5,4-c] pyridine-2-carboxylic acid 2-isopropoxybenzylamide # 60 To a solution of the thiazolo [5,4-c] pyridine-2-carboxylic acid ethyl ester (34 mg, 0.16 mmol) and 2-isopropoxybenzylamine (67 mg, 0.41 mmol) in 1.7 ml of dichloromethane is added a solution of trimethylaluminum in hexane (0.203 ml, 2.0M, 0.41 mmol). The solution is then stirred for 5 hours at room temperature. After the usual treatment, the product is purified by flash chromatography (CH2Cl2 / EtOAc 2: 1) to provide 30 mg of the thiazole derivative. XH NMR (400 MHz, CDC13): 9.32 (s, 1H), 8.72 (d, J = 6.0 Hz, 1H), 8.12 (broad s, 1H), 7.93 (d, J = 6.0 Hz, 2H), 7.35 ( m, 2H), 6.95 (m, 2H), 4.69 (m, 2H), 1.45 (d, J = 6 Hz, 6H).

Compound # 61 (Thiazolo [5,4-c] pyridine-2-carboxylic acid 1 (R) -phenyl-ethyl) -amide # 61 To a solution of the thiazolo [5, 4-c] pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1 (R) -phenylethylamine (0.03 ml, 0.23 mmol) in 0.3 ml of dichloromethane is added a Trimethylaluminum solution in hexane (0.115 ml, 2.0M, 0.23 mmole). The solution is then stirred for 5 hours at room temperature. After the usual treatment, the product is purified by flash chromatography (CH2Cl2 / EtOAc 1: 1) and triturated in hexane to provide 14 mg of the thiazole derivative. H NMR (400 MHz, CDC13): 9.33 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 7.95 (d, J = 5.2 Hz, 1H). , 7.70 (d, J = 7.6 Hz, 1H), 7.39 (m, 5H), 5.35 (m, 1H), 1.70 (d, J = 6.9 Hz, 3H).

Compound # 62 (Thiazolo [5,4-c] pyridine-2-carboxylic acid (1) S) -phenyl ethyl) amide # 62 To a solution of the thiazolo [5, 4-c] pyridine-2-carboxylic acid ethyl ester (16 mg, 0.08 mmol) and 1 (S) -phenylethylamine (0.03 ml, 0.23 mmol) in 0.3 ml of dichloromethane is added a solution of trimethylaluminum in hexane (0.115 ml, 2.0M, 0.23 mmole). The solution is then stirred for 5 hours at room temperature. After the usual treatment, the product is purified by flash chromatography (CH2Cl2 / EtOAc 1: 1) and triturated in hexane to provide 12 mg of the thiazole derivative. XH NMR (400 MHZ, CDC13): 9.33 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H ), 7.39 (m, 5H), 5.35 (m, 1H), 1.70 (d, J = 6.9 Hz, 3H).

EXAMPLE 3 Antiviral assays The anti-HIV activity of the test compounds was evaluated, according to standard procedures similar to those described in Ojwang et al., (J. Acquired Immune Deficiency Syndromes, 1994, 7: 560). Inhibition of other viruses is assayed according to standard techniques. The following general procedures were used: Inhibition of viral cytopathic effect (CPE) This test, which is performed in 96 well flat bottom microplates, is used to determine the initial antiviral evaluation of all new test compounds. In this CPE inhibition test, 7 semilogarithmic dilutions (log10) of each test compound are added to 4. vessels containing the cell monolayer; in the next 5 minutes, the virus is added and the plate is sealed and incubated at 37 ° C and the CPE is read microscopically when the untreated infected controls are grown at 3 to 4 + CPE (approximately 72 h to 168 h, depending on the virus). A known positive control drug is evaluated in parallel (ribavirin, HPMPA, acyclovir, ganciclovir, depending on the virus) in parallel with the test drugs, in each test. The data are expressed as 50% effective concentrations (virus inhibitors) (EC50).

Uptake of neutral red dye (NR) This test is carried out to validate the inhibition of CPE seen in the initial tests, and uses the same 96-well microplates after CPE has been read. A neural network is added to the medium; cells not damaged by the virus capture a greater amount of dye, which is read on a computerized microplate auto-reader. A CES0 is determined for this dye uptake.

Plaque reduction test (cytomegalovirus) They are exposed to monolayer cell viruses in 24 well microplates, and while the virus is absorbed, the plates are centrifuged at 2200 rpm for 30 minutes at room temperature to improve the formation of viral plaque. Then at 7 semilogarithmic concentrations of the test compound are added to 2 wells by dilution. The plates are incubated at 37 ° C in a humidity atmosphere of C02 5% and 95% air until the plates are examined. The cells are observed microscopically to determine morphological changes due to the toxicity of the test compound, with determined CC50 values, and then the medium is aspirated and the cells are stained by adding violet crystal in buffered formalin 10%. After staining, the plates are counted using a dissecting microscope, and the CES0 values are determined.

Methods for the cytotoxicity test A. Visual observation In the CPE inhibition test, 2 wells of uninfected cells treated with each concentration of the test compound are run in parallel in parallel with treated and infected wells. At the time when the CPE is microscopically determined, the toxicity control cells are also examined microscopically for any change in the appearance of the cells as compared to the normal control cells found on the same plate. These changes can be enlargement, granularity, cells with scraped edges, a film-like appearance, rounding, detachment from the well surface, or other changes. These changes are given a designation of T (100% toxic), Pyu (partially toxic, very heavy-80%), PH (partially toxic-heavy-60%), P (partially toxic-40%), Pß (partially toxic-light-20%) or O (without toxicity-0%), conforming to the degree of toxicity observed. An inhibitory (cytotoxic) concentration of 50% of cells (CC50) is determined by regression analysis of these data.

