TWI378926B - Amino-benzimidazoles derivatives as inhibitors of respiratory syncytial virus replication - Google Patents

Description

DESCRIPTION OF THE INVENTION: [Technical field to which the invention pertains] Toxic, antiviral activity 'especially*, an amine benzoic acid-derived derivative A having an inhibitory activity against respiratory fusion disease t-initiation, and its preparation and inclusion of such compounds The composition and its use as an agent. [Prior Art] The RSV-like or respiratory fusion virus system is a subfamily of the virus of the Paramyxoviridae. Humans are the eggs of the world's 2 populations of all ages. It is the main cause of lower respiratory diseases in children. There are half-baby before birth: RSV is also encountered in the year, and almost all of the first two years. Infant infections can lead to persistence. In the year, the lungs are damaged and may become chronic lung disease (chronic stag beating, asthma). Larger children and adults often develop (severe) common colds during RSV infection. In old age, susceptibility increased again, and RSV was associated with many outbreaks of pneumonia in the elderly, resulting in extremely high mortality. Infections from the virus of the scorpion group cannot be protected from RSV isolates from the same subpopulation in the following winter. Repetitive infections of RSV are therefore extremely common, although there are only two subtypes of Α & Ββ. Currently only three drugs have been shown to be useful against RSV infection. The first is rivavirin, a nucleoside homologue that provides aerosol therapy for severe RSV infection in hospitalized children. The efficacy of the aerosol route of administration, toxicity (risk of teratogenicity), cost and height changes limits its use of 1378926. Two other drugs, RespiGam® and palivizumab, multiple strains and monoclonal antibody immunostimulants, are used for prevention. Other attempts to develop safe and effective RSV vaccines have failed. Inactivated vaccines do not protect against disease and, in some cases, actually exacerbate the condition in subsequent infections. The results of live attenuated vaccines are limited. Obviously, there is a drug that is effective against non-toxic and easy to administer RSV replication. Benzimidazoles and imidazopyridines which are inhibitors of RSV replication are described in WO 01/00611, WO 01/00612 and WO 01/00615. SUMMARY OF THE INVENTION The present invention relates to an inhibitor of RSV replication, which can be represented by the formula (1)

a prodrug, an N-oxide, an addition salt, a quaternary amine, a metal complex, and a stereochemically isomeric form, wherein the Q system is Ar2, C3-7 cycloalkyl or, as the case may be, one or more substituents Substituted Cw alkyl 'the substituent is selected from the group consisting of trifluoromethyl, c3-7 cycloalkyl, Ar2, hydroxy, Cw alkoxy, Cw alkylthio, Ar2-oxy-, Ar2-thio-, Ar2 (CH2)noxy-, Ar2(CH2)nthio-, transcarbonylcarbonyl, aminocarbonyl, Cw alkylcarbonyl, Ar2carbonyl, Cm 1378926 alkoxycarbonyl, Ar2(CH2)ncarbonyl-, aminocarbonyl Oxy, C!_4 alkylcarbonyloxy, Ar2carbonyloxy, Δ, ((:za hexacarbonyloxy, hydroxy C2.4 alkyloxy, CN4 alkoxycarbonyl (CH2)noxy-, single - or di(Cw alkyl)aminocarbonyl., mono- or di(Cl_4 alkyl)aminocarbonyloxy, aminyl, mono- or di(Cm-dishyl)amine-based fluorenyl, In the case of one or two (γ-alkyl substituted dioxolanyl group and selected from the group of sylvestre, 吼P groups, dihydro II than Haki, ν» thiol, phenazolyl, Triazolyl, hexahydropyridyl, homohexahydron-pyridinyl, piperidinyl, acridinyl and tetrahydropyridyl a group consisting of a heterocyclic group of groups consisting of, wherein the heterocyclic ring may be optionally substituted by a keto group or a Cu alkyl group; and G is a direct bond or, as the case may be, substituted by one or more substituents. a diradical, the substituent is selected individually from a hydroxyl group, a Cl-6 alkyloxy group, an alkyloxy group, a Cl-6 alkylthio group, an Ai^-Cw alkylthio group, HO(-CH2-CH2-0)n-, a group consisting of Cw alkyloxy (-CH2, CH2-〇)n- and ΑιΆ_6 alkyloxy (-CH2-CH2-〇)n•; R1 is Ar1 or a monocyclic or bicyclic heterocyclic ring selected from Hexahydroacridinyl, piperidinyl, acenaphthyl, hydrazine, hydrazine, pyrimidinyl, furyl, tetrahydrofuranyl, thienyl, fluorenyl, thiazolyl, oxazolyl, imidazolyl, heterophilic Azyl, carbazolyl, isoxazolyl, oxadiazolyl, indolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazole , pyridopyridinyl, naphthyridinyl, 1H-flavored [4,5-b]pyridyl, 3H.-oxazolo[4,5-b], 1378926-based, imidazo[l,2- a] pyridyl, 2,3-dihydro-1,4-dioxohexa[2,3-b]n-pyridyl Or a group of the following formula

Wherein the monocyclic or bicyclic heterocyclic ring may be optionally substituted by 1 or possibly more (5, 2, 3, 4 or 5) substituents, each selected from the group consisting of a self group, a hydroxyl group, an amine group. , cyano group, carboxyl group, Cl6 alkyl group,

Cw alkyloxy, Cw alkylthio, Cl-6 alkyloxy Ci 6 alkyl, Ar1, Arkw alkyl, Artw alkyloxy, hydroxyCl 6 alkyl, mono- or di(Cw alkyl) Amino, mono- or di(Cu alkyl)amine 10 Cw alkyl, polydentate Cu alkyl, Cw alkylcarbonylamino,

Cw alkyl-S02-NR4a, Ad-SCVNR43, C _6 alkyloxycarbonyl' group, -C(=0)-NR4aR4b, H0(-CH2-CH2-0)n-, i group-(-CH2 -CH2-0)n->C1.6^&ftii(-CH2-CH2-0)n-'Ar1C1.6 alkyl fluorenyl (-CH2-CH2-0)n- and single- or two- a group of substituents consisting of a Cu alkyl)amino group (-CH2-CH2-0)n-; 11 15 each η individual system is! , 2, 3 or 4; one of R and Ra_ is C 6 alkyl and the other of R 2a and Rh is hydrogen; if R 2a is not hydrogen ' then 21 ) is hydrogen or Cw alkyl, and R 3b Is hydrogen; if R3a is non-hydrogen, then rw is hydrogen or Cl6 alkyl, and R2b is hydrogen; or R42aa, R2b, R3a and R3b are all hydrogen; or R4a and R4a may be the same or may be different from each other, and Each line is individually hydrogen or Q ray; or R4a and R4a may form a divalent group of formula -(CH2)S-; R5 is hydrogen or cv6 alkyl; m is 1 or 2; P is 1 or 2; s is 4 or 5;

Ar1 is a phenyl group or one or more (such as 2, 3 or 4) selected from a halogen group, a thiol group, a Cw alkyl group, a hydroxyCl.6 alkyl group, a polydentate CN6 alkyl group, and

