KR101187441B1 - Aminobenzimidazoles and Benzimidazoles as Inhibitors of Respiratory Syncytial Virus Replication - Google Patents

Abstract

Benzimidazoles and aminobenzimidazoles having inhibitory activity against RSV replication and formula (I), prodrugs thereof, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms; Here, G is either a direct bond, one or more hydroxyl, C _{1 - 6} alkyloxy, Ar ¹ C _{l - 6} alkyloxy, C _{1 - 6} alkylthio, Ar _¹ C ¹ _{- 6} alkylthio, HO (-CH ₂ - _{CH 2 -O) n -, C} 1 - 6 alkyloxy (-CH ₂ -CH ₂ -O) _n - or Ar ¹ C _{l -} optionally by - ₆ alkyloxy (-CH ₂ -CH ₂ -O) _n substituted C _{1 - 10} alkanediyl gt; R ¹ is Ar ¹ or is monocyclic or bicyclic heterocycle; Q is hydrogen, amino or mono- or di (C _1-4 alkyl) amino; R ^2a one of R ^3a is selected from halo, optionally mono- or poly-substituted C _{1 - 6} alkyl, optionally mono- or poly-substituted C _{2 - 6} alkenyl, nitro, ^{hydroxy, Ar 2, N (R 4a} R 4b ^{), N (R 4a R 4b} ) sulfonyl, N (R ^4a R ^4b) carbonyl, C _{1 - 6} alkyloxy, Ar ² oxy, Ar ² C _{1 - 6} alkyloxy, carboxyl, C _{1 - 6} alkyl Oxycarbonyl, or -C (═Z) Ar ² ; The other of R ^3a of R ^2a is hydrogen; When R ^2a is hydrogen and the other, R ^2b is hydrogen, C _{1 - 6} alkyl or halogen, R ^3b is hydrogen; When R ^3a is hydrogen and the other, R ^3b is hydrogen, C _{1 - 6} alkyl or halogen, R ^2b is hydrogen. A composition containing the compound as an active ingredient; And methods for preparing the compounds and compositions.

Respiratory syncytial virus, replication, inhibition, benzimidazole, aminobenzimidazole

Description

Aminobenzimidazoles and Benzimidazoles as Inhibitors of Respiratory Syncytial Virus Replication

The present invention relates to aminobenzimidazoles and benzimidazoles having antiviral activity, specifically inhibitory activity against replication of respiratory syncytial virus (RSV). The invention also relates to a composition comprising said compound and to the preparation thereof.

Human RSV or respiratory syncytial virus is a large RNA virus that is a member of the paramyxoviridae family, like the bovine RSV virus, which is a phneumophiri subfamily. Human RSV is involved in various respiratory tract diseases in people of all ages throughout the world. It is a major cause of lower respiratory tract disease during childhood and infancy. More than half of all infants develop RSV at 1 year of age, and almost all infants experience it within 2 years of age. Infection in young children can cause lung damage that lasts for years and may contribute to chronic lung disease in old age (chronic wheezing, asthma). Adolescents and adults can often suffer from (malignant) colds following RSV infection. In old age, susceptibility increases again, and RSV is involved in the induction of multiple pneumonia in older people, causing severe mortality.

Infection with viruses from a given subgroup does not protect against subsequent infection by RSV isolated from the same subgroup after winter. Thus, even though there are only two subtypes, A and B, reinfection with RSV is common.

Today, only three drugs are approved for the prevention of RSV infection. The first is the nucleoside analog ribavirin, which provides aerosol treatment for severe RSV infection in children under hospital care. The aerosol route of administration, toxicity (risk of teratogenicity), cost and highly variable efficiency limit its use. Two other drugs, polyclonal and monoclonal antibody immunostimulants, RespiGam ^® and palivizumab are those used for prevention.

All other efforts to develop safe and effective RSV vaccines have all failed and must continue. Inactivated vaccines failed to protect against disease, in fact in some cases, improved disease during subsequent infections. Life-saving vaccines have been tried with limited success. Clearly, administering drugs against RSV replication needs to be effective, nontoxic and easy.

Previously, inhibitors of RSV replication, benzimidazole and imidazopyridine, have been described in WO 01/00611, WO 01/00612 and WO 01/00615.

The present invention relates to inhibitors of RSV replication, prodrugs thereof, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms which can be represented by the following formula (I):

Here, G is a direct bond or a hydroxyl group, C _{1 - 6} alkyloxy, Ar ^l C _{1 - 6} alkyloxy, C _{1 - 6} alkylthio, Ar ₁ C ^l _{- 6} alkylthio, HO (-CH ₂ -CH ₂ - _{O) n -, C 1 -} 6 alkyloxy (-CH ₂ -CH ₂ -O) _n - independently from the group of substituents consisting of - or Ar1C _{1 -6} alkyloxy (-CH ₂ -CH ₂ -O) _n by one or more substituents selected an optionally substituted C _{1 - 10} alkanediyl gt;

Each n is independently 1, 2, 3 or 4;

R ¹ is Arl or a monocyclic or bicyclic heterocycle being selected from piperidinyl, piperazinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydro-furanyl, Thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, quinolinyl, quinoxalinyl, benzofuranyl, benzothienyl, benzimidazolyl , Benzoxazolyl, benzthiazolyl, pyridopyridyl, naphthyridinyl, 1H-imidazo [4,5-b] pyridinyl, 3H-imidazo [4,5-b] pyridinyl, imidazo [1 , 2-a] -pyridinyl, 2,3-dihydro-1,4-dioxino [2,3-b] pyridyl or a radical of the formula

;

;

Wherein each of said monocyclic or bicyclic heterocycle selected from halo, hydroxy, amino, cyano, carboxyl, C _{1 - 6} alkyl, C _{1 - 6} alkyloxy, C _{1 - 6} alkylthio, C _{1 - 6} alkyloxy C _{1- 6} alkyl, Ar ^1, Ar ¹ C _{1 - 6} alkyl, Ar ¹ C _{1 - 6} alkyloxy, hydroxy C _{1 - 6} alkyl, mono- or di (C _{1 -6} alkyl) amino, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, C ₁ to _poly-6 alkyl, C _{1 - 6} alkylcarbonylamino, C _{1 - 6} alkyl, -SO ₂ -NR ^5c -, Ar ^{_{1 -SO 2 -NR 5c -, C}} 1 - 6 ^{alkoxycarbonyl, -C (= O) -NR 5c} R 5d, HO (-CH 2 -CH 2 -O) n-, halo (-CH ₂ -CH _{2 -O) n-, C 1 -} 6 alkyloxy _{(-CH 2 -CH 2 -O) n-} , Ar 1 C 1 -6 alkyloxy (-CH ₂ -CH ₂ -O) n- and mono-or di (C _{1 - 6} alkyl) amino (-CH ₂ -CH ₂ -O) n-, if independently selected from one or possibly in a group of substituents consisting of more, for example two, three, four or Optionally substituted by 5 substituents ;

Each m is independently 1 or 2;

Each p is independently 1 or 2;

Each t is independently 0, 1 or 2;

Q is hydrogen, amino or mono- or di (C _{1 - 4} alkyl) amino;

One of R ^2a and R ^3a is selected from halo, optionally mono- or poly-substituted C _{1 - 6} alkyl, optionally mono- or poly-substituted C _{2 - 6} alkenyl, nitro, ^{hydroxy, Ar 2, N (R 4a} R 4b ^{), N (R 4a R 4b} ) sulfonyl, N (R ^4a R ^4b) carbonyl, C _{1 - 6} alkoxy, Ar ² oxy, Ar ² C _{1 - 6} alkyloxy, carboxyl, C _{1 - 6} alkyloxy Carbonyl, or -C (═Z) Ar ² ; The other of R ^2a and R ^3a is hydrogen;

here

- = Z is = O, = CH-C ( = O) -NR 5a R 5b, = CH2, = CH-C 1 - 6 alkyl, = N-OH or = NOC _{1 - 6} alkyl; And

_- C ₁ - ₆ alkyl and C _{2 - 6} optional substituents are the same or can be different relative to one another, each a hydroxyl group, cyano, halo, nitro, N on the alkenyl ^{(R 4a R 4b), N} (R 4a R ^{4b) _{sulfonyl, Het, Ar 2, C 1}} - 6 alkyloxy, C _{1 - 6} alkyl, _{-S (= O) t, Ar} 2 ^{oxy, Ar 2 -S (= O)} t, Ar 2 C 1 - 6 alkyloxy, Ar ² C _1-6 alkyl, -S (= O) _t, Het- oxy, Het-S (= O) t, HetC 1 - 6 alkoxy, HetC _{1 - 6} alkyl, -S (= O) _t, carboxyl, C _{1 - 6} alkyloxycarbonyl and -C (= Z) are independently selected from the group of substituents consisting of Ar ^2;

When R ^2a is hydrogen and the other, R ^2b is hydrogen, C _{1 - 6} alkyl or halogen, R ^3b is hydrogen;

When R ^3a is hydrogen and the other, R ^3b is hydrogen, C _{1 - 6} alkyl or halogen, R ^2b is hydrogen;

R ^4a and R ^4b may be the same or different to one another, each hydrogen, C _{1 - 6} alkyl, Ar ² C _1-6 alkyl, (Ar ²⁾ (hydroxy) C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, mono- and di - (C _{1 - 6} alkyloxy), C _{1 - 6} alkyl, (hydroxy-C _{1 - 6} alkyl) oxy-C _{1 - 6} alkyl, Ar ¹ C _{1 - 6} alkyloxy -C _{1 - 6} alkyl, di-hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, (Ar ¹ C _{1 - 6} alkyloxy) ( hydroxy) C _{1 - 6} alkyl, Ar ¹ oxy -C _{1 - 6} alkyl, (Ar ¹ oxy) (hydroxy) C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di - (C _{1 - 6} alkyl) amino -C _{1 - 6} alkyl, carboxyl -C _{1 - 6} alkyl, C _{1 - 6} alkyloxycarbonyl C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di - (C _{1 - 6} alkyl) aminocarbonyl C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl C _{1- 6} alkyl, (C _{1 - 4 alkyloxy) 2 -P (= O) -C} 1 - 6 alkyl, ( C _{1 - 4 alkyloxy) 2 -P (= O) -OC} 1 - 6 alkyl, amino Sulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl, Ar ² carbonyl, Het- carbonyl, Ar ² C _{1 - 6} alkylcarbonyl, Het-C _{1 - 6} alkylcarbonyl, C _{1 -6} alkyl sulfonyl, amino-sulfonyl, mono- and di (C _1-6 alkyl) aminosulfonyl, Ar ² sulfonyl, Ar ² C _{1 - 6} alkylsulfonyl, Ar ^2, Het, Het- sulfonyl, HetC _{1 - 6} alkylsulfonyl, and each independently selected from the group of substituents consisting of;

R ^5a and R ^5b may be the same or different to each other, each independently hydrogen or C _{1 - 6} alkyl; or

R ^5a and R ^5b together may form a divalent radical of the formula — (CH ₂ ) _s — where s is 4 or 5;

R ^5c and R ^5d may be the same or different to each other, each independently hydrogen or C _{1 - 6} alkyl; or

R ^5c and R ^5d together may form a divalent radical of formula — (CH ₂ ) _s — where s is 4 or 5;

R ^6a is hydrogen, C _{1 - 6} alkyl, Ar ^1, Ar ¹ C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl, Ar ¹ carbonyl, Ar ¹ C _{1 -6} alkylcarbonyl, C _{1 - 6} alkyl sulfonyl, Ar ¹ sulfonyl, Ar ¹ C _{1 - 6} alkylsulfonyl, C _{1 - 6} alkyloxy C _{1 - 6} alkyl, amino, C _{1- 6} alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (carboxyl) -C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) -C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, Het, Het-C _{1 - 6} alkyl, Het- carbonyl, sulfonyl Het-, Het-C _{1 - 6} alkylcarbonyl;

R ^6b is hydrogen, C _{1 - 6} alkyl, Ar ¹ or Ar _¹ C ¹ _{- 6} alkyl;

R ^6c is C _{1 - 6} alkyl, Ar ¹ or Ar _¹ C ¹ _{- 6} alkyl;

Or Ar ¹ is phenyl, halo, hydroxy, C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, C ₁ to _poly-to-6 alkyl, and C _{1 - 6 1} gae selected from alkyloxy or more, e. For example phenyl substituted with 2, 3 or 4 substituents;

Ar ² is either phenyl, halo, cyano, C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, Ar _¹ -C ¹ _{- 6} alkyl, cyano, C _{1- 6} alkyl, C _{2 - 6} alkenyl group, a cyano no-C _{2 - 6} alkenyl, R ^6b -OC _{3 - 6} alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{3 - 6} alkynyl, Ar ^1, Het, R ^{6b -O-, R 6b -S-, R} 6c -SO-, R 6c -SO 2 -, R 6b -OC 1 - 6 alkyl, -SO ₂ -, -N to be (R ^6a R ^6b), poly- C _{1 - 6} alkyl, C ₁ to _poly-6 alkyloxy, C ₁ to _poly-6 ^{alkylthio, R 6c -C (= O)} -, R 6b -OC (= O) -, N (R 6a ^{R 6b) -C (= O)} -, R 6b -OC 1 - 10 alkyl, R ^6b -SC _{1 - 6} ^{alkyl, R 6c -S (= O)} 2 -C 1-6 alkyl, N (R ^6a R ^6b) -C _{1 - 6} ^{alkyl, R 6c -C (= O)} -C 1 - 6 ^{alkyl, R 6b -OC (= O)} -C 1 - 6 ^{alkyl, N (R 6a R 6b)} -C (= O) -C _1-6 ^{alkyl, R 6c -C (= O)} -NR 6b -, R 6c -C (= O) -O-, R 6c -C (= O) -NR 6b -C 1 - 6 One or more selected from alkyl, R ^6c —C (═O) —OC _1-6 alkyl, N (R ^6a R ^6b ) —S (═O) ₂ —, H ₂ NC (═NH) —, eg For example phenyl substituted with 2, 3, 4 or 5 substituents;

Het is tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl , Oxadiazolyl, thiadiazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, _{4-isoquinolinyl,} benzo-dioxa-carbonyl, benzo-dioxide talking, India rinil, the heterocycle selected from a delivery reel, heterocyclyl of said each oxo, amino, Ar ^l, C _{1 - 4} alkyl, amino-C ₁ alkyl, Ar ₁ C ^l _{- 4} alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, mono- or di (C _1-6 alkyl) amino, (hydroxy-C _l-6 alkyl) by amino which may be optionally substituted, optionally one or two C _{1 - 4} alkyl radical can by be optionally further substituted.

The invention also provides for the use of a compound of formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex and stereochemically isomeric form thereof in the manufacture of a medicament for inhibiting RSV replication. It is about. Or the invention inhibits RSV replication in warm-blooded animals comprising administering an effective amount of a compound of Formula (I), or a prodrug, N-oxide, addition salt, quaternary amine, metal complex, and stereochemically isomeric form thereof It is about how to.

In another aspect, the present invention relates to novel compounds of formula (I) as well as to methods of preparing such compounds.

As used herein, the concept of 'prodrug' means that the biotransformation product of the resulting derivative may be an active drug, defined as a compound of formula (I), for example esters and amines. It means a pharmaceutically acceptable derivative such as. Goodman and Gilman, who describe prodrugs in general, The Pharmacological Basis of Therapeutics, 8 ^th ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of drug", p. 13-15 It is described in. Prodrugs are characterized by good aqueous solubility and bioavailability and are rapidly metabolized in vivo as active inhibitors.

_{'- 6} alkyl poly-substituted C ₁ "and" poly-substituted C _{2 - 6} alkenyl, R ^2a, and as used in the definition of R ^3a The concept is, for two or more substituents, for example two, three , four, five or six substituents, in particular two or three substituents, C ₁ having more specifically the a two _substituents meant to include ₆ alkyl radical. The upper limit of the number of substituents is determined not only by the general characteristics of the substituents such as bulkiness, but also by the number of hydrogen atoms that can be substituted, which characteristics allow those skilled in the art to determine the upper limit. do.

The concept of 'optionally C _1-10 alkanediyl substituted by one or more substituents' as used in the definition of G is 0, 1, 2 or more substituents, for example 0, 1, 2 , three, four, five or six substituents, in particular 0, 1, 2, or 3 substituents, more particularly, 0, C ₁ having one or two substituents _{- 10} alkanediyl It means to include one radical. Here too, the upper limit of the number of substituents is determined by the factors mentioned above.

As used above and below, a group or part of a group 'polyhaloC _1-6 alkyl', eg, polyhaloC _1-6 alkyloxy, is mono- or polyhalo substituted C _1-6 C _1-6 substituted with one, two, three, four, five, six or more halo atoms, such as alkyl, in particular methyl or ethyl with one or more fluoro atoms Alkyl, for example difluoromethyl, trifluoromethyl, trifluoroethyl. Also, included are all hydrogen atoms are fluoro atoms, for example, pentafluoroethyl a C _1-6 alkyl group, C _1-6 alkyl (perfluoroC _1-6 alkyl group), a pulse-fluoro substituted with. When one or more halogen atoms are bonded to an alkyl group within the definition of polyhaloC _1-4 alkyl, the halogen atoms may be the same or different.

Each monocyclic or bicyclic heterocycle in the definition of R ¹ may be optionally substituted by one or possibly more substituents, for example two, three, four or five substituents. In particular, the heterocycle may be optionally substituted by up to 4, up to 3, up to 2 substituents or up to 1 substituent.

Each Ar ^l or Ar ² is unsubstituted phenyl, or one or more substituents, for example five or four substituents, or preferably up to three substituents, or up to two substituents, or one Phenyl substituted with a substituent.

As it mentioned among the substituents of Ar ^2, a radical 'R ^6b -OC _{3 - 6} alkenyl' or 'R ^6b -OC _3-6 C _3-6 alkynyl, R ^6b -O-, especially on a saturated carbon atom Have a group.

When substituted on an oxygen atom or a nitrogen atom, hydroxy C _{1 - 6} alkyl group include a hydroxyl group and the oxygen or nitrogen is at least 2-hydroxy-C ₂ separated by the carbon _atoms is preferably ₆ alkyl group.

For example, R ^4a and R ^4b, as the di-hydroxy-mentioned definition of the C _{l - 6} alkyl groups are C _l with two hydroxy substituents substituted on different carbon _atoms is ₆ alkyl group. (C _{l - 6} alkyloxy) (hydroxy) C _{l - 6} alkyl, di (C _{l - 6} alkyl-oxy) _l- C ₆ alkyl, (Ar ¹ C _{l - 6} alkyloxy) (hydroxy) C _{l - 6} alkyl notion are each C _{1 - 6} alkyloxy and a hydroxy group, the two C _{1 - 6} alkyloxy group, and Ar ^l C _{l - 6} alkyloxy and a hydroxy group substituted by a C _{l -} refers to ₆ alkyl radical do. Preferably in the above radicals, C _{1 -} the substituent substituted on the _6-alkyl is on a carbon atom other than the carbon atom bonded to the nitrogen atom is R ^4a and / or R ^4b are connected.

