Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4196—1,2,4-Triazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the invention concerns novel substituted pyrazolo- and triazolo-pyrimidine compounds having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV).
• RSV respiratory syncytial virus
• the invention further concerns pharmaceutical compositions comprising these compounds and the compounds for use in the treatment of respiratory syncytial virus infection.
• Human RSV or Respiratory Syncytial Virus is a large RNA virus, member of the family of Paramyxoviridae, subfamily pneumoviridae together with bovine RSV virus.
• Human RSV is responsible for a spectrum of respiratory tract diseases in people of all ages throughout the world. It is the major cause of lower respiratory tract illness during infancy and childhood. Over half of all infants encounter RSV in their first year of life, and almost all within their first two years. The infection in young children can cause lung damage that persists for years and may contribute to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often suffer from a (bad) common cold upon RSV infection. In old age, susceptibility again increases, and RSV has been implicated in a number of outbreaks of pneumonia in the aged resulting in significant mortality.
• the present invention relates to compounds of formula (I)
• X is N or CR 6 wherein R 6 is hydrogen, halo or C ⁇ alkyl
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C3_6alkyl and R 3 is C ⁇ alkyl;
• radical (a-28) (a-29) (a-30) wherein R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 is absent in radical (a-6); or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a-30) are optionally substituted with one or two substituents each independently selected from C ⁇ alkyl and halo;
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• C3_6cycloalkyl amino carbonyl, mono- or d ⁇ C ⁇ alky ⁇ aminocarbonyl; oxetanyl optionally substituted with C ⁇ alkyl; Heteroaryl 1 ; C3_ 6 cycloalkyl; C 3.6 cycloalkyl substituted with one or two substituents each individually selected from hydroxy, halo, cyano, C ⁇ alkyl, C ⁇ alkyloxy, polyhaloC ⁇ alkyl, and polyhaloC ⁇ alkyloxy; or
• NR 7 R 8 wherein R 7 is selected from hydrogen and C ⁇ alkyl
• R 8 is C ⁇ alkyl or C3_ 6 cycloalkyl
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl
• naphthyl substituted with 1 , 2 or 3 substituents each independently selected from halo and hydroxycarbonyl;
• aminosulfonyl mono- or di(C ⁇ 4alkyl)aminosulfonyl;
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and
• C j alkyl substituted with one or two substituents each independently selected from hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl, C3. 6 cycloalkyl substituted with hydroxycarbonyl, C ⁇ alkylcarbonylamino, mono- or di(C ⁇ 4alkyl)amino, and
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, amino carbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl, Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heteroaryl 1 is imidazolyl or pyrazolyl; wherein each Heteroaryl 1 is optionally
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 2,5-dihydro-lH-pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or 3-oxo- 2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo, hydroxyC ⁇ alkyl, polyhaloC ⁇ alkyl, hydroxycarbonyl, and C ⁇ alkyl substituted with hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• Bicycle is 1,2,3,4-tetrahydronaphthalenyl, chromanyl or 2,3-dihydrobenzofuranyl;
• each Bicycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, halo and hydroxycarbonyl;
• - halo is generic to fluoro, chloro, bromo and iodo
• Ci_2 a lkyl defines saturated hydrocarbon radicals having from 1 to 2 carbon atoms such as methyl and ethyl;
• - C ⁇ alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl,
• C ⁇ alkyl is meant to include C ⁇ alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2 methylbutyl, pentyl, hexyl and the like;
• C3_6alkenyl defines straight and branched chain unsaturated hydrocarbon radicals having from 3 to 6 carbon atoms, such as propenyl, butenyl, pentenyl or hexenyl;
• C3_6alkynyl defines straight and branched chain unsaturated hydrocarbon radicals having from 3 to 6 carbon atoms, such as propynyl, butynyl, pentynyl or hexynyl;
• - C3_ 6 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;
• - C3_ 6 cycloalkenyl is generic to cyclopropenyl, cyclobutenyl, cyclopentenyl, and
• polyhaloC ⁇ alkyl is defined as polyhalosubstituted C ⁇ alkyl, in particular C ⁇ alkyl (as hereinabove defined) substituted with 2 to 6 halogen atoms such as difluoromethyl, trifluoromethyl, trifluoroethyl, and the like.
