MXPA06007324A - Polycyclic agents for the treatment of respiratory syncytial virus infections - Google Patents

Abstract

Compounds of formula (I), and their use as in the treatment of infections involving viruses of the Pneumovirinae sub-family (RSV) are disclosed. In the formula ring (A) may be phenyl, pyridyl etc., (B-C) may be CH2-CH2etc., (R1) may be phenyl and substituted forms thereof, (R2) may be assorted substituents.

Description

POLYCYCLIC AGENTS FOR THE TREATMENT OF RESPIRATORY INFECTIONS OF SYNCTIAL VIRUS Field of the Invention The present invention relates to antiviral compounds, methods for their preparation and compositions containing them, and use in the compounds and composition in the treatment of viral infections. In particular, the invention relates to the use of compounds of formula I for the treatment of respiratory infection of the syncytial virus. BACKGROUND OF THE INVENTION The respiratory syncytial virus (RSV) is the main cause of lower respiratory tract infection in adults and in young children. In the western world approximately all children have been infected at the age of two. In most cases RSV infections would be the only minor causes in upper respiratory diseases with symptoms that resemble that of the common cold. However, severe infection with the virus can result in bronchiolitis or pneumonia that can result in hospitalization or death. Infants who are born prematurely or have a pre-existing lung disease are at high risk of severe infection and complications. Respiratory syncytial virus (RSV) is a member of the order of Mononegalyla, which consists of negative-strand RNA viruses not segmented in the families Paramyxoviridae, Rhabdoviridae and Filoviridae. The human RSV (often called RSV or H RSV) is a member of the Pneumovirus genus of its b-family Pneumovirinae within the Paramyxoviridae Family. Other members of the genus Pneumovirus include viruses such as RSV bovi no (BRSV), ovine RSV (ORSV) and vi rus of murine pneumonia (M PV) among others. The Pneumovirinae sub-family also includes the genus Metapneumovirus that contains the metaneumophilus pathogen of recently identified and important humans. In addition to the aspects or features of the genome described above, the characteristics of the Family include a lipid layer containing one or more glycoprotein species considered to be associated with the binding and entry of the host cell. The input is considered to require a process by which the viral layer fuses with the membrane of the host cell. The fusion of the cells infected with, for example, their neighbors or nearby, can also result in the formation of fused lynuclear cells known as if they were found in some cases. The fusion process is believed to be mediated glycoprotein and is a trait formed with the various viruses developed in other taxonomic groups. In the case of Paramyxoviridae viruses of all genres, they characteristically express a fusion glycoprotein (F) that mediates mem brane fusion. The only currently approved drug for the treatment of severe RSV is antiviral medication, Virazole, also known as Ribavirin. This agent has a broad antiviral spectrum with virustatic effects, and acts by inhibiting the replication of RSV. It also improves the oxygenation of the arterial blood. Unfortunately, the agent is toxic so that the administration of the agent is confined to a hospital environment. Its ad ministration is also complicated by the need to follow a strict procedural process when the agent is administered to minimize the likelihood or likelihood of certain adverse effects. The agent has some adverse effects including sudden deterioration of respiratory function (bronchiospasm). The efficacy of the agent has remained indisputable and thus there is a real need to find an alternative agent for the treatment of RSV infection. Some agents are known to inhibit RSV. The published patent applications WO 01/9591 0 and WO 02/26228 (Bristol Myers Squib Company), the contents of which are incorporated by cross-reference, disclose several different types of compounds which exhibit anti-RSV activity in their description of the antecedent technique. In addition, these applications describe compounds that have antiviral activity against the RSV of the formula: There are also some patent specifications that describe imidazo- [2, 1-a] -isoi ndol derivatives for different uses of the RSV treatment. U.S. Patent 3, 507, 863 discloses a variety of polycyclic compounds that have anti-inflammatory and anticonvulsant activity. These compounds have the following general structure: where A is -NH-, -O- or -S-, and n is 1-3. U.S. Patent 3,770,766 describes polycyclic compounds having antidepressant activity, and has the following general structure: wherein R3 is selected from various aromatic substituents. U.S. Patent 4,058,529 describes polycyclic compounds of anti-inflammatory and anticonvulsant activity of the general formula A, and includes compounds of the formula B wherein R 2 is hydrogen or a lower alkyl group (including substituted amino groups) and n is 1- 3.

Formula A Formula B CH 482.697 (Graf) describes some compounds of the general formula B above, wherein R2 is -CO-CHR-N3 and R is hydrogen or alkyl, and the intermediates wherein R2 is -CO-CHR-NH2 , -CO-CHR-OH or hydrogen. Likewise, U.S. Patent No. 3,590,043 (Graf) refers to compounds of the formula B wherein R2 is -CO-CHR-NR'R. "In this document n is from 1 to 3, R is H or alkyl lower, R 'and R "may be lower alkyl or benzyl or together they form a piperidinyl or morpholinyl ring. The Graf compounds may have anti-inflammatory uses. WO 02/066479 (Banyu Pharmaceutical) lists some compounds of the general formula B, wherein R2 is lower alkyl, -CO-C2Hs and selected from other portions. It also seems to suggest a compound of formula B wherein the fused phenyl ring has been replaced with pyridyl and R2 is methyl. It is not clear if all these compounds have been made. The compounds are for use in the treatment of high blood pressure and diabetes. GB 1,038,735 describes anti-inflammatory compounds of the general formula B, wherein n is from 1 to 3, R 2 is lower alkyl or, for example, a dimethylaminoethyl group. The Canadian patent application No. 2,108,899 (also see WO 92/16207 family member) describes various oxazolo- [2,3-a] -isoindole and mldazo- [2,1-a] -isoindole derivatives for use in antiviral drugs, particularly for use in the treatment of AIDS and HIV. There are marked differences between HIV and AIDS viruses, diseases are associated with, and the respective modes of action of the described compounds. The specification generally describes compounds of the structure below wherein R is an alkyl group of C-i-Cß or an acyl group of C6-C6, and specifically describes compounds wherein R is -COCH3 or -CH3.

Some documents describe compounds of the above formula or substituted forms thereof, wherein R is hydrogen. See for example the herbicidal compounds described in U.S. Patent Nos. 4,726,838 and 4,846,876. Summary of the Invention The invention relates to the discovery that certain compounds exhibit favorable anti-RSV activity by inhibiting the essential fusion processes of the RSV virus. This invention provides for the use of a compound of formula I Formula I its salts, and pharmaceutically acceptable derivatives thereof, in the treatment of respiratory syncytial virus (RSV) infections, wherein R-i is selected from C- | 12 alkyl, C2 alkenyl. 2, C2.12 alkynyl, - (CH2) n-cycloalkyl of C3.7, (CH2) n-cycloalkenyl of C4.7, - (CH2) naril, - (CH2) naril-alkyl of C -? - 12, - (CH2) ) C2.12 - (CH2) naril alkynyl naril alkenyl, C2-12 alkynyl. and - (CH2) nheterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R2 is selected from -CH2R3, -C (Y) R3, -C (Y) OR3, -C (Y) N (R4) R3, -C (Y) CH2N (R4) R3, -C (Y) CH2SR3 and -S (O) w R 6, wherein R 3 is selected from hydrogen, C 1 -C 2 alkyl, C 2 alkenyl, C 2. 2 alkynyl, - (CH 2) cycloalkyl C 3,7, - ( CH2) C4.7 cycloalkenyl, - (CH2) maryl, - (CH2) maryl-C-? 12l- (CH2) alkyl, C2.12 alkenyl, - (CH2) maryl-alkynyl of C2_? 2 , and - (CH2) mheterocyclyl; and when R2 is -CH2R3, or -C (Y) R3, R3 can also be selected from -S-R5 and -O-R5; m is 0-6; R4 is hydrogen or C ^ e alkyl, "R5 is C6_6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3 cycloalkyl, C4.7 cycloalkenyl, benzyl, aryl or heterocyclyl; 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted: X and Y are independently selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy, A together with the atoms to which it is attached, forms an optionally substituted aromatic ring, BC together with the atoms to which they are attached, form an optionally substituted heterocyclic ring having from 5 to 8 ring atoms The invention also provides for the use of compounds of formula I, their salts, and pharmaceutically acceptable derivatives thereof, in the treatment of RSV infections by inhibiting the fusion processes of the virus. n provides novel compounds of formula I, their salts, and pharmaceutically acceptable derivatives thereof. Detailed Description of the Invention As used herein, the term "aromatic" refers to aryl ring systems or rings or aromatic heterocyclic ring systems, as well known as heteroaryl rings or heteroaromatics. As used herein the term "aryl" refers to carbocyclic aromatic (non-heterocyclic) rings or ring systems. The aromatic rings can be mono- or bi-cyclic ring systems. The rings or aromatic ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like. Preferred aryl groups include phenyl, naphthyl, n-nyl, azulenyl, fluorenyl or anthracenyl. The term "heterocyclic" or "heterocyclyl" as used herein refers to mono or bicyclic ring systems or systems that include one or more heteroatoms selected from N, S, and O. Rings or ring systems generally include 1 to 9 carbon atoms in addition to the heteroatom (s) and can be saturated, unsaturated or aromatic (including pseudoaromatics). The term "pseudoaromatic" refers to a ring system that is not strictly aromatic, but is stabilized by electron de-caking and behaves in a manner similar to aromatic rings. Aromatic includes pseudoaromatic ring systems, such as furyl, thienyl and pyrrolyl rings.