₃ alkyl is methyl, ethyl, propyl, 1-methylethyl and the like such as 1 to 3 carbon atoms having a straight-chain or branched saturated _{hydrocarbon-a,} a group or a part of the C ₁ group, as used herein, Define radicals; Group or part of C ₁ of the group _{- 4} alkyl C _{1 -} defines the group and from 1 to 4 saturated hydrocarbon radical of the type straight-chain or branched having a carbon atom as the like are defined for the _three alkyl and butyl; It is part of a group or a group C _{2 - 4} alkyl and defines saturated hydrocarbon radicals ethyl, propyl, 1-methylethyl, butyl and form a straight or branched chain having 2 to 4 carbon atoms such as an equivalent thereof; A C ₁ part of a group or a group _{- 6} alkyl is C _{1 - 4} of the saturated group, hexyl, 2-methylbutyl and form a straight or branched chain having 1 to 6 carbon atoms as defined for alkyl and the like pentyl Defining a hydrocarbon radical; Group or part of group of C _{1 - 8} alkyl is C _l-6 from 1 to 9 carbon atoms, as a group, an octyl, nonyl, 2-methylhexyl, 2-methylheptyl and the like are defined for the alkyl and heptyl Branch defines a straight or branched saturated hydrocarbon radical; Group or part of group of C _{1 - 10} alkyl is C _{1 - 9} alkyl and a group defined for decyl, 2-methyl-nonyl and the like and as a linear one having one to ten carbon atoms or a branched saturated hydrocarbon Define radicals.

It is part of a group or a group used in this specification 'C _{3 - 6} alkenyl "The concept is propenyl, buten-1-yl, butene-2-yl, penten-1-yl, penten-2-yl, hexene 3 to 6 carbon atoms and at least one double bond, preferably one, such as -1-yl, hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, and equivalents thereof It is meant to include straight chain or branched unsaturated hydrocarbon radicals having a double bond. A group or a part of "C _{2 - 6} alkenyl" as used herein means the group concept is C _{3 - 6} is intended to include alkenyl groups and ethylene. "C _{3 - 6} alkynyl" The concept is propenyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyne-1-yl, hexyn-2-yl, Define straight or branched chain unsaturated hydrocarbon radicals having 3 to 6 carbon atoms and one triple bond, such as hexyn-3-yl, 2-methylbutyn-1-yl, and equivalents thereof. A group or which is part of group used herein, "C _{2 - 6} alkynyl" is the concept of C _{3 -} meant to include ethynyl ₆ alkynyl group, and.

C _{2 - 6} alkenyl group when connected to a hetero atom, and is preferably connected via cut-saturated carbon atoms. C _{3 - 6} alkenyl group, when substituted with a hydroxyl group, and a hydroxyl group on a carbon atom is saturated.

C _{3 - 7} cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. C _{5 - 7} cycloalkyl is generic for a cyclopentyl, cyclohexyl or cycloheptyl.

C _{2 - 5} alkanediyl thing, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butane-diyl, 1,2-propanediyl, 2,3-butane-diyl, 1,5- Divalent straight chain and branched chain saturated hydrocarbon radicals having 2 to 5 carbon atoms, such as pentanediyl and its equivalents, and C _1-4 alkanediyl is, for example, methylene, 1,2-ethanediyl, Define saturated hydrocarbon radicals of divalent straight and branched chain having 1 to 4 carbon atoms, such as 1,3-propanediyl, 1,4-butanediyl and their equivalents; C _{1 - 6} alkanediyl job C _{1 - 4} alkanediyl and, for example, 1,5-diyl, 1,6-diyl, and including its higher homologues having 5 to 6 carbon atoms, such as an equivalent thereof To do; C _{1 - 10} alkanediyl job C _{1 - 6} alkanediyl and, for example, 1,7-heptane-diyl, octane-1,8-diyl, 1,9-Nadi yl, 1,10-decane-diyl and the like It means to include higher homologues thereof having 7 to 10 carbon atoms, such as.

As described above, (= O) is a carbonyl moiety when bonded to a carbon atom, a sulfoxide moiety when bonded to a sulfur atom and a sulfonyl moiety when two (= O) are bonded to a sulfur atom. Form. (= N-OH) forms a hydroxyimine moiety when bonded to a carbon atom.

The haloran concept is comprehensive for fluoro, chloro, bromo and iodo.

It should be noted that the radical positions on any molecular moiety used in the definition may exist anywhere in the moiety as long as it is chemically stable.

Radicals used in the definition of a variable include all possible isomers unless otherwise indicated. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; Pentyls include 1-pentyl, 2-pentyl and 3-pentyl.

The term 'poly substituted' means substituted with one or more substituents.

When a variation occurs more than once in a component, each definition is independent.

Whenever used herein, the concept of "compound of formula (I)", or "compound of the present invention" or similar concept refers to a compound of formula (I), a prodrug thereof, an N-oxide, an addition salt, a quaternary It is meant to include amines, metal complexes and stereochemically isomeric forms. Interesting subgroups or other subgroups thereof in the compounds of formula (I) are the N-oxides, salts and all stereoisomeric forms of the compounds of formula (I).

It will be apparent that some compounds of formula (I) may contain one or more chiral centers and may exist as stereochemical isomers.

The term "stereochemically isomeric form" used above defines all possible compounds which consist of identical atoms having the same order but having different three-dimensional structures which are not compatible, and the compound of formula (I) Can be processed.

Unless otherwise stated or indicated, chemical indications of a compound include mixtures of all possible stereochemically isomeric forms in which the compound can be processed. The mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of the compound. It will be apparent that all stereochemical isomers of the compounds of the present invention, both in pure form or in admixture with one another, are included within the scope of the present invention.

Pure stereochemically isomeric forms of the compounds and intermediates as described herein are isomers that are substantially free of diastereomeric or other enantiomeric forms of the same basic molecular structure of said compounds or intermediates. Specifically, the concept of 'stereoisomerically pure' means that at least 80% of stereochemically isomeric excess (eg, at least 90% of one isomer and up to 10% of other possible isomers) up to 100% stereochemically isomeric excess ), More specifically 90% to 100% stereochemically isomeric excess, more specifically 94% to 100% stereochemically isomeric excess, most specifically 97% to 100% It relates to compounds or intermediates having stereochemically isomeric excess. The concepts 'enantiomerically pure' and 'diastereomerically pure' can be understood in a similar manner, but each has a diastereomeric excess of the mixture in an aqueous state with respect to the enantiomeric excess.

Pure stereochemically isomeric forms of the compounds and intermediates of the invention can be obtained by the application of methods known in the art. For example, enantiomers can be separated from each other by selectively crystallizing their diastereomeric salts with any active acid or base. Examples are tartaric acid, dibenzoyl-tartaric acid, dytoluoyl tartaric acid and camphorsulfonic acid. Alternatively, enantiomers can be separated by chromatographic techniques using chiral stationary phases. The pure stereochemical isomers may be derived from the corresponding pure stereochemical isomers of suitable starting materials, provided that the reaction occurs stereospecifically. Preferably, if a particular stereochemical isomer is required, the compound will be synthesized by stereospecific preparation. The method will usefully use enantiomerically pure starting materials.

Diastereomeric racemates of formula (I) can be obtained separately using conventional methods. Suitable physical separation methods that can advantageously be used are, for example, chromatography such as selective crystallization and column chromatography.

For some compounds of formula (I), their prodrugs, N-oxides, salts, solvent compounds, quaternary amines, or metal complexes and intermediates used in their preparation, the complete stereochemical composition has not been determined experimentally. . Those skilled in the art can determine the complete composition of the compound using methods known in the art such as, for example, X-ray diffraction.

The present invention is also intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and not by way of limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

For treatment, the salt of the compound of formula (I) is one in which the counterion is pharmaceutically acceptable. However, non-pharmaceutically acceptable salts of bases and acids can be used, for example, in the manufacture or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

The pharmaceutically acceptable acid and base addition salts mentioned above are meant to include the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) can form. Pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrochloric acid or hydrofluoric acid such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and equivalent acids thereof; Or for example acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (eg ethandioic acid), malonic acid, succinic acid (eg butanedioic acid), maleic acid, Fumaric acid, malic acid (e.g., hydroxybutanedioic acid), tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, cyclomic acid, salicylic acid, p-aminosalicylic acid, pamophosphoric acid and their equivalents Organic acids such as acids.

Conversely, the salt form can be converted to the free base form by treating a suitable base.

Compounds of formula (I) containing acidic protons can be converted to their nontoxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include ammonium salts; Alkali and earth metal salts such as, for example, lithium, sodium, potassium, magnesium, calcium salts and the like; Salts with, for example, benzatin, N -methyl- D -glucamine, hydravamin salts; And salts with amino acids such as, for example, arginine, lysine and equivalent salts thereof.

The concept of additives described above includes not only the compounds of formula (I) but also the solvent compounds which their salts can form. The solvates are, for example, hydrates, alcoholates and their equivalents.

The concept of "quaternary amine" described above is suitable for quaternizing agents such as, for example, optionally substituted alkyl halides, aryl halides or arylalkyl halides (e.g., methyl iodide or benzyl iodide). ) And the basic nitrogen of the compound of formula (I). Other reactants with good leaving groups such as alkyl trifluoromethanesulfonate, alkyl methane sulfonate and alkyl p-toluenesulfonate can also be used. Quaternary amines have a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The selected counterion can be introduced using an ion exchange resin.

The N-oxide form of the compounds of the present invention is meant to include compounds of formula (I) in which one or several nitrogen atoms are oxidized as so-called N-oxides.

It will be apparent that the compounds of formula (I) may have metal binding, chelating, complex forming properties, and therefore may exist as metal complexes or metal chelates. Metallized derivatives of compounds of formula (I) are included within the scope of the present invention.

Some compounds of formula (I) may exist in their tautomer form. Although not explicitly indicated in the above formula, such forms are considered to be within the scope of the present invention.

One embodiment of the invention relates to compounds of formula (I-a):

Wherein Q, G, R ¹ , R ^2a , R ^2b are as described in the definition of a compound of formula (I) or a subgroup of a compound of formula (I) as specified herein.

Another embodiment of the invention relates to a compound of (I-b):

Wherein Q, G, R ¹ , R ^3a , R ^3b are as described in the definition of a compound of formula (I) or a subgroup of a compound of formula (I) as specified herein.

Certain embodiments of the invention relate to compounds of formula (I-a-1):

Wherein Q, G, R ¹ , R ^4a , R ^2b are as described in the definition of a compound of formula (I) or a subgroup of a compound of formula (I) as specified herein; Alk is C _{1 - 6} alkanediyl gt;

R ⁹ , R ¹⁰ , R ¹¹ independently of one another have the same meaning as substituents for Ar ² described in the definition of a compound of formula (I) or a subgroup thereof; R ¹⁰ and / or R ¹¹ may be hydrogen.

Another particular embodiment of the invention relates to compounds of formula (I-b-1):

Wherein Q, G, R ¹ , R ^4a , R ^2b are as described in the definition of a compound of formula (I) or a subgroup of a compound of formula (I) as specified herein; Alk is C _1-6 alkanediyl;

R ⁹ , R ¹⁰ , R ¹¹ independently of one another have the same meaning as substituents for Ar ² described in the definition of a compound of formula (I) or a subgroup thereof; R ¹⁰ and / or R ¹¹ may be hydrogen.

Interesting subgroups include compounds of the formula:

In (Ic-1) and (Ic-2), the radicals G, R ¹ , R ^2b , R ^3b are as described in the definition of a compound of formula (I) or a subgroup of a compound of formula (I) as specified herein. Equal to; The radicals Alk, R ⁹ , R ¹⁰ , R ¹¹ are as specified above or as defined in the definition of subgroups of compounds of formula (I) described herein; The radicals R ^6a and R ^6b are as described in the definition of compounds of formula (I) or subgroups of compounds of formula (I) as specified herein.

Preferred subgroups are those in which Alk is ethylene or methylene and more preferably Alk is methylene.

In (Ia-1) or (Ib-1), R ^4a is hydrogen, hydroxy C _{1 -} is preferably C _1-6 alkyl, - ₆ alkyl, aminocarbonyl.

In (I-a-1), (I-b-1), (I-c-1) or (I-c-2),

Radicals R ^9, R ^10, R ¹¹ preferably and independently of one another, C _{1 - 6} alkyl or R ^6b -OC _{1 - 6} alkyl will; R ¹⁰ and / or R ¹¹ may be hydrogen; or

R ^9, R ¹⁰ is more preferably and independently of one another, C _{1 - 6} alkyl, -OC _1-6 alkyl, R ^6b will; R ¹¹ is hydrogen; or

R ^9, R ¹⁰ are C _{1 -} to and even more preferably a _6-alkyl; R ¹¹ is hydrogen; or

R ⁹ is C _{1 - 6} alkyl, and, R ¹⁰ is R ^6b -OC _{1 - 6} alkyl, and, R ¹¹ is hydrogen.

In addition to the other subgroups specified herein, subgroups of compounds of the formulas (1-a), (1-b), etc., as defined above, are prodrugs, N-oxides, addition salts, quaternary amines of the compounds It may be understood to include any of the metal complex and stereochemically isomeric forms.

Interesting compounds G is C _{1 - 10} alkanediyl yl the compounds or a subgroup of formula (I); More specifically, it is a compound in which G is methylene.

One embodiment includes a compound of formula (I), as described above or any of the subgroups specified herein, wherein Q is hydrogen. Another embodiment includes a compound of Formula (I), as described above or as described in any of the subgroups specified herein; Wherein Q is amino; Is _- (C _{1 6} alkyl -) amino other than hydrogen, for example, amino, mono-or di.

To a _{10-alkanediyl,} more specifically _- a specific subgroup of compounds of formula (I) in any subgroup of compounds of the compound, or the general formula (I) of formula (I) specified herein, wherein G is C ₁ G is methylene.

Another particular subgroup of a compound of Formula (I) is a compound of Formula (I), or any subgroup of a compound of Formula (I), wherein:

(a) R ¹ is other than Ar ^l ; Or where

(b) R ¹ is Ar ^l or as specified in the definition of a compound of formula (I) or a subgroup thereof.

Another particular subgroup of a compound of Formula (I) is a compound of Formula (I), or any subgroup of a compound of Formula (I), wherein:

(c) R ¹ is halo, hydroxy, amino, cyano, carboxyl, C _{l - 6} alkyl, C _{l - 6} alkyloxy, C _l-6 alkylthio, C _{l - 6} alkyloxy C _{l - 6} alkyl, _{^{Ar 1, Ar 1 C l -}} 6 alkyl, Ar ¹ C _{l - 6} alkyl-oxy, hydroxy-C _{l -6} alkyl, mono- or di (C _l-6 alkyl) amino, mono- or di (C _{l- 6} alkyl) amino -C _{l - 6} alkyl, a C _l- poly to ₆ alkyl, C _{l - 6} alkylcarbonylamino, C _{l - 6} alkyl, _{^{-SO 2 -NR 4a -, Ar 1}} -SO 2 -NR 4a _-, C ₁ - ₆ ^{alkyloxycarbonyl, -C (= O) -NR 4a} R 4b, HO (-CH 2 -CH 2 -O) n -, halo _{(-CH 2 -CH 2 -O) n} - , C _{l - 6} alkyloxy _{(-CH 2 -CH 2 -O) n} -, Ar 1 C l - 6 alkyloxy _{(-CH 2 -CH 2 -O) n} - and mono-or di (C _l-6 Alkyl) amino (-CH ₂ -CH ₂ -O) _n -is pyridyl optionally substituted by one or two substituents independently selected from the group consisting of; Or in more detail

(d) R ¹ is hydroxyl, C _{1 - 6} alkyl, halo, C _{1 - 6} alkyloxy, Ar _¹ C ¹ _{- 6} alkyloxy and (C _{1 - 6} alkyloxycarbonyl) C _{1 - 6} from a group consisting of alkyloxy Pyridyl substituted with one or two substituents independently selected; Preferably here

(e) R ¹ is hydroxyl, C _{1 - 6} alkyl, halo and C _{1 - 6} is pyridyl substituted by one or two substituents independently selected from the group consisting of alkyloxy; Or where

(f) R ¹ is hydroxy, and C _{1 - 6} is pyridyl substituted by one or two substituents independently selected from the group consisting of alkyl; More preferably here

(g) R ¹ is hydroxy, and C _{1 - 6} is pyridyl substituted with alkyl; Or more preferably here

(h) R ¹ is pyridyl substituted with hydroxy and methyl; Or where

(i) R ¹ is 3-hydroxy-6-methylpyrid-2-yl.

Another embodiment includes either a compound of Formula (I) or a subgroup of a compound of Formula (I):

(j) R ¹ is Ar ^l , quinolinyl, benzimidazolyl, a radical of the formula: pyrazinyl, or pyridyl; Or where

(k) R ¹ is Ar ¹ , quinolinyl, benzimidazolyl or a radical of formula (c-4) wherein m is 2, pyrazinyl, or pyridyl;

Wherein each radical of (j) and (k) may be optionally substituted by substituents specified in the definitions of compounds of formula (I), and in particular pyridyl may be substituted as specified in (a) to (i) Can be.