a stupid group substituted with a substituent of a group consisting of a Cl 6 alkyloxy group; a phenyl group or a one or more (such as 2, 3 or 4) selected from a halogen group, a hydroxyl group, an amine group , cyano, Cw alkyl, hydroxy Cw alkyl, polyhalo Cl. 6 alkyl, amino Cw alkyl, Cw alkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl, alkylcarbonyl , mono- or di(fi-4 alkyl)amino, mono- or di(Cm alkyl)aminocarbonyl, mono- or bis(ci.4 alkyl)aminosulfonyl, mono- or di(Ci) A stupid group substituted with a substituent of a group consisting of a 4 alkyl)amino Cu group and a Cm alkoxycarbonyl group. 1378926 The invention further relates to the use of a compound of formula (1) or a prodrug thereof, an n-oxide, a salt, a quaternary amine, a metal complex and a stereochemically isomeric form for the manufacture of a medicament for inhibiting RSV replication. Or a method for inhibiting RSV replication in a warm-blooded animal according to the invention, which comprises administering an effective amount of a compound of the formula (1) or a prodrug thereof, an N-oxide, an addition salt, a quaternary amine, a metal complex And stereochemically isomeric forms. In another aspect, the invention relates to novel compounds of formula (1) and to processes for the preparation of such compounds. The term "prodrug" as used in the present invention means a pharmaceutically acceptable derivative of 10 such as an ester and an amide such that the biotransformation product formed by the derivative is an activity defined by the compound of formula (I). drug. Goodman and Gilman's reference (The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) generally describes prodrugs and is incorporated herein by reference. Prodrugs have good aqueous solubility and bioavailability and can be immediately metabolized into active inhibitors in the body. The term "C alkyl" as used in the definition of Q, as the case may be substituted by one or more substituents, or as used in the definition of G, is optionally substituted by one or more substituents. An alkanediyl group is used to specifically include 20 having zero, one, two or more substituents (eg zero, one, two, three, four, five or six substituents, especially zero, one, two or a Cw alkyl group and a Cuo calcined diyl group of three substituents, particularly zero, one or two substituents. The upper limit of the number of substituents is based on the number of hydrogen atoms which can be substituted and the general nature of the substituent (such as As determined by the bulkiness, such properties are such that the person skilled in the art has determined the upper limit. The term "Q" as used in the present invention, wherein the heterocyclic ring is substituted with a group or an alkyl group, includes one or more a heterocyclic ring (such as ^2 or up to 2 substituents or via one) each selected from the group consisting of a substituent of the yl group and the t-regular group. As used herein or as a group or group - The "polydentate Cl.6 alkyl group" in the eighth part of the titanyloxy group is a Cm alkyl group substituted by a = or an early or a halo group. Especially up to one or two,

Two, four, five, six or more Ci 6 alkyl groups substituted from atoms, methyl or ethyl groups of a plurality of fluorine atoms, such as difluoromethyl, di-, fluoroethyl. Also included are perfluoro-Ci6 alkyl groups, which are all "white" Cl. groups substituted by atoms, such as money ethyl. If more than one tooth atom is attached to a burnt-base atom within the definition of a multi-recorded Cd group Can be the same or different.

The monocyclic or bicyclic heterocyclic ring in the definition of R may each be substituted by a substituent or a substituent such as 2, 3, 4 or 5 substituents. In particular, the heterocyclic ring can be replaced by up to 4, up to 3, most substituents or up to 1 substituent.

Each of Ar1 or Ar2 may be an unsubstituted phenyl group or a phenyl group substituted with 1 or more groups such as 5 or 4 substituents, or up to 3 substituents, or up to two substituents, Or a substituent. When the hydroxyl group is substituted on the oxygen atom or the nitrogen atom, it is preferably a hydroxyl group C: 2-6 alkyl group, wherein the hydroxyl group and the oxygen or nitrogen are at least two carbon atoms; and the partition of the invention is based on (13) Or a portion of a Cm alkyl group is defined as a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl and the like; a group or a portion of a group of q.4 is defined as having a straight bond of up to 4 carbon atoms or a saturated chain of 5 1 chains such as c] 4 and butyl and the like; a C. 4 alkyl group as a part of a group defines a straight or branched chain saturated hydrocarbon group having 2 to 4 carbon atoms such as ethyl, propyl, fluorenylmethylethyl, butyl and the like; The Ci 6 alkyl group of a moiety or a part of the base ring defines a linear or branched bond saturated hydrocarbon group having 1 to 6 carbon atoms, such as 匚14 1〇 and pentyl, hexyl, 2-methylbutyl and A Cm alkyl group which is a moiety or a part of a group defines a straight or branched chain saturated hydrocarbon group having from 丨 to 9 carbon atoms, such as C -6 alkyl and heptyl, octyl , fluorenyl, 2-methylhexyl, 2-decylheptyl and the like; a CM() alkyl group which is a moiety or a part of a group defines a straight or branched chain having from 1 to 1 carbon atoms 15 Saturated hydrocarbon groups such as Cm alkyl and decyl, 2-indenyl fluorenyl and the like. A general term for a C3-7 cycloalkyl-based cyclopropyl, cyclobutyl, cyclonaphthyl, cyclohexyl and cycloheptyl group. The C2·5-sintered two-base system defines a divalent straight-chain or branched-chain saturated hydrocarbon group having 2 to 5 carbon atoms such as, for example, 1,2-ethanediyl, anthracene, 3-propylenediyl, anthracene, 4-butylene a 1,2-propanediyl group, a 2,3-butanediyl group, a pentanediyl group and the like, and a C μ calcination-based system defines a divalent straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms. Such as, for example, methylene, 1,2-diethylene, anthracene, 3-propylenediyl, I4.butadienyl, and the like, the Ck-sintering system is represented by a fluorene-containing dialkyl group and has 5 to 6 A higher homologue of a carbon atom, such as, for example, ^, ^ 15 1578926. a group, a 1,6-hexanediyl group and the like; a Ci, alkanediyl group means a higher homologue comprising a C16 alkyl group and having 7 to 10 carbon atoms such as, for example, a 1,7-heptanyl group, 1,8-octyldiyl, 1,9-fluorenyldiyl, 11-decyldiyl and the like. The term "0" as used herein before is used to form a carbonyl moiety when attached to a carbon atom, to form a sulfoxide moiety when attached to a sulfur atom, and to form a fluorenyl moiety when two terms are attached to a sulfur atom. The term (=N 〇H) forms a hydroxyimine moiety when attached to a carbon atom. In the term, the tooth base is a general term for chaos, gas, and indifference.鲁ίο It should be noted that the position of the group on any molecular moiety used in the definition may be any position on the moiety as long as the moiety is chemically stable. The group used in the meaning of the number is included. All possible isomers, unless otherwise stated. For example, a pyridyl group includes a 2-pyridine group, a 3-pyridine group, and a 4-n-pyridinyl group; and a pentyl group includes a pentyl group, a 2-pentyl group, and a 3-pentyl group. Soil When any variable appears more than once on any component, it is independent. 'Whenever the term is used, the compound of the formula (1), or the 'compound' or the like 'includes a compound of the formula (1), a compound of the pre-X-month compound, an addition salt, a quaternary amine , metal complexes and stereochemical data, oxygen sub-groups of interest - compounds or any of their systems; f form. N-oxides, salts and all stereoisomeric forms of the compound. I) It should be recognized that certain compounds of formula (I) may contain one or more cores and exist in stereochemically isomeric forms. TI Sex 16 20 1378926 The term stereochemically isomeric forms as used herein, defines the same sequence All of the elements of the same atomic structure but with the same three-dimensional structure (the compounds of formula (1) may have): Unless otherwise stated or stated, the chemical name of the compound = all possible stereotypes of the compound Chemically isomeric form = cover. The mixture may contain all - and / or mirror image isomers of the basic molecular structure of the compound. All stereoisomers of the compounds of the invention are in the form of pure substances or blended with each other. Two All cases are covered by & "Luo. The pure stereoisomers of the compounds and intermediates mentioned in the present invention" are the same basic molecules substantially free of the compound or isomer. Isomers of other mirror-isomeric or non-image-isomeric forms of the structure. In particular, the term "stereomerically pure" means having at least 8% steric 15 at least 90% of one isomer and up to 1% otherwise Possible isomers) up to 100% stereoisomeric excess (ie 1% by weight of one isomer and no $he) of the compound or intermediate, in particular, having from 90% to 1% Forming a compound or intermediate of f, especially 94% to 100%