Examples of monocyclic 5-membered heterocycles include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4-thiadiazolyl). Examples of monocyclic 6-membered heterocycles include pyridyl, pyrimidinyl, piridazinllo, pyranyl, pyrazinyl, piperidinyl, 1, 4-dioxanyl, morpholinyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-trithianyl and triazinyl. The heterocycles may be optionally substituted with a wide range of substituents, and preferably with C? _6 alkyl, C - ?. alkoxy, C 2-6 alkenyl. C2.6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono- or di (C1.6 alkyl) amino. The heterocycle can be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl and anthracel. Examples of bicyclic heterocycles of 8, 9 and 10 members include 1H thieno [2,3-c] pyrazolyl, thieno [2,3-b] furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl , Ndazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purylnyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like. These heterocycles can be optionally substituted, for example with alkyl of d. 6, C alkoxy, C2.6 alkenyl, C2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono- or di (C ?6) alkylamino. Examples of preferred heterocyclic radicals include (optionally substituted) isoxazoles, isothiazoles, 1,3,4-oxadiazoles, 1,4-thiadiazoles, 1,4-oxadiazoles, 1,2,4-thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines, pyrimidines, pyrazines, 1, 2,4-triazines, 1, 3,5-triazines, benzoxazoles, benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines and quinoxalines. These heterocycles can be optionally substituted with, for example, C 2-6 alkoxy alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, cyano or mono or di (alkyl). C -? - 6) amino. Examples of particularly preferred heterocyclic radicals include furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, sotiazolilo, 1, 2,3-triazolyl, 1, 3,4-triazolyl, 1, 2,3-thiadiazolyl, 1, 3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo [b] furanyl, benzo [b] thiophenyl and benzoisoxazolyl. Examples of unsaturated 5-membered heterocyclic rings include oxazole, thiazole, imidazole, 1,2,3-triazole, isoxazole, isothiazole, pyrazole, furan, thiophene and pyrrole. Examples of 6-membered, unsaturated heterocyclic rings include pyridine, pyrimidine, pyrazine, pyridazine and 1,2,4-triazine. In a preferred embodiment, the heterocyclic ring is an aromatic ring. Heteroaryl and heteroaromatics as used herein refer to this subset of heterocyclic rings. Heteroaryl rings include furyl, thienyl, pyridyl, plrrolilo, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolllo, sotiazolilo, 1, 2,3-oxadiazolllo, 1,2,4-oxadiazolyl, 1, 2,4-oxadiazol-5- ina, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1H-thieno [2,3-c] pyrazolyl, thieno [2,3-b] ] furyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzlmidazolyl, tetrazolyl, uridinyl and cltosinyl. More preferably heteroaryl or heteroaromatic is selected from isoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furazanyl, triazolyl, pyridyl, pyrimidinyl, furyl, pyrazolyl, pyridazinyl, thienyl and aryl, fused heteroaromatic rings such as benzofuranyl, benzothiophenyl and benzoisoxazolyl. In another preferred embodiment, the heterocyclic ring is a nonaromatic 2-imidazolidone ring selected from the group consisting of pirrolldina, imidazoline, 2-pyrrolidone, pyrrolin-2-one, tetrahydrofuran, 1, 3-dioxolane, piperidine, tetrahydropyran, oxazoline , 1,3-dioxane, 1,4-piperazine, morpholine and thiomorpholine. The heterocyclic ring containing the linker group B-C may be selected from the heterocyclic rings described above, provided that the ring meets the requirement to contain at least two nitrogen atoms and excludes the aromatic ring systems. Unless defined otherwise, the term "optionally substituted" as used herein means that a group may include one or more substituents that do not interfere with the binding activity of the compound of formula I. In some cases the substituent can be selected to improve the union. The group can be substituted with one or more substituents selected from halogens, C- [alpha] 6 alkyl, C2.6 alkenyl, C2.6 alkynyl, - (CH2) C3.7 cycloalkyl, - (CH2) cycloalkenyl C4.7, - (CH2) paryl, - (CH2) pheterocyclyl, -C6H4S (O) talkyl of, -C (Ph) 3, - (CH2) PZ, -COZ, -CN, -OR, OR, - OCOR, -COR, -COOR, -OCONR'R ", -NR'R", -NRCOR ', -NRCONR'R ", -NRC (S) NR'R", -NRSO2R \ -NRCOOR', C (NR ) NR'R ", -CRNOR ', -C (= NOH) NR'R", -CONR'R ", C (= NCN) -NR'R", -C (= NR) NR'R ", - C (= NR ') SR ", NR'C (= NCN) SR", -CONRSO2R', -C (S) NR'R ", -S (O) tR, -SO2NR'R", -SO2NRCOR ', -OS (O) 2R, -PO (OR) 2 and -NO2, where p is 0-6, t is 0-2, Z is an N-linked amino acid selected from the group consisting of alanine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, pipecolic acid, amino-butyric acid, a-amino-propanoic acid, and iminodiacetic acid, Z is bonded through a nitrogen atom of the N-linked amino acid to the carbon atom, and each R , R 'and R "is selected independently of H, C? _6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3.7 cycloalkyl, C7 cycloalkenyl, aryl, heterocyclyl, C? -6 alkylaryl, and C? alkylheterocyclyl? _6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkyl alkylaryl or C 1-6 alkylheterocyclyl, can optionally be substituted with one to six of the same or different ones selected from halogen, hydroxy, lower alkyl , lower alkoxy, -CO2H, CF3, CN, phenyl, NH2 and -NO2; or when R 'and R "are attached, they form a 5- to 7-membered nitrogen containing heterocyclic ring When the optional substituent is or contains an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic group, the group can itself being optionally substituted with one to six of the same or different halogen, hydroxy, lower alkyl, lower alkoxy, haloalkyl of C- | 6 (including -CF 3), phenol, benzyl, -CN, -C (O) -Calkyl -6, mercapto, -NH2, mono- or di (lower alkyl) amino or -NO2 In relation to the nitrogen-containing heterocyclic rings, unless otherwise defined optionally substituted includes Pyridinium salts and the N-oxide form of suitable nitrogens in the ring With regard to carbocyclic or non-aromatic heterocyclic compounds, unless otherwise defined, such compounds may also be optionally substituted with one or two = O groups , in place or in addition ion to the optional substituents described above. Examples of optional substituents include halogens, C? - alkyl, C2.4 alkenyl, C2 alkynyl. , C-? alkoxy? , haloalkyl of d.4, -CF3, -OH, phenyl, -NH2, -NH-alkyl of d-4, -N (C- | 4) 2, -CN, mercapto, C 1 alkoalcarbonyl and alkoxycarbonyl of C - ?. 4. As used herein the term "C 12 alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, rv-butyl, isobutyl, sec-butyl or tert-butyl. Similarly, "d-6 alkyl" or "lower alkyl" refers to such groups having from 1 to 6 carbon atoms.

As used herein the term "C3 cycloalkyl." Refers to saturated, non-aromatic cyclic groups having from 3 to 7 carbon atoms. Examples include cyclopentyl and cyclohexyl. As used herein the term "alkoxy" refers to a covalently branched or linear alkyl group, bonded via an O bond and the terms "d6 alkoxy" and "lower alkyl" refers to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t- butoxy and the like. As used herein the term "C2-? 2 alkenyl" refers to groups formed from straight-chain or branched C2-? 2 non-cyclic hydrocarbon containing one or more double bonds. Examples of C2.12 alkenyl include allyl, 1-methylvinyl, butenyl, iso-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,3-butadienyl, 1,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl and 1, 3,5-hexatrienyl. As used herein the term "C4.7 cycloalkenyl" refers to non-aromatic carbocycles having 4 to 7 carbon atoms and having one or more carbon double bonds. Examples include cyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl, 1,3-cyclopentadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl. As used herein the term "alkynyl of C2-12"refers to a linear or branched non-cyclic C2.12 hydrocarbon containing one or more triple bonds, preferably one or two triple bonds, examples include 2-propynyl and 2- or 3-butynyl. "aryl-d-2 alkyl" refers to carbocyclic aromatic ring or ring systems as previously described and substituted by an alkyl group of d-12, also as previously described, likewise the terms "aryl-alkenyl of C2.12. "and" C2.12 aryl-alkynyl "refer to carbocyclic aromatic ring or ring systems as previously described and substituted by an alkenyl group of C2.sub.2 or alkynyl of C2.sub.2, as previously described. The aryl group and the alkyl, alkenyl or alkynyl group can be optionally substituted, preferably the aryl group is not optionally substituted, preferably the alkyl, alkenyl or alkynyl group is optionally substituted, and more preferably with a substitute is selected from halogens, -CN, -NR'R ", -COR, -COOR, or -CONR'R". Preferably R, R 'and R "are independently selected from hydrogen or lower alkyl, and as used herein, the term" halo "or" halogen "refers to fluoro, chloro, bromo and iodo groups. present a "haloalkyl" groups has one or more of the hydrogen atoms on an alkyl group replaced with halogens. An example includes -CF3.

Particularly preferred compounds of the invention include those compounds wherein A is a bivalent bond of 3 or 4 atoms selected from C, N, O and S. In that arrangement A and the atoms to which they are attached together form an aromatic ring having Five or six atoms in the ring. When the binding atoms are all carbon, the ring formed is a ring or carbocyclic aromatic ring system. When the linking atoms include one or more of N, O or S then the ring formed is an aromatic heterocyclic ring. Examples include where the substructure is:- Ring A is preferably an optionally substituted aryl or heteroaryl ring, more preferably a phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring, and more preferably a phenyl or pyridyl ring. Substituents optionally include N-oxides of the nitrogen atoms in the ring. The aromatic rings may be optionally substituted, preferably by not more than 3 substituents. Of the optional substituents, it is particularly preferred for use of 1 to 3 substituents selected from halo, lower alkyl, halogenated forms of lower alkyl, hydroxy, lower alkoxy, nitro, amino, lower alkylamino, carboxy, carboxamido, phenyl and benzyl. N-oxide forms of the nitrogen atoms of the nitrogen-containing rings are also preferred. When A is a pyridyl ring, the nitrogen in the ring may be in an N-oxide form, or the ring may be in the form of a pyridinium salt. With respect to the heterocyclic ring formed by B-C, it would be understood that this ring may not be selected from all of the heterocyclic rings discussed in the foregoing regarding the meaning of the term due to the atoms to which B-C are attached. This ring is limited to non-aromatic, monocyclic heterocyclic rings that include at least two nitrogen atoms. The ring may include additional heteroatoms and may be partially unsaturated. Particularly preferred compounds are those in which B-C represents a bivalent bond of 1 to 3 atoms. The bond B-C together with the atoms to which it is bound form a non-aromatic heterocyclic ring. Examples include where the substructure: - is: In a preferred form of the invention, B-C represents -CH2- (CH2) Z-, where z is 1-4, more preferably 1, 2 or 3, more preferably 1 or 2 and more preferably z is 1. The atoms that form the B-C link can be optionally substituted, preferably by no more than 3 substituents. A wide range of substituents are possible and include halo, lower alkyl, hydroxy, lower alkoxy, phenyl and benzyl. A preferred form of the invention includes those compounds wherein B-C represents -CH2CH2-. Preferably X is oxygen or sulfur, more preferably X is oxygen. In one embodiment of the invention, the fused ring A and the ring containing the bivalent B-C bond are optionally substituted with one or two substituents independently selected from halogen, C | _6 alkyl. Preferably the fused ring A and the ring containing the bivalent B-C bond are not substituted. R-i may be an optionally substituted aryl, alkyl or heterocyclyl. Preferably Ri is an optionally substituted aryl or heterocyclyl group, more preferably a phenyl, thienyl, pyrrolyl or pyridyl ring. R ^ can also be an alkylphenyl group of d6. The Ri rings can optionally be substituted with halo, hydroxy, nitro, -N R'R "(where R 'and R" are selected independently from hydrogen, lower alkyl and -C (O) R, where R is C -? - 6 alkyl, phenyl or heterocyclyl), C? 2, phenyl and -O-Ra, where Ra is -alkyl of C- | 12, -cycloalkyl of C3.7, -alkyl of C? .12-cycloalkyl of C3.7, phenyl or -alkylphenyl of d.- ?2; and the d.sub.2 alkyl group, phenyl or Ra can be optionally substituted with halo, -CN, -NR'R ", -CO2R or -CONR'R", where R, R 'and R "are independently selected from hydrogen or lower alkyl Preferably, the ring is phenyl and is optionally substituted at the para or position 4. Ri can be -phenyl substituted with an alkyl chain of C.-10, where the alkyl chain is substituted with halo, -CN , -NR'R ", -CO2R or -CONR'R", wherein R, R 'and R "are independently selected from hydrogen or lower alkyl. More preferably the alkyl chain is in the 4-position of the phenyl ring, and the substituents are attached to the carbon at the free end of the alkyl group. Ri can be phenyl optionally substituted with a substituent selected from halo, -alkyl of d-6, -alkylhalo of C? _6, -alkyl of d.6CN, -alkyl of C- | .6, -Oalkylhalo of d-6, -Oalkyl of C1_6CO2NH2, -Oalkyl of d.6CN, -Oalkyl of C6-6-cycloalkyl of C3.7, -Oalkyl of C? -6C6H5, -Oalkyl of d.6OCH3, -OC6H5, -OC6H4halo, -CF3, - OCF3, -NR'R "(where R 'and R" are independently selected from hydrogen, -C (O) alkyl of d.6, -C (O) C6H5, C (O) CH = CHCO2H, -C (O) alkyl of d.6CO2H, -C (O) alkyl of C6- CO2CH3, -C (O) alkyl of C6-6C6H5, -C (O) alkyl From d. 6C6H4CH3, -C (O) alkyl of d.6-C6H4OCH3 and -C (O) alkyl of C1.6C6H4halo), -CO2H, -CO2alkyl of d.6, -NO2, -OH, -C6H5, -C6H4alkyl of C? .6, -C6H4halo and -OC (O) alkyl of Of preferably Ri is halophenyl, more preferably 4-chlorophenyl. Compounds where R2 is hydrogen are not part of the present invention. These compounds are useful as intermediates for the production of compounds of the invention wherein R2 is not hydrogen. Preferably, R 2 is not an unsubstituted d 6 -alkyl or unsubstituted C 6 0 -alkyl. When R2 is -CH2-R3, it is preferred that R3 is - (CH2) m aryl or - (CH2) m heterocyclyl, where m is from 0 to 3. R3 can be benzyl (m = 1). The ring atoms may be optionally substituted with a wide range of substituents. Preferred substituents are selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl. When R2 is -C (Y) -R3, it is preferred that Y is O. It is also preferred that R3 is - (CH2) m aryl or - (CH2) m heteroarylo, wherein m is from 0 to 3. It is particularly preferred for R3 to be aryl or heteroaryl (m = 0), and more preferably a 5 or 6 membered monocyclic heterocycle or a 9 or 10 membered bicyclic heterocycle or an aryl group. When R2 is -C (Y) CH2N (R4) R3 or -C (Y) CH2S R3, R3 is preferably - (CH2) m aryl or - (CH2) m heterocyclyl where m is from O to 3. The heterocyclic to itself to be substituted with an oxo, hydroxy or lower alkyl group. More preferably R3 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyl) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl. , pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4-triazolyl), tetrazolll, thiadiazolyl (including 1,2,3 and 1,3,4-thiadiazolyl), pyridyl, pyrimidinyl, pyridazinyl , pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-trityanil, triazinyl, 1H-thieno [2,3-c] pyrazolyl, thieno [2, 3-b] furyl, indolyl, isoindyl, benzofuranyl, benzothienyl, benzoxathiolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinilinyl, quinoxalinyl, uridinyl, purinyl, cinolini lo, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl or pteridinyl . The heterocyclic ring can be fused to a carbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl. The aryl or heterocyclic may be optionally substituted with a wide range of substituents and preferably with alkyl of d_6, alkoxy of Ci-β, alkenyl of C2.6, alkynyl of C2.6, halo, hydroxy, mercapto, trifluoromethyl, amino, nitro, cyano and mono or di (d.6) alkyl amino. Substituents also include phenyl, benzyl and heterocyclyl.