B. Capture of neutral red In the neutral red dye uptake phase of the antiviral test described above, the two toxicity control wells also receive neutral red and the degree of color intensity is determined spectrophotometrically. Subsequently, the neutral red CCS0 (NRCCS0) is determined.

Analysis of data Each antiviral activity of the test compounds is expressed as the selectivity index (SI), which is the CCS0 divided by the CES0.

Special procedures Except where indicated, the test compounds were solubilized in 100% DMSO at a concentration of 10 mg / ml, and then diluted until the DMSO is no longer toxic to the cells.

C. Thymidine 3 H uptake assay In 96-well flat-bottomed plates, they are seeded in plates with 5 x 103 Vero-34 cells / well and 1 x 104 Hs68 or Wi-38 / well cells, respectively and incubated overnight at 37 ° C and C02 5 %/air. After incubation, the supernatant medium is removed and replaced with dilutions of the test compounds in DMEM 2% (150 μl). The cells are then incubated for 48 hours in a 5% C02 incubator at 37 ° C. 50 μl / well of a solution of 10 μCi / ml of [3 H] -methyl thymidine (specific activity of approximately 2 Ci / mmoles) is added to the culture medium and incubated overnight (18 hours) in a C02 incubator 5% at 37 ° C. The cells are then harvested on a glass fiber filter (Printed Filtermat A 1450-421 Wallac) with a Tomtec cell harvester. Suspended cells are collected directly on the filter while for adherent cells, first the medium is removed, and then the cells are washed with PBS and trypsinized for 2-3 minutes (50 μl trypsin / well) before being harvested. The filters are dried for 1 hour at 37-40 ° C and then placed in bags (1450-microbeta # 1450-432 Wallac) with 4.5 ml of Betascint and accounts are obtained with the Microbeta 1450 Wallac equipment (protocol 1).

The percentage of cell proliferation is determined by comparison with the control (without test compound) and thus in this way the inhibitory concentration of 50% is established.

Table 2 Antiviral activity against HSV-1, HSV-2, respiratory syncytial virus (RSV) and influenza A Table 3 Antiviral activity against influenza B, rhinovirus (RV), parainfluenza and adenovirus Table 4 Antiviral activity against HIVROJO and HIV-.E CIS0 and CCS0 = μg / ml Table 5 Antiviral activity against HCMV: CIS0 and CCS0 = μg / ml It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (71)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for inhibiting the replication of a virus other than cytomegalovirus (CMV) replication in a mammal, characterized in that it comprises administering to the mammal an amount antiviral of a compound of formula (I): wherein W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y, and Z is N or NRS, while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is selected from CH, CR3, CH2, C = 0, CHR3, N, NRS, O, and S; B is selected from the group consisting of: (II) (III) (IV) where A is 0, N or S; Rx is selected from: C2.6 alkyl, C2.6 alkenyl or C3.7 cycloalkyl optionally substituted with OH, halogen, amino, carboxyl, or saturated or unsaturated C3.10 carbocycle or heterocycle optionally substituted with OH, halogen, amino, mercapto, carboxy, C 1 alkyl, C 1 alkoxy, CXL 4 alkylthio, C 1 acyl, C 1 or alkoxycarbonyl acyloxy) of x 4 optionally substituted with OH, halogen, amino or alkoxy from C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, C-. ^ alkyl, C ^ alkoxy, C ^ alkylthio, Ci.sub.4 acyl, acyloxy Cj._4 or alkoxycarbonyl of C ^ optionally substituted with OH, halogen, amino or alkoxy of Cj._4; Y (carbocycle or heterocycle) of C3.10, saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of C ^ optionally substituted with OH, halogen, amino or C ^ alkoxy; R2 and R * 2 are independently selected from H or Cx_4 alkyl, or ^ and R2, together, form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to C6.10 aryl or heteroaryl; R3 and R4 are independently selected from H, OH, halogen, amino, cyano, C1.6 alkyl, Cx.e alkenyl, C6 alkoxy, C6 acyl, C6 acyloxy or Ci alkoxycarbonyl. .g, optionally substituted with OH, halogen, amino, or alkoxy and C3.10 carbocycle or saturated or unsaturated C3.10 heterocycle optionally substituted with OH, halogen, amino, mercapto, C ^ alkylthio, Ci.4 alkoxycarbonyl, C ^ alkyl substituted with halo, C ^ substituted alkoxy. with halo, Cx_4alkyl, Cx_4alkoxy or carboxy; Rs is H, Cx..β alkyl or C.sub.4 acyl optionally substituted with OH, halogen, amino or Cx.sub.4 alkoxy; and n is 0, 1 or 2.

2. The method according to claim 1, characterized in that W is N or NRS, Y is N or NRS and Q is selected from CH, CH2, CR3 and CHR3.

3. The method according to claim 2, characterized in that n = 1.

4. The method according to claim 1, characterized in that W and Y are N, Q is CR3 or CHR3 and n is 1.

5. The method according to claim 4, characterized in that X and Z are independently selected from CH and CR4.

6. The method according to claim 4, characterized in that X and Z are CH.

7. The method according to claim 4, characterized in that A is 0.

8. The method according to claim 7, characterized in that Rx are selected from Cx_6 alkyl, C2.6 alkenyl optionally substituted with OH, halogen, amino, carboxyl or C3.10 carbocycle or C3.10 saturated or unsaturated heterocycle, optionally substituted with OH, halogen, amino, Cx_4 alkyl, .4 alkoxy and C3.X0 carbocycle or saturated or unsaturated C3.X0 heterocycle optionally substituted with OH, halogen, amino, mercapto, carboxy, C 1 alkyl, C x 4 alkoxy, C 1. 4 alkylthio, C x 4 acyl, C x 4 acyloxy or C x 4 alkoxycarbonyl optionally substituted with OH, halogen, amino or alkoxy C? _4.