• the invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.
• Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
• a 1 : 1 mixture of a pair of enantiomers is a racemate or racemic mixture.
• Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they are not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration.
• Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.
• stereoisomers also includes any rotamers, also called conformational isomers, the compounds of formula (I) may form. Therefore, the invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, rotamers, and mixtures thereof, whenever chemically possible.
• the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
• the configuration at an asymmetric atom is specified by either R or S.
• Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or ( ) depending on the direction in which they rotate plane polarized light.
• resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
• the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms that the compounds of formula (I) are able to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
• Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
• butane-dioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p toluenesulfonic, cyclamic, salicylic, p aminosalicylic, pamoic and the like acids.
• the compounds of formula (I) may exist in both unsolvated and solvated forms.
• the term 'solvate' is used herein to describe a molecular association comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, e.g. water or ethanol.
• the term 'hydrate' is used when said solvent is water.
• compounds of formula (I) may contain the stated atoms in any of their natural or non-natural isotopic forms.
• embodiments of the invention include those in which (a) the compound of formula (I) is not isotopically enriched or labelled with respect to any atoms of the compound; and (b) the compound of formula (I) is isotopically enriched or labelled with respect to one or more atoms of the compound.
• Compounds of formula (I) that are isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes include, for example, compounds of formula (I) that are isotopically enriched or labelled with one or more atoms such as deuterium, 13 C, 14 C, 14 N, 15 0 or the like.
• Particular compounds of formula (I) that are isotopically enriched are the compounds of formula (I) wherein R 6 is deuterium.
• the invention concerns compounds of formula (I), including any stereochemically isomeric forms thereof,
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 is absent in radical (a-6); or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a- 15) are optionally substituted with one or two substituents each independently selected from C ⁇ alkyl and halo;
• R 4 is C ⁇ alkyl; polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one C3_ 6 cycloalkyl; or NR 7 R 8 wherein R 7 is selected from hydrogen and C ⁇ alkyl; R is C ⁇ alkyl or C3_ 6 cycloalkyl;
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• naphthyl substituted with 1 , 2 or 3 substituents each independently selected from halo and hydroxycarbonyl;
• aminosulfonyl mono- or di(C ⁇ 4 alkyl)aminosulfonyl; and Heterocycle;
• R y and R iU are each independently selected from hydrogen; C ⁇ alkyl; S0 2 -R , and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, amino carbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl,
• Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, or 2,5-dioxopyrrolidinyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• the invention concerns compounds of formula (I), including any stereochemical ⁇ isomeric forms thereof, wherein
• X is N or CR 6 wherein R 6 is hydrogen or halo
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C3_6alkyl and R 3 is
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 is absent in radical (a-6); or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a- 15) are optionally substituted with one or two substituents each independently selected from C ⁇ alkyl and halo;
• R 4 is C ⁇ alkyl; polyhalo Chalky 1; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• NR 7 R 8 wherein R 7 is selected from hydrogen and C ⁇ alkyl
• R 8 is C ⁇ alkyl or C3_ 6 cycloalkyl
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl
• aminosulfonyl mono- or di(C ⁇ 4alkyl)aminosulfonyl; and
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, amino carbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 1 is C ⁇ alkyl, or C3_ 6 cycloalkyl
• Heteroaryl is thienyl, pyridinyl, 1-benzopyrazolyl, 2,3-dihydro-lH-indolyl, 2-oxo-2,3- dihydro-lH-indolyl, quinolinyl, 2-oxo-quinolinyl, benzimidazolyl, cinnolinyl, or 2H- chromenyl;
• each Heteroaryl is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, halo, aminocarbonyl, and