More preferably R3 is selected from phenyl, furyl, thienyl, pyridyl, oxazole, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, 1,2,3-thiadiazolyl , 1,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo [b] furanyl, benzo [b] thiophenyl and benzoisoxazolyl. When R2 is -COR3 it is also preferred for R3 to be phenyl-C1-10 alkyl, wherein the alkyl is substituted with halo, -CN, -NR'R ", -CO2R or -CONR'R", where R, R 'and R' are independently selected from hydrogen or lower alkyl, More preferably the alkyl chain is in the 4-position of the phenyl ring, and the substituents are attached to the carbon at the free end of the alkyl group When R2 is CON (R4) R3 is preferred for R4 to be hydrogen and R3 to be - (CH2) m aryl or - (CH2) m heterocyclyl, preferably m is from 0 to 2, more preferably from 0 to 1. The atoms of the aryl and heteroaryl ring can be optionally substituted with a wide range of substituents Preferred substituents include halo, lower alkyl, hydroxy, lower alkoxy and phenyl. Another preferred embodiment of the invention are those compounds wherein R2 is -COR3 and the fused ring A contains at least one nitrogen atom in the ring. When the invention relates to compounds of formula I per se, it is preferred that when Ri is unsubstituted phenyl, X is O, A together with the atoms to which it is attached forms an unsubstituted phenyl ring and BC is -CH2CH2-, R2 is unsubstituted d6 alkyl or -C (O) alkylo of d -6. It will be appreciated that the compound of formula I and some derivatives thereof may have at least one asymmetric center, and therefore are capable of existing in more than one stereoisomeric form. The invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers can be separated conventionally by chromatographic methods or by using a resolving agent. Alternatively individual isomers can be prepared by asymmetric synthesis using chiral intermediates. When the compound has at least one carbon-carbon double bond, it can occur in the Z and E forms and all isomeric forms of the compounds are included in the present invention. The salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that none of the pharmaceutically acceptable salts will also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. . The term "pharmaceutically acceptable derivatives" includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates, and pharmaceutically acceptable addition salts of the compounds or derivatives. The pharmaceutically acceptable derivatives can include any pharmaceutically acceptable salt, solvate, hydrate or any other compound or prodrug which, in administration to a subject, is capable of providing (directly or indirectly) a compound of formula 1 or an antivirally active metabolite or a residue of the same. The pharmaceutically acceptable salts include acid addition salts, base addition salts, pharmaceutically acceptable salts of esters and the salts of quaternary amines and pyridiniums. The acid addition salts are formed of a compound of the invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulfonic, benzenesulfonic, acetic, propionic, ascorbic, citric acids, malonic, fumaric, maleic, lactic, salicylic, sulphamic or tartaric. The counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, citrate, acetate, malonate, fumarate, sulfamate and tartate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium.

Also, groups containing basic nitrogen can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; sulfates such as dimethyl and diethyl sulfate; and others. The salts can be made in a known manner, for example by treating the compound with an appropriate acid or base in the presence of a suitable solvent. The compounds of the invention may be in crystalline form or as solvates (for example hydrates) and both forms are intended to be within the scope of the present invention. The term "solvate" is a complex of the variable stoichiometry formed by a solute (in this invention, a compound of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. The solvents may be, by way of example, water, ethanol or acetic acid. Solvation methods are generally known within the art. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a hydroxy group is converted to an ester derivative or a nitrogen atom in the ring is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphatesters and those formed of amino acids, preferably valenes. Any compound that is a prodrug of a compound of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in textbooks, such as "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985. The term "pharmaceutically acceptable ester" includes biologically acceptable esters of the compound of the invention as sulfonic, phosphonic and carboxylic acid derivatives. Thus, in another aspect of the invention, there is provided a pharmaceutically acceptable prodrug or ester of a compound of formula I. In another aspect of the invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of the anti-RSV compounds mentioned above of formula I, including pharmaceutically derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent. Unless otherwise specified the terms "treatment" or "treating", in the context of a method or use of the invention, includes both therapeutic and prophylactic treatments. In another aspect of the present invention, there is provided the use of a compound of formula I, its salts or pharmaceutically acceptable derivatives thereof in the preparation of a medicament for the treatment (therapeutic or prophylactic) of RSV infections. In another aspect of the invention, there is provided a method of treating RSV by administering a compound of formula I, including the administration of pharmaceutically acceptable salts, or derivatives such as prodrugs of formula I, or a composition containing minus a compound of formula I, to a patient in need of such treatment. In another aspect of the invention, there is provided a method for treating mammals infected with RSV, and in need thereof, which comprises administering to the mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I or derivatives thereof. pharmaceutically acceptable thereof. In another aspect of the invention, there is provided a method for preventing infection in mammals with RSV, which comprises administering to the mammal a therapeutically effective amount of one or more of the aforementioned compounds of formula I, or pharmaceutically acceptable derivatives of the same. Although the invention has been described with reference to the treatment of RSV, and in particular RSV in humans, it will be appreciated that the invention may also be useful in the treatment of other viruses of the Pneumovirinae sub-family, more particularly, the Pneumovirus and Metapneumovirus genera, more particularly RSV and animal and human strains. metapneumovirus. In a further form of the invention there is provided a process for the production of compounds of formula I. These compounds can be prepared using the procedure described in the following methods. Scheme 1 represents a general process for the preparation of compounds of formula III. The compounds of formula III are intermediates, similar to formula I but where R2 is H. The compounds of formula III can be prepared via appropriate starting materials of formula II. General methods for the preparation of 2- (aroyl) benzoic acids and 3- (aroyl) pyridine-2-carboxylic acids of formula II are described by Yamaguchi, M. et al., J. Med. Chem. 1993, 36, 4052 -4060 and Natsugari, H. et al., J. Med. Chem. 1995, 38, 3106-3120. Scheme 1 Formula II Formula III In general, an equivalent of an appropriate keto acid of formula II is reacted with about 3 equivalents of an appropriate diamine of the general formula H2N-B-C-NH2. The mixture is heated under reflux in an inert solvent, such as a toluene or xylene, with a Dean-Stark apparatus for 3-10 hours. A catalyst, such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product is filtered and recrystallized from an appropriate solvent. If the precipitate is not formed, the solvent is evaporated in vacuo and the residue recrystallized or purified using flash chromatography or preparative HPLC. The compounds of formula III can also be produced by the methods described in US 4,058,529, Suikowski, T.S., et al., J. Org. Chem. 1967, 32, 2180-2184 and Houlihan, W. J., et al., J. Med. Chem. 1975, 18, 182-185. Other (novel) compounds of formula I can be obtained by acylating compounds of formula III as described in Scheme 2. Scheme 2 Formula III Formula i In one method, two equivalents of diisopropylethylamine or triethylamine are added to one equivalent of a compound of formula I I in THF at 0 ° C. An acid chloride, or other acylating agent, is added to the mixture and the reaction is monitored by H PLC. When the reaction is complete, it is quickly cooled with water and the product is extracted in a suitable organic solvent and made according to standard methods. Similar acylation can also be carried out by reacting an equivalent of the compound of formula I I I with an equivalent of the appropriate acid chloride in xylene at 120 ° C for 1-24 hours. The reaction is then allowed to cool and the product is isolated. Alternatively, compounds of formula I I I may be treated with approximately 2.2 equivalents of an appropriate anhydride or acid chloride in pyridine at about -5 ° C. The mixture was allowed to warm to room temperature and after stirring for 2-24 hours the product was isolated by standard methods. Acylation can also be achieved by treating the appropriate compound of formula I I I with the appropriate carboxylic acid (3 equivalents), TFFH (3.3 equivalents) and DI EA (3.3 equivalents) in DM F and heating to 45CC for about 14 days. After this time the product was isolated by standard methods. The N-alkylated and N-sulfonylated compounds of Formula I are best obtained using suitable N-substituted diamines. These can be prepared by known methods, for example that described by Kruse L.I., et al., J. Med. Chem. 1990, 33, 781-789.

Where R2 is -CHR3 or -S (O) 2R5, as defined above in the summary of the invention. Therefore, the appropriate keto-acid (2 equivalents) and the N-substituted diamine (1 equivalent) in chlorobenzene, toluene and xylene are replaced in a flask equipped with a Dean-Stark stirrer and water separator and heated to a Reflux until no additional water is observed to separate (1-8 hours). The solvent is then removed by distillation and the residue is cooled. The residue can be purified using standard methods. Compounds of Formula I are prepared, where R2 is a urea or thiourea using the following method. An equivalent of the appropriate compound of formula III is reacted with an equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20-120 ° C for 1-24 hours. The reaction is then allowed to cool and the filtrate is washed and generally recrystallized from an appropriate solvent. If no precipitate is formed, the product can be purified using standard chromatographic methods. Other compounds of formula I can be prepared by the addition, removal or modification of existing substituents. This could be achieved using standard techniques for an inter-conversion functional group, well known in the industry such as those described in Comprehensive Organic Transformations: a guide for functional group preparations (Comprehensive organic transformations: a guide to functional group preparations by) Larock RC , New York, VCH Publishers, Inc. 1989. Examples of functional group interconversions are: -C (O) NR'R "of -CO2CH3 by heating with or without catalytic metal cyanide, for example NaCN, and HNR ' R "in CH3OH; -OC (O) R of -OH with, for example, CIC (O) R in pyridine; -NC (S) NR'R "of -NHR with an alkylsothiocyanate or thiocyanic acid; -NRC (O) OR 'of -NHR with alkyl chloroformate; -NRC (O) NR'R" of -NHR by treatment with a isocyanate, for example, HN = C = O or RN = C = O; -NRC (O) R 'of -NHR by treatment with CIC (O) R' in pyridine; -C (= NR) NR'R "of -C (NR'R" SR with H3NR + OAc "by heating in alcohol; -C (NR'R") SR of -C (S) NR'R "with Rl in an inert solvent, for example acetone; -C (S) NR'R "(where R 'or R" is not hydrogen) of -C (S) NH2 with HNR'R "; -C (= NCN) -NR 'R' of -C (= NR'R ") - SR with NH2CN by heating in anhydrous alcohol, alternatively of -C (= NH) -NR'R" by treatment with BrCN and NaOEt in EtOH; -NR-C ( = NCN) SR of -NHR 'by treatment with (RS) 2C = NCN; -NR "SO2R of -NHR' by treatment with CISO2R by heating in pyridine; -NR'C (S) R of -NR'C (O ) R by treatment with a Lawesson's reagent [2,4-bis (4-methoxyphenyl) -1, 3,2,4-dithiadiphosphetan-2,4-disulfide]; NRSO2CF3 of -NHR with a triflic anhydride and a base, -CH (NH2) CHO of -CH (NH2) C (O) OR 'with Na (Hg) and HCI / EtOH; -CH2C (O) OH of -C (O) OH by treatment with SOCI2 then CH2N2 then H2O / Ag2O; -C (O) OH of -CH2C (O) OCH3 by treatment with PhMgX / HX then acetic anhydride then CrO3; R-OC (O) R 'of RC (O) R' by R "CO3H; -CCH2OH of -C (O) OR 'with Na / R'OH; -CHCH2 of -CH2CH2OH by the Chugaev reaction; -NH2 of -C (O) OH by the Curtius reaction; -NH2 of -C (O) NHOH with TsCI / base then H2O; -CHC (O) CHR of -CHCHOHCHR using the Dess-Martin Periodinane reagent or CrO3 / H aqueous SO4 / acetone; -C 6 H 5 CHO of -C 6 H 5 CH 3 with CrO 2 Cl 2; -CHO of -CN with SnCl2 / HCl; -CN -C (O) NHR with PCI5; -CH2R of -C (O) R with N2H4 / KOH. During the reactions some of the portions may need to be protected. Suitable protecting groups are well known in the industry and have been described in many references such as Protective Groups in the Organic Synthesis (Protecting Groups in Organic Synthesis), Greene TW, Wiley-Interscience, New York, 1981. The abbreviations that may be used herein, including in Schemes 1-11, and experimental section are as follows unless otherwise indicated: DCM: dichloromethane DIEA: diisopropylethylamine DMF: dimethylformamide Et: ethyl EtOAc: ethyl acetate Me: methyl MeOH: methyl alcohol MS: mass spectrometry NMR: nuclear magnetic resonance Ph: phenyl HPLC: high performance liquid chromatography TEA: triethylamine TFA: trifluoroacetic acid TFFH: fluoro hexafluorophosphate -N, N, N ", N" -tetramethylformamidinium THF: tetrahydrofuran TsCI: tosyl chloride TsOH: toluenesulfonic acid The invention also pertains to therapeutic compositions containing at least one compound of formula I including pharmaceutically acceptable salts or prodrugs. The compositions may also contain one or more other compounds which have anti-viral activity with respect to RSV, such as Vi razole, or other agents such as RespiGam or Synag is. The compositions may also contain or be administered in combination with other drugs to treat symptoms of the disease, such as for example anti-inflammatory drugs. The term "com position" is intended for the formulation of an active ingredient with conventional carriers and excipients, and also with encapsulating materials such as the carrier, to give a capsule wherein the active ingredient (with or without other carriers) is enclosed by the encapsulation carrier. As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the animal to be treated. It is believed that the choice of a particular carrier or delivery system, and the route of administration could easily be determined by a person skilled in the art. In the preparation of any formulation containing the care of the compounds, they should be taken to ensure that the activity of the compound is not destroyed in the process and that the compound is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the compound by means known in the art, such as, for example, micro-encapsulation. Similarly, the chosen route of administration should be such that the compound reaches its site of action. The pharmaceutical compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a suitable form of administration by inhalation or insufflation. It is considered that the compositions should be provided in a form suitable for oral or nasal administration or by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier or diluent, can thus be placed in the form of pharmaceutical compositions and unit dosages thereof, and in such forms they can be employed as solids, such as tablets or filled capsules. , or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional ingredients or active ingredients, and such an oral dosage forms may contain any suitable effective amount of the active ingredient in proportion to the dosage interval intended daily for use. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (1 00) milligrams, per tablet, are accordingly adequate representative unit dosage forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It would be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention. To prepare pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. The solid form preparations include powders, tablets, pills, capsules, seals, suppositories and dispensable granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binder capacity in suitable proportions and compacted in the desired shape and size. The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without carriers, is enclosed by a carrier, which is thus in association with it. . Similarly, seals and pills are included. Tablets, powders, capsules, pills, seals and pills can be used as solid forms for oral administration. To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first fused and the active component dispersed homogeneously therein, as by agitation. The melting of the homogeneous mixture is then poured into molds of suitable size, allowing to cool, and thus solidify. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Liquid form preparations include solutions, suspensions and emulsions, for example, water or propylene glycol-water solutions. For example, liquid preparations for parenteral injection can be formulated as solutions in an aqueous polyethylene glycol solution. Compositions in sterile liquid form include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