Another embodiment includes any of a compound of Formula (I) or a subgroup of a compound of Formula (I): wherein

(l) R ¹ is Ar ^l, quinolinyl, benzimidazolyl and thiazolyl, or m is 2 the radicals, pyrazinyl, or pyridyl of formula (c-4), wherein each radical is selected from halo, hydroxyl, C _{1 - 6} alkyl, C _1-6 alkyloxy, Ar ¹ C1-6 alkyloxy, (C _{1 - 6} alkyloxycarbonyl) C _{1 - 6 1,} 2, or optionally substituted by three radicals selected from the group consisting of alkyloxy Can be; Or in more detail here

(m) R ¹ is Ar ^l, quinolinyl, benzimidazolyl and thiazolyl, or m is 2 the radicals, pyrazinyl, or pyridyl of formula (c-4), wherein each radical is selected from halo, hydroxyl, C _{1 -} Optionally substituted by one, two or three radicals selected from the group consisting of ₆ alkyl, C _1-6 alkyloxy, benzyloxy; Or in more detail here

(n) R ¹ is halo, hydroxy, C _{1 - 6} alkyl, C _{1 - 6 1} gae selected from the group consisting of alkyloxy, two or three radicals by optionally substituted phenyl; Quinolinyl; radical (c-4) in which m is 2 and is optionally substituted by up to two radicals selected from C _1-6 alkyl; C _{1 - 6} alkyl optionally substituted by a benzimidazole pyridazinyl; Hydroxyl, halo, C _{1 - 6} alkyl, benzyloxy and C _{1 -} optionally by the radical of from ₆ alkyl, up to three selected _{- 6} alkyl, by one or two radicals selected from oxy, optionally substituted pyridyl, C ₁ Substituted pyrazinyl; Or substituted or optionally substituted pyridyl as specified in (a) to (i) above; Or where

(o) R ¹ is halo, hydroxy, C _{1 - 6} alkyl, C _{1 - 6 1} gae selected from the group consisting of alkyloxy or 2 by the radical of an optionally substituted phenyl;

(p) R ¹ is quinolinyl;

(q) R ¹ is m is 2, C _{1 -} a by a radical of the _6-alkyl optionally substituted with up to two radicals selected (c-4), and;

(r) R ¹ is C _{1 - 6} alkyl optionally substituted by a thiazolyl and benzimidazolyl; Hydroxyl, halo, C _1-6 alkyl, benzyloxy and C _{1 - 6} and optionally substituted pyridyl by one or two radicals selected from alkyloxy,

(s) R ¹ is C _{1 -} is a pyrazinyl optionally substituted with up to three radicals selected from _6-alkyl.

Preferred subgroups of the compounds of formula (I) or any of the subgroups of compounds of formula (I) are those wherein G is a direct bond or methylene and R ¹ is as specified in (a) to (s) above. More preferred is that any of the subgroups of compounds of a compound or formula (I) of formula (I), wherein G is a direct bond, R ¹ is a radical (c-4), specifically, m = 2 C _{1 -} Optionally substituted with up to two radicals selected from ₆ alkyl. More preferred is either a compound of formula (I) or a subgroup of a compound of formula (I), wherein G is methylene and R ¹ is as specified in (a) to (s) above but is radical (c-4) Other than that.

Another subgroup of a compound of formula (I) is a compound of formula (I) above, or any subgroup of a compound of formula (I) specified herein:

(a) R ^4a and R ^4b are each independently hydrogen, C _{1 - 6} alkyl, Ar ² C _{1 - 6} alkyl, (Ar ²⁾ (hydroxy) C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, mono- and di - (C _{1 - 6} alkyloxycarbonyl) C _{1 -6} alkyl, (hydroxy-C _{1 - 6} alkyl) oxy-C _{1 - 6} alkyl, Ar _¹ C ¹ _{- 6} alkyl oxy -C _{1 - 6} alkyl, di-hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, (Ar _¹ C ¹ _{- 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, Ar ¹ oxy-C _{1- 6} alkyl, (Ar ^l oxy) (hydroxy) -C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl) amino- C _{1 - 6} alkyl, carboxyl C _{1 - 6} alkyl, C _{1 - 6} alkyloxycarbonyl -C _{1 - 6} alkyl, aminocarbonyl-C _{1- 6} alkyl, mono- and di (C _1-6 alkyl) amino carbonyl -C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl C _{1- 6} alkyl, (C _{1 - 4 alkyloxy) 2 P (= O) -C} 1 - 6 alkyl, (C _{1 - 4} alkyl- _{oxy) 2 P (= O) -OC} 1 - 6 alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl) - aminosulfonyl -C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl, Ar ² carbonyl, Het- carbonyl, Ar ² C _{1 - 6} alkylcarbonyl, Het-C _{1 - 6} alkylcarbonyl, Ar ² and are selected from Het; Or where

(b) R ^4a and R ^4b are each independently hydrogen, C _{1 - 6} alkyl, Ar ² C _{1 - 6} alkyl, (Ar ²⁾ (hydroxy) C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, mono- and di - (C _{1 - 6} alkyloxycarbonyl) C _{1 -6} alkyl, (hydroxy-C _{1 - 6} alkyl) oxy-C _{1 - 6} alkyl, Ar _¹ C ¹ _{- 6} alkyl oxy -C _{1 - 6} alkyl, di-hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, (Ar ^l C _{1 - 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, Ar-oxy ^l -C _{1 - 6} alkyl, (Ar ^l oxy) (hydroxy) -C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl) amino -C _{1 - 6} alkyl, carboxyl -C _{1 - 6} alkyl, C _{1 - 6} alkyloxycarbonyl C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl, C _{1 - 6} alkylcarbonyl C _{1- 6} alkyl, (C _{1 - 4 alkyloxy) 2 -P (= O) -C} 1 - 6 alkyl, (C _{1 - 4} alkyl _{oxy) 2 P (= O) -OC} 1 - 6 alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and Di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, Ar ² and are selected from Het; Or where

(c) R ^4a and R ^4b are each independently hydrogen, C _{1 - 6} alkyl, Ar ² C _{1 - 6} alkyl, (Ar ²⁾ (hydroxy) C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxy), C _{1 - 6} alkyl, (hydroxy-C _{1- 6} alkyl) oxy-C _{1- 6} alkyl, Ar _¹ C ¹ _{- 6} alkyloxy -C _{1 - 6} alkyl, Ar ¹ oxy -C _{1 - 6} alkyl, (Ar ¹ oxy) (hydroxy) -C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino -C _{1 - 6} alkyl, carboxyl C _{1 -6} alkyl, C _{1 - 6} alkyloxycarbonyl -C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl) amino carbonyl carbonyl -C _{1 - 6} alkyl, (C _{1 - 4 alkyloxy) 2 P (= O) -C} 1 - 6 alkyl, (C _{1 - 6 alkyloxy) 2 P (= O) -OC} 1-6 alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, and Ar is selected from ^1; Or where

(d) R ^4a and R ^4b are each independently hydrogen, C _{1 - 6} alkyl, (Ar ²⁾ (hydroxy) C _{1 - 6} alkyl, Het-C _1-6 alkyl, hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) C _{1 - 6} alkyl, (hydroxy hexyloxy-C _{1 - 6} alkyl, Ar ¹ C _1-6 alkyloxy -C _{1 - 6} alkyl, Ar ¹ oxy-C _{1 - 6} alkyl, ( Ar ¹ oxy) (hydroxy) -C _{1 - 6} alkyl, amino-C _{1 -6} alkyl, mono- and di (C _1-6 alkyl) amino -C _{1 - 6} alkyl, carboxyl C _{1 - 6} alkyl, amino carbonyl C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl) aminocarbonyl C _{1 - 6} alkyl, (C _{1 - 4 alkyloxy) 2 P (= O) -C} 1 - 6 alkyl, (C _{1-4 alkyloxy) 2 -P (= O) -OC} 1 - 6 alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino-sulfonyl ₁ -C ₆ is selected from alkyl and Ar ^l.

Interesting subgroups of compounds of formula (I) are the compounds of formula (I) above, or any subgroup of compounds of formula (I) specified herein:

(e) R ^4a and R ^4b are each independently selected from hydrogen, morpholinyl -C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino -C _{1 - 6} alkyl, carboxyl C _{1- 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, and Ar is selected from ^1; Or where

(f) R ^4a and R ^4b are each independently hydrogen, hydroxy C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- and di (C _{1 -6} alkyl) amino -C _{1 - 6} alkyl, carboxyl C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino-carbonyl -C _{1 - 6} alkyl Is selected from; Or where

(g) R ^4a and R ^4b are each independently hydrogen, hydroxy C _{1 - 6} alkyl, aminocarbonyl-C _1-6 alkyl, mono- and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl Is selected from; Or where

(h) RR ^4a and R ^4b are each independently hydrogen, hydroxy C _{1 - 6} is selected from alkyl and aminocarbonyl-C _{1- 6} alkyl.

Another interesting subgroup of the compound of formula (I) is the compound of formula (I) above, or any subgroup of compounds of formula (I) specified herein, wherein R ^4a is hydrogen and R ^4b is (a) To the definition as defined in (h) above.

Another subgroup of a compound of formula (I) is a compound of formula (I) above, or any subgroup of a compound of formula (I) specified herein:

(a) Ar ² is phenyl, C _{5 -} ahnel a rate of ₇ cycloalkyl, phenyl, or halo, cyano, C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, Ar _¹ -C ¹ _{- 6} alkyl, a cyano no C _{1 - 6} alkyl, C _{2 - 6} alkenyl, cyano-C _{2 - 6} alkenyl, R ^6b -OC _3-6 alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{3 - 6} ^{alkynyl, Ar 1, Het, R 6b} -O-, R 6b -S-, R 6c -SO-, R 6c -SO 2 -, R 6b -OC 1 - 6 alkyl, -SO ₂ -, -N (R ^6a R ^6b ), CF ₃ , CF ₃ -oxy, CF ₃ -thio, R ^6c -C (= 0)-, R ^6b -OC (= 0)-, N (R ^6a R ^6b ) -C (= O) -, R 6b -OC 1 - 6 alkyl, R ^6b -SC _{1 - 6} ^{alkyl, R 6c -S (= 0)} 2 -C 1-6 alkyl, N (R ^6a R ^6b) -C _{1 - 6} ^{alkyl, R 6c -C (= O)} -C 1 - 6 ^{alkyl, R 6b -OC (= O)} -C 1 - 6 ^{alkyl, N (R 6a R 6b)} -C (= O) -C _1-6 ^{alkyl, R 6c -C (= O)} -NR 6b -, R 6c -C (= O) -O-, R 6c -C (= O) -NR 6b -C 1 - 6 alkyl, 1, 2 or 3 substituents selected from R ^6c —C (═O) —OC _1-6 alkyl, N (R ^6a R ^6b ) —S (═O) ₂ —, H ₂ NC (= NH)- Phenyl substituted with;

(b) Ar ² is phenyl, C _{5 - 7} cycloalkyl ahnel the rate of alkyl, phenyl, or halo, cyano, C _1-6 alkyl, Het-C _{1 - 6} alkyl, Ar ₁ -C _{1 - 6} alkyl, a cyano no C _{1 - 6} alkyl, C _{2 - 6} alkenyl, cyano, -C _{2 - 6} alkenyl, R ^6b -OC _3-6 alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{3 - 6} ^{alkynyl, Ar 1, Het, R 6b} -O-, R 6b -S-, R 6c -SO-, R 6c -SO 2 -, R 6b -OC 1 - 6 alkyl, -SO _2- , -N (R ^6a R ^6b ), CF ₃ , R ^6c -C (= 0)-, R ^6b -OC (= 0)-, N (R ^6a R ^6b ) -C (= 0)-, R ^6b -OC _{1 - 6} alkyl, R ^6b -SC _{1 - 6} ^{alkyl, R 6c -S (= O)} 2 -C 1 - 6 ^{alkyl, N (R 6a R 6b)} -C 1-6 alkyl, R ^6c _{-C (= O) -C 1 -} 6 ^{alkyl, R 6b -OC (= O)} -C 1 - 6 ^{alkyl, N (R 6a R 6b)} -C (= O) -C 1 - 6 alkyl, R ^6c -C (= O) -NR ^6b -, H ₂ NC (= NH) - one selected from, 2 or 3 substituents, or 1 or 2, and phenyl substituted by one substituent;

(c) Ar ² is phenyl, C _{5 - 7} cycloalkyl ahnel the rate of alkyl, phenyl, or halo, cyano, C _1-6 alkyl, Het-C _{1 - 6} alkyl, Ar ₁ -C _{1 - 6} alkyl, a cyano no C _{1 - 6} alkyl, C _{2 - 6} alkenyl, cyano, -C _{2 - 6} alkenyl, R ^6b -OC _3-6 alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{3 - 6} ^{alkynyl, Ar 1, Het, R 6b} -O-, R 6b -S-, R 6c -SO 2 -, -N (R 6a R 6b), CF 3, R 6b -OC (= O) -, N ( R 6a R 6b) -C (= O) -, R 6b -OC 1 - 6 alkyl, -SC _1-6 alkyl, R ^{6b, R 6c -S (= O)} 2 -C _{1 - 6} ^{alkyl, N (R 6a R 6b)} -C 1 - 6 ^{alkyl, R 6c -C (= O)} -C 1 - 6 ^{alkyl, R 6b -OC (= O)} -C 1-6 alkyl, N ^{(R 6a R 6b) -C (} = O) -C 1 - 6 alkyl, R ^6c -C (= O) -NR ^6b - one selected from, two or three substituents, or one or two substituents Phenyl substituted with;

(d) Ar ² is phenyl, C _{5 -} ahnel a rate of ₇ cycloalkyl, phenyl, or C _{1 - 6} alkyl, Het-C _1-6 alkyl, Ar ₁ -C _{1 - 6} alkyl, cyano C _{1 - 6} alkyl, C _{2 - 6} alkenyl, cyano, -C _{2 - 6} alkenyl, R ^6b -OC _{3 - 6} alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{3 - 6} alkynyl, R ^6b -OC _{1 - 6} alkyl, R ^6b -SC _{1 - 6} ^{alkyl, R 6c -S (= O)} 2 -C 1-6 ^{alkyl, N (R 6a R 6b)} -C 1 - ₆ ^{alkyl, R 6b -OC (= O)} -C 1 - 6 ^{alkyl, N (R 6a R 6b)} -C (= O) -C 1 - 1 , 2 or 3 substituents selected from _6-alkyl, or Phenyl substituted with one or two substituents;

(e) Ar ² is phenyl, or C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, Ar ₁ -C _{1 - 6} alkyl, cyano C _{1 - 6} alkyl, C _2-6 alkenyl, cyano- C _{2 - 6} alkenyl, hydroxy, -C _{3 - 6} alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, hydroxy, -C _{3 - 6} alkynyl, R ^6b -OC _{1 - 6} alkyl, amino, _{-S (= O) 2 -C 1} - 6 ^{alkyl, N (R 6a R 6b)} -C 1 - 6 ^{alkyl, R 6b -OC (= O)} -C 1 - 6 alkyl, amino, -C ( = O) -C _{1 - 6} alkyl, mono- and di -C _{1 - 6} alkyl, _{amino-C (= O) -C 1 -} 1 , 2 or 3 substituents selected from _6-alkyl, or 1 or 2 Phenyl substituted with a substituent;

(f) Ar ² is phenyl, or C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, Ar ₁ -C _{1 - 6} alkyl, cyano C _{1 - 6} alkyl, C _2-6 alkenyl, cyano- C _{2 - 6} alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{1 - 6} alkyl, amino, -S (= O) ₂ -C _1-6 alkyl, R ^6b - _{OC (= O) -C 1 -} 6 alkyl, amino _{-C (= O) -C 1 -} 6 alkyl, mono- and di -C _{1 - 6} alkyl, amino-C (= O) -C _{1 - 6} alkyl selected Phenyl substituted with one, two or three substituents or one or two substituents;

(g) Ar ² is phenyl, or C _{1 - 6} alkyl, R ^6b -OC _{1 - 6} alkyl, amino, and -C (= O) -C _{1 - 6} alkyl Selected; Or C _{1 - 6} alkyl substituted with one selected from, two or three substituents, or one or two substituents _{- 6} alkyl, hydroxy -C _{1 - 6} alkyl, amino -C (= O) -C ₁ Phenyl.

The (a) to (g) limitations on the substituents on Ar ² as specified in the R ^4a and / or R ^4b is a radical Ar ² is a radical -NR ^4a R ^4b is substituted by C _{1 - 6} alkyl or R ^3a If Ar ² is part of the radical R ^2a , it is preferred to apply it to any.

Another subgroup of a compound of formula (I) is a compound of formula (I) above, or any subgroup of a compound of formula (I) specified herein:

(h) Ar ² is C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl, Ar _¹ -C ¹ _{- 6} alkyl, cyano C _{1 - 6} alkyl, C _{2 - 6} alkenyl, cyano-C _{2- 6} alkenyl, C _{2 - 6} alkynyl, cyano-C _{2 - 6} alkynyl, R ^6b -OC _{1 - 6} alkyl, amino, _{-S (= O) 2 -C 1} - 6 alkyl, R ^6b -OC (= O ) -C _{1 - 6} alkyl, amino _{-C (= O) -C 1 -} 6 alkyl, mono- and di -C _{1 - 6} alkyl, amino-C (= O) is substituted with -C _1-6 alkyl; Phenyl optionally further substituted by one or two substituents of Ar ² mentioned in the above pharmaceuticals (a) to (g); or

(i) Ar ² is R ^6b -OC _{1 - 6} alkyl, amino _{-C (= O) -C 1 -} 6 alkyl substituted phenyl; Or hydroxy -C _{1 - 6} alkyl, amino _{-C (= O) -C 1 -} 6 , yet phenyl substituted by alkyl; Phenyl optionally further substituted by one or two substituents of Ar ² mentioned in the above pharmaceuticals (a) to (g).

The (a) to restrictions on the substituent on Ar ² as specified in (g) is a C ₁ substituted with Ar ² _- is preferable to apply any that if ₆ alkyl, R ^3a, or be part of a radical R ^2a Ar ² Do.

Another subgroup of a compound of formula (I) is a compound of formula (I) above, or any subgroup of a compound of formula (I) specified herein:

(a) R ^6a is specifically hydrogen, C _{1 - 6} alkyl, Ar ^l, Ar _¹ C ¹ _{- 6} alkyl, C _{1 - 6} alkylcarbonyl, Ar ^l-carbonyl, Ar _¹ C ¹ _{- 6} alkylcarbonyl, C _{1 - 6} alkyloxy C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (carboxyl) - C _{1 - 6} alkyl, (C _{1 - 6} alkyl-oxycarbonyl) -C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino-carbonyl C _{1 - 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl -C _{1 - 6} alkyl, Het, Het-C _1-6 alkyl, Het- carbonyl, Het-C _{1 - 6} alkylcarbonyl, and;

(b) R ^6a is more specifically hydrogen, C _{1 - 6} alkyl, Ar ^l, Ar ^l C _{1 - 6} alkyl, C _{1 - 6} alkyloxy -C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (carboxyl) -C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) -C _{1 - 6} alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl, aminosulfonyl C _{1 - 6} alkyl, mono- and di (C _{1 - 6} alkyl ) aminosulfonyl -C _{1 - 6 alkyl, Het, Het-C 1 -} 6 alkyl;

(c) R ^6a is more specifically hydrogen, C _{1 - 6} alkyl, Ar _¹ C ¹ _{- 6} alkyl, C _{1 - 6} alkyloxy C _{1 - 6} alkyl, amino, C _{1- 6} alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, (carboxyl) -C _{1 - 6} alkyl, (C _{1 - 6} alkyloxycarbonyl) -C _{1 - 6} alkyl, amino-carbonyl carbonyl C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminocarbonyl-C _{1 - 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl sulfonyl -C _{1 - 6} alkyl, Het-C _{1 - 6} alkyl;

(d) R ^6a is more specifically hydrogen, C _{1 - 6} alkyl, Ar ^l C _{1 - 6} alkyl, amino C _{1 - 6} alkyl, hydroxy-C _{1- 6} alkyl, (carboxyl) -C _{1 - 6} alkyl , aminocarbonyl-C _{1 - 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl, morpholinyl -C _{1 - 6} alkyl; (e) R ^6a is more specifically hydrogen, hydroxy C _{1 - 6} alkyl, aminocarbonyl-C _{1- 6} alkyl, aminosulfonyl -C _{1 - 6} alkyl; Or where

(e) R ^6a is hydrogen, C _{1 - 6} alkyl, Ar ¹ or Ar _¹ C ¹ _{- 6} alkyl; Or R ^6a is hydrogen or C _{1 -6} alkyl; Or R ^6a is hydrogen.