9. The method according to claim 7, characterized in that Rx is selected from benzyl, pyridinylmethyl or cyclohexylmethyl optionally substituted with one or two substits that are selected from hydroxy; amino, Cx.sub.4 alkyl, halogen, C.sub.1 alkoxy, Cx.sub.4 alkoxycarbonyl, Cx.sub.4 alkylthio or Cx.sub.4 alkyl substituted with halo.

The method according to claim 7, characterized in that it is benzyl optionally monosuetituido or disubstituido in positions 2, 3, 5 or 6 of the ring with methyl, methoxy, ethoxy, hydroxy, fluoro, bromo, chloro, methoxycarbonyl, methylthio, trifluoromethyl , trifluoromethoxy, NH2 or NH3 + C1".

11. The method according to claim 7, characterized in that Rx is C3.7 cycloalkyl substituted with phenyl which is optionally substituted with one or two solvents that are selected from hydroxy, amino, Cx_4 alkyl, halogen, alkoxy of .4, alkoxycarbonyl of Cx_4, alkylthio of Cx_4 or alkyl of C1? replaced with halo.

12. The method according to claim 4, characterized in that B is (II) R2 and R'2 are independently selected from the group consisting of H and methyl.

13. The method according to claim 4, characterized in that B is (IV) and R2 and R'2 are independently selected from the group consisting of H and methyl.

14. The method according to any of claims 1 to 13, characterized in that R3 and R4 are independently selected from H, OH, halogen, amino, cyano, Cx.βalkyl, Cx.beta.-alkoxy, Cx.6 acyloxy and Cx.β.alkoxycarbonyl optionally substituted with OH, halogen, amino or Cx.4 alkoxy.

15. The method according to any of claims 1 to 13, characterized in that R3 is H and R4 is selected from C3.10 cabocycle or saturated or unsaturated C3.X0 heterocycle optionally substituted with OH, halogen, amino, mercapto, alkyl, Cx.4, CX_4 alkoxy or carboxy.

16. The method according to claim 15, characterized in that R4 is selected from 6-membered aryl, 6-membered heteroaryl or a 6-membered cycloalkyl ring optionally substituted by halogen, hydroxy, Cx_4 alkyl or Cx.4 alkoxy.

17. The method according to claim 16, characterized in that R < It is a 6-membered heteroaryl.

18. The method according to claim 2, characterized in that R4 is C2.6 alkenyl.

19. The method according to claim 18, characterized in that R4 is vinyl.

20. The method according to claim 2, characterized in that R3 is selected from H; OH; halogen and Cx.4 alkoxy.

21. The method according to claim 2, characterized in that R3 is H.

22. The method according to claim 2, characterized in that R4 is H.

23. The method according to claim 2, characterized in that R4 is Br.

24. The method according to claim 2, characterized in that R5 is H.

25. The method according to claim 1, characterized in that it comprises administering an antiviral amount of a compound of formula (V): (V) wherein W is N or NRS, wherein Rs is selected from H and Cx.6 alkyl is selected from the group consisting of: (II) (III) (IV) wherein, A is 0, Rx is selected from Cx_6 alkyl and C2.6 alkenyl optionally substituted with OH, halogen, amino, carboxyl or C3.10 carbocycle or saturated or unsaturated C3.10 heterocycle, optionally substituted with OH , halogen, amino, Cx_4 alkyl, Cx_4 alkoxy, and C3.X0 carbocycle or saturated C3.10 heterocycle, optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx.sub.4 alkyl, Cx alkoxy. 4, C 1 4 alkylthio, C x 4 acyl, C x 4 acyloxy or C x 4 alkoxycarbonyl optionally substituted with OH, halogen, amino or C x 4 alkoxy; R2 and R'2 are selected from H and Cx_4 alkyl; R3 and R are independently selected from H, OH, halogen, amino, cyano, C2.6 alkenyl, CX_6 alkyl, Cx.sub.x alkoxy / Cx_6 acyl, Cx_6 acyloxy, C ^ alkoxycarbonyl optionally substituted with OH, halogen, amino or alkoxy of Cx_4; and C3.10 carbocycle or C3.10 saturated or unsaturated heterocycle optionally substituted with OH, halogen, amino, mercapto, Cx.4 alkyl, Cx_4 alkoxy or carboxy.