The compositions according to the present invention can thus be formulated for parenteral administration (for example, by injection, for example bolus injection or continuous infusion) and can be presented in unit dosage form in ammonia. cocks, pre-filled syringes, small volume infusion or in multiple-dose containers with a water-soluble preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ng may be in the form of a powder, obtained by aseptic isolation of sterile solid or by freeze-drying solution, by constitution with a suitable sterile, eg, pyrogen-free, vehicle before use. Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They must be established under the conditions of processing and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi. Those skilled in the art can readily determine appropriate forms for the compounds of the present invention using conventional approaches. The identification of the preferred pH varies and suitable excipients, for example antioxidants, are routine in the art (see for example Cleland et al, 1993). Routine systems or buffers are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such forms including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulfite, and metal chelators such as EDTA. The solvent or dispersion medium for the injectable solution or dispersion may contain any conventional solvent or carrier systems for the compounds, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and polyethylene glycol). uid, and similar), suitable mixtures thereof, and vegetable oils. The flux itself can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants or surfactants. The prevention of the action of microorganisms can be caused when necessary by the exclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it would be preferable to include agents to adjust the osmolality, for example, sugars or sodium chloride. Preferably, the formula for injection would be isotonic with the blood. Prolonged absorption of the injectable compositions can be originated by use in the compositions of agents that retard absorption, for example, aluminum monostearate and gelatin. The pharmaceutical forms suitable for injectable use can be supplied by any suitable route by means of intravenous, intramuscular, intracerebral, intrathecal, epidural or infusion injection. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several different reagents such as those listed above, as required, followed by filtered sterilization. In general, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are by vacuum drying or lyophilization of a previously filtered, sterile solution of the active ingredient plus any additional ingredients desired.

When the active ingredients are suitably protected they can be administered orally, for example, with an inert diluent or with an edible assimilable carrier, or they can be enclosed in a gelatin capsule with a soft or hard coating, or they can be compressed into tablets, or It can be incorporated directly with the diet food. For oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations preferably contain at least 1% by weight of the active com pound. The percentage of the compositions and preparations can, of course, be varied and conveniently be between about 5 to about 80% of the unit's weight. The amount of active compound in therapeutically useful com positions should be sufficient that an adequate dosage would be obtained. The tablets, troches, pills, capsules and the like may also contain the components as listed hereinafter: an agglutinant such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, algic acid and the like; a brightening agent such as magnesium stearate; and an ulctant agent such as a sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring can be added. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl paraben as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in the preparation of any form of dosage unit should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, the active compound (s) can be incorporated into sustained release preparations and formulations, including those that allow the specific delivery of the active peptide to specific regions of the intestine. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and by adding suitable colorants, flavors, stabilizers and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural and synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents. Carrier and / or pharmaceutically acceptable diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and adsorption retarding agents and the like. The use of such media and agents for active pharmaceutical substances is well known in the art. Except for any conventional means or agent is incompatible with the active ingredient, the use thereof is contemplated in the therapeutic compositions. Active ingredients complementary to the compositions can also be incorporated. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. For topical administration to the epidermis, the compounds according to the invention can be formulated as ointments, creams or lotions, or as a transdermal patch. The substances and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. The lotions can be formulated with an oily or aqueous base and will also contain in general also one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising an active agent in a flavor base, usually sucrose and acacia or tragacanth.; the tablets comprise the active ingredient in an essential base such as gelatin and glycerin or sucrose and acacia; and mouth rinses comprise the active ingredient in a suitable liquid carrier. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, specimen or spray. The formulations may be provided in the form of multiple or multiple doses. In the latter case of a dropper or specimen, this can be achieved by administering to the patient a predetermined, appropriate volume of the solution or suspension. In the case of a sprayer, this can be achieved for example by means of a vaporization spray dosing pump. To improve nasal delivery and retention of compounds according to the invention, they can be encapsulated with cyclodextrins, or formulated with other agents that are expected to improve nasal mucosal delivery and retention. Administration to the respiratory tract can also be achieved by means of an aerosol formulation in which the active protein is provided in a container presumed with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug can be controlled by the condition of a dosed valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). . Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin, or ampoule containers of which the powder may be administered by means of a pump. In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound in general will have a small particle size, for example of the order of 5 to 10 microns or less. Such particle size can be obtained by means known in the art, for example by micronization. When desired, adapted formulations can be employed to provide prolonged release of active reinforcement. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package contains discrete quantities of preparation, such as packaged tablets, capsules and powders in small vials or ampoules. Also, the unit dosage form can be a capsule, tablet, seal, or lozenge itself, or it can be the appropriate number of any of these in packaged form. It is especially advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unit dosages for the subjects to be treated; each unit contains a predetermined quantity of active material calculated to produce the therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect that is achieved, and (b) the limitations inherent in the technique of composition such as an active material for the treatment of the disease in living subjects having a diseased condition in which the physical health is damaged as described herein in detail. The invention also includes the compounds in the absence of the carrier where the compounds are in unit dosage form. The amount of compound of formula I administered may be in the range of about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated. Liquids or powders for intranasal administration, tablets or capsules for oral administration and fluids for intravenous administration are the preferred compositions.

Experimental Data 1 H NMR spectra were recorded on any Bruker Avance DRX 400, AC 200 or AM 300 spectrometer. The spectra were recorded in CDCI3, d6-acetone, CD3OD or d6-DMSO using the residual solvent peak as a reference. Chemical changes were reported in the scale d in parts per million (ppm) using the following conventions to assign the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and b prefix (large). The mass spectra (ESI) were recorded on any Micromass Platform QMS or Finnigan LCQ Advantage spectrometer. Instant chromatography was performed on 40-63 μm of silica gel 60 (Merck No. 9385). Analytical HPLC was carried out using a Waters 600 Pump, a Waters 717 Auto Sampler and a Waters 490E UV detector. Preparative HPLC was carried out using a Gilson 322 pump with a Gilson 215 liquid handler and an HP1100 PDA detector. Both HPLC systems employ Phenomonex C8 (2) columns using either acetonitrile or acetonitrile containing 0.06% TFA in water or water containing 0.1% TFA. Method A An equivalent of an appropriate keto acid of formula II, it is reacted with about 3 equivalents of an appropriate diamine of the general formula H2N-B-C-NH2. The mixture is heated under reflux in an inert solvent, such as toluene or xylene, with a Dean-Stark apparatus for 3-10 hours. A catalyst, such as an acid tosylate, can be used. After this time the reaction is allowed to cool and the product is filtered and recrystallized from an appropriate solvent. If the precipitate is not formed, the solvent is evaporated in vacuo and the residue recrystallized or purified using flash chromatography or preparative HPLC. Compound 1 Compound 1 was prepared using Method A employing 2- (4-chlorobenzoyl) benzoic acid and ethylenediamine. 1 H NMR (300MHz, CDCl 3) d 2.05 (bs, 1H), 3.11-3.26 (m, 2H), 3.61-3.68 (m, 1H), 3.76-3.84 (m, 1H), 7.22-7.26 (m, 1H) , 7.30 (d, J 8.9 Hz, 2H), 7.42-7.48 (m, 2H), 7.62 (d, J 8.8 Hz, 2H), 7.74-7.80 (m, 1H). MS m / z 285 ([M + H +] Compound 2 Compound 2 was prepared using Method A of 2- (4-chlorobenzoyl) benzoic acid and 1,3-diaminopropane. 1 H NMR (300MHz, CDCl 3) d 1.48-1.62 (m, 2H), 2.83-2.96 (m, 1H), 2.97-3.13 (m, 2H), 4.47-4.60 (m, 1H), 7.22-7.29 (m, 1H), 7.31-7.37 (m, 2H), 7.38-7.47 (m, 2H), 7.48-7.56 (m, 2H), 7.82-7.89 (m, 1H). MS m / z ([M + H +] 299 Compound 7 Compound 7 was prepared using Method A of 2- (4-chlorobenzoll) benzoic acid and 1,4-diamnobutane. 1 H NMR (300MHz, CDCl 3) d 1.13-1.32 (m, 2H), 1.33-1.57 (m, 2H), 2.15-2.44 (m, 2H), 2.73-2.90 (m, 1H), 3.32-3.49 (m, 1H), 7.10-7.20 (m, 1H), 7.21-7.34 (m, 4H), 7.35-7.49 (m, 2H), 7.60-7.71 (m, 1H). MS m / z ([M + H +] 313 The methods for forming compounds of formula III are based on those described in US 4,058,529, Suikowski, TS et al., J. Org. Chem. 1967, 32, 2180-2184 and Houlihan, WJ, et al., J. Med. Chem. 1975, 18, 182-185.

Method B Two equivalents of diisopropylethylamine or triethylamine were added to one equivalent of the compound of formula III in THF at 0 ° C. An acid chloride, or other acylating agent was added to the mixture and the reaction was monitored by HPLC. When the reaction is complete, it is quickly cooled with water and the product is extracted into EtOAc. The EtOAc was subsequently washed with a saturated, aqueous NH 4 Cl solution: water 1: 1, saturated Na 2 CO 3, aqueous: water 1: 1 and saturated Na 2 CO 3, aqueous. The EtOAc was dried (Na2SO4), the solvent was evaporated in vacuo and the residue either recrystallized or purified by flash chromatography using EtOAc / hexanes or by preparative HPLC. Method C An equivalent of the appropriate compound of formula III is reacted with an equivalent of the appropriate acid chloride in xylene at 120 ° C for 1-24 hours. The reaction is then allowed to cool and the product is filtered and recrystallized from an appropriate solvent. If the precipitate is not formed, the reaction is purified using flash chromatography or preparative HPLC. Method D N-alkylated diamines can be prepared according to the procedure described in Kruse L.I., et al., J. Med. Chem. 1990, 33, 781-789.