Another subgroup is a compound of Formula (I) above, or any subgroup of a compound of Formula (I) as specified herein:

(f) R ^6b preferably is hydrogen or C _{1 - 6} alkyl; Or more preferably hydrogen;

(g) R ^6c preferably is C _{1 - 6} is alkyl.

In the group of a compound of formula (I) or a subgroup of a compound of formula (I):

(a) Ar ^l is or preferably phenyl, halo, hydroxy, C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyl, trifluoromethyl, and C _{1 - 6} substituents selected, up to three from alkyloxy, Or up to two substituents or phenyl substituted with one substituent;

substituted with ₆ substituents on alkyloxy up substituent, or two of the selected, up to 3, or 1 substituent _- (b) Ar ^l is more or preferably phenyl, halo, hydroxy, C _{1 - 6} alkyl and C ₁ Phenyl;

s a substituent, or one substituent in the _6-alkyl substituted by, or two of the selected, up to three optionally substituted phenyl _- (c) Ar ^l is more preferably phenyl or phenyl substituted with halo and C _1.

Another subgroup of a compound of formula (I) is a compound of formula (I) above, or any subgroup of a compound of formula (I) specified herein:

(a) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl, piperidinyl, homopiperidinyl, piperazinyl, Morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indolinyl, indolyl, which may optionally be substituted with oxo, amino, Ar _l, C _{1 - 4} alkyl, amino -C _{1 - 4} alkyl, Ar ^l C _l-4 alkyl, mono- or di (C _1-6 alkyl) amino C _{1 - 6} alkyl, mono- or di (C _1-6 alkyl) amino, (hydroxy-C _{1 - 6} alkyl) amino, and optionally may be substituted by, one or two C _{1 - 4} by an alkyl radical may be optionally further substituted, and; or

(b) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, Pyridyl, pyrazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzodioxanyl, benzodioxolyl, indorinyl, indoryl, which are oxo, amino, Ar ^l , C _{1 - 4} alkyl, amino-C _{1 - 4} by an alkyl and may be optionally substituted, one or two C _{1 - 4} by an alkyl radical may be optionally further substituted, and; or

(c) Het is furanyl, thienyl, pyrazolyl isoxazolyl, morpholinyl, pyrimidinyl, quinolinyl, indolinyl, optionally further substituted by one or two C _1-4 alkyl radicals Can be;

(d) Het is morpholinyl, and that one or two C _{1 - 4} by an alkyl radical may be optionally further substituted, and; or

(e) Het is morpholinyl.

Certain embodiments of the present invention provide that Q, G, R ¹ and R ⁵ are as specified above in the definition of formula (I), or as specified in any of the subgroups of compounds of formula (I) specified herein. Relates to a compound of formula (I)

(a) one of R ^2a and R ^3a is —N (R ^4a R ^4b ); (R ^4a R ^4b ) N—CO—; Substituted with hydroxy, cyano, Ar ^2, 1 or 2 substituents selected from Het or ^{-N (R 4a R 4b) C} 1 - 6 alkyl; And cyano, or a C ₂ substituted with Ar ² _- is selected from ₆ alkenyl; The other of R ^2a and R ^3a is hydrogen; or

(b) one of R ^2a and R ^3a is —N (R ^4a R ^4b ); (R ^4a R ^4b ) N—CO—; By a hydroxyl, cyano, Ar ^2, Het or -N (R ^4a R ^4b) optionally substituted C _{1 - 6} alkyl; C ₁ is substituted with a hydroxyl group and Ar _{2 - 6} alkyl; And cyano, or a C ₂ substituted with Ar ² _- is selected from ₆ alkenyl; The other of R ^2a and R ^3a is hydrogen; or

(c) one of R ^2a and R ^3a is (R ^4a R ^4b ) N—CO—; By a hydroxy group, Ar ^2, Het or -N (R ^4a R ^4b) optionally substituted C _{1 - 6} alkyl; It is selected from _{6-alkenyl -} and C ₂ is substituted by Ar ^2; The other of R ^2a and R ^3a is hydrogen; And

When R ^2a is hydrogen and the other, R ^2b is hydrogen, C _{1 - 6} alkyl or halogen, R ^3b is hydrogen;

When R ^3a is hydrogen and the other, R ^3b is hydrogen, C _{1 - 6} alkyl or halogen, R ^2b is hydrogen;

Ar ² , Het, R ^4a and R ^4b are as defined in the definition of a compound of formula (I) or any subgroup specified herein.

Other specific embodiments of the invention are those wherein Q, G, R ¹ and R ⁵ are as described above in the definition of formula (I) or as described in any of the subgroups of compounds of formula (I) specified herein. , To compounds of formula (I)

(d) one of R ^2a and R ^3a is selected from (R ^4a R ^4b ) N—CO—; By a hydroxy group, Ar ^2, Het or -N (R ^4a R ^4b) optionally substituted C _{1 - 6} alkyl; It is selected from _{6-alkenyl-substituted} with Ar ^l and C _2; The other of R ^2a and R ^3a is hydrogen; or

(e) one of R ^2a and R ^3a is (R ^4a ) HN—CO—; ^{Hydroxy, Ar 2, Het, -NH (} R 4a) or -N (R ^4a) optionally substituted by C ₁ to Ar ² _{- 6} alkyl; It is selected from _{6-alkenyl-substituted} with Ar ^l and C _2; The other of R ^2a and R ^3a is hydrogen; or

(f) one of R ^2a and R ^3a is a hydroxy ^{group, Ar 2, Het, -NH (} R 4a) or -N (R ^4a) Ar ² optionally substituted by a C _{1 - 6} alkyl; The other of R ^2a and R ^3a is hydrogen; or

(g) one of R ^2a and R ^3a is a hydroxy ^{group, Ar 2, -NH (R 4a} ) or -N (R ^4a) optionally substituted C by Ar ² _{1 - 6} alkyl; The other of R ^2a and R ^3a is hydrogen; or

(h) R ^2a and R ^3a is one of -NH (R ^4a) or -N (R ^4a) optionally substituted C by Ar ² _{1 - 6} alkyl; The other of R ^2a and R ^3a is hydrogen; or

(i) one of R ^2a and R ^3a is -NH (R ^4a) the optionally substituted by C _{1 - 6} alkyl, and; The other of R ^2a and R ^3a is hydrogen;

(j) one of R ^2a and R ^3a is -N (R ^4a) by the Ar ² is optionally substituted C _{1 - 6} alkyl; The other of R ^2a and R ^3a is hydrogen;

When R ^2a is hydrogen and the other, R ^2b is hydrogen or C _{1 - 6} alkyl, and, R ^3b is hydrogen;

When R ^3a is hydrogen and the other, R ^3b is hydrogen or C _{1 - 6} alkyl, and, R ^2b is hydrogen;

Ar ² , Het, R ^4a and R ^4b are as defined in the definition of a compound of formula (I) or any subgroup specified herein.

Other specific embodiments of the invention are those wherein Q, G, R ¹ and R ⁵ are as described above in the definition of formula (I) or as described in any of the subgroups of compounds of formula (I) specified herein. , A compound of formula (I): wherein R ^2a and R ^3a are as defined in (a) to (j), and R ^2b and R ^3b are both hydrogen.

Another embodiment of the invention provides that Q, G, R ¹ and R ⁵ are as described above in the definition of formula (I) or as described in any of the subgroups of compounds of formula (I) as specified herein. Relates to a compound of formula (I)

(k) one of R ^2a and R ^3a is C _{1 - 6} alkyl; The other of R ^2a and R ^3a is hydrogen;

When R ^2a is hydrogen and the other, R ^2b is C _{1 - 6} alkyl, and, R ^3b is hydrogen;

When R ^3a is hydrogen and the other, R ^3b is a C _{1 - 6} alkyl, and, R ^2b is hydrogen.

Another embodiment of the invention provides that Q, G, R ¹ and R ⁵ are as described above in the definition of formula (I), or as described in any of the subgroups of compounds of formula (I) specified herein. , To compounds of formula (I)

One of R ^2a and R ^3a is R is, is selected from a C _{1 -6} alkyl substituted with -N (R ^4a R ^4b) hydrogen; The other of R ^2a and R ^3a is hydrogen; And

When R ^2a is different from hydrogen, R ^2b is hydrogen and R ^3b is hydrogen;

When R ^3a is different from hydrogen, R ^3b is hydrogen and R ^2b is hydrogen.

Another embodiment of the invention provides that Q, G, R ¹ and R ⁵ are as described above in the definition of formula (I), or as described in any of the subgroups of compounds of formula (I) specified herein. , To compounds of formula (I)

One of R ^2a and R ^3a is a C ₁ substituted with -N (R ^4a R ^4b) _- is selected from _6-alkyl; The other of R ^2a and R ^3a is hydrogen; And

When R ^2a is different from hydrogen, R ^2b is hydrogen and R ^3b is hydrogen;

When R ^3a is different from hydrogen, R ^3b is hydrogen and R ^2b is hydrogen; Moreover here

R ^4a is Ar ² ,

R ^4b is C _{1 - 6} alkyl, Ar ² C _{1 - 6} alkyl, C _{1 - 6} alkyloxy C _{1 - 6} alkyl, hydroxy C _{1 - 6} alkyloxy C _{1 - 6} alkyl, Ar _¹ C ¹ _{- 6} alkyl oxy-C _{1 - 6} alkyl, (C _{1 - 6} alkyloxy) (hydroxy) C _{1 - 6} alkyl, (Ar _¹ C ¹ _{- 6} alkoxy) (hydroxy) C _{1 - 6} alkyl, amino C _{1 - 6} alkyl , mono- and di (C _1-6 alkyl) amino C _{1 - 6} alkyl, hydroxy -C _1-6 alkyl, aminocarbonyl-C _{1 - 6} alkyl, mono- and di (C _1-6 alkyl) amino carbonyl carbonyl C _{1 - 6} is alkyl, Het or Het-alkyl, _Cl-6 alkyl, C _{1 -4} alkyloxycarbonyl C _{1 - 6} alkyl, hydroxy-carbonyl C _1.

Preferred compounds are the compounds listed in Tables 1-6, more specifically Compound Nos. 1-75, 81-116, 129-165, 167-183, 191-192, 194-197, 205-214 and 238-239.

More preferred is 2- (2-amino-6-{[2- (3-hydroxy-propyl) -5-methyl-phenylamino] -methyl} -benzimidazol-1-ylmethyl) -6-methyl- In the name of pyridin-3-ol, compounds 90 as listed in Table 1, as well as their prodrugs, N-oxides, addition salts, quaternary amines and metal complexes, in particular the compounds and acid-addition salts thereof.

Any of the compounds of formula (I) or subgroups thereof can be prepared according to the following reaction schemes.

In the above schemes, G, R ¹ , R ^2a , R ^2b , R ^3a , R ^3b have the meanings defined above for any of the compounds of formula (I) or subgroups thereof. W is a suitable leaving group, preferably chloro or bromo. In the above scheme the reaction is carried out with a suitable solvent such as ether (e.g. THF), halogenated hydrocarbon (e.g. dichloromethane), CHC1 ₃ , toluene, polar aprotic solvents (DMF, DMSO, DMA) and their equivalents. Commonly used. Bases may be added to select the free acid during the reaction. If desired, certain catalysts can be added, such as iodide salts (eg KI).

In the process of conversion from (II) to (I), when the radical Q is amino, the radical Q is for example alkyloxycarbonyl (e.g., methoxycarbonyl, And ethoxycarbonyl, t.butyloxycarbonyl). When the radical Q is methoxycarbonylamino, the radical Q can be converted to a methylamino group by treating the starting methoxycarbonylamino benzimidazole with a complex metal hybrid such as LiAIH ₄ .

Compounds of formula (I) wherein Q is amino and represented by formula (I-d) can be prepared as outlined in the following reaction scheme.

In a first step, in order to obtain aminobenzimidazole (V), diaminobenzene (IV) is crystallized using a suitable reagent, for example cyanogen bromide, preferably a suitable solvent such as ethanol Crystallized in alcohol. In order to obtain intermediate (II), the latter intermediate (V) is reacted with reagent (III) in the N-alkylation reaction. One of the amino groups of the starting material (IV) can be substituted with the radical -GR ¹ , and the derivative of (IV) can be crystallized by sinogen bromide as described above to directly obtain (Id). Alternatively, in a suitable solvent such as xylene, it may be reacted with urea via a condensation reaction to obtain benzimidazole-2-one. The resulting product can be converted to the corresponding 2-substituted benzimidazole derivatives by reaction with a halogenating agent such as POC1 ₃ , where the groups in the 2-position are leaving groups, preferably halo such as chloro or bromo. The product obtained can be further reacted with ammonia to obtain (V).

The above-mentioned N-alkylation is carried out in a suitable solvent, preferably in the presence of a base.

Compounds of formula (I) can be converted to each other via functional group transformations known in the art, including those described below.

R ^2a or R ^3a is C _{1 - 6} alkoxycarbonyl or C _{1 - 6} alkoxy C ₁ substituted with a _{carbonyl-compound} of ₆ alkyl of the formula (I), for example by the use of LiAlH _4, R ^2a or R ^3a has to be reduced to hydroxy-C _{1- 6} alkyl, the above-mentioned compound. The latter group are amine, for example, by reductive amination step, the corresponding mono (derived C _{l - 6} alkyl) -, for which may be further induced to an amine, e.g., using MnO _2, Can be oxidized to aldehyde groups. Alternatively, R ^2a or R ^2b is hydroxy C _{1 -} can be converted to the _6-alkyl compound _{- 6} alkyl, a precursor of the compound of formula (I) is halo C _l corresponding to process the appropriate halogen agent such as SOC1 ₂ Which is then reacted with an amine or an amine derivative.

R ^2a or a compound of formula (I), wherein R ^3a is an aldehyde can Wittig (Wittig) reaction or a Wittig-Horner (Wittig-Horner) by reaction R ^2a or R ^3a is C _{2 - 6} alkenyl, or substituted C _{2 -} it may be converted to the above-mentioned compound ₆ alkenyl al. In the former example, starting with triphenylphosphine and halo derivatives, Wittig-type reagents such as triphenylphosphonifylide in suitable reaction-inert solvents such as ethers are used. The Witig-Honener reaction is a force such as a reagent of the formula di (C _1-6 alkyloxy) -P (= 0) -CH ₂ -CH ₂ -CN in the presence of a base, preferably a strong base, in an aprotic organic solvent. It is performed using fonate.

R ^2a or R ^3a is C _{2 - 6} alkenyl, or substituted C _{2 - 6} alkenyl which compounds include, for example, can be reduced to the saturated alkyl appropriate using hydrogen in the presence of a suitable catalyst such as Raney Ni have.

Compounds of formula (I), in which R ^2a or R ^3a is an aldehyde, may also be derivatized by a reaction of the Grignard type to introduce aryl or alkyl groups.

The nitro group can be reduced to an amino group, which can then be alkylated with a mono- or dialkylamino group or acylated with arylcarbonylamino or alkylcarbonylamino and equivalent groups thereof. Cyano groups can be reduced to aminomethylene groups which can be similarly derivatized.

Many of the intermediates used in the preparation of the compounds of formula (I) are known compounds that can be prepared by the following modifications of known methodologies in the art that are readily available to those skilled in the art or are known Analogues. The preparation of a number of intermediates is described in more detail below.

Intermediates of formula (VII) can be obtained by converting the corresponding alcohols into leaving groups with a suitable alcohol, for example by reaction of an alcohol with SOC1 ₂ . Intermediates of formula (VII), wherein G is a direct bond and R ^l is a radical (c-4) or a similar radical, for example, halogenated reactions of intermediate R ¹ -H with N-bromo succinimide It can be prepared by.

Compounds of formula (I) can be entrapped in the corresponding N-oxide form by methods known in the art for the conversion of trivalent nitrogen to its N-oxide form. The N-oxidation reaction can generally be carried out by reacting a starting material of formula (I) with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides (eg sodium peroxide, potassium peroxide); Suitable organic peroxides are, for example, benzene carboperoxy acid or benzene carboperoxy acid (eg, 3-chlorobenzene carboperoxy acid) substituted with halo, peroxalkanoic acid (eg, peroxacetic acid), Peroxy acids, such as alkylhydroperoxides (eg, t.butyl hydro-peroxide). Suitable solvents include, for example, water, lower alcohols (eg ethanol and equivalents), hydrocarbons (eg toluene), ketones (eg 2-butanone), halogenated hydrocarbons (eg , Dichloromethane), and mixtures of the above solvents.

Pure stereochemical isomers of the compounds of formula (I) can be obtained through methods known in the art. Diastereomers can be separated by physical methods such as selective crystallization and chromatography techniques (eg, counter-current distribution, liquid chromatography and equivalents thereof).

Compounds of formula (I) prepared according to the processes described above are generally racemic mixtures of enantiomers which can be separated from one another by separation methods known in the art. Racemic compounds of formula (I) which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively a chiral base. The diastereomeric salt forms are then separated, for example, by screening or fractional crystallization, and the enantiomers are liberated therefrom by alkali or acid. Alternative ways of separating the enantiomeric forms of the compounds of formula (I) include liquid chromatography, in particular liquid chromatography using chiral stationary phases. The pure stereochemical isomers may be derived from the corresponding pure stereochemical isomers of the suitable starting materials, which provide for the stereospecific reaction to occur. Preferably if specific stereochemical isomers are required, the compounds will be synthesized by stereospecific methods of preparation. The method will usefully use enantiomerically pure starting materials.

In another aspect, the invention provides a pharmaceutical effective amount of a compound of formula (I) as specified herein, or a compound of any of a subgroup of a compound of formula (I) as specified herein, and pharmaceutical It relates to a pharmaceutical composition comprising an acceptable carrier. As used herein, a therapeutically effective amount is an amount sufficient to act prophylactically adversely in order to reduce or stabilize viral infections, particularly RSV viral infections, in infected subjects or at risk of being infected. In another aspect, the present invention provides a method for admixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I) as specified herein or a compound of any of the subgroups of a compound of formula (I) as specified herein. It relates to a method of preparing a pharmaceutical composition as described herein, including.