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl,
• each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen and halogen;
• the invention concerns compounds of formula (I), including any stereochemically isomeric forms thereof, wherein
• X is N or CR 6 wherein R 6 is hydrogen, halo or C ⁇ alkyl
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C3_6alkyl and R 3 is C ⁇ alkyl;
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 is absent in radical (a-6); or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and radical (a-1) to (a- 15) are optionally substituted with one or two substituents each independently selected from C ⁇ alkyl and halo;
• R 4 is C ⁇ alkyl; polyhaloC ⁇ alkyl; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• NR 7 R 8 wherein R 7 is selected from hydrogen and C ⁇ alkyl
• R 8 is C ⁇ alkyl or C3_ 6 cycloalkyl
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl
• Heteroaryl substituted with 1 , 2 or 3 substituents each independently selected from halo and hydroxycarbonyl;
• aminosulfonyl mono- or di(C ⁇ 4alkyl)aminosulfonyl; and Heterocycle;
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R n is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, amino carbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3. 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl,
• Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl,
• each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• a first group of compounds are compounds of formula (I-a)
• R 6 is hydrogen, halo or C ⁇ alkyl
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C3_6alkyl and R 3 is C ⁇ alkyl;
• R 4 is C ⁇ alkyl; polyhalo Chalky 1; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl,
• Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo- pyrrolidinyl or 3-oxo-2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• a second group of compounds are compounds of formula (I-b)
• R 1 is CH 3 or CH 2 CH 3 , and R 1 is hydrogen; or R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; and R 2 is C3_6alkyl and R 3 is C ⁇ alkyl;
• R 4 is C ⁇ alkyl; polyhalo Chalky 1; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• R 7 is selected from hydrogen and C ⁇ alkyl;
• R 8 is C ⁇ alkyl or C3_6cycloalkyl; or
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or 3 substituents each independently selected from halo and hydroxycarbonyl; phenyl substituted with 1 , 2 or 3 substituents each independently selected from hydroxy; halo; C ⁇ alkyl; C ⁇ alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl; C 3 . 6 alkenyl; C3_ 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl, hydroxy, hydroxycarbonyl and
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl, Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo- pyrrolidinyl, or 3-oxo-2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• a third group of compounds are compounds of formula (I-c)
• R 6 is hydrogen, halo or C ⁇ alkyl
• R 4 is C ⁇ alkyl; polyhalo Chalky 1; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• R 7 is selected from hydrogen and C ⁇ alkyl;
• R 8 is C ⁇ alkyl or C3_6cycloalkyl; or
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or 3 substituents each independently selected from halo and hydroxycarbonyl; phenyl substituted with 1 , 2 or 3 substituents each independently selected from hydroxy; halo; C ⁇ alkyl; C ⁇ alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl; C 3 . 6 alkenyl; C3_ 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl, hydroxy, hydroxycarbonyl and
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl,
• Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo- pyrrolidinyl or 3-oxo-2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• a fourth group of compounds are compounds of formula (I-d)
• R 4 is C ⁇ alkyl; polyhalo Chalky 1; C3_ 6 cycloalkyl; C ⁇ alkyl substituted with one
• R 7 is selected from hydrogen and C ⁇ alkyl;
• R 8 is C ⁇ alkyl or C3_6cycloalkyl; or
• R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl;
• R 5 is C3_ 6 cycloalkyl; Heteroaryl; naphthyl substituted with 1, 2 or 3 substituents each independently selected from halo and hydroxycarbonyl; phenyl substituted with 1 , 2 or 3 substituents each independently selected from hydroxy; halo; C ⁇ alkyl; C ⁇ alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl; C 3 . 6 alkenyl; C3_ 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl, hydroxy, hydroxycarbonyl and
• R 9 and R 10 are each independently selected from hydrogen; C ⁇ alkyl; SO2-R 12 ; and C ⁇ alkyl substituted with hydroxy, hydroxycarbonyl, C3_ 6 cycloalkyl,
• R 1 1 is C ⁇ alkyl; C 3 . 6 alkenyl; C3_ 6 cycloalkyl; Aryl; Heterocycle; or C ⁇ alkyl substituted with one substituent selected from C3_ 6 cycloalkyl, C ⁇ alkyloxy, hydroxy, cyano, hydroxycarbonyl, aminocarbonyl, mono- or di(C ⁇ 4alkyl)aminocarbonyl,