26. A method for inhibiting the replication of a virus other than CMV in a mammal, characterized in that it comprises administering to the mammal an antiviral amount of a compound selected from the group consisting of N- (2-methylbenzyl) -2- (1, 6) ) naphthyridine carboxamide; N-benzyl-2- (1,6) naphthyridinecarboxamide; N- (2-bromobenzyl) -2- [1,6] naphthyridinecarboxamide; N- (2-chlorobenzyl) -2- (1,6) naphthyrin-carboxamide; N- (2-bromobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (3-bromobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-fluorobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (4-chlorobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-ethyloxybenzyl) -2- (1, 6) naphthyridine-carboxamide, [1, 6] naptyridine-2-carboxylic acid indan-1-ylamide; (1, 2, 3, 4-tetrahydro-naphthalen-1-yl) -amide of the acid [1,6,6] naphthyridine-2-carboxylic acid; N- (3-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-trifluoromethylbenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2,6-dimethoxybenzyl) -2- (1,6) naphthyridinecarboxamide; (1, 6) naphthyridine-2-carboxylic acid trans-2-phenyl-cyclopropyl) -amide; N- (2-amino-6-fluorobenzyl) -2- [1,6] naphthyridinecarboxamide; [1, 6] naphthyridine-2-carboxylic acid (1-phenyl-ethyl) -amide; [1, 6] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl) -amide; [1, 6] naphthyridine-2-carboxylic acid cyclohexylmethylamide; (3,4-dihydro-lH-isoquinolin-2-yl) - [1,6] naphthyridin-2-yl-methanone; N- (2-methylthiobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-hydroxybenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-methoxycarbonyl-benzyl) -2- (1,6) naphthyridinecarboxamide; aliphatic acid (1, 6) naphidin-2-carboxylic acid (PFC-029); N- (2-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; (2- {[[([1, 6] naphthyridine-2-carbonyl) -amino] -methyl} -phenyl) -carbonic acid tert-butylester; (1, 6) naphthyridin-2-carboxylic acid (2,3,4,5-tetrahydrobenzo [B] oxepin-5-yl) -amide, - (1, 6) naphyridine-2-carboxylic acid (chroman-4-yl) -amide; N- (2'-methoxybenzyl) -5-amino-2- [1,6] naphthyridinecarboxamide; 2, 3- (methylenedioxy) -benzylamide acid [1, 6] naphyridine-2-carboxylic acid; 7,8-Dihydroisoquinolin-6-carboxylic acid methoxy-benzylamide; (2-N-ethylaminobenzylamine) of 8-bromo [1, 6] naphthyridine-2-carboxylic acid; (2-isopropoxybenzylamine) of 8-bromo- [1, 6] naphyridin-2-carboxylic acid; (2-methoxybenzylamine) of 8-bromo- [1, 6] naphthyridine-2-carboxylic acid; 2-isopropoxybenzylamine of 8-chloro- [1, 6] naphyridin-2-carboxylic acid; (2-N-ethylaminobenzylamine) of 8-chloro- [1, 6] naphyridin-2-carboxylic acid; (2-isopropoxybenzylamine) of 8- (2-pyridyl) - [1,6] -naphthyridine-2-carboxylic acid; 2 - t r i f luorome t i lbenc i 1 acid amine [1, 6] naphyridin-2-thiocarboxylic acid, [1, 6] naphthyridin-2-thiocarboxylic acid-2-isopropoxybenzylamine; 3-methoxybenzylamine [1, 6] naphyridin-2-thiocarboxylic acid; 2-isopropoxybenzylamine of 8-bromo- [1, 6] naphthyridin-2-thiocarboxylic acid; [1-, 6] naphthyridin-2-thiocarboxylic acid-2-methoxy-benzylamide; [1-, 6] naphidin-2-thiocarboxylic acid-2-ethoxy-benzylamide; [1, 6] naphthyridine-2-thiocarboxylic acid-2-methoxy-cyclohexylmethylmethallylamide; 1- (2-iso-propoxy-phenyl) -3- [1,6] naphyridin-2-yl-urea; 1- (2-iso-propoxybenzyl) -3- [1,6] naphthyridin-2-yl urea; 1- (N- (boc-4-aminobutyl) -3- [1, 6] naphthyridin-2-yl-urea; 1- (4-aminobutyl) -3- [1, 6] naf iridin- 2- hydrochloride il-urea; 1- [(S) -a-methylbenzyl] -3- [1, 6] naphyridin-2-yl-urea; 1- [(R) -a-methylbenzyl] -3- [1, 6 ] naphthyridin-2-yl-urea; 1- (2-methoxy-enyl) -3- [1,6] naphyridin-2-yl-urea; l-butyl-3- [1,6] naf tiridin-2- il-urea; 1- (2-methoxy-enyl) -3- [1, 6] naf-iridin-2-yl-urea; 1- (2-ethoxyphenyl) -3- [1, 6] naf-tiridin-2-yl -urea; 1- (2-methyl-phenyl) -3- [1, 6] naphyridin-2-yl-urea; (2-isopropoxybenzylamine) of 8- (2-pyridyl) - [1,6] naph tiridin-2-carboxylic acid; 8- (Vinyl) - [1,6] naphthyridine-2-carboxylic acid 2-isopropoxybenzylamine; 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; (S) - (+) - 8-bromo- [1,6] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide; 8-Bromo- [1, 6] naphthyridine-2-carboxylic acid (1-phenylethyl) -amide; 7, 8-dihydro-isoquinoline-6-carboxylic acid phenethylamide; [7- (lff-indol-3-yl) ethyl-amide of 7,8-dihydro-isoquinoline-6-carboxylic acid; [1-6] naphthyridine-2-carboxylic acid [2- (lJa-indol-3-yl) -ethyl] -amide].