Therefore, the compounds of the present invention or subgroups thereof can be formulated in various pharmaceutical forms for administration purposes. Any composition commonly used to administer the drug systemically in a suitable composition can be cited. To prepare a pharmaceutical composition of the present invention, in any addition salt form or metal complex, an effective amount of a particular compound, which is an active ingredient, is combined in admixture with a pharmaceutically acceptable carrier, which carrier is a preferred preparation for administration. Depending on the form can take a wide variety of forms. It is preferred that the pharmaceutical composition is in particular a single formulation suitable for oral, rectal, transdermal, or parenteral infusion. For example, in preparing the compositions in oral formulations, conventional pharmaceutical media include oral liquid formulations such as suspensions, syrups, elixirs, emulsions and solutions, for example, water, glycols, oils, Alcohols and their equivalents; Or in the case of powders, pills, capsules, and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants and the like may be used. Because of their ease of administration, when solid pharmaceutical carriers are explicitly used, tablets and capsules represent the most beneficial oral dosage unit form. For non-curable compositions, the carrier will generally comprise sterile water in at least a large portion, for example, through other ingredients that may be included to increase solubility. Injectable solutions can be prepared, for example, in which the carrier comprises saline, glucose solution or a mixture of saline and glucose solution. Injectable suspensions can be prepared such that suitable liquid carriers, suspending agents and equivalents thereof are used. Also included are solid preparations which are simply converted to liquid form preparations before being used. In a composition suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant, which at least partially binds with a suitable additive of any natural product, and the additive does not cause a severely deleterious effect on the skin.

The compounds of the present invention may also be administered via oral inhalation or aeration by means of methods and formulations used in the art for administration by the following means. Therefore, in general, the compounds of the present invention may be administered to the lungs in the form of solutions, suspensions, or dry powders, but solutions are most preferred. Systems developed for the delivery of solutions, suspensions or dry powders via oral inhalation or aeration can be any suitable one for the administration of the compounds of the invention.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suited for a single dosage, wherein each unit containing a predetermined amount of active ingredient is formulated to combine with the required pharmaceutical carrier to produce the desired therapeutic effect. It became. Embodiments of each unit dosage form are tablets (including successful or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and equivalents thereof, and isolated complexes thereof.

Compounds of formula (I) are antiviral. Viral infections that can be treated using the compounds and methods of the present invention include infections caused by ortho- and paramyxoviruses, and specifically include infections caused by human and bovine respiratory syncytial virus (RSV). Include. Moreover, many of the compounds of the present invention have activity against the mutant lineage of RSV. In addition, many of the compounds of the present invention exhibit an advantageous pharmacokinetic profile and include an acceptable half-life, AUC and peak values, but are interesting properties of the concept of bioavailability, which lacks adverse phenomena such as insufficiently fast onset and tissue accumulation. Has

In vitro antiviral activity against RSV of the compounds of the present invention was tested by the assays described in the experimental section of the specification and may be demonstrated in viral yield reduction assays. In vitro antiviral activity against RSV of the compounds of the invention has been demonstrated in test models using cotton rats described in Wyde et al. (Antiviral Research (1998), 38,31-42).

Because of their antiviral, in particular anti-RSV properties, the compounds of formula (I) or subgroups thereof, prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemical isomers are particularly effective for viral infections, in particular It is useful in treating individuals suffering from RSV infection and in preventing such infection. In general, the compounds of the present invention may be useful for treating warm blooded animals infected with viruses, in particular respiratory syncytial virus.

Therefore, the compounds of the present invention or subgroups thereof can be used as medicines. The use as a medicine or method of treatment includes systemic administration to an individual infected with the virus or to an individual susceptible to the virus, in an amount effective to eliminate viral infections, in particular the conditions associated with RSV infection.

The invention also relates to the use of a compound of the invention or a subgroup thereof in the manufacture of a medicament for the treatment and prevention of viral infections, in particular RSV infection.

The invention also relates to a method of treating a warm blooded animal infected with a virus or a warm blooded animal at risk of being infected by a virus, in particular RSV, which method comprises a compound of formula (I) Administering an antiviral effective amount of a compound of any subgroup of the compound of formula (I) specified in the specification.

In general, the antivirally effective daily amount is considered to be 0.01 mg / kg to 500 mg / kg body weight, more preferably 0.1 mg / kg to 50 mg / kg body weight. It is desirable to administer the required dose in 2, 3, 4 or more sub-doses at appropriate intervals throughout the day. Said sub-dose unit dosage forms can be formulated in unit dosage forms containing, for example, 1 to 1000 mg, specifically 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration are well known to those skilled in the art, as well as other medications that the subject may experience, as well as the particular compound of formula (I) used, the particular therapeutic condition, the environment being treated It depends on the severity, age, weight, sex, spread of the disease and the general physical conditions of the particular patient. Moreover, it is apparent that the effective daily amount may be reduced or increased depending on the response of the treated subject and / or the assessment of the clinician prescribing the compound of the present invention. Thus, the range of effective daily amounts described above is only a guideline.

In addition, combinations of other antiviral agents and compounds of formula (I) may be used as medicines. Therefore, the present invention also contains (a) a compound of formula (I) and (b) other antiviral compounds, which are combinations for simultaneous use, individual use, or continuous use in antiviral treatment. It's about products. The other drug may be combined into a single agent with a pharmaceutically acceptable carrier. For example, the compounds of the present invention may be combined with interferon-β or tumor necrosis factor-α to treat or prevent RSV infection.

The following examples are intended to illustrate the invention, but not to limit the scope of the invention. The concepts of 'compound 1', 'compound 4' and the like used in this example refer to the same compound as in the table.

Compounds were analyzed by LC / MS using the following device:

LCT : Electrospray ionization in positive mode, scanning mode 100 to 900 amu;

    Xterra MSC18 (Waters, Milford, Mass.) 5 μm, 3.9 × 150 mm); Flow rate 1 ml / min.

    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) were 100% B (5 minutes) at 100% A (3 minutes) To, 100% B (6 minutes) to 100% A (3 minutes) were used to perform gradient conditions and 100% A (3 minutes) again to equilibrate.

ZQ : electrospray ionization in both positive and negative (pulse) modes scanning at 100-1000 amu; Xterra RP C18 (Waters, Milford, Mass. 5 μm, 3.9 × 150 mm); Flow rate 1 ml / min. 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) were 100% B (5 minutes) at 100% A (3 minutes) To, 100% B (6 minutes) to 100% A (3 minutes) were used to perform gradient conditions and 100% A (3 minutes) again to equilibrate.

Example 1 Preparation of Dimethylbenzimidazol-2-amine

Scheme A

Preparation of Intermediates a-3 and a-4:

A mixture of potassium carbonate (0.0938 mol), a-1 (0.0268 mol), and a-2 (0.0321 mol) in dimethylformamide (100 ml) was stirred at 70 ° C. for 12 hours. The solvent was evaporated. The residue was captured in 2-propanone. The precipitate was filtered off. The solvent of the mother layer was evaporated. The residue (13.6 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 92/8 / 0.5; 20-45 μm). The pure fractions were collected and the solvent was evaporated to give 6.2 g of a mixture of a-3 and a-4 (50/50) (total yield 71%).

Intermediate  Preparation of a-5 and a-6:

At 0 ° C. under nitrogen flow, lithium aluminum hydride (0.0367 mol) was added in portions to a mixture of a-3 and a-4 in tetrahydrofuran (THF) (100 ml). The mixture was stirred at 5 ° C. for 30 minutes and then at room temperature for 2 hours.

Ethyl acetate (5 ml) was added dropwise at 0 ° C., and then H ₂ O (5 ml) was added dropwise. The mixture was filtered over celite. Celite was washed with THF and then with water. The filtrate was extracted with CH ₂ Cl ₂ solution with 10% methanol. The organic layer was dried over magnesium sulphate, filtered and concentrated. The residue (5 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 92/8 / 0.5; 15-40 μm). Two fractions were collected and the solvent was evaporated to yield 1.45 g of a-5 (28%, melting point:> 250 ° C.) and 1.4 g of a-6 (27%, melting point: 222 ° C.).

Intermediate  manufacture of a-7:

MnO ₂ (10 g) was added to a mixture of a-5 (0.0035 mol) in methanol (5 ml) and CH ₂ C1 ₂ / THF (50 ml, 50/50). The reaction was stirred at rt for 3 h and then filtered over celite. Celite was washed with CH ₂ C1 ₂ / methanol (90/10). The filtrate was evaporated to give 0.6 g of a-7 (60%). The product was used directly in the next reaction step.

Intermediate  manufacture of a-8:

The intermediate was prepared analogously to the method for preparing intermediate a-7.

Preparation of Compounds of Formulas a-9 and a-10:

Variant 1 : At room temperature, meta-methylaniline (0.0017 mol) was added to a mixture of a-7 (0.0017 mol) and CH ₂ C1 ₂ (15 ml). The mixture was stirred at rt for 30 min. Acetic acid (0.5 ml) and NaBH ₃ CN (0.0017 mol) were added at room temperature. The reaction mixture was stirred at rt for 5 h, poured into water, saturated with K ₂ CO ₃ and extracted with CH ₂ C1 ₂ . The organic layer was washed with H ₂ O, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (0.45 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 90/10 / 0.5; 15-35 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.26 g, 40%) was crystallized in 2-propanone / diethyl ether. The precipitate was filtered off and dried to give 0.195 g (30%) of 2- [2-amino-6- (m tolylamino-methyl) -benzoimidazol-1-ylmethyl] -6-methyl-pyridin-3-ol , Compound 1, melting point: 234 ° C.) was obtained.

Variant 2 : A mixture of acetic acid (6 drops), a-7 (0.001 mol), meta- (OCF ₃ ) -aniline (0.0015 mol), and supported cyano-borohydride (0.0021 mol) in methanol Stir at room temperature for 48 hours and then filter. The filtrate was evaporated. The residue was captured in CH ₂ C1 ₂ / methanol. The organic layer was washed with K ₂ CO ₃ 10% solution, dried over magnesium sulfate and then filtered to evaporate the solvent. The residue (0.42 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 93/7 / 0.5; 15-35 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.15 g, 32%) was crystallized in CH ₃ CN / methanol. The precipitate was filtered off and dried to give 2- {2-amino-6-[(3-trifluoromethoxy-phenylamino) -methyl] -benzoimidazol-1-ylmethyl} -6-methyl-pyridine- 0.085 g (18%, compound 4, melting point: 156 ° C) of 3-ol were obtained.

Variant 3 : Ortho-methylaniline (0.000265 mol) was added to a solution of a-7 (0.000177 mol) in methanol (7 ml). Then cyano borohydride (0.000265 mol) and acetic acid (3 drops) on a solid support were added. The reaction was carried out for 48 hours at room temperature. Supported reagents were removed by filtration. Triethylamine (0.2 ml) was added to the filtrate. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 90/10 / 0.5; 10 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.050 g, 65%) was crystallized in diisopropyl-ether. The precipitate was filtered off and dried to give 2- [2-amino-6- (o-tolylamino-methyl) -benzoimidazol-1-ylmethyl] -6-methyl-pyridin-3-ol acetic acid salt 0.027 g (35%, compound 8, melting point: 120 ° C) was obtained.

Example 2 Preparation of 6-Aminomethyl Substituted Benzimidazol-2-amines

Scheme B

Intermediate  Preparation of b-2:

At 5 ° C., SOC1 ₂ (0.0021 mol) was added dropwise to a solution of f-1 (0.0014 mol) in CH ₂ C1 ₂ (10 ml). The mixture was stirred at rt for 4 h. The precipitate was filtered off, washed with CH ₂ C1 ₂ , then with diisopropyl ether and dried to give 0.49 g of b-2 (100%).

Preparation of a compound of formula b-3:

Variant 1 : A mixture of potassium carbonate (0.003 mol), b-2 (0.0008 mol), and (N-ethanol) -meth-methylaniline (0.0013 mol) in dimethylformamide (5 ml) at 80 ° C Stir for 12 h, then pour into water and extract with CH ₂ C1 ₂ . The organic layer was washed with water, dried over magnesium sulfate and then filtered to evaporate the solvent. The residue (0.4 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 93/7 / 0.5; 15-35 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.13 g, 35%) was crystallized in methanol. The precipitate was filtered off and dried to give 2- (2-amino-6-{[(2-hydroxy-ethyl) -m-tolyl-amino] -methyl} -benzoimidazol-1-ylmethyl) -6 0.06 g (16%, compound 129, melting point: 210 ° C) -methyl-pyridin-3-ol were obtained.

Variant 2 :

a) 3-bromo-butyric acid ethyl ester (0.029 mol) and triethylamine (0.0436 mol) were added to a solution of 3-bromo-aniline (0.029 mol) in toluene (50 ml). The reaction was stirred at reflux for 12 h and then cooled to room temperature. The precipitate was removed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: cyclohexane: AcOEt 80/20; 20-45 μm). Pure fractions were collected and the solvent was evaporated to give 5 g of 4- (3-bromo-phenylamino) -butyric acid ethyl ester (60%, melting point: 65 ° C.).

b) LiAIH in tetrahydrofuran (15 ml) with 4- (3-bromo-phenylamino) -butyric acid ethyl ester (0.00524 mol) in tetrahydrofuran (15 ml) at 5 ° C. under N ₂ flow. _To the slurry of ₄ was added dropwise. The reaction was stirred at 5 ° C. for 1 hour. Ethyl acetate and water were carefully added. The reaction was extracted with a CH ₂ C1 ₂ / methanol (90/10) mixture. The organic layer was separated and dried (phase MgSO ₄ ) and filtered. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 96/4 / 0.3; 15-40 μm). Pure fractions were collected and the solvent was evaporated to give 0.76 g of 4- (3-bromophenylamino) -butan-1-ol (60%).

c) 2- (2-amino-6-{[(3-bromo-phenyl)-(4-hydroxy-butyl) -amino] -methyl}-benzoimidazol-1-ylmethyl) -6-methyl -Pyridin-3-ol (compound 139, melting point: 120 ° C gum) is a method similar to the method described in Variant 1 for the synthesis of compound b-3, with 4- (3-bromo-phenylamino) -butane-1 Synthesized starting with -ol.

Variant 3 :

a) A mixture of saturated solution of NH ₃ in methanol (15 ml) and 3- (3-bromo-aniline) -propionic acid ethyl ester (0.0037 mol) was placed in a PARR apparatus and heated at 80 ° C. for 12 hours. . The reaction was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: cyclohexane: ethyl acetate 80/20; 20-45 μm). Pure fractions were collected and the solvent was evaporated to give 0.75 g of 3- (3-bromo-phenylamino) -propionamide (83%).

b) 3-[[2-amino-3- (3-hydroxy-6-methyl-pyridin-2-ylmethyl) -3H-benzoimidazol-5-yl-methyl] -3 bromo-phenyl) -Amino] -propionamide (Compound 137, Melting Point: 245 ° C.) is similar to the method described in Variation 1 for the synthesis of Compound b-3, starting at 3- (3-bromo-phenylamino) -propionamide Synthesis was carried out.

Variant 4 :

a) K 2 CO 3 (0.0109 mol) and 4- (2-chloro-ethyl) -morpholine (1 HC1) (0.0036 mol) were added to a solution of 2-ethanol-aniline (0.0036 mol) in CH ₃ CN (15 ml). Added. The reaction was stirred at 80 ° C. for 24 hours and then cooled to room temperature. The precipitate was filtered off and washed with CH ₃ CN. The solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 98/2 / 0.1; 35-70 μm). Pure fractions were collected and the solvent was evaporated to give 0.7 g of 2- [2- (2-morpholin-4-yl-ethylamino) -phenyl] -ethanol (77%).

b) 2- (2-amino-6-{[[2- (2-hydroxy-ethyl) -phenyl]-(2-morpholin-4-yl-ethyl) -amino] -methyl} -benzoimidazole -l-ylmethyl) -6-methyl-pyridin-3-ol (compound 160, melting point: 184 ° C.) is a method similar to the method described in variant 1 for the synthesis of compound b-3, using 2- [2- ( It was synthesized starting from 2-morpholin-4-yl-ethylamino) -phenyl] -ethanol.

Variant 5 :

3-{[2-amino-3- (3-hydroxy-6-methyl-pyridin-2-ylmethyl) -3H-benzoimidazole in a mixture of tetrahydrofuran (10 ml) and water (10 ml) To a solution of -5-ylmethyl] -m-tolyl-amino} -propionic acid ethyl ester (0.000464 mol) was added lithium hydroxide hydrate (0.00093 mol). The reaction was stirred at rt for 12 h. Tetrahydrofuran was removed under reduced pressure and the solution acidified to pH 4 with HCl IN solution in water. The precipitate was filtered off, washed with water, then washed with diethyl ether and dried, 3-{[2-amino-3- (3-hydroxy-6-methyl-pyridin-2-ylmethyl) -3H 0.157 g of -benzoimidazol-5-ylmethyl] -m-tolyl-amino} -propionic acid (76%, compound 161, melting point: 165 ° C) was obtained.

Variant 6 :

a) a mixture of K ₂ CO ₃ (0.0048 mol), b-2 (0.0016 mol), and N- (ethylamino-Boc) -meth-methylaniline (0.0016 mol) in dimethylformamide (10 ml) was added to 80 Stir at 12 ° C. for 12 h. The reaction was poured into water and extracted with CH ₂ C1 ₂ / methanol. The organic layer was washed with water, dried over magnesium sulfate and then filtered to evaporate the solvent. The residue (4 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 95/5 / 0.5; 10 μm). The pure fractions were collected and the solvent was evaporated to yield 2- {2-amino-6-[(propyl-m-tolyl-amino) -methyl] -benzoimidazol-1-yl-methyl} -6-methyl-pyridine- 0.1 g (13%) of 3-ol (b-4) was obtained.

b) At room temperature, a solution of HCl 5-6N in 2-propanol (0.5 ml) was added to a mixture of b-4 (0.0002 mol) in 2-propanol (15 ml). The mixture was stirred at 60 ° C. for 2 hours and then cooled to room temperature. The precipitate was filtered off, washed with diethyl ether and dried to give 2- (2-amino-6-{[(2-amino-ethyl) -m-tolyl-amino] -methyl} -benzoimidazole- 0.075 g (65%, compound 131, melting point: 200 ° C) of I-ylmethyl) -6-methyl-pyridin-3-ol HCl salt were obtained.