• R 12 is C ⁇ alkyl, C3_ 6 cycloalkyl, or C ⁇ alkyl substituted with one C3_ 6 cycloalkyl,
• Heteroaryl is thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, 1-benzopyrazolyl,
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxo- pyrrolidinyl, or 3-oxo-2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo and hydroxycarbonyl;
• Aryl is phenyl substituted with one or two substituents each independently selected from hydrogen, halogen, C ⁇ alkyl, C ⁇ alkyloxy, and trifluoromethyl;
• a fifth group of compounds are those compounds of formula (I),
• X is CR 6 wherein R 6 is hydrogen; the I moiety is a radical of formula : I . N>
• R 1 is CH 3 , and R 1 is hydrogen
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• R 5 is naphthyl substituted with 1 , 2 or 3 substituents each independently selected from halo and hydroxycarbonyl ; or
• Ci _ 6 alky loxy optionally substituted with hydroxycarbonyl; polyhaloC i _ 4 alkyl;
• Heterocycle is azetidinyl, tetrahydroiuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 2,5-dihydro-lH-pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo-azepanyl, 2,5-dioxopyrrolidinyl, or 3-oxo- 2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo, hydroxyC ⁇ alkyl, polyhaloC ⁇ alkyl, hydroxycarbonyl, and C ⁇ alkyl substituted with hydroxycarbonyl
• a sixth group of compounds are those compounds of formula (I),
• X is CR 6 wherein R 6 is hydrogen; the r2 I r ' moiety is a radical of formula :
• R 1 is CH 3 , and R 1 is hydrogen
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• NR 7 R 8 wherein R 7 and R 8 are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl or piperidinyl; substituted with 1 , 2 or 3 substituents each independently selected from hydroxy;
• Heterocycle is azetidinyl, tetrahydrofuranyl, pyrrolidinyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 2,5-dihydro-lH-pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, 2-oxo- azepanyl, 2,5-dioxopyrrolidinyl, or 3-oxo-2,3-dihydro-l,2-oxazolyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl,
• a seventh group of compounds are those compounds of formula (I),
• X is CR 6 wherein R 6 is hydrogen
• R 1 is CH 3 , and R 1 is hydrogen
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• R 5 is phenyl substituted with 1, 2 or 3 substituents each independently selected from
• C3_ 6 cycloalkyl C3_ 6 cycloalkyl substituted with one or two substituents each independently selected from C ⁇ alkyl, halo, hydroxycarbonyl, and C ⁇ alkyl substituted with hydroxycarbonyl;
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• R 5 is naphthyl substituted with 1, 2 or 3 substituents each independently selected from halo and hydroxycarbonyl ; or
• Heterocycle is azetidinyl, pyrrolidinyl, pyrazolyl or pyridinyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo, hydroxyC ⁇ alkyl, polyhaloC ⁇ alkyl,
• a ninth group of compounds are compounds of formula (I-f)
• R 4 is C ⁇ alkyl; C3_ 6 alkenyl, polyhaloC ⁇ alkyl; C ⁇ alkyl substituted with one
• R 13 is C3_ 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl,
• C3_ 6 cycloalkyl substituted with one, two or three substituents each independently selected from C ⁇ alkyl, halo, hydroxycarbonyl, and C ⁇ alkyl substituted with hydroxycarbonyl; or
• Heterocycle is azetidinyl, pyrrolidinyl, pyrazolyl or pyridinyl; wherein each Heterocycle is optionally substituted with one or two substituents each independently selected from C ⁇ alkyl, C3_ 6 cycloalkyl, halo, hydroxyC ⁇ alkyl, polyhaloC ⁇ alkyl,
• X is CR 6 wherein R 6 is hydrogen or halo;
• R 1 is CH 3 , and R 1 is hydrogen;
• R 1 and R 1 are taken together with the carbon atom to which they are attached to form cyclopropyl; or
• R 3 is CH 3 or CH 2 CH 3 ;
• R 4 is C ⁇ alkyl in particular ethyl
• R 4 is C3_ 6 cycloalkyl in particular cyclopropyl
• R 5 is phenyl substituted with 1 , 2 or 3 substituents each independently selected from hydroxy; halo; C ⁇ alkyl; C ⁇ alkyl substituted with one substituent selected from hydroxy, hydroxycarbonyl and aminocarbonyl; C3_ 6 alkenyl; C3_ 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl; C3_ 6 alkynyl; C3_ 6 alkynyl substituted with one hydroxycarbonyl; C3_ 6 cycloalkyl; C3_ 6 cycloalkyl substituted with one hydroxycarbonyl;
• R 5 is phenyl substituted with 1 , 2 or 3 substituents each independently selected from halo; or C ⁇ alkyl substituted with one substituent selected from hydroxy,
• R 5 is phenyl substituted with 1 , 2 or 3 substituents each independently selected from halo, or C 3 . 6 alkenyl substituted with one or two substituents selected from C ⁇ alkyl, hydroxy, hydroxycarbonyl and aminocarbonyl; and
• R 5 is phenyl substituted with 1 , 2 or 3 substituents each independently selected from halo, or C3_ 6 cycloalkyl substituted with hydroxycarbonyl.