The amount/particularly a stereoisomeric excess of 97% to 1%. The same applies to the heterogeneous pure and "non-image isomerically pure", but individually represents the mixture of the study, the excess and the non-image isomerization excess. The compounds and intermediates of the invention in technically isomeric forms It can be obtained by a method of learning. For example, the mirror image isomer can be separated from each other by selective crystallization of light 3 and a non-image mirror salt of a base. Examples thereof include tartaric acid and diphenyl.醯-tartaric acid, diterpene benzoic acid 1 acid and camphor sulfonic acid. Or mirror image isomers can be separated by static chromatography using chromatographic techniques. The pure stereochemically isomeric forms can also be derived from appropriate starting materials. The corresponding pure stereochemically isomeric forms are derivatized, with the proviso that the reaction is carried out under stereospecificity. Preferably, if a particular stereoisomer is desired, the compound is synthesized by stereospecific preparation. Preferably, the method employs a mirror image-isolated pure starting material. ίο The non-image-image isomers of formula (I) can be separated by conventional methods. Suitable physical separation methods which are advantageous for use are, for example, selective crystallization and chromatography. For example, tube chromatography. Non-experimental determination of the absolute stereochemical configuration of certain compounds of formula (I), prodrugs thereof, N-oxides, salts, solvent barriers, quaternary amines or metal complexes, and intermediates useful in their preparation Those skilled in the art will be able to determine the conformational configuration of such compounds by methods known in the art, such as, for example, X-ray diffraction. The present invention also encompasses all isotopes of atoms including the compounds of the present invention. Atoms of the same atomic order but different mass numbers. One or two and non-restricted isotopes of argon including gas H carbon include CM3 and c_14. The salt of the compound of formula (1) is the heterogeneous The ionic system is on the rise. However, it has been found that non-medicine::also:::' For example, for the preparation or purification of medicine == two = class 'whether pharmaceutically acceptable or not, is included in 18 1378926 The pharmaceutically acceptable acid and base addition salts mentioned above include therapeutically active non-toxic acid and base addition salt forms which may be formed by the compound of formula (1). The pharmaceutically acceptable acid addition salt can be conveniently obtained by The proper acid treatment of the base form Suitable acid systems include, for example, mineral acids such as hydrogen functional acid such as hydrochloric acid or hydrobromic acid 'sulfuric acid, nitric acid 'phosphoric acid and its acids; or organic acids such as, for example, acetic acid, propionic acid, transacetic acid, lactic acid , propyl citrate, oxalic acid (ie oxalic acid), malonic acid, succinic acid (ie succinic acid), maleic acid, fumaric acid, malic acid (ie hydroxysuccinic acid), tartaric acid, Lemon berylic acid, sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylamine 10 sulfonic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and the like Conversely, the salt forms can be converted to the free form by treatment with a suitable base. The compound of formula (1) containing an acidic proton can also be converted to its non-toxic metal or amine by treatment with a suitable organic and inorganic base. Addition salt form. Suitable 15 base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts and the like, and salts with organic bases such as benzathine ), N-mercapto-D-glucosamine, hydrabamine salt, and amino acid For example arginine, lysine and classes) of salt. The term addition salt as used hereinabove also includes solvates which can be formed from the compounds of formula (I) and salts thereof. Such solvates are, for example, hydrates, alcohols, and the like. The term "quaternary amine" as used hereinbefore defines a compound of formula (1) which may be derived from a basic nitrogen of a compound of formula (I) with a suitable quaternizing agent such as, for example, a selectively substituted base, an aryl group or A quaternary ammonium salt formed by the reaction between an aryl base tooth, such as a sulfhydryl group or a 19 i378926 gekier. Other reactions with good leaving groups can also be used, such as alkyl triflate, alkyl sulfonate and alkyl p-toluenesulfonate. The quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable isoionic ions include gas, bromine, iodine, trifluoroethyl and acetate. The selected iso-ion ions can be introduced using an ion exchange resin. 5 The N-oxide form of the compound of the invention includes a compound of formula (I) wherein one or more of the II atoms are oxidized to the so-called oxide. It is recognized that the compound of formula (I) may have a metal bond, a clamp, a miscibility, and thus may be present as a metal complex or a metal clamp. Such metallated derivatives of the compound of formula (1) are included within the scope of the invention. Some of the compounds of formula (1) may also exist in their tautomeric form. Such forms (although not explicitly shown in the preceding formula) are included within the scope of the invention. Any of the subgroups of the compounds of formula (I) according to the invention also include prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemistry of the compounds of formula (I) of this subgroup Heterogeneous form. A specific embodiment of the invention relates to a compound of formula (I-a):

Wherein Q, R5, G and R1 are as defined above or any of the subgroup compounds as described herein; and 2〇 R2a is a Q.6 alkyl group; R2b is hydrogen or a Ci-6 alkyl group. 20 1378926 Another embodiment of the invention relates to a compound of formula (I-b):

Wherein Q, R5, G and R1 are as described above or any of the subgroup compounds as described herein; and R3a is CN6 alkyl; R3b is hydrogen or Cw alkyl. Another embodiment of the invention relates to a compound of formula (I-c):

Wherein Q, R5, G and R1 are as described above or as any of the subgroup compounds as described herein. It should be understood that the subgroups (Ia), (Ib) and the like as defined above and any other subgroups defined by the present invention also include any prodrugs, N-oxides, addition salts, quaternary amines of such compounds. , metal complexes and stereochemically isomeric forms. The compound of the formula (1) of a specific subgroup is a compound of the formula (I) wherein the G system is a CM() alkanediyl group or a compound of the subgroup (I) according to any of the present invention, especially wherein the G system is a methylene group. 21 1378926 Other special subgroups of formula (1) are compounds of formula (I) or any subgroup of compounds of formula (I), wherein: (a) 11| is not ΑΓ1; or wherein (b) R is Ar1 or Monocyclic heterocycles as detailed in the definition of a compound of formula (1) or any of its subgroups 5. The other specific subgroups of the formula (I) are compounds of the formula (I) or any of the subgroups of the formula (I) which satisfy the following conditions, wherein the (C) R is one or two selected from the group consisting of halo, Hydroxy, amine, cyano, several, C!-6 alkyl, Cl-6 alkyloxy, Cl-6 alkylthio, 10 Cl·6 alkyloxy CN6 alkyl, Ar1, Art 6 alkyl, a/Ck alkyloxy, hydroxy Cm alkyl, mono- or di(Cm alkyl)amino, mono- or di(Ci-6 alkyl)amino Cu alkyl, polyhalo Ck Alkyl, Ci-6 alkylcarbonylamino, C 6 alkyl-S02-NR4a-, Ar1-S02-NR4a- ^ Cj.6 > -C(=0)-NR4aR4b ^ 15 H0(-CH2- CH2-0)n-, halo (-CH2-CH2-0)n-, Cu carbonyloxy (-CH2-CH2-0)n·, Ai^-Cu carbonyloxy (-CH2-CH2- 0) a pyridyl group substituted with a substituent of a group consisting of n- and mono- or di-(Cw alkyl)amino (-CH2-CH2-0)n-; or especially (d) R1 is 1 Or two selected from the group consisting of hydroxyl, (^-6 alkyl, halo, 2〇Cm alkyloxy, A/CV6. alkyloxy and (〇丨-6 alkyloxy)Cl 6 alkyloxy The substituent of the group consisting of π is substituted with a bite group; preferably wherein (e) R1 is 1 or 2 Substituting a group of substituents selected from the group consisting of a hydroxyl group, a Cl 6 alkyl group, a halogen group and a C 6 .6 decyloxy group, the bite 22 1378926 group; or wherein the (1) R 1 group is 1 or 2 selected from a hydroxyl group, respectively. And a substituent of the group consisting of a C 6 alkyl group substituted by a n-bite group; more preferably wherein the P ring R is an acridinyl group substituted by a hydroxyl group and a Cw alkyl group; or more preferably, ', (h (i) ι is a ratio of a base to a base and a thiol group; or a 3-meryl-6-methyl π ratio _2_ base. ίο where Ar1, 4咁Other specific embodiments of the formula, benzopyrene, or the following formula, include formula (I) or any subgroup of formula (1), _ is 叱D well base or *» ratio bite; or K) 1 is an Ar1, a fluorenyl group, a benzimidazolyl group or a group of the formula (c_4) (the sugar thereof, 111 is 2), 0 is a cultivating group or an acridinyl group; in the middle (Ί, (1) and Each of the groups in k) may be optionally substituted by a butyl group as defined in the compound of the formula (I), and in particular, the pyridyl group may be substituted on the ground as described in (a) to (1). The state system comprises a compound of formula (I) or any subgroup of U) The ί inclusion 'where is the group of Ar1, fluorenyl, benzimidazolyl or formula (c-4) (where m is 2), ruthenium or "pyridyl" wherein each of these groups Visible to 23 5 $ conditions -, two or three selected from the group, secret, h alkyl, ^ carbonyloxy, this hexyloxy, (Ci 6 dadyloxy) C] 6 ^ Substituted by a group consisting of a group of oxy groups; wherein (4) R is an A/, a phenyl group, a benzene (tetra) sial group or a group of the formula (4) (where m is 2), an anthracene or an acridine a group wherein each of the groups may be selected from -, two or three selected from the group consisting of a fluorenyl group, a thiol group, a Cn6 group, and a 10 (n) R1 group, one, two or three selected from the group consisting of a stupid group substituted with a group consisting of a group consisting of a hydroxyl group, a Cl 6 alkyl group, and a C! 6 alkyl group; a porphyrin group; a group (c-4), wherein the m system is 2, and optionally up to two Substituted by a group selected from a Ck alkyl group; a benzimidazolyl group optionally substituted with a Ci-6 alkyl group; optionally, one or two selected from the group consisting of a hydroxyl group, a dentate group, a C -6 group, a pyridyl group substituted with a group of alkoxy and c!_6 alkyloxy groups, optionally up to a ruthenium group substituted with three groups selected from a Cu alkyl group; or a pyridyl group substituted or optionally substituted as in the above (a) to (1); or wherein the (〇) R1 system is optionally used a phenyl group substituted with a group selected from the group consisting of a dentate group, a hydroxyl group, a CU6 alkyl group, and a Ci-6 alkyloxy group; a group of a group consisting of 20 ci-6 alkyloxy group and benzyloxy group Replaced by the regiment; or more specifically

