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HK1129670B - Tricyclic n-heteroaryl-methyl carboxamide derivatives containing a benzimedazole unit, method for preparing same and their therapeutic use - Google Patents

Tricyclic n-heteroaryl-methyl carboxamide derivatives containing a benzimedazole unit, method for preparing same and their therapeutic use Download PDF

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HK1129670B
HK1129670B HK09107854.1A HK09107854A HK1129670B HK 1129670 B HK1129670 B HK 1129670B HK 09107854 A HK09107854 A HK 09107854A HK 1129670 B HK1129670 B HK 1129670B
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Hong Kong
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compound
formula
group
pyrrolo
mmol
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HK09107854.1A
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HK1129670A1 (en
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Laurent Dubois
Yannick Evanno
Luc Even
Catherine Gille
André Malanda
David Machnik
Nathalie Rakotoarisoa
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赛诺菲-安万特
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Publication of HK1129670A1 publication Critical patent/HK1129670A1/en
Publication of HK1129670B publication Critical patent/HK1129670B/en

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Tricyclic N-heteroaryl-carboxamide derivatives containing a benzimidazole structural element, their preparation and their therapeutic use
The present invention relates to tricyclic N-heteroaryl-carboxamide derivatives containing a benzimidazole structural unit, their preparation and their therapeutic use.
The present invention is directed to tricyclic N-heteroaryl-carboxamide compounds containing a benzimidazole structural unit, which have TRPV1 (or VR1) receptor antagonist or agonist activity in vitro and in vivo.
The object of the present invention is a compound corresponding to formula (I) below:
in the formula:
a represents a 4-7 membered monocyclic heterocyclic or monocyclic heteroaryl group fused to the C-N bond of the benzimidazole structural unit, containing 1-3 heteroatoms selected from O, S or N, including the nitrogen atom of the benzimidazole structural unit;
p represents an 8-, 9-, 10-or 11-membered bicyclic heterocycle or bicyclic heteroaryl group containing 1 to 6 heteroatoms selected from N, O and S; p is linked to the-C (Y) -group through a carbon atom; with the proviso that when A represents a saturated heterocycle having 7 members, P is different from 2, 3-dihydro-1, 4-benzodiAlkyl groups, 1-benzopyran-2-one groups, isoindolyl groups;
R1represents 1 to 4 identical or different atoms or groups selected from the following groups: hydrogen atom, halogen atom, oxo, thioxo, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6Alkyl, aryl-C1-C3Alkylene oxide radical-C1-C6-alkyl, heteroaryl-C1-C3Alkylene oxide radical-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6Alkyl, aryl-C1-C3-Alkylenethio-C1-C6-alkyl, heteroaryl-C1-C3-Alkylenethio-C1-C6Alkyl radical, C1-C6-alkoxy, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3Alkylene oxide radical, C1-C6-fluoroalkoxy, cyano, C (O) NR4R5Nitro, NR4R5、C1-C6Alkylthio radical, C3-C7Cycloalkylthio radical, C3-C7-cycloalkyl-C1-C3-alkylenethio, -S (O) -C1-C6-alkyl, -S (O) -C3-C7-cycloalkyl, -S (O) -C1-C3alkylene-C3-C7-cycloalkyl, C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-、SO2NR4R5、SF5、NR6C(O)R7、NR6SO2R8、R4R5NC(O)-C1-C3Alkylene, aryl, heteroaryl, aryl-C1-C5Alkylene, heteroaryl-C1-C5Alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio;
said R1Is optionally substituted by one or more substituents R which are identical to or different from one another9Substitution; with the proviso that when R1When attached to the nitrogen atom of P, then R1Different from halogen atom, oxo, thio, cyano, nitro, SF5、NR4R5、C1-C6Alkylthio, arylthio, heteroarylthio, C1-C6Alkoxy, aryloxy, heteroaryloxy, -NR6COR7And NR6SO2R8A group;
y represents an oxygen or sulfur atom;
R2represents a hydrogen atom, a halogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl or C1-C6-an alkoxy group;
when R is carried by a carbon atom3When R is3Represents 1 to 3 identical or different atoms or groups selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, hydroxy, C1-C6Alkoxy radical, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3-an alkyleneoxy group;
or
When the nitrogen atom carries R3When R is3Represents 1 to 2 identical or different atoms or groups selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C (O) -, C1-C6alkyl-C (O) -, C3-C7cycloalkyl-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-C (O) -, C1-C6fluoroalkyl-C (O) -, aryl-S (O)2-、C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-、C1-C6alkyl-O-C (O) -, aryl-C1-C3alkyl-O-C (O) -, C3-C7cycloalkyl-O-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-O-C (O) -, C1-C6-fluoroalkyl-O-c (O) -, aryl-O-c (O) -, heteroaryl-O-c (O) -groups;
R4and R5Independently of one another represent a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C5-an alkylene or aryl group;
or R4And R5Together with the nitrogen atom to which they are attached, to form azetidines, pyrrolidines, piperidines, azenesMorpholine, thiomorpholine, piperazine, homopiperazine radicals, radicals NR4R5Optionally substituted with: c1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6Alkylene, aryl, heteroaryl, aryl-S (O)2-、C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-C (O) -, C1-C6alkyl-C (O) -, C3-C7cycloalkyl-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-C (O) -, C1-C6fluoroalkyl-C (O) -, hydroxy, C1-C6-alkoxy, C1-C6-fluoroalkyl, aryloxy-C1-C6Alkylene, aryloxy, heteroaryloxy-C1-C6-alkylene, heteroaryloxy groups;
R6and R7Independently of one another represent a hydrogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-an alkylene or aryl group;
or R6And R7Lactams which together form 4 to 7 units and contain the nitrogen atom and the group C (O) which they carry;
R8represents C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl groups:
or R6And R8Sultams (sultams) forming together 4 to 7 units, containing nitrogen atoms and the groups S (O) they carry2；
R9Represents a halogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro, cyano, NR4R5、R4R5N-C1-C3-alkylene, aryl, heteroaryl, aryloxy, arylthio, heteroaryloxy or heteroarylthio groups, these said heteroaryl or aryl groups being optionally substituted by one or more substituents selected from the group consisting of: halogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro, cyano, NR4R5、R4R5N-C1-C3-an alkylene group.