The keto-acid (2 equivalents) and the N-substituted diamine (1 equivalent) in chlorobenzene, toluene or xylene are placed in a flask equipped with a stirrer and a Dean-Stark water separator. The mixture was refluxed until no additional water was observed to separate (1-8 hours) after which the solvent was then distilled and the residue was cooled. This was purified using flash chromatography or preparative HPLC. Method E An equivalent of the appropriate compound of formula III is reacted with an equivalent of the appropriate isocyanate or isothiocyanate in THF or xylene at a temperature ranging from 20-120 ° C for 1-24 hours. The reaction was then allowed to cool and the product was filtered, washed and recrystallized from an appropriate solvent. If the precipitate was not formed, the reaction was purified using flash chromatography or preparative HPLC. Compound 12 Compound 12 was prepared using Method C using Compound 1 and 4-fluorobenzoyl chloride. H NMR (300MHz, CDCl 3) d 3.22-3.34 (m, 1H), 3.73-3.82 (m, 1H), 3.91-4.03 (m, 1H), 4.28-4.36 (m, 1H), 7.05-7.13 (m, 2H), 7.17 (d, J 7.8 Hz, 2H), 7.33 (d, J 7.8 Hz, 2H), 7.43-7.52 (m, 2H), 7.54-7.65 (m, 2H), 7.84-7.90 (m, 1H ), 8.00-8.06 (m, 1H). MS m / z 407 ([M + H +] Compound 13 Compound 13 was prepared using Method C using Compound 1 and benzoyl chloride. 1 H NMR (300MHz, CDCl 3) d 3.21-3.31 (m, 1H), 3.72-3.79 (m, 1H), 3.91-4.00 (m, 1H), 4.26-4.33 (m, 1H), 7.20 (d, J 8.8 Hz, 2H), 7.34 (d, J 8.8 Hz, 2H), 7.38-7.48 (m, 5H), 7.56-7.61 (m, 2H9, 7.85-7.88 (m, 1H), 8.04-8.07 (m, 1H) MS m / z 389 ([M + H +] Compound 23 Compound 23 was prepared using Method D of 2- (4-chlorobenzoyl) benzoic acid and N-benzyl-ethylenediamine. 1 H NMR (300MHz, CDCl 3) d 2.97 (d, JAB 13Hz, 1H), 3.07-3.32 (m, 3H), 3.42 (d, JAB 13H, 1H), 3.83-3.96 (m, 1H), 7.04-7.09 ( m, 1H), 7.17-7.38 (m, 8H), 7.39-7.46 (m, 1H), 7.66-7.73 (m, 2H), 7.81-7.86 (m, 1H). MS m / z ([M + H +] 375 Compound 24 Compound 24 was prepared using Method D of 2-benzoylbenzoic acid and N-benzyl-ethylenediamine. 1 H NMR (300MHz, CDCl 3) d 2.99 (d, JAB 13HZ, 1H), 3.10-3.29 (m, 3H), 3.44 (d, JAB 13Hz, 1H), 3.84-3.99 (m, 1H), 7.07-7.13 ( m, 1H), 7.18-7.44 (m, 10H), 7.73-7.81 (m, 2H), 7.82-7.87 (m, 1H). MS m / z ([M + H +] 341 Compound 25 Compound 25 was prepared using Method D of 2- (4-toluoyl) benzoic acid and N-benzyl-ethylenediamine. 1 H NMR (300MHz, CDCl 3) d 2.36 (s, 3H), 3.00 (d, JAB 13Hz, 1H), 3.11-3.29 (m, 3H), 3.45 (d, JAB 13Hz, 1H), 3.86-3.98 (m, 1H), 7.08-7.14 (m, 1H), 7.15-7.21 (m, 2H), 7.22-7.44 (m, 7H), 7.63-7.69 (m, 2H), 7.81-7.86 (m, 1H). MS m / z ([M + H +] 355 Compound 106 Compound 106 was prepared using Method A using 3-bromo- (4-chlorobenzoyl) benzoic acid and ethylenediamine H-NMR (300MHz, CDCl 3) d 3.12-3.25 (m , 2H), 3.64-3.71 (m, 1H), 3.76-3.83 (m, 1H), 7.13 (dd, J 8.1, 0.6 Hz, 1H), 7.33 (d, J 8.7 Hz, 2H), 7.57-7.61 ( m, 3H), 7.91 (dd, J 1.8, 0.6 Hz, 1H) MS m / z ([M + H +] 365 Compound 107 Compound 107 was prepared using Method A using 4-bromo- (4-chlorobenzoyl ) benzoic acid and ethylenediamine, 1 H NMR (300MHz, CDCl 3) d 3.11-3.24 (m, 2H), 3.69-3.63 (m, 1H), 3.76-3.82 (m, 1H), 7.34, (d, J 8.7 Hz, 1H ), 7.39 (dd, J 1.5, 0.6 Hz, 1H), 7.59-7.66 (m, 4H) MS m / z ([M + H +] 365 Method F Two equivalents of boronic acid or ester, five equivalents of Na2CO3 and palladium on carbon (catalytic) or 0.1 equivalents of [PdCl2 (dppf)] (adduct of dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane) were added to the appropriate compound substituted with bromine of formula III in DME / H2O (93: 7) The reaction is heated at 50 ° C for 1-4 hours. The reaction is then cooled, filtered and evaporated in vacuo to give an oily solid or residue. The residue is then either recrystallized or purified by flash chromatography using EtOAc / hexanes or by preparative HPLC. Method G Three equivalents of boronic acid or ester, six equivalents of K2CO3 and 0.3 equivalents of tetrakis (triphenylphosphine) palladium were added to the appropriate compound substituted with bromine of formula III in toluene. The reaction was heated to 100 ° C for 1-24 hours. The reaction was then quenched with CH2Cl2 and washed with water. The CH2Cl2 layer was dried (Na2SO4) and evaporated in vacuo to give an oily solid or residue. The residue is then either recrystallized or purified by flash chromatography using EtOAc / hexanes or by preparative HPLC. Method H The chloride or acid anhydride or isocyanate or isothiocyanate (2.2 eq.) Was added directly for liquids or as a solution in pyridine (~ -1M) for solids to a solution of the appropriate compound of formula III (0.1 mmol) in pyridine ( 500 μL) at -5 ° C. The reaction was stirred and allowed to warm to room temperature for 2-24 hours after which time the starting material was consumed. The reaction was subsequently diluted with water and extracted with CH2Cl2 (3x). The combined CH2Cl2 extracts were washed with 1N NaOH (3x) and 10% HCl (3x). In the case of basic products acid washing is omitted and in the case of acidic products the basic washing is omitted. For neutral or basic products the crude purity is markedly improved by stirring the combined CH2Cl2 extract in the presence of a carbonate resin (MP-Carbonate ~ 3 eq.) For 0.5-12 hours. The CH2Cl2 extracts were dried (MgSO4) and the solvent was evaporated in vacuo. The crude products were subsequently purified by flash chromatography using a solvent system of EtOAc / Hexane. Compound 120 Compound 120 was prepared using Method F using compound 107 and 4-tolylboronic acid. 1H NMR (300MHz, CDCI3): d 3.19-3.26 (m, 2H), 3.65-3.72 (m, 1H), 3.86-3.89 (m, 1H), 7.23 (d, J 8.1 Hz, 2H), 7.34 (d, J 8.7 Hz , 2H), 7.39-7.45 (m, 3H), 7.65-7.71 (m, 3H), 7.82 (dd, J 8.1, 0.6 Hz, 4H). MS m / z ([M + H] +) 375 Compound 132 Compound 132 was prepared using Method G using compound 107 and n-butylboronic acid. 1 H NMR (300MHz, CDCl 3): d 0.89 (t, J 7.5 Hz, 3H), 1.23-1.37 (m, 3H), 1.48-1.56 (m, 2H), 2.59 (t, J 7.8 Hz, 2H), 3.12 -3.26 (m, 2H), 3.62-3.69 (m, 1H), 3.83-3.78 (m, 1H), 7.26-7.35 (m, 3H), 7.62-7.69 (m, 3H). MS m / z ([M + H] +) 341 Method I A mixture of an appropriate carboxylic acid (3 eq.) And TFFH (3.3 eq.) Was suspended in anhydrous DMF (0.25M) and DIEA (3.3 eq.) Under nitrogen. The mixture was heated at 45 ° C for 30 minutes. This solution was added to the appropriate compound of Formula III (1 eq.) Under nitrogen and heated at 45 ° C for 14 days. The reaction mixture was transferred to a 10 mL tube and diluted with CH2Cl2 (2 mL). The organic phase was washed with 10% citric acid (2 mL), saturated, aqueous NaHCO3 (2 mL) and evaporated to dryness. The residue was purified by flash chromatography on silica, using 0.4% methanol / CH CI2 as eluent, to isolate the desired product. Method J This method is an adaptation of the method described by Copéret, C. et al., J. Org. Chem., 1998, 63, 1740-1741. 30% hydrogen peroxide (10 eq.) Was added to a solution of either an appropriate compound of Formula I or Formula II (1 eq.) And 2.5% trioxorenium in mol in CH 2 Cl 2 (4 x volume of peroxide solution of hydrogen) at room temperature. The mixture was stirred overnight at which time the mixture was then diluted with water and stirred for an additional 30 minutes. After this time the CH2Cl2 was separated and the aqueous layer was further extracted with CH2Cl2 (2x). The combined extracts were dried and the solvent was evaporated in vacuo to yield the desired product which was purified by crystallization or chromatography as required. Method K An appropriate substrate of Formula I, wherein R2 = 6-fluoronicotinoyl or 6-chloronicotinoyl, was produced using Method H. To this substrate was added an excess of an appropriate amine. In a suitable solvent, such as THF or ethanol, the mixture was heated in a sealed vessel at about 150 ° C for 1-5 hours (or 60 ° C for 72 hours in the case where the nucleophilic aldehyde is). After this time the solvent was evaporated and the residue was purified using flash chromatography or preparative HPLC. Method L A suitable phenolic compound of formula III was acylated according to Method H. The hydrolysis of the ester was then carried out by dissolving the product in a minimum volume of methanol and by treating with an excess of 1M NaOH (aqueous) at room temperature . The reaction mixture was then acidified, extracted with dichloromethane and purified by flash chromatography to produce a phenolic compound of formula I. If desired, the conversion of this phenol to a phenyl ether is then carried out using standard techniques known in the industry. such as those described in Vogel's Textbook of Practical Organic Chemistry by BS Furniss et al., Harlow, Longman Scientific & Technical, 1989 or Mitsunobu, O. Synthesis 1981, 1. Crude products were subsequently purified using flash chromatography or preparative HPLC. Compounds 239 Compound 239 was prepared from 9b- (4-hydroxyphenyl) -1, 2,3,9b-tetrahydroimidazo [2,1-a] isoindol-5-one using Method L. Tetrahydroimidazo-isoindolone was bis-acylated with 4-fluorobenzoyl chloride according to Method H and the function of the resulting phenolic ester was converted to a phenyl by basic hydrolysis. The product was then treated with chloroacetonitrile and K2CO3 in acetone and heated to reflux for 30 hours to yield the phenyl ether compound 239. 1 H NMR (300 MHz, d6-acetone) d 3.28-3.38 (m, 1H), 3.91-3.97 (m, 1H), 4.09-4.27 (m, 2H), 5.12 (s, 2H), 7.08 (d, J 9.0 Hz, 2H), 7.17-7.26 (m, 2H), 7.30 (d, J 9.0 Hz, 2H), 7.61-7.71 (m, 4H), 7.79-7.82 (m, 1H), 8.05-8.08 (m, 1 HOUR). Method M This method involves the nucleophilic displacement of R2 when it represents 2-haloethanoyl. A solution or suspension of an appropriate compound of Formula I (R2 = COCH2Br) (1 eq.) And an appropriate amine (3 eq.) Were allowed to stand at room temperature for 3 days. The mixture was allowed to evaporate to dryness, the residue was lyophilized from 30% acetonitrile / water and the resulting crude product was purified by preparative HPLC. Method N This method was used to prepare compound 153.