Or (p) R1 is a fluorenyl group; or (q) R1 is a group (c-4) wherein m is 2, optionally substituted with up to two groups selected from Cw alkyl groups; Or (r) R1 is a benzimidazolyl group optionally substituted with a Cu alkyl group; as the case 24 1378926, one or two selected from a hydroxyl group, a self group, a cW6 alkyl group, a benzyloxy group or a Ci_6 surface group Pyridyl group substituted with an oxy group; or (s) R1 is a well group optionally substituted with up to three groups selected from Cw alkyl groups. 5 Preferred compounds of the formula (I) or any of the subgroups of the formula (1) are those wherein the G system is a direct bond or a methylene group and the R1 group is as described in the above (a) to (S). More preferably, wherein the G system is a direct bond and the R1 is a group (C-4) which is optionally substituted with up to two groups selected from a C1-6 alkyl group (especially where m is 2) Any one of the compound of the formula (1) or the subgroup of the present invention. More preferably, it is a compound in which the G system is a methylene group and R1 is a compound of the formula (I) as described in the above (a) to (4) but is not a group (c-4) or any one of the subgroups of the present invention. The morphology includes a compound of formula (1) wherein R5 is hydrogen or a compound of formula (I) of any of the subgroups herein. Other specific embodiments include a compound of formula (I) or any of the 15 groups of compounds of formula (I) of the invention wherein (a) Q is Ar2, C3_7 cycloalkyl or, as appropriate, or two a Cw alkyl group substituted by a substituent, each of which is a group consisting of a substituent of the formula (1) or any of the subgroups thereof, and wherein the Cw alkyl group is further subjected to - Substituted by a hydroxyl group; 2° or (b) Q is an Ar2, C3_7 cycloalkyl group or, optionally, a Cw alkyl group substituted with one substituent selected from a compound of formula (I) or any subgroup thereof The group of the substituents mentioned in the definition is 'and the 25 1378926 C -6 alkyl group is further substituted with a monohydroxy group as the case may be; (c) the Q system is Ar2, c: 3·7 naphthenic a Cw alkyl group substituted by one or two substituents, each of which is selected from the group consisting of a trifluoromethyl group, an Ar2, a hydroxyl group, a Cw alkoxy group, a Cm alkylthio group, and an Ar2-oxy group, respectively. Ar2(CH2)noxy-, hydroxycarbonyl, aminocarbonyl, Cw alkylcarbonyl, Ar2carbonyl, C-7-4 alkoxycarbonyl, Cw alkylcarbonyloxy, hydroxyl10-C2·4 An oxy, mono- or di(Ci_4-alkyl)amino group, optionally substituted by one or two CN6 alkyl groups, and selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, a group consisting of a heterocyclic group of a group consisting of a mercapto group, an imidazolyl group, a triazolyl group, a hexahydropyridyl group, a high hexahydropyridyl group, a piperylene group, a pyridyl group, and a tetrahydropyridyl group, wherein the heterocyclic ring each Substituting up to two substituents selected individually from a keto group or a C1_6 alkyl group; or (d) the Q system is an Ar2, C3_7 cycloalkyl group or, as the case may be, a substituent

20 Cw alkyl, each of which is selected from the group consisting of trifluoromethyl, Ar2, thio, C4 alkoxy, alkylthio, Ar2-oxy-, Ar2(CH2)noxy-, hydroxy Carbonyl group, aminocarbonyl group, c丨·4 alkyl group, Ar2 carbonyl group, c14 alkoxycarbonyl group, Cl 4 alkylcarbonyloxy group, several group-Cw alkyloxy group, mono- or di(Ci_4 alkyl)amine a carbonyl group, optionally substituted by one or two Ci-6 alkyl groups, and selected from pyrrolidinyl, pyrrolyl, dihydropyrrolyl, fluorenyl, imidazolyl, monoazolyl, a group consisting of a heterocyclic group of a group consisting of a thiol group, a high hexahydropyridyl group, a piperylene group, a siggiopyridinyl group and a tetrahydrocinyl group, wherein each of the diheterocycles may be up to two Individually selected from a keto group or a CN6 26 5 group substituted with a substituent, and the Cl 6 alkyl group is optionally substituted with a monohydroxy group; or step (4) = 1, C; i cyclodyl group or optionally - or The two substituents are substituted for the Cw pit group, and the substituents are each selected from the group consisting of &2, ςL, oxy, Cl. thiol, amine, oxime, and aryl-C2.4 alkyl oxygen. Substituted by two Ci 6 alkyl groups

An oxopentyl group and a heterocyclic oxime group selected from the group consisting of pyrrolidinyl, fluorenyl, imidazolyl, and hexamethylene groups; Substituted by a substituent of up to two or Cw alkyl groups; or a fluorenone (0 Q is Ar2, c3-7 cycloalkyl or optionally Αγ2, hydroxy, & 15 decyloxy, Cw a sulfur-burning group, an amino group, a Ci 4 anthracene group, a — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — a C1_6 alkyl group substituted with a heterocyclic group of an imidazole group, an imidazolyl group, a hexahydropyridyl group, a piperidinyl group and a pyridyl group, wherein each of the heterocyclic rings may be optionally substituted with up to two substituents selected from a keto group or a C16-sintering group. Substituted, and the C -6 alkyl group is further substituted by a ruthenyl group; or 20 (g) Q is Ar2, C3·7 cycloalkyl or, as the case may be, Ar2, one or two, and Cm Alkoxy group, Ci.4 thiol group, amino group, Cm compound oxy group, hydroxy-〇2_4 alkyloxy group, dioxolane group substituted by two Cw alkyl groups or selected from D ratio Slightly burnt base, whistle base, taste saliva, a gas substituted with a heterocyclic group of a sulfonic acid, a piperidinyl group and a pyridine group; wherein the heterocyclic ring may be optionally selected from two ketone groups or a core group of 6 1378926 Substituted by a substituent; or (h) Q is optionally substituted with Ar2, one or two hydroxyl groups, a Cl.4 alkoxy group, a CV4 alkylthio group, an aminocarbonyl group, a Cw alkoxycarbonyl group or a pyrrolidinyl group, a Cu alkyl group substituted with a heterocyclic ring of imidazolyl, hexahydropyridinyl and piperylene, wherein the heterocyclic ring may be optionally substituted by a keto group or a Cw alkyl group; or (i) the Q system is Ar2. A particularly interesting subgroup in the subgroup referred to in paragraph J is where the Ar2 is phenyl or has 1, 2, 3 substituents or i or 2 substituents, or preferably a phenyl group substituted with a substituent selected from the group consisting of a halogen group, a hydroxyl group, an amine group, a cyano group, a hydroxyCl.6 alkyl group, an amino group Ci 6 alkyl group, a Ci-6 alkyloxy group, and an aminosulfonyl group. Another particularly interesting subgroup in the subgroup referred to in the preceding paragraph is where the Ar2 is phenyl or fluorene, 2, 3 substituents or 1 or 2 substituents' or preferably one Substituted by 15

The phenyl group is selected from the group consisting of an amine group, a cyano group, a hydroxy Ci6 alkyl group, an amine Ci-6 alkyl group, and an amine base group.

In particular, r is a phenyl group substituted by a phenyl group or a 2, 3 substituent or a 2 substituent, which is selected from the definitions of the formula or its subgroup.