• substituents each independently selected from halo, or C3_ 6 cycloalkyl substituted with hydroxycarbonyl.
• Compounds of formula (I) can generally be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) in a reaction-inert solvent, such as dichloromethane or DMF, in the present of a suitable reagent, such as BOP ((benzotriazol- l-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), and a base such as diisopropylethylamine or triethylamine.
• a reaction-inert solvent such as dichloromethane or DMF
• the compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
• the starting materials and some of the intermediates are known compounds and are commercially available or may be prepared according to conventional reaction procedures generally known in the art.
• the compounds of formula (I) as prepared in the hereinabove described processes may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
• Those compounds of formula (I) that are obtained in racemic form may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
• An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
• Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemical ⁇ isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
• said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
• the compounds of formula (I) show antiviral properties.
• Viral infections treatable using the compounds and methods of the present invention include those infections brought on by ortho- and paramyxoviruses and in particular by human and bovine respiratory syncytial virus (RSV).
• RSV human and bovine respiratory syncytial virus
• a number of the compounds of this invention moreover are active against mutated strains of RSV.
• many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties in terms of bioavailabilty, including an acceptable half-life, AUC and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
• the in vitro antiviral activity against RSV of the present compounds was tested in a test as described in the experimental part of the description, and may also be demonstrated in a virus yield reduction assay.
• the in vivo antiviral activity against RSV of the present compounds may be demonstrated in a test model using cotton rats as described in Wyde et al. in Antiviral Research, 38, p. 31 - 42(1998).
• compositions comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). Also provided are pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a therapeutically active amount of a compound of formula (I), and another antiviral agent, in particular a RSV inhibiting compound.
• compositions of this invention an effective amount of the particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with at least one pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
• These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for oral administration, rectal administration,
• any of the usual liquid pharmaceutical carriers may be employed, such as for instance water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
• the pharmaceutical carrier will mainly comprise sterile water, although other ingredients may be included in order to improve solubility of the active ingredient.
• Injectable solutions may be prepared for instance by using a pharmaceutical carrier comprising a saline solution, a glucose solution or a mixture of both. Injectable suspensions may also be prepared by using appropriate liquid carriers, suspending agents and the like.
• the pharmaceutical carrier may optionally comprise a penetration enhancing agent and/or a suitable wetting agent, optionally combined with minor proportions of suitable additives which do not cause a significant deleterious effect to the skin. Said additives may be selected in order to facilitate administration of the active ingredient to the skin and/or be helpful for preparing the desired compositions.
• These topical compositions may be administered in various ways, e.g., as a transdermal patch, a spot-on or an ointment.
• Dosage unit form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
• dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
• compositions of the present invention may take the form of solid dose forms, for example, tablets (both swallowable and chewable forms), capsules or gelcaps, prepared by conventional means with pharmaceutically acceptable excipients and carriers such as binding agents (e.g. pregelatinised maize starch,
• Liquid preparations for oral administration may take the form of e.g. solutions, syrups or suspensions, or they may be formulated as a dry product for admixture with water and/or another suitable liquid carrier before use.
• Such liquid preparations may be prepared by conventional means, optionally with other pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non aqueous carriers (e.g. almond oil, oily esters or ethyl alcohol), sweeteners, flavours, masking agents and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
• suspending agents e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats
• emulsifying agents e.g. lecithin or acacia
• non aqueous carriers e.g. almond oil, oily esters or ethyl alcohol
• sweeteners e.g. methyl or propyl p-hydroxybenzoates or sorbic acid
• Pharmaceutically acceptable sweeteners useful in the pharmaceutical compositions of the invention comprise preferably at least one intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4, ,6'-trichloro-4, ,6'-trideoxygalactosucrose) or, preferably, saccharin, sodium or calcium saccharin, and optionally at least one bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.