In these compounds of formula (I):
the sulfur atom or atoms of the heterocycle A may be oxidized (S (O) or S (O)2) Forms thereof;
the nitrogen atom(s) may be in oxidised (N-oxide) form.
These compounds of formula (I) may contain one or more asymmetric carbon atoms. They can therefore be in enantiomeric or diastereomeric form. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, are part of the present invention.
These compounds of formula (I) may be present in the form of bases or of addition salts with acids. Such addition salts are part of the present invention.
These salts may be prepared from pharmaceutically acceptable acids, but salts of other acids, for example for the purification or isolation of compounds of formula (I), are also part of the invention.
These compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. associated or combined with one or more water molecules or with a solvent. Such hydrates or solvates are also part of the present invention.
Within the scope of the invention, it should be understood that:
-a halogen atom: fluorine, chlorine, bromine or iodine;
-Ct-Cz: there may be a carbon chain of t-z carbon atoms, where t and z may be 1-7; e.g. C1-C3Is a carbon chain which may have 1 to 3 carbon atoms;
-an alkyl group: a straight or branched chain saturated aliphatic group. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like;
-alkylene groups: saturated divalent straight-chain or branched alkyl radicals, e.g. C1-3An alkylene radicalA divalent linear or branched carbon chain having 1 to 3 carbon atoms, more particularly methylene, ethylene, 1-methylethylene, propylene;
-a cycloalkyl group: a cycloalkyl group. Examples include the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;
-a fluoroalkyl group: an alkyl group in which one or more hydrogen atoms have been substituted with a fluorine atom;
-an alkoxy group: -O-alkyl, wherein the alkyl group is as previously defined;
-a fluoroalkoxy group: alkoxy groups in which one or more hydrogen atoms have been replaced by fluorine atoms;
-alkylthio or alkylthio groups: -S-alkyl, wherein the alkyl group is as previously defined;
-aryl: a mono-or bicyclic aromatic radical containing from 6 to 10 carbon atoms. As examples of aryl groups, mention may be made of phenyl or naphthyl groups;
-a heterocycle: 5-17 membered saturated or partially unsaturated mono-, bi-or tricyclic group containing 1-8 heteroatoms selected from O, S or N.
As examples of monocyclic heterocycles, azetidinyl, pyrrolidinyl, piperidinyl and aza radicals may be mentionedMesityl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydroAn oxazolyl, dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridinyl group;
examples of bicyclic heterocycles which may be mentioned are indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl and dihydrobenzofuranylOxazolinyl, dihydroisobenzofuranyl, dihydrobenzimidazolyl, dihydroisobenzothiazolyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydrobenzoAzinyl, benzothiazinyl, dihydrobenzothiazinyl, dihydroquinazolinyl, tetrahydroquinazoline, dihydroquinoxalinyl, tetrahydroquinoxalinyl, dihydro 2, 3-naphthyridinyl, tetrahydro 2, 3-naphthyridinyl, tetrahydrobenzazepinylTetrahydrobenzo [1, 4 ]]Diaza derivativesTetrahydrobenzo [1, 4 ]]Oxazazem(oxapinyle) or tetrahydrobenzo [1, 4 ]]Sulfoazazepine(thiazepinyle) group; as examples of tricyclic heterocycles, dihydroimidazo [1, 2-a ] s are mentioned]Benzimidazolyl dihydropyrrolo [1, 2-a ]]Benzimidazolyl, tetrahydropyrido [1, 2-a ]]Benzimidazolyl or dihydrothiazolo [1, 2-a ]]Benzimidazolyl, tetrahydropyrimidino [1, 2-a ]]Benzimidazolyl, tetrahydrodiazepinesAnd [1, 3 ]][1，2-a]Benzimidazolyl and dihydroOxazino [1, 4 ]][4，3-a]Benzimidazolyl, tetrahydropyrazino [1, 2-a ] s]A benzimidazolyl group;
-heteroaryl: mono-, bi-or tricyclic aromatic groups having 5 to 14 members and containing 1 to 8 heteroatoms selected from O, S or N.