Aluminum chloride (2.88 mol) was added to a stirred suspension of 3,4-pyridine anhydride (1.31 mol) in chlorobenzene (1.2 I) at room temperature to give an orange suspension and heated at 110 ° C for 5 hours. The mixture was cooled and carefully hydrolyzed with water (2 I), heated to reflux for 1 hour, filtered when hot and dried to give a brown solid. The solid was suspended in water (3.5 L) and basified with a 10% NaOH solution (350 ml). The resulting solution was filtered, acidified to pH = 3.1 with 2N HCl. The formed precipitate was filtered and refluxed with ethanol (2 I) to give a white solid (67 g). This material was dissolved in 10% NaOH (400 ml), acidified to pH 6.3 with 2N HCl and filtered to yield 3- (4-chloro-benzoyl) -isonicotinic acid (53 g) as a white solid. NMR-1H (400MHz, DMSO-d6) d 7.59 (d, J 8.6 Hz, 2H), 7.68 (d, J 8.6 Hz, 2H), 7.88 (dd, J 0.7, 5.0 Hz, 1H), 8.74 (d, J 0.7 Hz, 1H), 8.93 (d, J 5.0 Hz, 1H). 13.9 (bs, 1H) ppm. 3- (4-Chloro-benzoll) -isonicotinic acid (53 g) and ethylenediamine (67.7 ml) in xylenes (1.8 I) were refluxed for 4 hours. The solution was filtered when hot and the filtrate was evaporated under reduced pressure to give a yellow solid (58 g). This material was recrystallized from ethanol to give Compound 153 as a white solid (46.4 g). NMR-1H (400MHz, CDCl 3) d 2.12 (bs, 1H, NH), 3.19 (m, 1H), 3.21 (m, 1H), 3.71 (m, 1H), 3.83 (m, 1H), 7.36 (d, J 8.8 Hz, 2H), 7.63 (d, J 8.8 Hz, 2H), 7.66 (dd, J 1.1, 4.9 Hz, 1H), 8.64 (d, J 1.1 Hz, 1H), 8.79 (d, J 4.9 Hz, 1H) ppm. MS m / z ([M + H] +) 286 The methods described above were used to make the compounds described in Tables 1 to 3 below. All the compounds represented in the tables were obtained. The tables establish a reference number of the compound, structure, mass observed (not calculated) and the method used to make the compound (based on the correspondingly varied starting materials). The mass observed for the two compounds marked with * have not been included.

Table 1: Compounds of Formula II (Intermediates).

Table 2: Compounds of the Invention (Formula I, where A is Aryl) Table 3: Compounds of the Invention (Formula I where A is heteroaryl) Method O: Separation of Stereoisomers by Chromatography Chiral Selected compounds of the invention can be separated into simple stereoisomers by HPLC using chromatographic columns with a chiral stationary phase.

For example, the following racemic compounds were separated into enantiomers under the conditions detailed below. Column: Chirex 3014 (Chirex (S) -VAL and (R) -NEA)) 250 x 10.0 mm Wavelength detector: 220 nm Separation of Compound 12 Mobile Phase A: Hexane Mobile Phase B: Isopropanol Flow Rate: 4 mL / min. Isocratic Elution: 93% of Mobile Phase A, 7% of Mobile Phase B Test time: 20 minutes Column Temperature: 35 ° C Injection Volume: 20 μl Separation of Compound 188 Mobile Phase A: Hexane Mobile Phase B: Isopropanol Flow Rate: 4 mL / min. Isocratic Elution: 93% of Mobile Phase A, 7% of Mobile Phase B Test time: 26 minutes Column Temperature: 35 ° C Injection Volume: 15 μl Separation of Compound 306 Mobile Phase A: Hexane Mobile Phase B: Ethanol Speed Flow rate: 4 mL / min. Column Temperature: 25 ° C Injection Volume: 20 μl Gradient Time: Separation of Compound 336 Mobile Phase A: Hexane Mobile Phase B: Isopropanol Flow Rate: 4 mL / min. Isocratic Elution: 93% of Mobile Phase A, 7% of Mobile Phase B Test time: 50 minutes Column temperature: 35 ° C Injection volume: 25 μl Separation of Compound 352 Mobile Phase A: Hexane Mobile Phase B: Ethanol Flow rate: 4 mL / min. Column Temperature: 25 ° C Injection Volume: 15 μl Gradient Hours: Separation of Compound 363 Mobile Phase A: Hexane Mobile Phase B: Isopropanol Flow Rate: 4 mL / min. Column Temperature: 50 ° C Injection Volume: 15 μl Gradient Hours: Separation of Compound 368 Mobile Phase A: Hexane Mobile Phase B: Ethanol Flow Rate: 4 mL / min. Column Temperature: 25 ° C Injection Volume: 15 μl Gradient Hours: Separation of Compound 381 Mobile Phase A: Hexane Mobile Phase B: Ethanol Flow Rate: 4 mL / min. Column Temperature: 30 ° C Injection Volume: 20 μl Gradient Hours: Separation of Compound 414 Mobile Phase A: Hexane Mobile Phase B: Ethanol Flow Rate: 4 mL / min. Isocratic Elution: 92% of Mobile Phase A, 8% of Mobile Phase B Test time: 25 minutes Column temperature: 40 ° C Injection volume: 20 μl Table 4: Separation of Enantiomers Using a Column Chirex 3014 Column: Chiracel OD-H (250 mm x 4.6 mm) Isocratic Elution: hexane: ethanol (70:30) Wavelength detector: 254 nm Flow rate: 0.7 ml / min. Injection Volume: 20 μl Column Temperature: 25 ° C Table 5: Separation of Enantiomers Using a Column Chiracel OD-H Method P: Resolution of Type III Compounds by Diastereomeric Salt Formation A mixture of Compound 153 (1.0 g, 3.5 mmol) and acid phosphate (R) - (-) - 1,1'-binaphthyl-2,2'-diyl (0.85 g, 2.44 mmol, 0.7 eq.) In ethanol (90 ml) was brought to reflux until a clear solution formed. After 15 minutes, the mixture was allowed to cool to room temperature for 1 hour and then stirring was continued under ice cooling for 1.5 hours. The white crystalline salt was filtered, rinsed with ethanol (5 ml) and dried under suction for 30 minutes to yield 1.09 g of salt. The white salt was suspended in water (25 ml) and basified with 10% NaOH solution (0.7 ml) to pH 11. The aqueous phase was extracted with ethyl acetate (100 ml then 2 x 75 ml). The combined organic extracts were washed with saturated NaCl solution, dried (MgSO) and concentrated to yield Compound 153B (0.49 g) as a white powder. The acidic (R) - (-) - 1,1'-hydrophyl-2,2'-diyl acid phosphate was recovered from the acidified aqueous layer (pH 2) by extraction with ethyl acetate (2 x 100 ml). The combined organic phases were washed with saturated NaCl solution, dried (MgSO4) and concentrated to yield a white powder (0.54 g). RSV Antiviral Assays Method Q: RSV Antiviral Assay Protocol The compounds of the invention were tested for their antiviral activity against the respiratory syncytial virus. Cytopathic effect (CPE) assays were performed essentially as described in the literature (see for example Watanabe et al., J. Virological Methods, 1994, 48., 257). Serial dilutions of the test compounds were made in a test medium. HEp2 cells (1.0 x 104 cells / well) were infected with RSV at a low multiplicity of infection (for example, RSV A2 at a moi of 0.01) and 100 μL were added to cultures that assessed the antiviral activity and the cells without virus added to it. those that value the cytotoxicity of the compound. The assays were incubated for approximately 5 days at 37 ° C in a 5% CO2 atmosphere. The degree of CPE was determined via the metabolism of the vital dye of 3- (4,5-dimethylthiaxol-2-yl) -2,5-diphenyltetrazolium bromide (MTT). A 3 mg / ml bar of MTT was made in a test medium and 1 00 μL was added to each well, taking the final MTT concentration at 1 mg / ml. After 2 hours of incubation at 37 ° C, the MTT solution was removed from the media and 200 μL of isopropanol was added to dissolve the vital color crystals. The plates were shaken and the absorbance was recorded at 540 nm. Compound concentrations that inhibit CPE by 50% (EC50) and developed cytotoxicity (CC50) were calculated using an Excel curve adjustment program. Representative data for compounds of the invention against RSV A2 are shown in Tables 6-8 where the EC50 values are in the ranges A: < 1 00 ng / ml, B: 1 00-250 ng / ml and C: 250-1,000 ng / ml. Table 6: RSV A2 Antiviral Data for Compounds of Table 2 Table 7: RSV A2 Antiviral Data for Compounds of Table 3 Table 8: Antiviral Data of RSV A2 for Compounds of Tables 4 and 5 (the B-enantiomer) No. Interval of Activity Compound 12B A 188B B 306B A 336B A 352 BA 363B A 368B A 381 BA 414B A Method R: Test of RSV Fusion Selected compounds of the invention were tested for their ability to inhibit the essential fusion processes of the respiratory syncytial virus. Generation of RSV-F constructs Single-stranded synthetic DNA (DNA) oligonucleotides encoding portions of the RSV A2 F glycoprotein that incorporates optimal codons and without adduction of potential poly (A) or binding sites. they generated synthetically (Mason eí al, WO0242326). Essentially, a full length F clamped membrane was generated according to the method described herein and in Morton et al., Virology, 2003, 31 1. 275. Assay of the formation of the syncytium The fusion activity of the constructs of RSV-F in 293 cells essentially in accordance with the method described in Morton et al., Virology, 2003, 31, 275. For example: cells were transfected into six well plates in approximately 80% confluence by adding DNA from Plasmid (2 μg / well) transporting the constructs of interest in Ca PO solution for 4 hours. After choking and washing with glycerol, the transfected cells were trypsinized and 1.5 x 1 04 cells / well were added to 96-well plates containing serial dilutions in logarithmic medium of the test compound. Syncytium formation was evaluated by visual inspection and quantified at 48 hours post-transfection by the addition of 20 μL of CelITiter 96 One Solution (Promega) followed by incubation for 4 hours at 37 ° C. The color reaction was then stopped by the addition of 25 μL of 10% SDS for each well and the absorbance was measured at 492 nm. The concentration concentration of the reduced absorbance relative to untreated control rates by 50% (EC50) was calculated using an Excel curve fitting program. Representative data for the compounds of the invention are shown in Table 9, where the EC50 values are in the ranges A: < 750 ng / ml, B: 750- 1500 ng / ml and C: 1500-2250 ng / ml. Table 9: RSV Fusion Test Data Method S: Rat Model of Cotton RSV The rat cotton model was performed essentially as described in the literature (Wyde et al., Antiviral Res. 2003, 60, 221). Briefly, the cotton rats weighing 50-100 g were lightly anesthetized with isofl urane and dosed orally with 1000 mg / kg / day of the control compound or vehicle. Viral infection followed 2 hours post-treatment in rats if similarly anesthetized by intranasal instillation with approximately 1000 TC I D50 of RSV A2 per animal. Four days after virus inoculation, each cotton rat was sacrificed and its lungs removed and the RSV titers were determined by plaque assay. Table 1 0: Data of Rat Model of Cotton RSV Method T: Mouse Model Bal b / c RSV The mouse model was performed essentially as described by Ciancl et al. { Antimicrobial Agents and Chemotherapy. 2004, 48, 413). Briefly, eight-week-old Balb / c hem bras mice were weighed, anesthetized intraperitoneally with Avertin ™ and the compound or vehicle was orally administered 6 hours preinfection. The mice were inoculated intranasally with approximately 10,000 TCID50 RSV A2 per animal. Three days after virus inoculation, each mouse was sacrificed and their lungs were removed and the RSV titrations were determined by plaque assay. Table 11: Data of the Balb / c Mouse Model of the RSV It would be appreciated by a person skilled in the art the various variations and / or modifications that can be made to the invention as shown in the specific embodiments without departing from the spirit and scope of the invention as broadly described. The present modalities are, therefore, to be considered in all aspects as illustrative and not restrictive. In all this specification and the claims that follow, unless the context requires otherwise, the word "comprises", and variations such as "comprise" and "comprising", shall be understood to imply the inclusion of an integer or stage or group of integers or established stages, but not the exclusion of any other integer or stage or group of integers or stages. The reference for any prior art in this specification is not, and should not be taken as an acknowledgment or any form or suggestion that the prior art forms part of the general common knowledge in Australia.