27. The method according to claim 26, characterized in that the compound is selected from: N-benzyl-2- (1,6) naphthyridinecarboxamide; N- (2-chlorobenzyl) -2- (1,6) naphthyridinecarboxamide; N- (3-methoxybenzyl) -2- (1,6) naphthyridinecarboxamide; N- (2,6-dimethoxybenzyl) -2- (1,6) naphthyridinecarboxamide; [1, 6] naphthyridinecarboxylic acid cyclohexylmethylamide; aliphatic acid (1, 6) naphyridine-2-carboxylic acid (PFC-029); N- (2-methoxybenzyl) -2- (1,6) naphryldidinecarboxamide; N- (2-propoxybenzyl) -2- [1, 6] naphyridin-2-carboxamide; (1, 6) naphidin-2-carboxylic acid (2, 3, 4, 5-tetrahydrobenzo [B] oxepin-5-yl) -amide; 2, 3 - (methylenedioxy) -benzylamide acid [1, 6] naphidin-2-carboxylic acid; 2'-mebibenzylamide of 7,8-dihydroisoquinolin-6-carboxylic acid, (8-bromo- [1,6] naphidin-2-carboxylic acid (2-N-ethylaminobenzylamine); (2-methoxybenzylamine) of 8-bromo- [1, 6] naphyridine-2-carboxylic acid; (2-isopropoxybenzylamine) of 8-chloro- [1,1,6] naphidin-2-carboxylic acid; 2-isopropoxybenzylamine [1, 6] naphyridin-2-thiocarboxylic acid; [1-, 6] naphthyridin-2-thiocarboxylic acid-2-methoxy-benzylamide; 1- (2-iso-propoxyphenyl) -3- [1,6] naphyridin-2-yl-urea; 1- (2-iso-propoxybenzyl) -3- [1,6] naphthyridin-2-yl-urea; 1- [(R) -a-methylbenzyl] -3- [1,6] naphthyridin-2-yl-urea; 2-isopropoxybenzylamine of 8- (vinyl) - [1, 6] naphyridin-2-carboxylic acid; 2 - . 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphyridin-2-carboxylic acid; 2-S-butoxy-benzylamide of (S) - (+) - 8-bromo- [1, 6] naphyridin-2-carboxylic acid; 8-Bromo- [1, 6] naphyridin-2-carboxylic acid (1-phethylethyl) -amide; 7-, 8-dihydroisoquinoline-6-carboxylic acid phenethylamide; [2- (lH-indol-3) -ethylamide of 7,8-dihydro-isoquinolin-6-carboxylic acid and [2- (l-indol-3-yl) -ethyl] -amide of acid [1, 6] naphthyridine-2-carboxylic acid.

28. The method according to claim 26, characterized in that the compound is selected from: N- (2 -propoxybenzyl) -2- [1, 6] naphyridin-2-carboxamide; 2'-methoxybenzylamide of 7,8-dihydroisoquinolin-6-carboxylic acid; (2-N-ethylaminobenzylamine) of 8-bromo- [1,6] naphyridin-2-carboxylic acid, - (2-isopropoxybenzylamine) of 8-chloro- [1,6] naphthyridine-2-carboxylic acid; 2-isopropoxybenzylamine [1, 6] naphyridin-2-thiocarboxylic acid; [1, 6] naphthyridine-2-thiocarboxylic acid 2-methoxy-benzylamide; 1- (2-iso-propoxyphenyl) -3- [1, 6] naphthyridin-2-yl-urea, -1- (2-iso-propoxybenzyl) -3- [1, 6] naphthyridin-2-yl-urea; 1- [(R) -a-methylbenzyl] -3- [1,6] naphthyridin-2-yl-urea; 2-isopropoxybenzylamine of 8- (vinyl) - [1, 6] naphidin-2-carboxylic acid; 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; (S) - (+) - 8-bromo- [1,6] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide; 8-Bromo- [1, 6] naphthyridine-2-carboxylic acid (1-phenylethyl) -amide; 7-, 8-dihydroisoquinoline-6-carboxylic acid phenethylamide; [2- (1H-indol-3) -ethylamide of 7,8-dihydro-isoquinoline-6-carboxylic acid and [2- (1-indol-3-yl) -ethyl] -amide of the acid [1, 6] Naphthyridine-2-carboxylic acid.

29. The method according to claim 26, characterized in that the compound is selected from: N- (2-propoxybenzyl) -2- [1,6] naphthyridine-2-carboxamide; 2'-methoxybenzylamide of 7,8-dihydroisoquinolin-6-carboxylic acid; (2-N-ethylaminobenzylamine) of 8-bromo- [1, 6] naphidin-2-carboxylic acid; 2-isopropoxybenzylamine [1, 6] naphyridin-2-thiocarboxylic acid; 1- (2-iso-propoxyphenyl) -3- [1,6] aftiridin-2-yl-urea; 2-isopropoxybenzylamine of 8- (vinyl) -ll, 6] naphyridine-2-carboxylic acid; 2-isopropoxybenzylamine of 8- (methyl) - [1, 6] naphidin-2-carboxylic acid; 2-S-butoxy-benzylamide of (S) - (+) - 8-bromo- [1, 6] naphthyridine-2-carboxylic acid; 8-Bromo- [1, 6] naphyridine-2-carboxylic acid (1-f-enylethyl) -amide; 7, 8-dihydroisoquinoline-6-carboxylic acid phenethyl and 7,8-dihydro-isoquinoline-6-carboxylic acid [2- (1H-indol-3) -ethylamino].

30. The method according to claim 1, characterized in that the compound is selected from: N- (2 -propoxybenzyl) -2- [1,6] naphyridin-2-carboxamide; 2,8-dihydroisoquinoline-6-carboxylic acid methoxybenzylamide; 8- (Vinyl) [1, 6] naphthyridine-2-carboxylic acid 2-isopropoxybenzylamine; 2-isopropoxybenzylamine of 8- (methyl) - [1,6] naphthyridine-2-carboxylic acid; 8-Bromo- [1-6] naphthyridine-2-carboxylic acid (1-phenylethyl) -amide; 7.8-dihydroisoquinoline-6-carboxylic acid phenethylamide and 7,8-dihydro-isoquinoline-6-carboxylic acid [2- (1H-indol-3) -ethylamide.

31. The method according to claim 1, characterized in that the virus is selected from the group consisting of HIV, HBV, HCV, HSV-1, HSV-2, parainfluenza, influenza A, influenza B, adenovirus, RV and SVR.

32. The method according to claim 2, characterized in that the virus is selected from the group consisting of HIV, HBV, HCV, HSV-1, HSV-2, for influenza, influenza A, influenza B, adenovirus, RV and RVS.