Ar2 is a phenyl group or a phenyl group, 2, 3 substituents or 2 substituents. The substituent is selected from the group consisting of the formula or the group thereof. The compound of formula (1) or (a) Ar1 is preferably phenyl or 7 J砰·4, 3 substituents or up to 28 20 substituents or one by one. a phenyl group substituted by a substituent selected from the group consisting of a dentate group, a hydroxyl group, an alkyl group, a hydroxy Cw alkyl group, a trifluoromethyl group, and a Cl. 6 alkyloxy group; (b) Ar is more preferably a phenyl group. Or a phenyl group substituted with up to 3 substituents or up to 2 substituents or substituted by a substituent selected from the group consisting of i, hydroxy, C 6 alkyl and Ci 6 alkyloxy; (c) Ar is preferably a phenyl group or a phenyl group substituted with up to 3 filaments or up to 2 10 substituted by one substituent selected from the group consisting of a dentate group and a Cl 6 alkyl group. The compound of the formula (1) is a subgroup in which the Af2 system such as w is defined as a compound or a compound of the formula (1). The compound or the formula S ί subgroup is the formula (I) of the present invention

Any subgroup of Ac, wherein 15 of R2a and R3a is CU6 alkyl, and R2a & R3 'κ T is R2b when the R2a is non-hydrogen, R2b is one of the gas; when non-gas, R3b It is a "6 alkyl group, and R3b is hydrogen; a preferred compound is a fluorene, a .6 alkyl group, and a ruler 21) is hydrogen. Nos. 1 to 11 and 25 to 28 are listed in The 'in particular compound 20 2 formula (1) compound or any of its w′ is prepared according to the following reaction scheme. 29 1378926

In these schemes, Q, G, Ri, R2a, R2b, R3a, R3b, R5 have the meanings previously defined for the compound of formula (I) or any subgroup thereof. W is a suitable deionization group, preferably chlorine or bromine. The reaction of these schemes is generally carried out in a suitable solvent such as an ether such as THF, a halogenated hydrocarbon such as dichloromethane, CHC13, toluene, a polar aprotic solvent such as DMF, DMSO, DMA and the like. A base may be added to absorb the acid released during the reaction. If necessary, a specific catalyst such as an iodide salt (e.g., KI) may be added. The compounds of formula (I) can be converted into each other according to functional group conversion reactions known in the art, including those described below. A compound of formula (I) wherein R5 is hydrogen may be converted to a compound of formula (I) wherein R5 is nonhydrogen by an N-alkylation reaction which may be converted to (II) or (IV) as previously described ( Under the conditions described in I). 15 A compound wherein the Q group is a Cw alkyl group substituted with a CN4 alkoxycarbonyl group can be reduced to a corresponding compound wherein the Q system is a 30 I51 2b group substituted by a hydroxyl group, using, for example, LiAlH4. The same starting material can be reacted with an amine to form a corresponding amine. The 5 gas (5) which is Ar having a cyano or cyanoCl-5 alkyl substituent can be used in a suitable catalyst (such as Raney nickel). Reduction in the presence of hydrogen to produce the corresponding methylene amine or amine CM alkyl substituent. 10 Several intermediates used to prepare the compound of formula (I) are known compounds or are homologous to known compounds. , which can be prepared according to methods known to those skilled in the art and which can be easily accomplished by those skilled in the art. Several preparations of intermediates are shown in more detail below. Intermediates of formulas (II) and (IV) It can be prepared as shown in the following reaction scheme.

31 1378926 In the first step, the diaminobenzene (νι) is cyclized with urea, preferably in a suitable solvent (e.g., xylene) to produce benzimidazolone (VI1). The latter is converted to a stupid and stilbene derivative (VIII)' wherein w is the aforementioned decomposing group, in particular by (νπ) with an appropriate i-agent (e.g., poc^3). The intermediate (VIII) is reacted with the cyclic amine derivative (IX) in an N-alkylation reaction to give (VIII-a) which is converted to the intermediate (X). The group PG in (IX) and (X) represents a suitable N-protecting group, such as an alkyloxycarbonyl group, such as an ethyloxycarbonyl group, which can be easily removed (e.g., by a base) to produce an intermediate (II) ). The Ru 10 intermediate (VIII) can also react with a cyclic amine (ΧΠ) by N-alkylation reaction to produce an intermediate (IV). The above N-alkylation is carried out in a suitable solvent, if necessary, in the presence of the test. The compound of formula (1) can be converted to the corresponding N-oxide form by methods known in the art for converting trivalent nitrogen to its N-oxide form. The 15 oxime oxidation reaction can usually be carried out by reacting a starting material of the formula (1) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, argon peroxide, caustic or alkaline earth metal peroxides (e.g., sodium peroxide, potassium peroxide); suitable organic peroxides may include peroxyacids such as, for example, stupid Percarboxylic acid or benzene-formic acid substituted by a base (for example, % benzoic acid), peroxylizing acid (for example, peroxyacetic acid), or pyridyl hydrogen peroxide (for example, first gasification & Suitable solvents are, for example, water, lower alcohols (e.g., E), by-types (e.g., toluene), _ (e.g., 2-butanone), functional (e.g., dioxane), and mixtures of such solvents. Pure stereochemically isomeric forms of the compounds of formula (1) can be prepared by methods known in the art 32 1378926. Non-image isomers can be separated by physical methods, selective crystallization and chromatographic techniques such as countercurrent dispensing, liquid chromatography, and the like. The compounds of formula (1) prepared by the foregoing methods are generally racemic mixtures of the mirror image isomers which can be separated from one another by known methods of separation known in the art. A sufficiently basic or acidic racemic compound of formula (1) can be converted to the corresponding non-imagewise isomeric salt form by reaction with a palmitic acid and a palmitic test, respectively. The non-imagewise isomeric salt form is then separated, e.g., by selective bite-step crystallization, and the Spiegelmer is released from it by a base or acid. Separate formula (1)

Alternatives to the image-isolated form of the material include liquid chromatography, especially liquid chromatography for the palmitic static phase. The pure stereochemically isomeric form may also be derived from the corresponding pure stereochemically isomeric form of the appropriate starting material, with the proviso that the reaction is carried out stereospecifically. If a particular stereoisomer is desired, it is preferred that the compound be synthesized by stereospecific methods of preparation. Preferably, the method of using 15 is a mirror image isomerization pure starting material. In another aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) of the invention or a compound of any of the compounds of formula (I) according to the invention, and a pharmaceutical Acceptable carrier. The therapeutically effective amount in the present invention is sufficient for the infected patient or is infected