Claims (82)

1. CLAIMS 1. Use of a compound of formula I Formula I its salts, and pharmaceutically acceptable derivatives thereof, in the treatment of infections involving viruses of the Pneumovirinae sub-family, wherein A together with the atoms to which it is attached, forms an optionally substituted aromatic ring; the bond B-C together with the atoms to which they are attached, form an optionally substituted heterocyclic ring having from 5 to 8 ring atoms; RI is selected from C? -? 2 alkyl, C2 -? 2 alkenyl, C2_? 2 alkynyl, - (CH2) nC3.7 cycloalkyl, (CH2) C4.7 cycloalkenyl, - (CH2) naril, - (CH2) naril-C-? -? 2 alkyl, - (CH2) naril-alkenyl of C2 .-? 2, - (CH2) naril- C2-? 2 alkynyl, and - (CH2) nheterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R2 is selected from -CH2R3, -C (Y) R3, -C (Y) OR3, -C (Y) N (R4) R3, -C (Y) CH2N (R4) R3, -C (Y) CH2SR3 and -S (O) w R 5, wherein R 3 is selected from hydrogen, C 1 -C 2 alkyl, C 2 al 2 alkenyl, C 2 al 2 alkylene, - (CH 2) C 3,7 cycloalkyl, - (CH 2) ) C7 cycloalkenyl, - (CH2) maryl, - (CH2) alkyl-C-alkyl. 2, - (CH2) -alkenyl of C2.?2, - (CH2) maryl-alkynyl of C2-? 2, and - (CH2) mheterocyclyl; and when R2 is -CH2R3, or -C (Y) R3, R3 can also be selected from -S-R5 and -O-R5; m is 0-6; R is hydrogen or C | _6 alkyl; R5 is C- [alpha] 6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3 cycloalkyl. , C4.7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; X and Y are independently selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy.
2. 2. Use according to claim 1, characterized in that R2 is not an unsubstituted C6-6 alkyl or -C (O) -dubstituted d.6 alkyl. 3. Use according to claim 1, characterized in that ring A is an optionally substituted aryl ring. 4. Use according to claim 1, characterized in that ring A is an optionally substituted phenyl ring. 5. Use according to claim 1, characterized in that ring A is an optionally substituted heteroaryl ring. 6. Use according to claim 1, characterized in that the ring A, together with the atoms to which it is attached, represents a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl or optionally substituted -soxazolyl ring. . 7. Use according to claim 1, characterized in that ring A is an optionally substituted pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring. 8. Use according to claim 1, characterized in that ring A is an optionally substituted pyridyl ring. 9. Use according to claim 1, characterized in that the ring A is optionally substituted with one or more substituents independently selected from halo, -NH2, NO2, C- | 6 alkyl, aryl and heterocyclyl, the aryl and heterocyclyl groups optionally substituted with halo, C? .6 alkyl or C- | 6 alkyl substituted with halo and, when ring A contains one or more nitrogens in the ring, optional substituents include N-oxides of one or more of the nitrogens in the ring or pyridinium salts thereof. 0. Use according to claim 1, characterized in that ring A is optionally substituted with a substituent selected from halo, alkyl, C6H5-CH3C6H4-, CF3-C6H4-, pyridyl, NO2 and when ring A contains or not more nitrogens in the ring, the substituent optionally also includes an N-oxide form of a nitrogen in the ring, and pyridinium salts thereof. eleven . Use according to claim 1, characterized in that ring A is not substituted. 12. Use according to claim 1 of a compound of formula IV Formula IV its pharmaceutically acceptable salts, N-oxides and derivatives thereof, wherein B-C, X, R-i and R2 are in accordance with claim 1.
3. 3. Use according to any of claims 1 to 12, characterized in that R2 is selected from -CH2R3, -C (Y) R3, -C (Y) OR3, -C (Y) N (R4) R3 , -C (Y) CH2N (R4) R3, -C (Y) CH2SR3 and -S (O) wR5, wherein R3 is selected from hydrogen, C? -? 2 alkyl, C2.12 alkenyl, alkynyl of C2.?2, - (CH2) C3.7 cycloalkyl, (CH2) C4.7 cycloalkenyl, - (CH2) maryl, - (CH2) maryl-C1.12 alkyl, - (CH2) maryl-alkenyl of C2.?2, - (CH2) maryl-alkynyl of C2.?2, and - (CH2) mheterocyclyl; and when R2 is -CH2R3, or -C (Y) R3, R3 can also be selected from -S-R5 and -O-R5; m is 0-6; R is hydrogen or C? -6 alkyl; R5 is selected from C2.6 alkenyl alkyl, C2.6 alkynyl, C3.7 cycloalkyl, C7 cycloalkenyl, benzyl, aryl and heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted with one or more substituents selected from C? .6 alkyl, C? .6 alkoxy, alkenyl C2.6, C2.6 alkynyl, halo, haloalkyl of C-? 6 (including CF3), hydroxy, mercapto, nitro, cyano, NH2, mono or di (C? -6 alkyl) aml, phenyl, benzyl and heterocyclyl. 14. Use according to claim 1, characterized in that R2 is -CH2-R3, and R3 is - (CH2) maryl or - (CH2) mheterocyclyl and m is from 0 to 3 and the aryl or heterocyclyl ring is optionally substituted. 15. Use according to claim 1, characterized in that R2 is -COR3 and R3 is aryl or heterocyclyl and is optionally substituted. 16. Use according to claim 14 or 15, characterized in that R3 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyl) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (including 1,2,3 and 1, 3,4-thiadiazolyl), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-trityanil, triazinyl, 1H-thieno [2 , 3-c] pyrazolyl, thieno [2,3-b] furyl, indolyl, isoindyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinilinyl, quinoxalinyl, uridinyl, purinyl, cinolinyl, phthalazinyl , quinazolinyl, quinoxallyl, benzotriazinyl, naphthyridinyl or optionally substituted pteridinyl. 17. Use according to claim 16, characterized in that R3 is optionally substituted with one or more substituents selected from C? _6 alkyl, C? -6 alkoxy, C2-b alkenyl, C2.6 alkynyl) halo, haloC1-6 alkyl (including CF3), hydroxy, mercapto, nitro, cyano, NH2, mono or di (alkyl, phenyl, benzyl and heterocyclyl) 18. Use according to claim 1, characterized in that R2 is -CON (H) R3, and R3 is - (CH2) maryl or - (CH2) mheterocyclyl and m is from 0 to 2 and the aryl or heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo, lower alkyl, hydroxy , lower alkoxy and phenyl 19. Use according to claim 1, characterized in that the -BC bond is an optionally substituted bond of the formula -CH2- (CH2) Z-, where z is 1-4. according to claim 19, characterized in that z is 1 or 2. 21. Use in accordance with the claim ation 1, characterized in that -B-C- is a bond of the formula -C H2C H2-. 22. Use according to claim 1, characterized in that the -B-C- bond is optionally substituted with no more than three optional substituents, the substituents are selected from halo, lower alkyl, hydroxy, lower alkoxyl, phenyl and benzyl. 23. Use according to claim 1, characterized in that the -B-C- bond is not substituted. 24. Use according to any of claims 1 to 21, characterized in that X is oxygen or sulfur. 25. Use according to claim 1, characterized in that Ri is an optionally substituted aryl or heterocyclyl group. 26. Use according to claim 1, characterized in that Ri represents a phenyl, thienyl, pyrrolyl or pyridyl ring or an alkyl group of C? -6, the rings are optionally substituted with halo, hydroxy, nitro, -NR'R "(where R 'and R "are independently selected from hydrogen, lower alkyl and -C (O) R, where R is alkyl, phenyl or heterocyclyl), C alquilo.12 alkyl, phenyl and -O-Ra, where Ra is -alkyl of C-? _ 12, -cycloalkyl of C3.7, -alkyl of C? _2-cycloalkyl of C3.7, phenyl or -alkylphenyl of C-? -? 2; and the alkyl group of C?.? 2, phenyl or Ra can be optionally substituted with halo, -CN, -NR'R ", -CO2R or -CONR'R", where R, R 'and R "are independently selected of hydrogen or lower alkyl 27. Use according to claim 1, characterized in that Ri is phenyl optionally substituted with a substituent selected from halo, -C6 alkyl, -6C alkyl, -6alkyl. 6CN, -Oalkyl of C? _6, -Oalkylhalo of d.6, -Oalkyl of C? .6CO2NH2, -Oalkyl of d.6CN, -Oalkyl of C? 6-cycloalkyl of C3.7, -Oalkyl of CL 6C6H5 , -Oalkyl of C1.6OCH3, -OC6H5, -OC6H4halo, -CF3, -OCF3, -NR'R "(where R 'and R" are independently selected from hydrogen, -C (O) C? -6 alkyl, -C (O) C6H5, -C (O) CH = CHCO2H, -C (O) alkyl of d.6CO2H, -C (O) C1-6alkyl-CO2CH3, -C (O) alkyl of d-eCeHs , -C (O) C1.6C6H4CH3 alkyl, -C (O) C1.6-C6H4OCH3 alkyl and -C (O) d6C6H4halo alkyl), -CO2H, -CO2alkyl of d.6, -NO2, -OH, -C6H5, -C6H alkyl of d.6, -C6H4halo and -OC (O) alkyl or C1-6. 28. Use according to claim 1, characterized in that Ri is phenyl substituted with halo, -Oalkyl of d.6, -Oalkylhalo of d-6, -Oalkyl of Ci-6CO2NH2, -Oalkyl of d.6CN, -Oalkyl of C? .6 cycloalkyl of C3.7, -Oalkyl of d.6C6H5 or -Oalkyl of d.6OCH3. 29. Use according to claim 1, characterized in that R-i is 4-chlorophenyl. 30. A method for the treatment of infections, characterized by implicating the viruses of the Pneumovirinae sub-family by inhibiting the virus fusion process by administering a therapeutically effective amount of a compound of formula I in accordance with any of the claims 1 to 29, the pharmaceutically acceptable salt or derivatives thereof, to a patient in need of treatment. 31. A pharmaceutical formulation for the treatment of infections involving sub-family viruses Pneumovirinae, characterized in that it comprises a compound of formula I according to any of claims 1 to 29, the pharmaceutically acceptable salt or derivatives thereof. 32. Use of a compound of formula I according to any of claims 1 to 29, the pharmaceutically acceptable salt or derivatives thereof in the manufacture of a medicament for the treatment of infections involving the viruses of the Pneumovirinae sub-family. . 33. A method for treating mammals infected with viruses of the Pneumovirinae sub-family, characterized in that it comprises administering to the mammal, a therapeutically effective amount of one or more of the compounds of formula I according to any of claims 1 to 29, or pharmaceutically acceptable derivatives thereof. 34. A method for preventing infection of mammals with viruses of the Pneumovirinae sub-family, characterized in that it comprises administering to the mammal, a therapeutically effective amount of one or more of the compounds of formula I according to any of claims 1 to 29 , or pharmaceutically acceptable derivatives thereof. 35. The use or method according to any of claims 1 to 34 in the treatment of infections involving the viruses of the genus Neumovirus and Metapneumovirus. 36. The use or method according to any of claims 1 to 34 in the treatment of respiratory syncytial virus (RSV). 37. The use or method according to any of claims 1 to 34 in the treatment of human RSV or human metapneumovirus. 38. A compound of formula I Formula I its salts, and pharmaceutically acceptable derivatives thereof, wherein A together with the atoms to which it is attached, represents a phenyl, pyridyl, pyridazinyl, pyrimidinyl or optionally substituted pyrazinyl ring; B-C is an optionally substituted bond of the formula -CH2- (CH2) Z-, where z is 1-4; R-i is selected from d.sub.2 alkyl, C2-? 2 alkenyl, C2.sub.2 alkynyl, - (CH2) n-C3-7 cycloalkyl, (CH2) C7 cyanoalkenyl, - (CH2) naril, - (CH2) naril-C2-C12 alkyl, - (CH2) naril-alkenyl of C2-? 2, - (CH2) naril-alkynyl of C2 .12, and - (CH2) nheterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R2 is selected from -CH2R3, -C (Y) R3, -C (Y) OR3, -C (Y) N (R4) R3 and S (O) wR5, wherein R3 is selected from hydrogen, C? 2, C2.sub.2 alkenyl, C2 alkynyl. 12, - (CH2) C3.7 cycloalkyl, - (CH2) C4.7 cycloalkenyl, - (CH2) maryl, - (CH2) maryl-C1.12 alkyl, - (CH2) maryl-C2- alkenyl 12, - (CH2) aryl-alkynyl of C2-12, and - (CH2) mheterocyclyl; and when R2 is -CH2R3, or -C (Y) R3, R3 can also be selected from -S-R5 and -O-R5; m is 0-6; R is hydrogen or d.6 alkyl; R5 is C6.6 alkyl, C2-6 alkenyl, C2-6 alkynyl. C3.7 cycloalkyl, C4.7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted, X and Y are independently selected from O, S and NRβ, where R6 is independently selected from hydrogen, alkyl lower, hydroxy and lower alkoxy; with the provisos that when A is phenyl and R-i is 4-chlorophenyl or unsubstituted phenyl (i) R3 is not unsubstituted cyclopropyl, halomethyl, unsubstituted phenyl or phenyl with only halo substituents, -CH3 and / or -OCH3 when R2 is COR3; (ii) R3 is not unsubstituted phenyl or phenol with only halo substituents, -CH3, -OCH3 and / or -C (O) OCH2CH3 when R2 is C (O) NHR3; (iii) R3 is not unsubstituted phenyl or phenyl with only halo substituents, -CH3, -OCH3 and / or -C (O) OCH2CH3 when R2 is C (S) NHR3; and with the provisos that (iv) when A is phenyl and R2 is CH2R3, R3 is not hydrogen, unsubstituted C6-6alkyl or d.6alkyl only substituted with divalent mono- or di-alkylamino NH2 groups.; (v) when A is phenyl and R-i is 4-methoxyphenyl, R2 is not CHO; (vi) when A is phenyl and R? is phenyl optionally substituted with halo only, d.sub.10 alkyl and / or d-6 alkoxy and R2 is COR3, R3 is not methylene substituted with NH2, mono or di-alkylamino of C? .6, N-piperidinyl or N -morpholinyl; (vii) when A is phenyl and R-t is 3-CH3, 4-CH3CH2CH2NHC (O) CH2? -phenyl, R2 is not -S (O) 2CH2SO2CH3, -CHO, -COCH2CH3, -CH2CH2OH, -CH2CH2OCH3, CH2CO2C (CH3) 3 or alkyl of d.6; (viii) when A is pyridyl and R-i is 3-CH3, 4-CH3CH2CH2NHC (O) CH2O-phenyl, R2 is not CH3. 