Example 3 : Synthesis of 5- and 6-formyl Substituted Benzimidazol-2-amines

Scheme C

Intermediate  Preparation of c-3 and c-4:

At room temperature, intermediate c-2 (0.051 mol) was added to a mixture of K ₂ CO ₃ (0.053 mol) and intermediate c-1 (0.051 mol) in DMF (150 ml). The mixture was stirred at rt for 24 h. The solvent was evaporated. The residue was captured in CH ₂ C1 ₂ . The organic layer was washed with H ₂ 0, saturated with NaCl, dried (over MgSO ₄ ) and filtered to evaporate the solvent. The residue (24 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 96/4 / 0.1; 20-45 μm). Pure fractions were collected and the solvent was evaporated to give: 13.4 g of intermediate c-3 + c-4 (63%).

Intermediate  Preparation of c-5 and c-6:

At 5 ° C. under N ₂ flow, LiAlH ₄ (0.0619 mol) was added in portions to a mixture of c-3 + c-4 (0.031 mol) in THF (150 ml). The mixture was stirred at 5 ° C. for 30 minutes and then at room temperature for 2 hours. H ₂ 0 (10 ml) was carefully added dropwise at 0 ° C. EtOAc (100 ml) was added. The mixture was filtered over celite. Celite was washed with EtOAc and then with CH ₂ C1 ₂ / CH ₃ 0H. The filtrate was evaporated. The residue was captured in CH ₂ C1 ₂ / CH ₃ 0H. The organic layer was washed with H ₂ O, dried (MgSO ₄ phase), filtered and the solvent was evaporated. The residue (10.2 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 94/6 / 0.5; 15-40 μm). Pure fractions were collected and the solvent was evaporated to give: 3 g of intermediate c-5 (26%, melting point: 216 ° C.) and intermediate c-6 (20%).

Intermediate  Preparation of c-Z:

CH ₂ C1 ₂ at room temperature To a mixture of c-5 (0.008 mol) in (200 ml) MnO ₂ (20 g) was added in portions. The mixture was stirred at rt for 4 h and then filtered over celite. Celite was washed with CH ₂ C1 ₂ / CH ₃ 0H (70/30). The filtrate was evaporated. Yield: intermediate c-7 (89%, melting point: 199 ° C.) 2.65 g.

Intermediate  manufacture of c-8:

The intermediate was synthesized according to the method described for intermediate c-7.

Example 4 Synthesis of Hydroxymethylene Substituted Benzimidazol-2-amines

Scheme D

Intermediate  Preparation of d-3:

A mixture of NEt ₃ (0.0584 mol), d-1 (0.0292 mol), and d-2 (0.0438 mol) in CH ₃ CN (150 ml) was stirred and refluxed for 12 hours, then cooled to room temperature, solvent Was evaporated. The mixture was poured into water and extracted with EtOAc. The organic layer was separated and dried (phase MgSO ₄ ), filtered and the solvent was evaporated. The residue (12.5 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / EtOAc 96/4, 20-45 μm). Yield: intermediate d-3 (45%, melting point: 140 ° C.) 2 g.

Intermediate  Manufacture of d-4:

A mixture of Raney nickel (3 g) and d-3 (0.0081 mol) in CH ₃ 0H (100 ml) was hydrogenated at room temperature for 2 hours and then filtered over celite. Celite was washed with CH ₃ 0H. The filtrate was concentrated to give 2.9 g of intermediate d-4 (100%).

Intermediate  Preparation of d-5:

A mixture of BrCN (0.0091 mol) and b-4 (0.0083 mol) in EtOH (50 ml) was stirred for 1 hour and refluxed, then cooled to room temperature and the solvent was evaporated. The residue was captured in CH ₂ C1 ₂ . The organic layer was washed with 10% solution of K ₂ CO ₃ , dried (on MgSO ₄ ), filtered and the solvent was evaporated. The residue (3 g) was crystallized in CH ₃ CN. The precipitate was filtered off and dried to give 2.2 g of intermediate d-5 (71%).

Example 5 Synthesis of Arylamino Substituted Benzimidazol-2-amines

Scheme E

3- (4- methyl 2-nitro- Phenyl ) - Prof -2-ene-l-ol, Intermediate  Preparation of (e-2):

Dibal-H (0.0255 mol) was added to a mixture of 3- (4-methyl-2-nitro-phenyl) -acrylic acid ethyl ester (0.0085 mol) in THF (80 ml) dp under N ₂ flow. . The mixture was stirred at -35 ° C for 15 minutes. H ₂ 0 (20 ml) was added dropwise at −35 ° C. under a N ₂ flow. Half of the mixture was evaporated. CH ₂ Cl ₂ was added. The mixture was filtered over celite. Celite was washed with CH ₂ Cl ₂ . The filtrate was washed with H ₂ O. The organic layer was separated, dried (MgSO ₄ phase), filtered and the solvent was evaporated. Yield: 2 g of 3- (4-methyl-2-nitro-phenyl) -prop-2-en-1-ol (e-2) (100%).

Intermediate  3- (2-amino-4- methyl - Phenyl ) - Propane Preparation of -1-ol (e-3):

Under pressure of 3 bar, Raney nickel (1.6 g) and 3- (4-methyl-2-nitro-phenyl) -prop-2-en-1-ol (e-2) in MeOH (30 ml) ( 0.0085 mol) of the mixture was hydrogenated at room temperature for 2 hours and then filtered over celite. Celite was washed with CH ₃ 0H. The filtrate was evaporated. Yield: 1.7 g of 3- (2-amino-4-methyl-phenyl) -propan-1-ol (e-3) (86%, melting point: 65 ° C.).

Intermediate  Manufacture of e-5:

At room temperature, AcOH (10 drops) in a mixture of 3- (2-amino-4-methyl-phenyl) -propan-l-ol (e-3) and e-4 (0.0035 mol) in MeOH (50 ml) Was added followed by BH ₃ CN (0.007 mol) on a solid support. The mixture was filtered and then washed with CH ₃ 0H. The filtrate was evaporated. The residue was captured in CH ₂ C1 ₂ / CH ₃ 0H. The organic layer was washed with 10% K ₂ CO ₃ , dried (on MgSO ₄ ), filtered and the solvent was evaporated until dry. The residue (2.7 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ OH 95/5 / 0.1). Pure fractions were collected and the solvent was evaporated. Yield 1.3 g (71%). The fraction was crystallized in 2-propanone / diethyl ether. The precipitate was filtered off and dried. Yield: 0.026 g of intermediate e-5 (Compound 128, Melting Point: 129 ° C).

Preparation of the final compound e-6:

A mixture of Pd / C (0.3 g) and e-5 in CH ₃ OH (60 ml) was hydrogenated at room temperature for 1 hour, hydrogenated at 1 bar for 30 minutes and then filtered over celite. Celite was washed with CH ₃ 0H. The filtrate was evaporated. The residue (1.1 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ OH 90/10 / 0.1; 15-40 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.88 g) was crystallized in 2-propanone / diethyl ether. The precipitate was filtered off and dried. Yield: 0.735 g of final compound e-6 (68%, compound 90, melting point: 248 ° C).

Example 6 Synthesis of Arylamino Substituted Benzimidazol-2-amines

Scheme F

Intermediate  2- (4- Bromo 2-nitro- Phenyl Preparation of) -ethanol (f-2):

A mixture of para-formaldehyde (0.009 mol) and 4-bromo-1-methyl-2-nitro-benzene (f-1) (0.01134 mol) in Triton-B (0.35 ml) and DMSO (5 ml) Stir at 50 ° C. for 2 hours, then cool to room temperature and purify by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 98.5 / 1.5; 35-70 μm). Pure fractions were collected and the solvent was evaporated. Yield: 1.18 g of 2- (4-bromo-2-nitro-phenyl) -ethanol (f-2) (42%).

Intermediate  2- (2-amino-4- Bromo - Phenyl Preparation of) -ethanol (f-3):

Under pressure of 3 bar, Raney nickel (0.5 g) and 2- (4-bromo-2-nitro-phenyl) -ethanol (f-2) (0.00203) in thiophene (0.5 ml) and MeOH (20 ml) mol) mixture was stirred at room temperature for 2 hours and then filtered over celite. Celite was washed with CH ₃ OH. The filtrate was concentrated. Yield: 1.7 g of 2- (2-amino-4-bromo-phenyl) -ethanol (f-3) (91%).

Preparation of the final compound f-5 (Compound 93):

The compound was synthesized according to the method described for compound e-5.

Example 7 Synthesis of Ethynylphenylamino Substituted Benzimidazol-2-amines

Scheme G

Intermediate  Preparation of g-2:

Diisopropyl-ethylamine (23.5) in a mixture of Cul (0.0002 mol), g-1 (0.0047 mol), and Pd (PPh ₃ ) ₂ Cl ₂ (0.0002 mol) in THF (50 ml) under N ₂ flow m1) was added dropwise. Ethynyl-trimethyl-silane (0.0095 mol) was added dropwise at room temperature. Under N ₂ flow, the mixture was stirred at 50 ° C. for 12 h, poured into H ₂ 0 and extracted with EtOAc. The organic layer was washed with H ₂ O, dried (on MgSO ₄ ), filtered and the solvent was evaporated. The residue (3.1 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H 99/1). Pure fractions were collected and the solvent was evaporated. Yield: 1 g of intermediate c-2 (80%).

Intermediate  manufacture of g-3:

At 0 ° C., TiCl ₃ (0.0334 ml) was added dropwise to a mixture of g-2 (0.0041 mol) in THF (50 ml). The mixture was stirred at rt for 12 h. EtOAc was added. The mixture was washed several times with H ₂ O, washed with K ₂ CO ₃ 10%, which was then finally washed with H ₂ O. The organic layer was separated, dried (MgSO ₄ phase), filtered and the solvent was evaporated. Yield: 0.8 g of intermediate g-3 (84%).

Intermediate  manufacture of g-4:

A mixture of K ₂ CO ₃ (0.0066 mol) and g-3 (0.0022 mol) in H ₂ O (4 ml) and CH ₃ OH (20 ml) was stirred at room temperature for 2 hours. The solvent was evaporated until dryness. The residue was captured at CH ₂ Cl ₂ / H ₂ 0. The organic layer was washed with H ₂ O, dried (MgSO ₄ phase), filtered and the solvent was evaporated to give: 0.29 g of intermediate g-4 (81%).

Preparation of the final compound g-6:

The compound was synthesized according to the method described for compound c-5 (yield 33%, compound 92, melting point: 252 ° C.).

Example 8 Synthesis of Alkylsulfonylphenylamino Substituted Benzimidazol-2-amines

Scheme H

Intermediate  Preparation of h-2:

A mixture of K ₂ CO ₃ (0.0139 mol), h-1 (0.0092 mol), and 2-mercapto-ethanol (0.0102 mol) in CH ₃ CN (50 ml) was stirred and refluxed for 6 hours, then H Poured into ₂ 0 and extracted with EtOAc. The organic was washed with H ₂ O, dried (MgSO ₄ phase), filtered and the solvent was evaporated. Yield: 2.1 g of intermediate h-2 (100%). The fraction was used directly in the next reaction step.

Intermediate  manufacture of h-3:

A mixture of Raney nickel (2 g) and h-2 (0.0098 mol) in CH ₃ 0H (50 ml) was hydrogenated at room temperature under a pressure of 3 bar for 1 hour and then filtered over celite. Celite was washed with CH ₃ 0H. The filtrate was evaporated. Yield: 1.5 g of intermediate h-3 (83%).

Intermediate  manufacture of h-4:

At 0 ° C., sodium perborate (NaB0 ₃ , 0.005 mol) was added portionwise to AcOH (5 ml) in a mixture of h-3 (0.0025 mol). The mixture was stirred at rt for 12 h, poured into ice, basified with K ₂ CO ₃ and extracted with EtOAc. The organic layer was separated and dried (phase MgSO ₄ ), filtered and the solvent was evaporated until dryness. The residue (0.46 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ 0H 98/2; 10 μm). Pure fractions were collected and the solvent was evaporated. Yield: 0.16 g of intermediate h-4 (30%).

Preparation of the final compound h-6 (Compound 100, Melting Point:> 260 ° C.):

The compound was synthesized according to the method described for compound e-6.

Example 9 Synthesis of Phenylamino Substituted Benzimidazol-2-amines

Scheme I

Intermediate  Preparation of i-2:

A mixture of i-1 (0.0185 mol) and H ₂ SO ₄ 36N (5 ml) in ethanol (60 ml) was stirred for 24 hours and refluxed. The solvent was evaporated. The residue was captured in CH ₂ Cl ₂ . The organic layer was washed with a 10% solution of K ₂ CO ₃ in water, dried over magnesium sulfate, filtered and the solvent was evaporated to give 3.2 g of i-2 (89%). The crude fraction was used directly in the next step.

Intermediate  Manufacture of i-3:

A mixture of BrCN (0.0158 mol) and i-2 (0.0144 mol) in ethanol (30 ml) was stirred for 2 hours and refluxed. The solvent was evaporated. The residue was captured in a 10% solution of K ₂ CO ₃ in water and then extracted with CH ₂ Cl ₂ / methanol. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated to yield 2.3 g of i-3 (73%). The crude fraction was used directly in the next step.

Intermediate  Manufacture of i-5:

A mixture of K ₂ CO ₃ (0.0335 mol), c-3 (0.0095 mol), and i-4 (0.0115 mol) in dimethyl-formamide (50 ml) was stirred at 70 ° C. for 12 hours and then allowed to room temperature. Cool and select in 2-propanone. The precipitate was filtered off and then washed with 2-propanone. The filtrate was evaporated. The residue (4.5 g) was crystallized in CH ₂ Cl ₂ / methanol. The precipitate was filtered off and dried to give 2.4 g of c-5 (74%, melting point:> 250 ° C.).

Intermediate  Manufacture of i-6:

At 5 ° C. under nitrogen flow, LiAlH ₄ (0.0106 mol) was added in portions to a mixture of i-5 (0.0052 mol) in THF (50 ml). The reaction was stirred at 5 ° C. for 30 minutes and then at room temperature for 6 hours. Water was added carefully. The mixture was filtered through a pad of celite. The pad was washed with water and then with THF. The filtrate was evaporated. The residue was captured in CH ₂ Cl ₂ / methanol. The organic layer was separated, dried over magnesium sulphate and filtered to evaporate the solvent to give 1.7 g of i-6 (100%).

Intermediate  Manufacture of i-7:

At room temperature, Mn0 ₂ (4 g) was added in portions to a mixture of i-6 (0.0013 mol) in methanol (2 ml) and CH ₂ Cl ₂ (20 ml). The reaction was stirred at room temperature for 30 minutes and then filtered through a pad of celite. The pad was washed with CH ₂ Cl ₂ / methanol. The filtrate was evaporated to give 0.5 g of i-7 (69%).

Preparation of Compound i-8:

A mixture of acetic acid (6 drops), i-7 (0.0006 mol), m-methylaniline (0.0008 mol), and supported cyano-borohydride (0.001 mol) in methanol (20 ml) was prepared at room temperature 48. Stir for hours, then filter and wash with CH ₂ Cl ₂ / methanol. The filtrate was evaporated. The residue (0.32 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol NH ₄ OH 90/10 / 0.5; 10 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.054 g, 31%) was crystallized in diethyl ether. The precipitate was filtered off and dried to give 2- [2-amino-4-methyl-6- (m-tolylamino-methyl) -benzoimidazol-1-ylmethyl] -6-methyl-pyridin-3-ol 0.036 g (21%) was obtained.

Example 10 Synthesis of Aminoalkyl Substituted Benzimidazol-2-amines

Scheme J

Intermediate  Preparation of j-2:

At 5 ° C. under a nitrogen stream, diethylcyanomethyl phosphonate (0.0021 mol) was added dropwise to a solution of NaH (0.0043 mol) in THF (10 ml). The mixture was stirred at 5 ° C. under nitrogen flow for 30 minutes. j-1 (0.0007 mol) was added in portions. The mixture was stirred at 5 ° C. for 1 hour and then at room temperature for 12 hours and poured onto ice. The aqueous layer was saturated with K ₂ CO ₃ and extracted with CH ₂ Cl ₂ / methanol. The organic layer was separated, dried over magnesium sulphate and filtered to evaporate the solvent to give 0.5 g of j-2 (100%). The crude product was used directly in the next reaction step.

Intermediate  Manufacture of j-3:

A mixture of Pd / C (0.1 g) and j-2 (0.0007 mol) in methanol (20 ml) was hydrogenated at room temperature under a pressure of 3 bar for 12 hours and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol / NH ₄ OH 90/10 / 0.5; 15-40 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.25 g, 100%) was crystallized in CH ₃ CN / diisopropyl ether. The precipitate was filtered off and dried to afford 0.055 g of j-3 (25%, compound 198, melting point: 242 ° C.).

Preparation of Compound j-4:

Methanol / NH ₃ A mixture of Raney nickel (0.2 g) and j-3 (0.0006 mol) in 7N (30 ml) was hydrogenated at room temperature under a pressure of 3 bar for 12 hours and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated. The residue was dissolved in isopropanol / HCl and converted to hydrochloride salt. The precipitate was filtered off and dried to afford 0.058 g of j-4 (22%, compound 196, melting point: 195 ° C.).

Example 11 Synthesis of Dimethyl Substituted Benzimidazol-2-amines

Scheme K

A mixture of K ₂ CO ₃ (0.0183 mol), f-1 (0.031 mol), and k-2 (0.0372 mol) in dimethyl-formamide (150 ml) was stirred at 70 ° C. for 24 hours. The solvent was evaporated. The residue was captured in CH ₂ Cl ₂ . The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated. The residue (12 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol / NH ₄ 0H 90/10 / 0.5; 20-45 μm). Pure fractions were collected and the solvent was evaporated. Residue (6.8 g, 78%) crystallized in CH ₃ CN / diisopropyl ether. The precipitate was filtered off and dried to afford 0.506 g of k-3 (Compound 199, Melting Point:> 260 ° C).

Example 12 Synthesis of Phenyl (hydroxymethyl) Substituted Benzimidazol-2-amines

Scheme L

Under nitrogen flow, bromobenzene (0.0026 mol) was added dropwise to a mixture of magnesium (0.0026 mol) in THF (3 ml). The mixture was stirred at room temperature under a nitrogen stream until magnesium disappeared. 1-1 (0.0002 mol) was added in portions. The mixture was stirred at rt for 2 h. At 0 ° C., NH ₄ C1 10% solution in water (3 ml) was added dropwise. The mixture was extracted with CH ₂ C1 ₂ . The organic layer was separated, dried over magnesium sulphate and filtered to evaporate the solvent. The residue (0.2 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / methanol / NH ₄ OH 90/10 / 0.5; 5 μm). Pure fractions were collected and the solvent was evaporated to afford 0.035 g of l-2 (Compound 197, 36%).