Patients in danger can prevent, stabilize, or reduce viral infections, especially RSV infections. In another aspect, the invention relates to a method of preparing a pharmaceutical composition of the invention comprising: finely mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I) of the invention or the invention Any of the compounds of the subgroup of compounds of formula (1). 33 20 The drug allows the compound of the invention or any of its subgroups to be formulated into a variety of compositions for use in the administration of time. The preparation of the pharmaceutical composition salt of the present invention or the specific compound (in the case of an adult form) which is active: is mixed with a pharmaceutically acceptable carrier in a fine manner, and the carrier can be used in various forms, depending on the form, Formulations required for administration: medicinal compositions are unit dosage forms suitable for (especially) oral 'rectal, open' parenteral injection. For example, any of the medicinal media can be used. Such as, for example, agents such as suspensions, syrups, elixirs, lotions, and solutions, and those of the class, the remedies, and the agents, or the pills, and the agents are solid carriers such as starch, sugar, kaolin, and moisturizing agents. 15 20 : Shaanxi Qin adhesive, disintegrating agent and the like. Because of its simplicity of administration, the tablet drug i is the best oral dosage unit form. In the case of a parenteral composition, the carrier usually comprises sterile, at least for the most part, and may contain other ingredients, such as indwelling solubility. For example, a solution for injection may be prepared, wherein the carrier comprises a saline solution, a solution, and a solution. Or a mixture of saline and glucose solution. Preparation of A-injection solution for injection, wherein a suitable liquid carrier, suspending agent and the like can be used. A solid forming agent which is converted into a liquid form preparation in a short time before use. In a composition suitable for transdermal administration The carrier, as the case may be, includes a osmotic agent, a stimulating agent and/or a suitable wetting agent, optionally in combination with a small amount of any suitable additive which does not cause significant damage to the skin. The compounds of the invention may also be inhaled via the mouth. Or insufflation by the technical community using 34 t methods and formulations administered in this manner to administer the drug. Therefore, the sigma compound of the present invention is usually administered to the lungs in the form of a solution, a suspension or a dry powder, preferably as a solution. Any system for inhaling or insuffusing a delivery solution, suspension or dry powder 5 by oral administration is suitable for administration of the compound of the present invention. π4 Therefore, the present invention also provides a pharmaceutical composition suitable for administration by oral inhalation or insufflation. A compound comprising a compound of the formula (1) and a pharmaceutically acceptable carrier. Preferably, the compound of the present invention is administered as a solution by nebulization or aerosolization of a dose by inhalation. The pharmaceutical compositions are formulated in unit dosage forms for ease of administration and dosage. The unit dosage form used in the present invention is a physically discrete unit suitable for use as a unit dosage form, each unit containing a predetermined amount of activity calculated to produce the desired therapeutic effect. The ingredients and the desired pharmaceutical carrier. Examples of the unit dosage form are a tablet (including a key or a key), a capsule, a pill, a suppository, a powder package, a wafer, an injection solution or a suspension, and the like. A compound of formula (I) exhibits antiviral properties. Viral infections which can be treated using the compounds and methods of the invention include infections caused by both paramyxoviruses, particularly human and bovine respiratory fusion viruses (RSV). Several of the compounds of the invention also have activity against mutant strains of RSV. Furthermore, many of the compounds of the invention 20 exhibit advantageous pharmacokinetic properties and have better bioavailability' including acceptable half-life, AUC and peaks. Values and no adverse phenomena such as insufficient quick onset and tissue retention. The in vitro antiviral activity of the compounds of the invention against RSV is demonstrated in the test strips described in the experimental section (4) of the present invention and can also be demonstrated in the vims yield reduction assay. The in vivo antiviral activity of the compounds of the invention against RSV can be demonstrated in a test model using cotton rats as described by Wyde et al. (Antiviral Research (1998), 38, 31-42). Due to its antiviral properties, especially its resistance to RSV, compounds of formula (1) or any subgroup thereof, prodrugs thereof, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms are available For the treatment of patients with viral infections, especially RSV infection, to prevent such infections. In general, 10 compounds of the invention are useful in the treatment of warm-blooded animals infected with viruses, particularly respiratory fusion viruses. 15 The compounds of the invention or any subgroup thereof are therefore useful as pharmaceuticals. The use or method of treatment as a "J</RTI> drug comprises the amount of a systemic administration of a disease associated with a viral infection, particularly an RSV infection, in a patient infected with a virus or a patient susceptible to a virus. The invention also relates to the use of a compound of the invention or any subgroup thereof for the manufacture or treatment of a viral infection (especially an Rsv infection) such that the invention also has a treatment of a virus or a prion (especially 7) The risk (4) warm blood flow. The method comprises administering a compound of the formula (1) of the present invention or any subgroup of the compound of the formula (I) according to the present invention to the antiviral effective f. Usually, the effective daily dose of antiviral is 〇.〇1 mg/kg to 5〇〇mg/kg body weight, (U mg/kg to 50 mg/kg body weight is preferred. 36 20 1378926 The required dose can be appropriately Divided into two, three, four or more sub-doses at appropriate intervals throughout the sputum. The sub-dose may be formulated in a unit dosage form, for example containing from 1 to 1000 mg, especially from 5 to 200 mg of active ingredient per unit dosage form. The actual dosage and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, condition and general physiological condition of the particular patient and the Depending on the other agents, it is well known to those skilled in the art. Furthermore, the effective daily dose will obviously be reduced or increased depending on the patient to be treated and/or depending on the evaluation of the compound of the invention by the designated physician. The aforementioned effective dose range is therefore only For reference, a composition of another antiviral agent and a compound of formula (I) can be used as a medicament. Therefore, the present invention also relates to a compound containing (a) formula (I). (b) a product of another antiviral compound as a combined preparation for use in 15 antiviral therapy, when used alone or continuously. Different drugs may be combined with a pharmaceutically acceptable carrier into a single formulation. For example, a compound of the invention It can be combined with interferon-β or tumor necrosis factor-α to treat or prevent RSV infection. [Embodiment] The following examples are intended to illustrate and not to limit the invention. The terms used in these examples. The compounds Γ', "Compound 4" and the like represent the same compounds as in the table. The compounds were analyzed by LC/MS using the following equipment: 37 1378926 LCT. Electrospray ionization in positive mode 'Scan mode 1 〇〇 to amu Xterra MS Cl8 (Waters, Milford, MA) 5 microcards, 150 mm); flow rate 1 ml/min. Two mobile phases were used (mobile phase ^9 χ 85% 6.5 mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6 5 · 5 ammonium acid + 80% acetonitrile) 100% A for 3 minutes, at 5 minutes ^ · 100% B, 100% B for 6 minutes, within 1 minute, 1 〇〇〇 /. A, Then balance the 3 minute gradient with 100% A.) Electrospray ionization in both positive and negative (pulse) modes, scan mode 1 〇〇ίο to 1000 amu; Xterra RP Cl8 (Waters, Milford, MA) 5 μm, · 3.9 x 150 mm); flow rate 1 ml / Minutes. Use two mobile phases (mobile phase

A: 85% 6.5 mM ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mM ammonium acetate + 80% acetonitrile) 100% A over 3 minutes, up to -100% B in 5 minutes B, 100% B 6 minutes, 1〇〇% a in 3 minutes, and 15 is further balanced by 100% A for 3 minutes).

Example 1: Preparation of Dimercaptobenzimidazole Amines Flowchart A

38 1378926 Preparation of intermediate a-2 · S〇Cl2 (14 ml) at 5. The underarm is added dropwise to a solution of (3_octyloxymethylene-indenyl-2-yl)-sterol (〇._6 mol). The reaction was allowed to be allowed to stand for 3 hours at room temperature. The solvent was evaporated under reduced pressure. The residue was placed in a diethyl hydrazine and dried to give 16.9 g of a 2 (98%, m.p.: 182. 〇. Preparation of intermediate α·4············ • Stupid imidazole (〇〇83 mol), w (〇mole) and K2C〇3 (0.332 mol) in the dimethyl ketoamine (Gang 1 〇 * liter) Stir at ambient temperature for 24 hours. Then add h2 〇. The mixture was extracted three times with CH 2 Cl 2 . The organic layer was separated and dried (used

MgS04), filtered, at 30. The solvent was evaporated under reduced pressure. The residue was placed in ch3cn/diisopropyl ether. The precipitate was filtered off and dried to give <RTI ID=0.0>> 15 Preparation of Intermediate a-5: The mixture of ears) was stirred at 130 C for 2 hours. The residue was crystallized from ch3CN. The precipitate was filtered off and dried to give 〇 174 g [丨兴弘benzyloxy_6_ 2〇methyl than bit-2-ylmethyl)·4,6' dimethyl-1H-benzimidazole-2 -yl]-(3_hexahydro 11-indol-1-yl-propyl)-amine (46%). Preparation of the final compound α-6: [Η3-subsyloxy-6-methyl" than biti-2_ylmethyl)_4,6-dimethyl 39 1378926 -1 Η-benzo σ m嗤_2 a mixture of -(3 - hexaza-D-Bist-1-yl-propyl)-amine (0.0003 mol) and Pd/C (0.06 g) in CH3OH (10 mL) at room temperature at 3 Hydrogenation was carried out for 1 hour under bar pressure, followed by filtration with calcium ore. The filtrate was evaporated. The residue was purified by chromatography on EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: The solvent was evaporated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs Aminoamino)-benzimidazol-1-ylindenyl]-6-methyl-pyridin-3-ol (Compound 1, 51%, melting point: > 260 ° C). 10 Example 2: Dihydroxyl Preparation of alkyl-substituted dimercaptobenzimidazole amine