33. The method according to claim 25, characterized in that the virus is selected from the group consisting of HIV, HBV, HCV, HSV-1, HSV-2, for influenza, influenza A, influenza B, adenovirus, RV, and SVR.

34. The method according to claim 26, characterized in that the virus is selected from the group consisting of HIV, HBV, HCV, HSV-1, HSV-2, for influenza, influenza A, influenza B, adenovirus, RV and RVS.

35. A compound according to formula (I) and pharmaceutically acceptable salts thereof: characterized in that W is selected from CH, CR3, CH2, C = 0, CHR3, N and NRS; and it is N or NR5, X and Z are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is S; B is selected from the group consisting of: (ID (III) (IV) where A is 0, or S; Rx is selected from: C2.6 alkyl / C2.6 alkenyl or C3.7 cycloalkyl optionally substituted with OH, halogen, amino, carboxyl, or saturated or unsaturated C3.10 carbocycle or heterocycle optionally substituted with OH, halogen , amino, mercapto, carboxy, C 1 alkyl, C x 4 alkoxy, C x 4 alkylthio, C x 4 acyl / C x 4 acyloxy or C x 4 alkoxycarbonyl optionally substituted with OH, halogen, amino or alkoxy of C3.7 cycloalkyl fused to C.sub.x aryl or optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx.sub.4 alkyl, C ^ alkoxy, C ^ alkylthio, Cx_4 acyl, Cx_4 acyloxy or alkoxycarbonyl of Cx_4 optionally substituted with OH, halogen, amino or C alco alkoxy; and (carbocycle or heterocycle) of C3.10, saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of Cx_4 optionally substituted with OH, halogen, amino or Cx.4 alkoxy; Ra and RI2 are independently selected from H or Cx_4 alkyl, or Rx and R2, together, form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to C6.10 aryl or heteroaryl; R3 and R4 are independently selected from H, OH, halogen, amino, cyano, Cx.β alkyl, C1.6 alkenyl, Cx.6 alkoxy / Cx.6 acyl / acyloxy or Cx.6 alkoxycarbonyl, optionally substituted with OH, halogen, amino, or Cx.4 alkoxy and C3.10 carbocycle or C3.10 saturated or unsaturated heterocycle optionally substituted with OH, halogen, amino, mercapto, alkylthio of Cx_4, alkoxycarbonyl of Cx_4 Cx_4 alkyl substituted with halo, alkoxy of. Cx_4 substituted with halo, C 1 alkyl, C 1 alkoxy or carboxy; R 5 is H, C x 6 alkyl or C x 6 acyl optionally substituted with OH, halogen, amino or C 1 alkoxy; and n is 0.

36. The compound according to claim 35, characterized in that W is N or NRS.

37. The compound according to claim 36, characterized in that W and Y are N.

38. The compound according to claim 36, characterized in that X and Z are independently selected from CH and CR4.

39. The compound according to claim 38, characterized in that X and Z are CH.

40. The compound according to claim 35, characterized in that A is 0.

41. The compound according to claim 36, characterized in that B is (II) and Rx is selected from benzyl, pyridinylmethyl or cyclohexylmethyl optionally substituted with one or two substituents that are selected from hydroxy; amino, C 1 alkyl, halogen, C x 4 alkoxy, C x 4 alkoxycarbon, C x 4 alkylthio or C x 4 alkyl substituted with halo.

42. The compound according to claim 33, characterized in that B is (II) and Rx is C3.7 cycloalkyl fused to phenyl which is optionally substituted with one or two substituents that are selected from hydroxy, amino, Cx_4 alkyl, halogen , Cx_4 alkoxy, Cx_4 alkoxycarbon, CX_4 alkylthio or Cx_4 alkyl substituted with halo.

43. The compound according to claim 36, characterized in that R2 and R'2 are independently selected from the group consisting of H and methyl.

44. The compound according to claim 35, characterized in that R4 ee H.

45. The compound according to claim 35, characterized in that R3 is H.

46. The compound according to claim 35, characterized in that Rs is H.

47. The compound according to claim 35, of formula (VIII): (VIII) characterized because. A is 0 or S Rx is selected from C3.x0 carbocycle or C3.10 saturated or unsaturated heterocycle, optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx.4 alkoxy / Cx_4 alkylthio, Cx_4 acyl, Cx_4 acyloxy or Cx.4 alkoxycarbonyl optionally substituted with OH, halogen, amino or C alco alkoxy; and C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx_4 alkoxy, Cx.4 alkylthio, Cx_4 acyl, Cx_4 acyloxy or C 1_ 4 alkoxycarbonyl. Cx_4 optionally substituted with OH, halogen, amino or C alco alkoxy; R2 is selected from H or Cx_4 alkyl.

48. A compound, characterized in that it is selected from: thiazolo [5, 4-c] pyridine-2-carboxylic acid 2-methoxybenzylamide; Thiazolo [5,4-c] pyridine-2-carboxylic acid 2-iopropoxybenzylamide; (Thiazolo [5, 4-c] pyridine-2-carboxylic acid 1 (R) -phenylethyl) -amide; and thiazolo [5,4-c] pyridine-2-carboxylic acid (1 (S) -phenylethyl) -amide.