Example 13 : Synthesis of 1- (pyridinylmethyl) -6-benzoylamido-benzimidazole

Scheme M

Intermediate  Preparation of mixtures of m-3 and m-4:

To a mixture of K ₂ CO ₃ (0.107 mol) and m-1 (0.03 mol) in CH ₃ CN (200 ml) was added m-2 (0.0368 mol). The reaction was stirred for 12 hours and refluxed. The solvent was evaporated. The residue was captured in CH ₂ Cl ₂ . The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated to give 15.5 g (100%) of a mixture of m-3 and m-4.

Intermediate  Preparation of m-5 and m-6:

A mixture of Raney nickel (1 g) and m-3 and m-4 (0.03 mol) in methanol (200 ml) was hydrogenated for 1 hour at room temperature under a pressure of 3 bar and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated. The residue (12 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol / NH ₄ OH 97/3 / 0.1; 20-45 μm). Pure fractions were collected and the solvent was evaporated to give 5 g of m-5 (48%) and 4.8 g of m-6 (45%).

Intermediate  Manufacture of m-7:

At room temperature, benzoic acid (0.0005 mol) in a mixture of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0006 mol) and m-5 (0.0005 mol) in CH ₂ Cl ₂ (5 ml). ) Was added. The reaction was stirred at rt for 12 h and poured into water. The organic layer was separated, dried over magnesium sulphate and filtered to evaporate the solvent to give 0.27 g of m-7 (100%). The crude compound was used in the next reaction step.

Preparation of Compound m-8:

A mixture of Pd / C (0.05 g) and m-7 (0.0005 mol) in methanol (30 ml) was hydrogenated for 8 hours at room temperature under a pressure of 5 bar and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated. The residue (0.42 g) was purified by column chromatography (eluent: CH ₂ Cl ₂ / methanol / NH ₄ OH 95/5 / 0.5; 10 μm). Pure fractions were collected and the solvent was evaporated. The residue (0.09 g, 43%) was crystallized in ethanol. The precipitate was filtered off and dried to give 0.057 g of m-8 (27%, compound 198, melting point:> 250 ° C).

Example 14 Synthesis of l- (pyridylmethyl) 5- and 6-formyl-benzimidazole

Scheme N

Intermediate  Preparation of a mixture of n-3 and n-4:

A mixture of K ₂ CO ₃ (0.02455 mol), n-1 (0.0708 mol), and n-2 (0.077 mol) in dimethyl-formamide (130 ml) was stirred at 70 ° C. for 24 hours. The solvent was evaporated. The residue was captured in CH ₂ Cl ₂ . The organic layer was washed with water, dried over magnesium sulphate and filtered to evaporate the solvent. The residue was captured in acetone. The precipitate was filtered off and dried to give 16.2 g of a mixture of n-3 and n-4 (74%).

Intermediate  Preparation of n-5 and n-6:

At 5 ° C. under a nitrogen stream, LiAlH ₄ (0.052 mol) was added in portions to a mixture of n-5 and n-6 (0.026 mol) in THF (160 ml). The reaction was stirred at 5 ° C. for 2 hours. Ethyl acetate and water were added carefully. The mixture was filtered through a pad of celite. The pad was washed with water and then with THF. The filtrate was evaporated. The residue was selected for CH ₂ Cl ₂ / methanol. The organic layer was separated, dried over magnesium sulphate and filtered to evaporate the solvent to give 13 g (92%) of a mixture of n-5 and n-6. Two compounds were separated via column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol / NH ₄ OH 90/10 / 0.5; 10 μm).

Intermediate  Manufacture of n-7:

MnO ₂ (36 g) was added to a mixture of n-5 (0.014 mol) in CH ₂ Cl ₂ / THF (400 ml) and methanol (20 ml). The reaction was stirred at rt for 3 h and then filtered through a pad of celite. The pad was washed with CH ₂ Cl ₂ / methanol. The filtrate was evaporated to give 3.5 g of n-7 (93%). The product was used directly in the next reaction step.

Intermediate  Manufacture of n-9:

At 5 ° C. under a nitrogen stream, diethylcyanomethyl phosphonate (0.0033 mol) was added dropwise to a mixture of NaH (0.0011 mol) in THF (15 ml). The mixture was stirred at 5 ° C. under nitrogen flow for 30 minutes. At 5 ° C., a solution of n-7 (0.0011 mol) in THF (15 ml) was added dropwise. The reaction was stirred at 5 ° C. for 1 hour, then at room temperature for 2 hours and poured into water. The aqueous layer was saturated with K ₂ CO ₃ and extracted with ethyl acetate / methanol. The organic layer was separated, dried over magnesium ulphate and filtered to evaporate the solvent to give n-9 (100%, compound 189, melting point:> 250 ° C., mixture E / Z (90/10)) lg. Obtained.

Intermediate  Manufacture of n-10:

A mixture of Pd / C (0.l g) and n-9 (0.0007 mol) in methanol (15 ml) was hydrogenated at room temperature under a pressure of 3 bar for 12 hours and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated to give 0.2 g of n-10 (91%). The crude product was used directly in the next reaction step.

Preparation of Compound n-11:

A mixture of Raney nickel (0.2 g) and n-10 (0.0006 mol) in methanol / NH ₃ 7N (20 ml) was hydrogenated at room temperature under a pressure of 3 bar for 4 hours and then filtered through a pad of celite. The pad was washed with methanol. The filtrate was evaporated. The residue (0.33 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / methanol / NH 4 OH 85/14/1; 15-35 μm), n-11 (72%) of free base 0.128 g was obtained. The compound was dissolved in CH ₃ CN and converted to ethanedioic acid salt. The precipitate was filtered off and dried to give 0.031 g of n-11 (10%, compound 188, melting point: 205 ° C).

Example 15 Synthesis of 1- (pyridylmethyl) -6-aminomethylbenzimidazole

Scheme 0

To a solution of o-1 (0.187 mmol) in methanol (5 ml) was added meta-chloroaniline (0.000224 mol). Then cyano borohydride (0.224 mmol) and acetic acid (1 drop) on solid support were added. The reaction was carried out for 48 hours at room temperature. Supported reagents were removed by filtration. The solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ 0H / NH ₄ OH 90/10 / 0.5; 10 μm). Pure fractions were collected and the solvent evaporated to 0.044 g of 2- {6-[(3-chloro-phenylamino) -methyl] -benzoimidazol-1-ylmethyl} -6-methyl-pyridin-3-ol ( 62%, compound 186) were obtained.

Example 16 Synthesis of 1- (pyridylmethyl) -6-aminomethyl-benzimidazol-2-amine

Scheme P

Intermediate  Preparation of p-3:

Intermediate p-3 was prepared from p-1 and p-2 (same as k-2) following the same method as for preparing k-3.

Intermediate  Preparation of p-5 and p-6:

From 5 ℃ under N2 flow, tetrahydrofuran (50 ml) for all p-3 and p-4; LiAlH To a solution of (0.00494 mol intermediates c-3 and c-4 Intermediates similarly manufactured with) ₄ ( 0.0198 mol) was added in portions. The reaction was stirred at 5 ° C. for 30 minutes and then at 40 ° C. for 12 hours. The reaction was cooled to 5 ° C. and ethyl acetate and water were added very carefully drop by drop. The solution was filtered over celite. The pad was washed with water and tetrahydrofuran. The solution was saturated with K ₂ CO ₃ powder and extracted with CH ₂ Cl ₂ / methanol (90/10) mixture. The organic layer was separated, dried (phase MgSO ₄ ) and evaporated to dryness. Two isomers were separated via column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH / NH ₄ OH 90/10/1; 15-40 μm). Pure fractions were collected and the solvent was evaporated to yield 0.21 g of p-5 (14%, melting point:> 260 ° C.) and 0.35 g of p-6 (24%, melting point:> 260 ° C.).

Intermediate  Preparation of p-7 and Compound p-8:

In a similar manner to the preparation of the compound of formula b-3, 2- (6-{[(2-hydroxy-ethyl) -m-tolyl-amino] -methyl} -2-methylamino-benzoimidazole-l- To prepare monomethyl) -6-methyl-pyridin-3-ol (compound 188, melting point: 204 DEG C), 2- (6-chloromethyl-2-methylamino-benzoimidazol-1-yl as starting material Methyl) -6-methyl-pyridin-3-ol hydrochloride salt (prepared similar to the preparation of intermediate b-2) was used.

Example 17 Synthesis of l-quinolylmethyl-6-aminomethylbenzimidazol-2-amine

Scheme Q

Synthesis of Intermediates q-5 and q-6:

The intermediate was synthesized similar to the method described for intermediates c-5 and c-6. Separation of the two isomers was carried out via column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ 0H / NH ₄ 0H 92/8 / 0.5; 15-40 μm). Pure fractions were collected and the solvent was evaporated to afford (2-amino-3-quinolin-8-ylmethyl-3H-benzoimidazol-5-yl) -methanol (q-5, 18%, compound 222, melting point: 230 0.43 g) and 0.24 g (2-amino-1-quinolin-8-ylmethyl-1H-benzo imidazol-5-yl) -methanol (q-6, compound 224, 10%, melting point:> 260 ° C.) Obtained.

Intermediate  Preparation of q-7 and Compound q-8:

In a similar manner to the preparation of the compound of d-3, 3-[(2-amino-3-quinolin-8-ylmethyl-3H-benzoimidazol-5-ylmethyl) -m-tolyl-amino] -propane- 6-chloromethyl-1-quinolin-8-ylmethyl-1H-benzoimidazol-2-ylamine hydrochloride salt (intermediate d-2) for the preparation of 1-ol (compound 222, melting point: 191 ° C.) Prepared in analogy to the preparation of) as a starting material.

Example 18 Synthesis of Bicyclic Intermediate R ^l -GW

Scheme R

A mixture of benzoyl peroxide (0.0017 mol), 2,3-dimethyl-5,6,7,8-tetrahydro-quinoxaline (0.0198 mol), and NBS (0.0198 mol) in CC1 ₄ (237 ml) Stir for 30 minutes, reflux and filter. The filtrate was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 100/0 and 95/5; 35-70 μm). Pure fractions were collected and the solvent was evaporated. Yield: 2.61 g of intermediate r-2 (55%).

Example 19 Synthesis of Intermediate R ¹ -GW

Scheme S

Intermediate Synthesis of -2:

NaH (0.054 mol) was added in portions to a mixture of lH-benzoimidazole-4-carboxylic acid ethyl ester (0.045 mol) in DMF (50 ml) at 5 ° C. under N ₂ flow. The mixture was stirred at 0 ° C. under N ₂ flow for 1 h. At 0 ° C. under N ₂ flow, CH ₃ I (0.045 mol) was added dropwise. The mixture was stirred at room temperature under N ₂ flow for 2 hours, hydrolyzed with ice water and then extracted with CH ₂ C1 ₂ . The organic layer was separated, washed several times with H 2 O, dried (MgSO ₄ Phase), and then the solvent is evaporated. The residue (10.5 g) was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ 0H 97/3; 20-45 μm). Two pure fractions were collected and the solvent was evaporated. Yield: intermediate s-2 (76%, melting point: 86 ° C.) 7 g.

Intermediate  Synthesis of s-3:

At 0 ° C. under N ₂ flow, LiAlH ₄ (0.0342 mol) was suspended in THF (100 ml) little by little. A solution of s-2 (0.0342 mol) in a small amount of THF was added dropwise at 0 ° C. under N 2 flow. The mixture was stirred at 0 ° C. for 2 h, then hydrolyzed with EtOAc and H ₂ O, discarded and extracted with EtOAc. The organic layer was separated, washed with H ₂ O, dried (on MgSO ₄ ) and filtered to evaporate the solvent. The residue (4.3 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 97/3 / 0.1; 15-40 μm). Desired fractions were collected and the solvent was evaporated. Yield: 2.6 g of intermediate s-3 (47%, melting point: 116 ° C).

Intermediate  Synthesis of s-4:

At 5 ° C., SOC1 ₂ (0.0222 mol) was added dropwise to a solution of s-3 (0.0148 mol) in CH ₂ C1 ₂ (70 ml). The mixture was stirred at rt for 2 h, poured onto ice, basified with 10% K ₂ CO ₃ and extracted with CH ₂ C1 ₂ . The organic layer was separated, washed with H ₂ O, dried (on MgSO ₄ ) and filtered to evaporate the solvent. Yield: 2.8 g of intermediate s-4 (100%). The product was used without further processing.

Example 20 Synthesis of 1-Substituted Benzimidazol-2-amines

Scheme T

A mixture of K ₂ CO ₃ (0.0074 mol), t-1 (0.005 mol), and t-2 (0.0059 mol) in DMF (25 ml) was stirred at room temperature for 24 hours, then poured onto ice and K ₂ Saturated with CO ₃ (powder) and extracted with CH ₂ C1 ₂ . The organic layer was separated, dried (MgSO ₄ phase), filtered and the solvent was evaporated until dry. The residue (2 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 89/10 / 0.1; 15-40 μm). Pure fractions were collected and the solvent was evaporated. Yield: 1.285 g of mixture t-3 + t-4 (50/50, 70%).

Under an N ₂ flow, LiAlH ₄ (0.007 mol) was added in portions to a mixture of t-3 + t-4 (0.0035 mol) in THF (30 ml). Under N ₂ flow, the mixture was stirred at 5 ° C. for 30 minutes and then at room temperature for 2 hours. H ₂ 0 (10 ml) was added. The mixture was filtered over celite. Celite was washed with CH ₂ C1 ₂ / CH ₃ 0H (50/50). The filtrate was evaporated. The residue (1.1 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 88/12/1; 15-40 μm). Two fractions were collected and the solvent was evaporated. Yield: 0.15 g of t-5 (13%) and 0.115 g of t-6 (10%).

A mixture of MnO ₂ (1.5 g) and t-5 (0.0004 mol) in CH ₂ C1 ₂ (40 ml) was stirred at room temperature for 4 hours and then filtered over celite. Celite was washed with CH ₂ C1 ₂ . The filtrate was evaporated. The residue (0.16 g) was purified by column chromatography on silica gel (eluent: CH ₂ C1 ₂ / CH ₃ 0H / NH ₄ 0H 94/6 / 0.5; 10 μm). Pure fractions were collected and the solvent was evaporated to give 0.059 g of t-7 (40%).

Example 21 Synthesis of 1-bicyclyl-6-substituted benzimidazol-2-amines

Scheme U

A mixture of CH ₃ CO ₂ H (3 drops), BH ₃ CN-solid support (0.0002 mol), u-1 (0.0001 mol), and u-2 (0.0002 mol) in CH ₃ 0H (10 ml) Was stirred at rt for 12 h. The solvent was evaporated until dryness. The residue was captured in CH ₂ C1 ₂ / CH ₃ 0H. The mixture was basified with K ₂ CO ₃ 10%, saturated with K ₂ CO ₃ (powder) and extracted with CH ₂ C1 ₂ . The organic layer was separated, dried (MgSO ₄ phase), filtered and the solvent was evaporated until dryness. The residue was crystallized in 2-propanone / diisopropylether. The precipitate was filtered off and dried to afford 0.042 g of u-3 (49%, compound 206, melting point: 165 ° C).

Example 22 Synthesis of 1-[(4-benzimidazolyl) methyl-5-formyl-benzimidazol-2-amine

Scheme V

A mixture of intermediate v-3 + v-4 (50/50, 93%, melting point: 144 ° C.) was synthesized according to the method described for the mixture of intermediate t-3 + t-4.

Compound v-5 (33%, compound 223, melting point: 258 ° C.) and v-6 (35%, melting point: 260 ° C.) were synthesized according to the methods described for intermediates t-5 and t-6.

Compound v-7 (81%) was synthesized according to the method described for intermediate t-7.

Final compound v-9 (28%, compound 211, melting point: 174 ° C.) was synthesized according to the method described for final compound u-3.

Example 23 Synthesis of l-quinoloylmethyl-benzimidazol-2-amine

Scheme W

Intermediate w-2 is the same as intermediate q-2.

A mixture of intermediate w-3 + w-4 (50/50, 32%) was synthesized according to the method described for the mixture of intermediate t-3 + t-4.

Intermediates w-5 (18%, melting point: 230 ° C.) and w-6 (10%, melting point:> 260 ° C.) were synthesized according to the methods described for intermediates t-5 and t-6.

Intermediate w-7 (81%) was synthesized according to the method described for intermediate t-7.

Example 24 Synthesis of l-quinoloylmethyl-6-phenylaminomethyl-benzimidazol-2-amine

Scheme X

Final compound x-2 (26%, compound 214, melting point: 194 ° C.) was synthesized according to the method described for final compound u-3.

Example 25 Synthesis of l-pyridylmethyl-6-phenylaminomethyl-benzimidazol-2-amine

Scheme Y

A mixture of intermediates y-3 and y-4 (50/50, 57%) was synthesized according to the method described for mixtures of intermediates t-3 and t-4.

Intermediates y-5 (12%) and y-6 (9%) were synthesized according to the methods described for intermediates t-5 and t-6.

Intermediate y-7 (91%) was synthesized according to the method described for intermediate t-7.

Final compound y-9 (30%, compound 209, melting point: 212 ° C.) was synthesized according to the method described for final compound u-3.

Example 26 Synthesis of (6-Bromo-1-pyridyl) methyl 5- and 6-aminomethyl-benzimidazol-2-amines

Scheme Z

A mixture of intermediate z-3 + z-4 (50/50, 40%) was synthesized according to the method described for the mixture of intermediate t-3 + t-4.

Intermediates z-5 (18%, Compound 226, Melting Point: 221 ° C.) and z-6 (16%, Compound 227, Melting Point: 230 ° C.) were synthesized according to the methods described for Intermediates t-5 and t-6. It was.

Intermediate z-7 (80%) was synthesized according to the method described for intermediate t-7.

Final compound z-10 (48%, compound 212, melting point: 158 ° C.) was synthesized according to the method described for final compound u-3.

Example  27

scheme AA

A mixture of intermediates aa-3 + aa-4 (50/50, 35%) was synthesized according to the method described for the mixture of intermediates t-3 + t-4.

Intermediates aa-5 (24%) and aa-6 (18%) were synthesized according to the methods described for intermediates t-5 and t-6.

Intermediate aa-7 (100%) was synthesized according to the method described for intermediate t-7.

Example  28

scheme AB

Final compound ab-3 (43%, compound 217, melting point: 175 ° C.) was synthesized according to the method described for final compound u-3.

Example  29

scheme AC

A mixture of intermediate ac-3 + ac-4 (50/50, 46%, melting point: 193 ° C.) was synthesized according to the method described for the mixture of intermediate t-3 + t-4.

Intermediates ac-5 (33%, Compound 236, Melting Point: 202 ° C.) and ac-6 (21%, Compound 237, Melting Point:> 260 ° C.) were prepared according to the methods described for intermediates t-5 and t-6. Synthesized.

Intermediate ac-7 (100%) was synthesized according to the method described for intermediate t-7.