Flowchart B

40 Preparation of intermediate b-3: a mixture of b-1 (0.0014 mol) and b-2 (0.0012 mol) was stirred at 130 ° C for 3 hours, then stirred at 160 ° C for 2 hours and cooled to room temperature. And placed in CH2C12. The organic layer was washed with a 10% K2CO3 solution, dried (MgSO. The residue was purified by column chromatography on silica gel (solvent: CH2Cl2/CH3OH/NH4OH97/3/0.1). The pure fractions were collected and the solvent was evaporated to yield 0.55 g of intermediate b-3 (81%). Preparation of compound h-4: A mixture of b-3 (0.0011 mol) and Pd/C (0.18 g) in CH3OH (10 ml) was hydrogenated at a pressure of 3 bar for 1 hour and then filtered over calcium ore. Calcium ore is rinsed with CH3OH. The filtrate was concentrated under reduced pressure. The residue (0.47 g) was crystallised from CH3OH (10 ml). The precipitate was filtered off and dried to give 0.27 g of 2-{2-[(2,2-didecyl-[1,3]dioxolan-4-ylindenyl)amino]-4,6-di Mercapto-benzimidazolylmethyl b 6-methyl-pyridine-3-ylphenol (Compound 21 '60%, melting point: 225 ° C). Preparation of compound h-5: 2-{2-[(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)amino]_4,6-didecyl- stupid A mixture of imidazol-1-ylindenyl}whenyl-butanyl-3-butanol (0.0005 mol) in 3NHC1 solution (15 ml) and tetrahydrofuran (15 ml) was stirred for 4 hours. Tetrahydrofuran was evaporated under reduced pressure. The mixture was adjusted to face with κ/Ο3 (powder). The aqueous layer is saturated with k2co3 (powder). A solution of CH2Cl2/CH3〇H (90/10) was added. Separate the organic layer and dry it (using 1378926

MgS04), filtered and evaporated solvent. The residue (0.17 g, 88%) was crystallised from CH3CN / diisopropyl ether. The precipitate was filtered off and dried. Yield: 0.085 g of 3-[l-(3-hydroxy-6-methyl-pyridin-2-ylindenyl)-4,6-dimercapto-1H-benzimidazole_2-ylamino]-propane- 1,2-diol (Compound 4, melting point: 205 ° C). Example 3: Preparation of hydroxyalkyl-substituted dimercaptobenzimidazole amine

Flow chart C

Preparation of intermediate c-S:

A mixture of ίο c-2 (0.004 mol) and c-1 (0.006 mol) was stirred at 130 ° C for 12 hours before being placed in CH 2 C 12 . The organic layer was washed with a 10% K.sub.2CO.sub.3 solution, dried (MgSO.sub.4), filtered and evaporated. The residue (0.6 g) was purified by column chromatography on silica gel (solvent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 10 micron). The pure fractions 15 were collected and the solvent was evaporated to yield 0.4 g of intermediate c-3 (38%). Preparation of compound c-5: 42 1378926

Cd(oo〇15 莫耳), c_4 (0 0016 莫默莫) in dimethyl carbamide (2 〇 Λ, 2 3 (0.0052 J (ml) of the present compound in 7G ° C 4 2 ° ί ° residue ^ CH2Cl2. The organic layer is dried by postal washing strip (using MgS〇4), sputum is evaporated, solvent is evaporated. Residual 5 10 g) (4) Upper tube (4) Analysis · (Solution _: A (4) Occupation h 90/10/0.5: 10 μm) Collect the pure soluble fraction and evaporate the solvent. The residue is called 2 g) crystallized from 2-propanol/CH3CN/diisopropyl scale.遽 沉 并 并 并 并 并 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 产生 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 _2_ylamino]-propionic acid ethyl vinegar (compound 12, 21%, melting point: 180 ° C). Preparation of final compound c-6:

LiAlH: 4 (0.0003 mol) was added in batches at 5 ° C under N2 flow to 3-[1-(3-light-based-6-fluorenyl-0-buty-2-ylindenyl)-4,6- A mixture of dimethyl-1H-p- and 15-oxan-2-ylamino]-propionic acid in ethyl acetate (0.0001 mol) in tetrahydrofuran (1 mL). The mixture was stirred at 5 ° C for 1 hour and then at room temperature for 3 hours. Ethyl acetate and H2 hydrazine were added. The mixture was extracted with ethyl acetate. The organic layer was separated, dried (using <RTI ID=0.0>M </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The sediment was filtered and dried, 20 yielding 0.025 g of 2-[2-(3-propylpropylamino)-4,6-dimethyl-benzopyran-1-ylindenyl]-6- Mercapto-0 is more than a bite (compound 7, 73%, melting point: 170 ° C). Example 4: Preparation of a decylamine-substituted dimethylbenzimidazole amine 43 1378926

Flow chart D

3-[l-(3-Hydroxy-6-fluorenyl-pyridin-2-ylindenyl)-4,6-dimercapto-1H-benzoimidazol-2-ylamino]-propionic acid ethyl ester ( A mixture of 0.0001 moles in a solution of saturated NH3 in CH3OH (10 mL) was stirred at 70 ° C for 6 hr. Steam # 5 dry solvent. The residue (0.05 g) was purified by chromatography on silica gel (solvent: CH.sub.2Cl.sub.2/CH.sub.3. The pure fractions were collected and the solvent was evaporated. The residue (0.022 g, 48%) was crystallised from 2-acetone / CH3CN / diisopropyl ether. The precipitate was filtered off and dried to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&& m ° -2 - decylamino] - propylamine d-2 (compound 8, 30%, melting point: 229 ° C).

Example 5: Preparation of an aryl-substituted dimercaptobenzimidazole amine

Flow chart E

44 1378926 Preparation of intermediate e-3: A mixture of e-l (0.0022 mol) and e_2 (0.0023 mol) was spoiled at 130 C for 1 hour', then cooled to room temperature and placed in ch2c12. The precipitate was filtered off. Evaporate the mother liquor. The residue (0.522 g) was purified by chromatography on silica gel eluting elution elution elution elution (CH2Cl2/CH3OH/NH4OH 99/1/0.1 to 90/10/1; 5 micron). The pure fractions were collected and the solvent was evaporated to give 〇36 g of intermediate e-3 (62%). Preparation of oxime compound e-5··· 4-[l-(3-hydroxy-6-methylpyridinyl·2_ Methyl)_4,6-dimethyl-1H-benzopyridin-2-ylamino]-benzonitrile (Compound 2, melting point: &gt; 26 〇. 〇 is as described in c-5) Preparation of final compound e-6: Nickel (0.2 g) was added to a mixture of e_5 (0.0001 mol) in saturated NH3 in CH.sub.3 H (20 mL). Hydrogenation was carried out for 3 hours under bar pressure, followed by filtration with calcium ore. The calcium ore was rinsed with HsO. The filtrate was evaporated to dryness. The residue (0.07 g) was purified on silica gel eluting with column chromatography (solvent: CH2Cl2/CH3〇H/ NH4OH 85/15/1; 10 μm. The pure fractions were collected and evaporated solvent. EtOAc (EtOAc: EtOAc:EtOAc: Yield 0.022 g of 2-[2-(4-aminomethyl-phenylamino)-4,6-dimethyl-benzimidazol-1-ylmethyl]-6-mercapto-pyridine-3. Phenol, e-6 (compound 9, 44%, melting point: 255 ° 〇. 45 1378926 Example 6: aryl substituted by aryl Amine-benzimidazole

Flowchart F

Preparation of intermediate f-3: Intermediate f-3 was prepared as described for intermediate e-3. Preparation of intermediates f-5 and f-6 Intermediates f-5 and f-6 were prepared as described in the intermediate c-5. Preparation of FJ and f-8: Compounds f-7 and f-8 were prepared as described in e-6 to give 〇18 g of Part 1 (1%) and 0.36 g of Part 2 (20%). . Part 1 46 1378926 was converted in acetate and crystallized from 2-propanone/CH3CN/diisopropyl ether. The precipitate was filtered off and dried to give &lt;RTI ID=0.0&gt;&gt;&gt; Part 2 is dissolved in 2-propanol/HC1 and converted to the hydrochloride salt. The precipitate was filtered off and dried. The residue was crystallized from 2-propanol / diisopropyl ether. The precipitate was filtered off and dried to give &lt;RTI ID=0.0&gt;&gt;&gt;

The table below lists the compounds of the invention prepared as in any of the foregoing synthetic schemes. I ίο Table 1