• intense sweetener such as aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose (4, ,6'-trichloro-4, ,6
• Intense sweeteners are conveniently used in low concentrations.
• concentration may range from about 0.04% to 0.1% (weight/volume) of the final formulation.
• the bulk sweetener can effectively be used in larger concentrations ranging from about 10% to about 35%, preferably from about 10% to 15%) (weight/volume).
• the pharmaceutically acceptable flavours which can mask the bitter tasting ingredients in the low-dosage formulations are preferably fruit flavours such as cherry, raspberry, black currant or strawberry flavour. A combination of two flavours may yield very good results.
• stronger pharmaceutically acceptable flavours may be required such as Caramel Chocolate, Mint Cool, Fantasy and the like.
• Each flavour may be present in the final composition in a concentration ranging from about 0.05% to 1% (weight/volume). Combinations of said strong flavours are advantageously used.
• flavour is used that does not undergo any change or loss of taste and/or color under the circumstances of the formulation.
• the compounds of formula (I) may be formulated for parenteral administration by injection, conveniently intravenous, intra-muscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
• Formulations for injection may be presented in unit dosage form, e.g. in ampoules or multi-dose containers, including an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as isotonizing, suspending, stabilizing and/or dispersing agents.
• the active ingredient may be present in powder form for mixing with a suitable vehicle, e.g. sterile pyrogen free water, before use.
• the compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter and/or other glycerides.
• an antivirally effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form. The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art.
• said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
• the effective daily amount ranges mentioned hereinabove are therefore only guidelines.
• the combination of another antiviral agent and a compound of formula (I) can be used as a medicine.
• the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antiviral compound, as a combined preparation for simultaneous, separate or sequential use in antiviral treatment.
• the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
• the compounds of the present invention may be combined with interferon- beta or tumor necrosis factor-alpha in order to treat or prevent RSV infections.
• Other antiviral compounds (b) to be combined with a compound of formula (I) for use in the treatment of RSV are RSV fusion inhibitors or RSV polymerase inhibitors.
• RSV inhibiting compounds selected from ribavirin, 4 * -chloromethyl-2 * -deoxy-3 * ,5 * -di-0-isobutyryl-2 , -fluorocytidine (ALS-8176), N-(2-((S)-2- (5-((S)-3-aminopyrrolidin- 1 -yl)-6-methylpyrazolo[ 1 ,5-a]pyrimidin-2-yl)piperidine- 1 - carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), MDT-637, BTA-9881, BMS-433771 , YM-543403, A-60444, TMC-353121, RFI-641, CL-387626, MBX-300, 3-( ⁇ 5-chloro- 1 -[3-(methylsulfonyl)
• R or S The stereochemical configuration for some compounds has been designated as R or S (or *R or *S) when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure.
• the reaction mixture was stirred at RT for 2 hours.
• the solvent was
• the reaction mixture was stirred at RT for 2 hours.
• the solvent was
• the mixture was heated at 120°C using a single mode microwave (Biotage® initiator60) with a power output ranging from 0 to 400 W for 20 min.
• the mixture was poured out into water, extracted with EtOAc, the organic layer was separated, washed with water then brine, dried over MgS0 4 and evaporated till dryness (0.74 g).
• Purification of the residue was carried out by column chromatography (silica gel, from Heptane/EtOAc 80/20 to Heptane/EtOAc 70/30). The pure fractions were collected and evaporated to dryness to afford a mixture of 2 isomers.
• the resulting mixture was purged by N 2 bubbling, then heated at 80°C using one single mode microwave (Biotage® Initiator EXP 60) with a power output ranging from 0 to 400 W for 30 minutes.
• the crude was poured into DCM, washed with water (twice), brine, dried over MgS0 4 , filtered and evaporated in vacuum.
• the residue was purified by column chromatography (silica gel, from DCM/EtOAc 100:0 to 90: 10). The fractions containing product were combined and the solvent was removed to give 252 mg (60%) of

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