Example  30

scheme AD

Final compound ad-2 (46%, compound 219, melting point: 179 ° C.) was synthesized according to the method described for final compound o-5.

The compounds listed in the table below were prepared analogously to one of the synthetic schemes exemplified above. The table includes physicochemical data such as mass spectral data (MH +) and / or melting point. The radicals indicated in the table above are linked to the residues of the molecule by any 'open' bond, such as, for example, a bond without a radical on one side.

Compound number Active categories MH + Melting point (℃) 128 6.9 522 129

Example 31 : in of a compound of Formula (I) in activity against RSV in vitro screening

, A cell protective% (antiviral activity or EC _5O) of the pathology caused by a virus obtained by the tested toxic compound and its cell (CC _5O) is both dose-response curve was calculated by. The selectivity of the antiviral effect is expressed as the Selection Index (SI), calculated by dividing CC ₅₀ (cytotoxic dose for 50% of cells) by EC ₅₀ (antiviral activity for 50% of cells). The table in the experimental section lists the categories to which each prepared compound belongs: Compounds belonging to the active category "A" have a pEC50 (-log of EC _5O when expressed in molar units) equal to or greater than 7 Have Compounds belonging to the active category "B" have a pEC50 between 6 and 7. Compounds belonging to the active category "C" have a pEC50 equal to or less than 6.

Automated tetrazolium-based colorimetric assays were used to determine the EC ₅₀ and CC ₅₀ of test compounds. Flat-bottom, 96-well plastic microtiter trays were filled with 180 μl of Eagle's basal medium, supplemented with 5% FCS (0% for FLU) and 20 mM Hopes buffer. A stock solution of the compound (7.8 x final test concentration) was then placed in a series of triplicate wells to allow for simultaneous evaluation of its effect on virus- and mock-infected cells. Added freshly. Five-fold dilutions were performed directly in the microtiter tray using a robotic system. Untreated virus controls, and HeLa cell controls are included in each test. Approximately 100 TCID ₅₀ of respiratory syncytial virus was added to two of three lines in a volume of 50 μl. In order to measure the cytotoxicity of the compounds at the same concentrations required to determine antiviral activity, equal volumes of culture were added to the third row. After incubation for 2 hours, suspension of HeLa cells (4 × 10 ⁵ cells / ml) was added to each well in a volume of 50 μl. The culture was incubated at 37 ° C. in 5% CO ₂ atmosphere. Seven days after infection, cytotoxicity and antiviral activity were spectrophotometrically analyzed. To each well of the microtiter tray, 25 μl of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) solution was added. The trays were further incubated at 37 ° C. for 2 hours, then the culture was removed from each cup. 100 μl of 2-propanol was added to dissolve the formazan crystals. The tray was placed in a plate shaker for 10 minutes to completely dissolve the formazan crystals. Finally, absorbance was measured at two wavelengths (540 and 690 nm) using an 8-channel computer-controlled photometer (Multiskan MCC, Flow Laboratories). To eliminate the effect of non-specific absorbance, the absorbance measured at 690 nm was automatically subtracted from the absorbance measured at 540 nm.

, A cell protective% (antiviral activity or EC _5O) of the pathology caused by a virus obtained by the tested toxic compound and its cell (CC _5O) is both dose-response curve was calculated by. The selectivity of the antiviral effect is expressed as the Selection Index (SI), calculated by dividing CC ₅₀ (cytotoxic dose for 50% of cells) by EC ₅₀ (antiviral activity for 50% of cells).

Claims (28)

A compound of the formula:

or

Where G is a direct bond or methylene; R ¹ is a monocyclic or bicyclic heterocycle selected from pyridyl, pyrazinyl, quinolinyl, benzimidazolyl or a radical of formula (c-4);

Wherein each said monocyclic or bicyclic heterocycle is one or more independently selected from the group of substituents consisting of halo, hydroxy, C _1-6 alkyl and C _1-6 alkyloxy, for example Unsubstituted or substituted by 2, 3, 4 or 5 substituents; Each m is independently 1 or 2; Q is hydrogen, amino, or mono- or di (C _1-4 alkyl) amino; R ^2b is hydrogen, C _1-6 alkyl or halogen; R ^3b is hydrogen, C _1-6 alkyl or halogen; R ^4a is hydrogen, C _1-6 alkyl, Ar ² C _1-6 alkyl, (Ar ² ) (hydroxy) C _1-6 alkyl, Het-C _1-6 alkyl, hydroxyC _1-6 alkyl, mono And di- (C _1-6 alkyloxy) C _1-6 alkyl, (hydroxyC _1-6 alkyl) oxyC _1-6 alkyl, Ar ¹ C _1-6 alkyloxyC _1-6 alkyl, dihydr HydroxyC _1-6 alkyl, (C _1-6 alkyloxy) (hydroxy) C _1-6 alkyl, (Ar ¹ C _1-6 alkyloxy) (hydroxy) C _1-6 alkyl, Ar ¹ oxy-C _1-6 alkyl, (Ar ¹ oxy) (hydroxy) C _1-6 alkyl, aminoC _1-6 alkyl, mono- and di- (C _1-6 alkyl) amino-C _1-6 alkyl, carboxyl- C _1-6 alkyl, C _1-6 alkyloxycarbonylC _1-6 alkyl, aminocarbonylC _1-6 alkyl, mono- and di- (C _1-6 alkyl) aminocarbonylC _1-6 alkyl, C _1-6 alkylcarbonylC _1-6 alkyl, (C _1-4 alkyloxy) ₂ -P (= O) -C _1-6 alkyl, (C _1-4 alkyloxy) ₂ -P (= O) -OC _1-6 alkyl, aminosulfonyl-C _1-6 alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl-C _1-6 alkyl, C _1-6 alkylcarbonyl, Ar ² carbonyl , Het- Viterbo carbonyl, Ar ² C _1-6 alkylcarbonyl, Het-C _1-6 alkylcarbonyl, C _1-6 alkylsulfonyl, aminosulfonyl, mono- and di (C _1-6 alkyl) aminosulfonyl, Ar ² sulfonyl, Ar ² C _1-6 alkylsulfonyl, Ar ² , Het, Het-sulfonyl, HetC _1-6 alkylsulfonyl; R ^6a is hydrogen, C _1-6 alkyl, Ar ¹ , Ar ¹ C _1-6 alkyl, C _1-6 alkylcarbonyl, Ar ¹ carbonyl, Ar ¹ C _1-6 alkylcarbonyl, C _1-6 alkyl Sulfonyl, Ar ¹ sulfonyl, Ar ¹ C _1-6 alkylsulfonyl, C _1-6 alkyloxyC _1-6 alkyl, aminoC _1-6 alkyl, mono- or di (C _1-6 alkyl) aminoC _1-6 alkyl, hydroxyC _1-6 alkyl, (carboxy) -C _1-6 alkyl, (C _1-6 alkyloxycarbonyl) -C _1-6 alkyl, aminocarbonylC _1-6 alkyl, mono And di (C _1-6 alkyl) aminocarbonylC _1-6 alkyl, aminosulfonyl-C _1-6 alkyl, mono- and di (C _1-6 alkyl) aminosulfonyl-C _1-6 alkyl, Het, Het-C _1-6 alkyl, Het-carbonyl, Het-sulfonyl or Het-C _1-6 alkylcarbonyl; R ^6b is hydrogen, C _1-6 alkyl, Ar ¹ or Ar ¹ C _1-6 alkyl; R ^6c is C _1-6 alkyl, Ar ¹ or Ar ¹ C _1-6 alkyl; Alk is C _1-6 alkanediyl; R ⁹ , R ¹⁰ , R ¹¹ are each independently halo, cyano, C _1-6 alkyl, Het-C _1-6 alkyl, Ar ¹ -C _1-6 alkyl, cyanoC _1-6 alkyl, C _{2 -6} alkenyl, cyanoC _2-6 alkenyl, R ^6b -OC _3-6 alkenyl, C _2-6 alkynyl, cyanoC _2-6 alkynyl, R ^6b -OC _3-6 alkynyl, Ar ¹ , Het, R ^6b -O-, R ^6b -S-, R ^6c -SO-, R ^6c -SO _2- , R ^6b -OC _1-6 alkyl-SO _2- , -N (R ^6a R ^6b ), _Polyhalo- C _1-6 alkyl, polyhaloC _1-6 alkyloxy, polyhaloC _1-6 alkylthio, R ^6c -C (= 0)-, R ^6b -OC (= 0) -, N (R ^6a R ^6b ) -C (= 0)-, R ^6b -OC _1-6 alkyl, R ^6b -SC _1-6 alkyl, R ^6c -S (= 0) ₂ -C _1-6 alkyl , N (R ^6a R ^6b ) -C _1-6 alkyl, R ^6c -C (= 0) -C _1-6 alkyl, R ^6b -OC (= 0) -C _1-6 alkyl, N (R ^6a R ^{6b) -C (= O) -C} 1-6 ^{alkyl, R 6c -C (= O)} -NR 6b -, R 6c -C (= O) -O-, R 6c -C (= O) -NR ^6b- C _1-6 alkyl, R ^6c -C (= 0) -OC _1-6 alkyl, N (N ^6a R ^6b ) -S (= 0) ₂ -or H ₂ NC (= NH)- , R ¹⁰ or R ¹¹ , or R ¹⁰ and R ¹¹ can also be hydrogen; Ar ¹ is phenyl; Or one or more, for example two, three selected from halo, hydroxy, C _1-6 alkyl, hydroxyC _1-6 alkyl, polyhaloC _1-6 alkyl and C _1-6 alkyloxy Phenyl substituted with 4 or 4 substituents; Ar ² is phenyl; Phenyl annealed with C _5-7 cycloalkyl; Or halo, cyano, C _1-6 alkyl, Het-C _1-6 alkyl, Ar ¹ -C _1-6 alkyl, cyanoC _1-6 alkyl, C _2-6 alkenyl, cyanoC _2-6 Alkenyl, R ^6b -OC _3-6 alkenyl, C _2-6 alkynyl, cyanoC _2-6 alkynyl, R ^6b -OC _3-6 alkynyl, Ar ¹ , Het, R ^6b -O-, R ^6b -S-, R ^6c -SO-, R ^6c -SO _2- , R ^6b -OC _1-6 alkyl-SO _2- , -N (R ^6a R ^6b ), polyhalo-C _1-6 alkyl , _{PolyhaloC 1-6} alkyloxy, polyhaloC _1-6 alkylthio, R ^6c -C (= 0)-, R ^6b -OC (= 0)-, N (R ^6a R ^6b ) -C (= O)-, R ^6b -OC _1-10 alkyl, R ^6b -SC _1-6 alkyl, R ^6c -S (= O) ₂ -C ^1-6 alkyl, N (R ^6a R ^6b ) -C _{1 -6} alkyl, R ^6c -C (= 0) -C _1-6 alkyl, R ^6b -OC (= 0) -C _1-6 alkyl, N (R ^6a R ^6b ) -C (= 0) -C _{1 -6} ^{alkyl, R 6c -C (= O)} -NR 6b -, R 6c -C (= O) -O-, R 6c -C (= O) -NR 6b -C 1-6 alkyl, R ^6c - One or more, for example two, selected from C (═O) —OC _1-6 alkyl, N (R ^6a R ^6b ) —S (═O) ₂ —, H ₂ NC (═NH) —, Phenyl substituted with 3, 4 or 5 substituents; Het is tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, pyrazolyl, isoxazolyl , Oxadiazolyl, thiadiazolyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzo-dioxa-carbonyl, benzo solril-dioxide, indolinyl, and the heterocycle selected from indolyl, each of said heterocycles is oxo, amino, Ar ^l, C _1-4 alkyl, amino C _1-4 alkyl, Ar ^l C _1-4 alkyl, mono- or di (C _1-6 alkyl) amino C _1-6 alkyl, mono- or di (C _1-6 alkyl) amino, (hydroxy-C _l-6 alkyl) It may be unsubstituted or substituted by amino and further substituted by one or two C _1-4 alkyl radicals. The compound of claim 1, wherein Alk is methylene. The compound of claim 1, wherein R ⁹ , R ¹⁰ , R ¹¹ are halo, cyano, C _1-6 alkyl, Het-C _1-6 alkyl, Ar ¹ -C _1-6 alkyl, cyanoC _1-6 alkyl , C _2-6 alkenyl, cyanoC _2-6 alkenyl, R ^6b -OC _3-6 alkenyl, C _2-6 alkynyl, cyanoC _2-6 alkynyl, R ^6b -OC _3-6 Alkynyl, Ar ^l , Het, R ^6b -O-, R ^6b -S-, R ^6c -SO-, R ^6c -SO _2- , R ^6b -OC _1-6 alkyl-SO _2- , -N (R ^6a R ^6b ), CF ₃ , R ^6c -C (= O)-, R ^6b -OC (= O)-, N (R ^6a R ^6b ) -C (= O)-, R ^6b -OC _1-6 Alkyl, R ^6b -SC _1-6 alkyl, R ^6c -S (= 0) ₂ -C _1-6 alkyl, N (R ^6a R ^6b ) -C _1-6 alkyl, R ^6c -C (= 0)- C _1-6 alkyl, R ^6b -O-(= O) -C _1-6 alkyl, N (R ^6a R ^6b ) -C (= O) -C _1-6 alkyl, R ^6c -C (= O) -NR ^6b -, and H ₂ NC (= NH) - a compound selected from the. The compound of claim 1, wherein R ⁹ , R ¹⁰ , R ¹¹ are C _1-6 alkyl, Het-C _1-6 alkyl, Ar ¹ -C _1-6 alkyl, cyanoC _1-6 alkyl, C _2-6 Alkenyl, cyano-C _2-6 alkenyl, R ^6b -OC _3-6 alkenyl, C _2-6 alkynyl, cyanoC _2-6 alkynyl, R ^6b -OC _3-6 alkynyl, R ^6b- OC _1-6 alkyl, R ^6b -SC _1-6 alkyl, R ^6c -S (= O) ₂ -C _1-6 alkyl, N (R ^6a R ^6b ) -C _1-6 alkyl, R ^6b- OC-(= 0) -C _1-6 alkyl and N (R ^6a R ^6b ) -C (= 0) -C _1-6 alkyl. The compound of claim 1, wherein R ⁹ , R ¹⁰ , R ¹¹ are C _1-6 alkyl, Het-C _1-6 alkyl, Ar ¹ -C _1-6 alkyl, cyanoC _1-6 alkyl, C _2-6 Alkenyl, cyano-C _2-6 alkenyl, C _2-6 alkynyl, cyanoC _2-6 alkynyl, R ^6b -OC _1-6 alkyl, amino-S (= 0) ₂ -C _{1- At 6} alkyl, R ^6b -OC (= 0) -C _1-6 alkyl, amino-C (= 0) -C _1-6 alkyl, mono- and diamino-C (= 0) -C _1-6 alkyl Compound selected. The compound of claim 1, wherein R ⁹ , R ¹⁰ , R ¹¹ are C _1-6 alkyl or R ^6b -OC _1-6 alkyl; R ¹⁰ or R ^ll , or R ¹⁰ and R ^ll may be hydrogen. The compound of claim 1, wherein G is methylene. The compound of claim 1, wherein R ¹ is quinolinyl, benzimidazolyl, a radical of formula (c-4), pyrazinyl, or pyridyl:

Wherein the quinolinyl, benzimidazolyl, or radical of formula (c-4) is independently selected from the group consisting of halo, hydroxy, C _1-6 alkyl and C _1-6 alkyloxy; It may be substituted with three or three substituents. The compound of claim 1, wherein R ¹ is quinolinyl; radical (c-4), wherein m is 2 and is substituted or unsubstituted by up to two radicals selected from C _1-6 alkyl; Benzimidazolyl unsubstituted or substituted by C _1-6 alkyl; Pyridyl unsubstituted or substituted by one or two radicals selected from hydroxy, halo, C _1-6 alkyl and C _1-6 alkyloxy; Or pyrazinyl unsubstituted or substituted by up to 3 radicals selected from C _1-6 alkyl. The method of claim 1, wherein, R ¹ is hydroxy, C _1-6 alkyl and C _l-6 alkyl substituted by one or two radicals selected from oxy unsubstituted pyridyl compound. The compound of claim 1, wherein R ¹ is pyridyl substituted with hydroxy and methyl. The compound of claim 1, wherein R ¹ is 3-hydroxy-6-methylpyrid-2-yl. A 2- (2-amino-6-{[2- (3-hydroxy-propyl) -5-methyl-phenylamino] -methyl} -benzoimidazol-1-ylmethyl) -6 according to claim 1 -Methyl-pyridin-3-ol. A 2- (2-amino-6-{[2- (3-hydroxy-propyl) -5-methyl-phenylamino] -methyl} -benzoimidazol-1-ylmethyl) -6 according to claim 1 -Methyl-pyridin-3-ol and its acid-addition salts. A pharmaceutical composition for treating or preventing respiratory syncytial virus (RSV) infection comprising a pharmaceutically acceptable carrier and an active ingredient in a therapeutically effective amount of the compound of any one of claims 1 to 14. A method of preparing a pharmaceutical composition for treating or preventing RSV infection, comprising intimately mixing a therapeutically effective amount of a compound of any one of claims 1 to 14 with a pharmaceutically acceptable carrier. 15. A pharmaceutical for treating or preventing RSV infection comprising the compound of any one of claims 1-14. Reacting the intermediate of formula (II-1) or (II-2) with reagent (III) according to the following reaction scheme; The obtained compound of formula (Ia-1) or (Ib-1) is optionally converted to its pharmaceutically acceptable base-addition salt or acid addition salt form by treatment with a base or an acid, and vice versa. Or treating an acid addition salt form with an acid or a base to obtain a free form of a compound of formula (la-1) or (lb-1). How to:

or

Where Q, G, R ¹ , R ^2b , R ^3b , R ^4a , R ⁹ , R ¹⁰ , R ¹¹ and Alk are as defined in claim 1; W represents chloro or bromo. Reacting the intermediate of formula (V-1) or (V-2) with reagent (III) according to the following reaction scheme to obtain a compound of formula (I-d-1) or (I-d-2); Here, optionally, intermediate (V-1) or (V-2) may be prepared by cyclization reaction of intermediate (IV-1) or (IV-2); The obtained compound of formula (Id-1) or (Id-2) is optionally converted to its pharmaceutically acceptable base-addition salt or acid addition salt form by treatment with base or acid, and vice versa. Or treating the acid addition salt form with an acid or a base to obtain a free form of the compound of formula (Id-1) or (Id-2). How to:

or

Where G, R ¹ , R ^2b , R ^3b , R ^4a , R ⁹ , R ¹⁰ , R ¹¹ and Alk are as defined in claim 1; W represents chloro or bromo. delete delete delete delete delete delete delete delete delete