39. The compound in accordance with the claim 38, the pharmaceutically acceptable salt or derivative thereof, with the proviso that when ring A is phenyl (i) R3 is not hydrogen or optionally substituted d6 alkyl when R is -CH2R3 or -COR3; (ii) R3 is not (CH2) mheterocyclyl where m is 1 or 2 and the heterocyclyl ring is piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, when R2 is -COR3 and R- [is 4-chlorophenyl, 4-methoxyphenyl or phenyl unsubstituted (iii) R2 is not benzyl; and with the proviso that (iv) R2 is not -CH3 when A is pyridyl. 40. The compound in accordance with the claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that when A is phenyl and R2 is -CH2R3 or -C (O) R3, and R3 is selected from C7.12 alkyl, alkenyl is C2-12, C2-12 alkynyl. - (CH2) C3.7 cycloalkyl, - (CH2) C4.7 cycloalkenyl, - (CH2) maryl, - (CH2) maryl-C1.12 alkyl, - (CH2) maryl-C2-12 alkenyl, - (CH2) C2-12 alkynyl, - (CH2) mheterocyclyl, -SR5 and -OR5. 41. The compound in accordance with the claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that the ring A is optionally substituted with one or more substituents independently selected from halo, -NH2, NO2, C6 alkyl, aryl and heterocyclyl, the aryl and heterocyclyl groups optionally substituted with halo, d-6 alkyl or C1.6 alkyl substituted with halo and, when ring A contains one or more nitrogens in the ring, optional substituents include N-oxides of one or more of the nitrogens in the ring. 42. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that ring A is optionally substituted with a substituent selected from halo, alkyl, C6H5-CH3-C6H-, CF3-C6H4-, pyridyl , NO2 and when ring A contains one or more nitrogens in the ring, the optional substituent also includes an N-oxide form of a nitrogen in the ring. 43. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that ring A is not substituted. 44. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R2 is selected from -CH2R3, -C (Y) R3, -C (Y) OR3, -C (Y) N ( R4) R3, -C (Y) CH2N (R4) R3, -C (Y) CH2SR3 and -S (O) wR5, wherein R3 is selected from hydrogen, d-12 alkyl, C2-12 alkenyl, alkynyl of C2-12, - (CH2) C3.7 cycloalkyl, - (CH2) mC .7 cycloalkenyl, - (CH2) rtyl, (CH2) maryl-C1-121 alkyl- (CH2) rt? aryl-alkenyl of C2-12, - (CH2) maryl-alkynyl of C2-12. and - (CH2) mheterocyclyl; and when R2 is -CH2R3, or -C (Y) R3, R3 can also be selected from -S-R5 and -O-R5; m is 0-6; R 4 is hydrogen or d-β alkyl; R5 is selected from d6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C7 cycloalkenyl, benzyl, aryl and heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted with one or more substituents selected from C 1-6 alkyl, d 6 alkoxy, C 2- alkenyl 6, C2-6 alkynyl, halo, haloalkyl of d-6 (including CF3), hydroxy, mercapto, nitro, cyano, NH2, mono or di (alkyl of d.6) amine, phenyl, benzyl and heterocyclyl, the substituents are optionally substituted. 45. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R2 is -CH2-R3, and R3 is - (CH2) aryl or - (CH2) mheterocyclyl and m is from 0 to 3 and the aryl or heterocyclyl ring is optionally substituted. 46. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R2 is -COR3 and R3 is aryl or heterocyclyl and is optionally substituted. 47. The compound according to claim 45 or 46, the pharmaceutically acceptable salt or derivative thereof, characterized in that R3 is phenyl, naphthyl, furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4-oxadiazolyl) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and 1,3,4-triazolyl), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyl), pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1, 3,5-trityanyl, triazinyl, 1H-thieno [2,3-c] pyrazolyl, thieno [2,3-b] furyl, indolyl, isoindylyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzlmidazolyl, indazolyl, isoquinolinyl , quinilinyl, quinoxalinyl, uridinyl, purinyl, cinolinyl, phthalazi nyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl or optionally substituted pteridinyl. 48. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R3 is optionally substituted with one or more substituents selected from C? .6 alkyl, C-? 6 alkoxy, C2.6 alkenyl, C2.6 alkynyl, halo, haloC1-6alkyl (including CF3), hydroxy, mercapto, nitro, cyano, NH2, mono odi (at I qui I of d.6) amino, phenyl, benzyl and heterocyclyl, the phenyl, benzyl groups and heterocyclyl are optionally substituted. 49. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R2 is -CON (H) R3, and R3 is - (CH2) maryl or - (CH2) mheteroclclyl and m is 0 to 2 and the aryl or heterocyclyl ring is optionally substituted with one or more substituents independently selected from halo, lower alkyl, hydroxy, lower alkoxy and phenyl. 50. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that z is 1 or 2. 51. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that -B-C- is a link in the formula -C-H2C H2-. 52. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that the -BC- bond is optionally substituted with no more than three optional substituents, the substituents are selected from halo, lower alkyl , hydroxy, lower alkoxy, phenyl and benzyl. 53. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that the -B-C- bond is not substituted. 54. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that X is oxygen or sulfur. 55. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that X is oxygen. 56. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R ^ is an optionally substituted aryl or heterocyclyl group. 57. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that Ri represents a phenyl, thienyl, pyrrolyl or pyridyl ring or an alkyl group of C? .6, the rings are optionally substituted with halo, hydroxy , nitro, -NR'R "(wherein R 'and R" are independently selected from hydrogen, lower alkyl and -C (O) R, where R is d6 alkyl, phenyl or heterocyclyl), C? 12, phenyl and -O-Ra, where Ra is -d -12alkyl, -3,7-cycloalkyl, -3-cycloalkyl-C3.7-alkyl, phenyl or -alkylphenyl-d-2; and the alkyl group of d-12, phenyl or Ra can be optionally substituted with halo, -CN, -NR'R ", -CO2R or -CONR'R", where R, R 'and R "are independently selected from hydrogen or lower alkyl 58. The compound according to the claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that Ri is phenyl optionally substituted with a substituent selected from halo, -C6 alkyl, -6C alkyl, -6CN alkyl, -OC alkyl; .6, -Oalkullhalo of d-6, -Oalkyl of C? .6CO2NH2, -Oalkyl of d. 6CN, -C3.7alkyl-C3.7alkyl, -D6C6H5alkyl, -OC6OCH3alkyl, -OC6H5, -OC6H4halo, -CF3, -OCF3, -NR'R "(where R ') and R "are independently selected from hydrogen, -C (O) alkyl of C? .6l -C (O) C6H5, -C (O) CH = CHCO2H, -C (O) C? -6CO2H alkyl, -. C (O) alkyl of d.6-CO2CH3, -C (O) alkyl of d.6C6H5, -C (O) alkyl of d.6C6H4CH3, -C (O) alkyl of d.6-C6H4OCH3 and -C ( O) C? .6C6H4halo alkyl), -CO2H, -CO2alkyl of C? .ß > -NO2, -OH, -C6H5, -C6H4alkyl of C? .β, -C6H halo and -OC (O) alkyl of d.6. 59. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R-i is halo-phenyl. 60. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that Ri is 4-chlorophenyl. 61. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that A is an optionally substituted phenyl ring. 62. The compound according to claim 38, the pharmaceutically acceptable salt or derivative thereof, characterized in that R2 is C (O) -R3 and R3 is - (CH2) m-aryl or (CH) m-heteroaryl, where m is from 0 to 6, and the aryl or heteroaryl group is optionally substituted. 63. The compound according to claim 38 of formula IV Formula IV characterized in that Ri, R2, X and -B-C are in accordance with claim 38, and the N-oxide and pyridinium salt form thereof. 64. The compound according to claim 63, and the N-oxide and pyridinium salt form thereof, characterized in that R2 is C (O) R3 and R3 is - (CH2) m-aryl or (CH2) m-heteroaryl , where m is from 0 to 6, and the aryl or heteroaryl group is optionally substituted. 65. A compound, characterized in that it is described in table 2 or 3. 66. A pharmaceutical formulation for the treatment of infections involving viruses of the Pneumovirinae sub-family, characterized in that it comprises a compound of formula I in accordance with any of claims 38 to 65, the pharmaceutically acceptable salt or derivative thereof. 67. A compound of formula and salts thereof, characterized in that the pyridyl ring is optionally substituted; B-C is an optionally substituted bond of the formula -CH 2 - (CH 2) z-, where z is 1-4; Ri is selected from C? 12 alkyl, C2-12 alkenyl, C2-12 alkynyl, - (CH2) n C3.7 cycloalkyl, (CH2) n C .7 cycloalkenyl, - (CH2) naril, - ( CH2) naril-C1.12 alkyl, - (CH2) naril-C2-12 alkenyl. - (CH2) C2-12 naril-alkynyl, and - (CH2) nheterocyclyl; n is 0-6 and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; X is selected from O, S and NR6, where R6 is independently selected from hydrogen, lower alkyl, hydroxy and lower alkoxy; with the proviso that when -B-C- is -CH2CH (CH (CH3) 2) -, R-, it is not 3-CH3, 4-CH3CH2CH2NHC (O) CH2? -phenyl-. 68. The compound according to claim 67 and salts thereof, characterized in that the pyridyl ring is optionally substituted with one or more substituents independently selected from halo, -NH2, -NO2, -C1-6 alkyl, aryl and heterocyclyl, the aryl and heterocyclyl groups optionally substituted with halo, C? .6 alkyl or d.6 alkyl substituted with halo, and the nitrogen in the pyridyl ring ring may optionally be an N-oxide. 69. The compound according to claim 67 and salts thereof, characterized in that the pyridyl ring is optionally substituted with a substituent selected from halo, alkyl, C6H5-, CH3-C6H-, CF3-C6H4-, pyridyl and NO2. , and the nitrogen in the annulus ring of the ridyl pi may optionally be an N-oxide. 70. The compound according to claim 67 and salts thereof, characterized in that the pyridyl ring is not substituted. 71 The compound according to claims 67 and salts thereof, characterized in that the linkage -BC is in accordance with any of claims 21 to 23. 72. The compound according to claim 67 and salts thereof, characterized because X is oxygen or sulfur. 73. The compound according to claim 67 and salts thereof, characterized in that X is oxygen. 74. The compound according to claims 67 and salts thereof, characterized in that Ri is in accordance with any of claims 25 to 29. 75. A compound of formula and salts thereof, characterized in that the pyridyl ring it is optionally substituted and Ri and X are in accordance with claim 67, with the proviso that Ri is not 4-chlorophenyl. 76. A compound of the formula and salts thereof, characterized in that the fused pyridazo n ring is optionally substituted and Ri and X are in accordance with claim 67, with the proviso that Ri is not phenyl, 4-chlorophenyl or 4-methoxyphenyl. 77. A compound of the formula and salts thereof, characterized in that the fused pyridyl, pyrazinyl, pyridazinyl or pyrimidinyl ring is optionally substituted and Ri and X are in accordance with claim 67. 78. Use of a compound of formula III, Formula III and salts thereof, characterized in that R-, ring A, -BC and X are in accordance with claim 38, as an intermediate for the production of a compound of formula I according to claim 38. 79. A method for separating the enantiomers of a compound of formula III by forming diastereomeric salts of the compounds using an enantiomerically enriched chiral hydrogen phosphate. 80. A method for separating the enantiomers of a compound according to claim 67, characterized by the formation of diastereomeric salts of the compound using an enantiomerically enriched chiral hydrogen phosphate. 81. The compound according to claim 38, characterized in that it is in the substantially pure optically active form. 82. The compound according to claim 67, 75, 76 or 77, characterized in that it is in the substantially pure optically active form.