49. A method for inhibiting the replication of cytomegalovirus (CMV) in a mammal, characterized in that it comprises administering to the mammal an amount against CMV of a compound according to (I) and 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 N or NRS, while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is S; B is selected from the group consisting of: (II) (III) (IV) where A is O, or S; Rx is selected from: Cx_6 alkyl, C2.6 alkenyl or C3.7 cycloalkyl optionally substituted with OH, halogen, amino, carboxyl, or C3.10 carbocycle or heterocycle of C3.10 saturated or unsaturated optionally substituted with OH, halogen, amino , mercapto, carboxy, Cx_4alkyl, Cx_4alkoxy, C3_4alkyl acyl, C4_alkyloxy or C4_alkoxycarbonyl optionally substituted with OH, halogen, amino or alkoxy C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx.4 alkoxy, Cx_4 alkylthio, Cx_4 acyl, Cx_4 acyloxy or Cx_4 alkoxycarbonyl optionally substituted with OH, halogen, amino or Cx_4 alkoxy; and (C3. X0 carbocycle or heterocycle), saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx.4 (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) optionally substituted with OH, halogen, amino or Cx_4 alkoxy; R2 and 'j are independently selected from H or Cx_4 alkyl, or Rx and R2, together, form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to C6.10 aryl or heteroaryl; Rj and R4 are independently selected from H, OH, halogen, amino, cyano, C1.6alkyl, alkenyl Cx_6 alkoxy, Cx.sub.x acyl, Cx. 6 alkoxy or Cx.6 alkoxycarbonyl, optionally substituted with OH, halogen, amino, or Cx.sub.4 alkoxy, and C3.10 carbocycle or C3.10 saturated or unsaturated heterocycle optionally substituted with OH, halogen, amino, mercapto, Cx_4 alkylthio, Cx_4 alkoxycarbon, Cx_4 alkyl substituted with halo, C_4 alkoxy substituted with halo, Cx_4 alkyl, C ^ or carboxy alkoxy; Rs is H, Cx.6 alkyl or acyl optionally substituted with OH, halogen, amino or C alco alkoxy; and n is 0.

50. The method according to claim 49, characterized in that W is N or NR5 and Y is N or NRS.

51. The method according to claim 50, characterized in that W and Y are N.

52. The method according to claim 50, characterized in that X and Z are independently selected from CH and CR4.

53. The method according to claim 52, characterized in that X and Z are CH.

54. The method according to claim 49, characterized in that A is O.

55. The method according to claim 50, characterized in that B is (II) and Rx is selected from benzyl, pyridinylmethyl or cyclohexylmethyl optionally substituted with one or two substituents that are selected from hydroxy; amino, C ^ alkyl, halogen, Cx_4 alkoxy, Cx_4 alkoxycarbon, C1.4 alkylthio or Cx.4 alkyl substituted with halo.

56. The method according to claim 50, characterized in that B is (II) and Rx is C3.7 cycloalkyl fused to phenyl which is optionally substituted with one or two substituents that are selected from hydroxy, amino, Cx_4 alkyl, halogen , Cx.sub.4 alkoxy, Cx.sub.4 alkoxycarboxy, Cx.sub.4 alkylthio or Cx.sub.4 alkyl substituted with halo.

57. The method according to any of claims 49 to 56, characterized in that R2 and R'2 are they independently select from the group consisting of H and methyl.

58. The method according to claim 50, characterized in that R4 is H.

59. The method according to claim 50, characterized in that R3 is H.

60. The method according to claim 50, characterized in that Rs is H.

61. The method according to claim 49 of formula (VIII): (VIII) characterized because A is O Rx is selected from C3.10 carbocycle or saturated or unsaturated C3.10 heterocycle, optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx_4 alkoxy, C ^ alkylthio, Cx_4 acyl, Cx_4 acyloxy or alkoxycarbonyl of Cx.4 optionally substituted with OH, halogen, amino or Cx.4 alkoxy; C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx_4 alkoxy, C ^ alkylthio, Cj_4 acyl, Cx_4 acyloxy or alkoxycarbonyl of Cx_4 optionally substituted with OH, halogen, amino or C alco alkoxy; and (C10.10 saturated or unsaturated carbocycle or heterocycle) optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of Cx.4 optionally substituted with OH, halogen, amino or alkoxy of Cx_4; and R2 is selected from H and Cx_4 alkyl.

62. The compound according to claim 49, characterized in that the compound is selected from: thiazolo [5, 4-c] pyridine-2-carboxylic acid 2-methoxybenzylamide; Thiazolo [5,4-c] pyridine-2-carboxylic acid 2-isopropoxybenzylamide; (Thiazolo [5,4- c] pyridine-2-carboxylic acid (1) (R) -phenylethyl) -amide; and thiazolo [5,4- c] pyridine-2-carboxylic acid (1 (S) -phenylethyl) -amide.

63. The compound according to claim 35, characterized in that it is of formula (VIII): (VIII) characterized in that A is O Rx is selected from: C3.X0 carbocycle or saturated or unsaturated C3.10 heterocycle, optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx_4 alkoxy, C12 alkylthio , acyl of Cx_4, acyloxy of Cx_4 or alkoxycarbonyl of Cx_4 optionally substituted with OH, halogen, amino or alkoxy of Cx_4; C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4alkyl, Cx_4alkoxy, C12alkylthio, Cx_4 acyl, Cx_4 acyloxy or C4_4alkoxycarbonyl optionally substituted with OH, halogen, amino or C1.ialkoxy; and (C10.10 saturated or unsaturated carbocycle or heterocycle) optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of Cx_4 optionally substituted with OH, halogen, amino or Cx_4 alkoxy; and a is selected from H and Cx_4 alkyl.

64. The antiviral compound, characterized in that it is the 2-isopropoxybenzylamine of 8- (vinyl) - [1, 6] naphthyridine-2-carboxylic acid.