47 15 1378926 Compound number R Active mass spectrometry melting point synthesis flow chart / salt form 2 7.7 ΜίΓ = 394 225°CA 3 7·6 1^ = 423 225°GA 4 7.4 &gt;11^ = 357 205°CBV 〒η3 :: Light: 7. (. MH+ = 394 185°CA 6 : to 7.2;. ^ = 394 :230bC A 7 :: 6.8 1^ = 341 170°C :;e· : '8.. ·〇:·.. ·: 6:8 MH+ = 354 229°CD 9 : η2ν^Α^Η ::: im MH+ = 388 255°C .:..E.·..:. 10 -|——~ ι ... 6.3 ^ = 391 : 255^ :: ' A:...· 11 Ν-—^ : 6.2 MH+ = 377 &gt;260°C .' ..X:::.: 12 ..0: i.: '. ;5:5 : MH+ = 383 :180°CG :.1+3. ·: :::: f^:: .......· ΙΓ . :.·&gt;! \ 5.5 _ = 402 171°CF/HCI 14 4.0 MH+ = 374 : 254°CEC 15 r^N uo 5.8 MtT = 374 208°C 16 4:0 MH+ = 355 206°CC 17 v Team,: 4 0 MH+ = 365 : 176° C .: F . 18 0^, :4.0 .:Μ1·Γ = 387 232°C c 48 1378926

Compound number; R 'Active mass spectrometry melting point synthesis scheme circle/salt form 19 shoulder 4.0 MH+=384 &gt; 260°CE 20 h3c^ch3 4.0 MH+ = 397 225°CB 21 〇° 4,0 '_ = 408 170°GA 22 Π 0 4.2 ΜΗ4 = 466 &gt; 260°CA Table 2

Compound Preparation R' -- - ..... Active Mass Spectrometry: Melting Point Synthesis Scheme. / Salt Form 23 : ;: 5.2 Mif = 402 1716C F / acetate . Let: 4.0 1^ = 379: 222°C • F Table 3

HO

CH,

Compound Codification R Activity Mass Spectrometry Melting Point Synthesis Flow Circle 49 1378926 Compound No. R Active Mass Spectrometry Melting Point Synthesis Flow Circle 25,5 Mtr = 380 195°GC 26 ΥΊ 6.5 ^ = 395 190 °C c '27 . QH 6.3 ΜΗ+ = 329 170QC c ;;:V.28; Λ \ / .. 6.2 ;ΜΗ+-366 190°C ..c ::: 29 Η^〇Α^:: ':';5:6·: ΜΗ&quot; = 389 215 °CG 30 ? 1 H3C — :GH3 5.4 1^ = 369 ^ 221°C c 31 5.3 ΜΗ+ = 341 182°C ...c. . .: :.32;'; 5:0 ΜΗ+ = 313 210ό0 ' c ..::: . 33.::: 5;0 : ΜΗ+ = 355 185°G; C - Η , ·3ν :; LI /%. 1' j&gt;J M3C^〇^N^ 5.0 :1^ = 4;19 180°C c 35 :and:...::Guang Cheng:;;;: .〇:. ,:]4:9. :· MPT = 380 :175°ec 36 ; Λ Άδ:::.: &gt;11^ = 343;' 205°C :c ::\ 37 G •11 ... 4.0 -ΜΗ+ = 369 215°CG 38 0 II .If· 4J ; MtT = 340 - 220°C c 39 : • 1 i π 4.0 1^ = 398 245°C c 40 (Χ^ 4,3 ^ = 360 225°C c 41 4.0 ΜΗ* = 377 245°C c R~ ~ __ • Active Mass spectrometry • 熔点 Melting point flow 圊 42 : 'Smoke. 4.0 ΜΗ+=377 2 50°C c 43 4.1 1^-343 215°C c tAfcLZ: In Vitro Screening Against Activity of Respiratory Fusion Virus Calculates the Percentage of Protection of Anti-Virus Activity of Test Compounds Against Viral-Induced Cytopathic Diseases from Dose-Response Curves Or ec5()) and its cytotoxicity &amp; The selectivity of antiviral effect is expressed by the selectivity index (SI) 'by cytotoxic dose of CC5〇 (500/❶ cell) divided by EC5〇 (50% of cells) Calculated by the antiviral activity. The table of the foregoing experimental part lists the range of each compound prepared: the compound belonging to the active range "A" has pEC5〇 equal to or greater than 6 (when expressed in units of molar concentration) EC50·1〇§). The compound belonging to the active range, Έ" has a pEC5 〇 value of less than 6. The test compound is used to measure the EC5Q and CC5 自动 of the test compound based on tetrazolium. The flat bottom 96 plastic microtiter plate is filled with 1 Microliters of Eagle's basal medium supplemented with 5% FCS (0% FLU) and 20 mM Hepes buffer. Thereafter, a 45 μl volume of compound stock (7.8x final test concentration) was added to a series of three replicate wells. To simultaneously assess its effects on the virus- and mock-infected cells. Five five-fold dilutions were performed directly in the microtiter plate using a mechanical system. Each test contained an untreated virus control group and a HeLa cell control group. Add 50 μl of the loo TCID5〇 respiratory fusion virus to the 51 1378926 column of the three columns. Add the same volume of medium to the third column to measure the compound cell at the same concentration as the antiviral activity. Toxicity. After two hours of incubation, 5 liters of a volume of HeLa cell suspension (4 X 1 〇 5 cells/ml) was added to all wells. The culture was at 37. 〇 at 5〇/〇c〇2 In the atmosphere The cytotoxicity and antiviral activity were measured by spectrophotometry seven days after infection. Add 25 μl of MTT (3-(4,5-dimethylthiazole-2) to each well of the microtiter plate. -Based -2,5-diphenyltetrazolium) solution. The tray was then removed from the cups after 37 hours of incubation. The solution of formazan crystals was added by adding 100 μl of 2-propanol. Completed. The complete dissolution of the crystallization is obtained after the tray is placed on the tray shaker for 10 minutes. Finally, at the two wavelengths (540 and 690) in the eight-channel electricity · month b control luminosity beta ten (Multiskan MCC, Flow Laboratories) The absorbance was read under the nanometer. The absorbance measured at 690 nm was automatically subtracted from the absorbance at 540 nm to eliminate the effect of non-specific absorbance.

52

Claims (1)

Patent Application No. 93丨39736. ROC Patent Aimtn. No. 93139736 I. Repairing iptt Heina's genius 凼 'Chinese text - attached fK two) Replacement (Submitted on May 4, 2012) Ι·378926 X. Patent application scope: 1. A compound of formula (1), Wherein Q is a C -6 alkyl group substituted by one or two hydroxy groups; G is a fluorenylene group; and R 1 is a substituent selected from one or two groups each consisting of a hydroxyl group and a Cu alkyl group. Substituted pyridyl; one of R2a and R3a is C -6 alkyl and the other of 1123 and R3a is hydrogen; if R 2a is not argon, then 215 is hydrogen or CN6 alkyl, and ruler 1 2 Is hydrogen; if R3a is not argon, then the ruler 31) is hydrogen or Cu alkyl, and the ruler 215 is hydrogen; or R2a, R2b, R3a and R3b are all hydrogen; · R5 is hydrogen or Cw alkyl. 2. The compound of claim 1, wherein R1 is a ratio of a hydroxyl group and a C!_6 alkyl group. -53- 1 The compound of claim 1, wherein R1 is a thiol group substituted with a hydroxy group and a thiol group. 4. 4. For example, the patented range of pyridylpyridin-2-yl. A compound of the formula 1, wherein R1 is 3-hydroxy-6. • The compound of claim 1 is wherein the rule 5 is gas. 6 'A compound of the scope of the patent application, wherein the ruler and the ruler "in the case of C". 6 alkyl and the other of Rh and Rh is hydrogen; if R is not hydrogen, then R b is Cl ό And R3b is such that if R3a is non-hydrogen, then R3b is a Cl_6 alkyl group, and R2b is a chlorine. 7. If the compound of any of the above-mentioned items of the scope of the invention is a pharmaceutical agent. A composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as claimed in any one of claims 6 to 9, as claimed in claim 6 to 6, The use of a compound of any one for the manufacture of a medicament for inhibiting RSV replication. iO. A method of preparing a compound according to any one of claims 1 to 6 which comprises (a) (11) Intermediate and reagent (III) are reversed according to the following reaction scheme -54· 1.378926 (π) 〇) (b) The intermediate of formula (IV) is reacted with reagent (v) according to the following reaction scheme: Where Q, G, Rim, R3b, R^M_ are defined in any of items 1 to 6 of the range of interest, w is a detachment basis; and depending on the fact that the mud is treated by appropriate line, the bribe is cut) Compound: Its pharmaceutically acceptable base addition salt or acid addition "= and phase? also, the base addition or acid addition salt form is treated with an acid or a base to give a free form of the compound of formula (1).