65 The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the inhibition of replication of viruses other than cytomegalovirus (CMV) in a mammal, characterized in that: W is selected from CH, CR3, CH2, C = 0, CHR3, N and NRS; one of X, Y, and Z is N or NR5, while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is selected from CH, CR3, CH2, C = 0, CHR3, N, NRS, O or S; B is selected from the group consisting of: (II) (III) (IV) where A is O, N or S; Rx is selected from: Cx_6 alkyl, C2.6 alkenyl or cycloalkyl C3.7 optionally substituted with OH, halogen, amino, carboxyl, or saturated or unsaturated C3.10 carbocycle or heterocycle optionally substituted with OH, halogen, amino, mercapto, carboxy, C3.4 alkyl, Cx4 alkoxy , alkylthio of Cx_4, acyl of Cx_4, acyloxy of Cx_4 or alkoxycarbonyl) of Cx.4 optionally substituted with OH, halogen, amino or alkoxy of * - l-4 / C3.7 cycloalkyl fused to C6.x0 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx.4 alkoxy, C ^ alkylthio, Cx_4 acyl , Cx_4 acyloxy or Cx_4 alkoxycarbonyl optionally substituted with OH, halogen, amino or Cx_4 alkoxy; and (C10.10 carbocycle or heterocycle), saturated or unsaturated, optionally substituted with OH, halogen, amino, mercapto, carboxy, (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) of Cx_4 optionally substituted with OH, halogen, amino or alkoxy of Cx_4; j and R'j are independently selected from H or Cx_4 alkyl, or Rx and R2, together, form a saturated or unsaturated 5- or 6-membered heterocycle optionally fused to aryl or C6.x0 heteroaryl; j and R4 are independently selected from H, OH, halogen, amino, cyano, alkyl, alkenyl of Cx.g, Cx_6 alkoxy, Cx_6 acyl, Cx.β acyloxy or Cx.β.alkoxycarbonyl, optionally substituted by OH, halogen, amino, or Cx.sub.4 alkoxy, and C3.10 carbocycle or C3 heterocycle Saturated or unsaturated optionally substituted with OH, halogen, amino, mercapto, CX_4 alkylthio, Cx_4 alkoxycarbonyl, Cx_4 alkyl substituted with halo, Cx_4 alkoxy substituted with halo, Cx_4 alkyl, Cx.4 alkoxy or carboxy; Rs is H, Cx.6 alkyl or Cx_6 acyl optionally substituted with OH, halogen, amino or Cx_4 alkoxy; and n is 0, 1 or 2.

66 The use of a compound of formula (I) in the manufacture of a medicament for the inhibition of cytomegalovirus (CMV) replication in a mammal, characterized in that: W is selected from CH, CR3, CH2, C = 0, CHR3, N and NR5; one of X, Y, and Z is N or NRS, while the other two are independently selected from CH, CR4, CH2, C = 0 and CHR4; Q is S; B is selected from the group consisting of: (ID (III) (IV) where A is 0, N or S; Rx is selected from: Cx_6 alkyl, C2.6 alkenyl or cycloalkyl C3.7 optionally substituted with OH, halogen, amino, carboxyl, or C3.10 carbocycle or C3.10 saturated or unsaturated heterocycle optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx.sub.4 alkyl, Cx alkoxy .4, Cx_4 alkylthio, Cx_4 acyl, Cx_4 acyloxy or Cx_4 alkoxycarbonyl optionally substituted with OH, halogen, amino or alkoxy of Cx.4; and C3.7 cycloalkyl fused to C6.10 aryl optionally substituted with OH, halogen, amino, mercapto, carboxy, Cx_4 alkyl, Cx.4 alkoxy, Cx.4 alkylthio, Cx_4 acyl, Cx_4 acyloxy or Cx_4 alkoxycarbonyl optionally substituted with OH, halogen, amino or Cx_4 alkoxy; R2 and R'2 are independently selected from H or Cx_4 alkyl, or Rx and R2 together form a saturated or unsaturated 5-6-membered heterocycle optionally fused to C6_X0 aryl or heteroaryl; R3 and R4 are independently selected from H, OH, halogen, amino, cyano, Cx_6 alkyl, alkoxy acilo de Cx_6, Cx.6 acyloxy or Cx.6 alkoxycarbonyl, optionally substituted with OH, halogen, amino, or C ^ alkoxy, and C3.x0 carbocycle or saturated or unsaturated C3.10 heterocycle optionally substituted with OH, halogen, amino, mercapto, CX_4 alkylthio, C4 alkoxycarbonyl, Cx_4 alkyl substituted with halo or Cx_4 alkoxy substituted with halo, Cx_4, Cx.4 alkoxy or carboxy; Rs is H, Cx_6 alkyl or Cx.g acyl optionally substituted with OH, halogen, amino or Cx_4 alkoxy; and n is 0.

The method according to claim 1, characterized in that Q is CHR3, W is CH, Y is N, and X and Z are independently selected from CH and CR4, and n is 1

68. A pharmaceutical composition, characterized in that it comprises a pharmacologically acceptable and effective amount of a compound of formula (I), according to any of claims 35 to 48, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

69. A viral replication inhibitory pharmaceutical composition for inhibition of virus replication other than cytomegalovirus, characterized in that it comprises an acceptable inhibitory amount of a compound of formula (I), according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

70. The pharmaceutical composition inhibiting "the replication of cytomegalovirue (CMV), characterized in that it comprises an CMV-acceptable amount of a compound of formula (I), as defined according to any of claims 49 to 63, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

71. An antiviral pharmaceutical composition, characterized in that it comprises an acceptable antiviral amount of a compound according to claim 64, in association with a pharmaceutically acceptable carrier. COMPOUNDS ANTIVIRA IS SUMMARY OF THE INVENTION The present invention relates to heterocyclic compounds having antiviral activity. In particular, compounds of formula (I) wherein B, W, X, Y, Q, Rx, R2, R3, R4 and n are as defined herein, which are useful in therapy and prophylaxis of viral infection in mammals.