Examples of monocyclic heteroaryl groups include imidazolyl, pyrazolyl, thiazolyl,Azolyl, isothiazolyl, iso-thiazolylAzolyl, furyl, thienyl,Oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl radicals;
as examples of bicyclic heteroaryl groups, mention may be made of indolyl, isoindolyl, benzofuranyl, benzothienyl, benzofuranylOxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzofuranyl, isobenzothiazolyl, pyrrolo [2, 3-c]Pyridyl, pyrrolo [2, 3-b]Pyridyl, pyrrolo [3, 2-b]Pyridyl, pyrrolo [3, 2-c]A pyridyl, quinolyl, isoquinolyl, cinnolinyl, quinazoline or quinoxalinyl group;
as examples of tricyclic heteroaryl groups there may be mentioned the groups pyrido [1, 2-a ] benzimidazolyl, thiazolo [1, 2-a ] benzimidazolyl or imidazo [1, 2-a ] benzimidazolyl, pyrimido [1, 2-a ] benzimidazolyl, pyrazino [1, 2-a ] benzimidazolyl;
- "oxo" means "═ O";
- "thio" means "═ S".
Among the compounds of the present invention, the first group of compounds consists of the compounds of the following formula (II):
in the formula:
x represents a carbon atom or a nitrogen atom; these said xs being the same or different from each other, and the number of X ═ N is not more than 2;
R1、R2、R3y and A are as defined for formula (I), R1May be linked to a structural unit of the bicyclic ring having 6 elements or 5 elements.
Among the compounds of the present invention, the second group of compounds consists of the compounds of the following formula (III):
in the formula:
R1arepresents one or more identical or different atoms or groups selected from hydrogen, halogen or C1-C6Alkyl radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C1-C6Alkylthio radical, C1-C6alkyl-S (O)2-、NR4R5A nitro group;
R1brepresents a hydrogen atom, C1-C6-alkyl, heteroaryloxy-C1-C6Alkyl, aryl-C1-C3Alkylene oxide radical-C1-C6-alkyl, R4R5NC(O)-C1-C3Alkylene, aryl, heteroaryl, aryl-C1-C6Alkylene or heteroaryl-C1-C6-an alkylene group;
r as mentioned above1bHeteroaryl or aryl groups optionally substituted by one or more substituents R which may be the same or different from one another9Substitution;
R9represents a halogen atom or C1-C6Alkyl radical, C1-C6-alkoxy, C1-C6Fluoroalkyl, aryl, heteroaryl, NR4R5Arylthio groups, said heteroaryl or aryl groups optionally substituted by one or more groups selected from halogen atoms, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro, cyano, R4R5N-C1-C3-substituent substitution of an alkylene group;
R2、R3、R4、R5a, X and Y are as defined for formula (II).
Among the compounds of the present invention, the third group of compounds includes compounds of the following formula (IV):
wherein W is a tricyclic heterocycle or tricyclic heteroaryl selected from the group consisting of:
R1、R2、R3p and Y are as defined for formula (I).
Among the compounds of the present invention, the fourth group of compounds includes compounds of the following formula (V):
in the formula:
R1、R2、R3a and P are as defined for formula (I).
In the compounds of the present invention, the fifth group of compounds includes compounds of the following formula (V) wherein:
R2represents a hydrogen atom, C1-C6-alkyl or C1-C6-an alkoxy group;
when the carbon atom carries R3When R is3Represents 1 to 3 identical or different atoms or groups selected from hydrogen atom, C1-C6Alkyl radical, C1-C6-alkoxy or hydroxy groups;
or
When the nitrogen atom carries R3When R is3Represents 1 to 2 identical or different atoms or groups selected from hydrogen atom, C1-C6Alkyl radical, C1-C6alkyl-O-C (O) -, aryl-C1-C3-an alkyl-O-c (O) -group;
R1a and P are as defined for formula (I).
Among the compounds of the present invention, the sixth group of compounds includes compounds of the following formula (V) wherein:
a together with the C-N bond of the benzimidazole structural element to which it is fused represents a monocyclic heterocycle or monocyclic heteroaryl having 5 to 7 members and containing 1 to 3 heteroatoms selected from O, S or N, including the nitrogen atom of the benzimidazole structural element;
R1、R2、R3and P is as defined for formula (I).
Among the compounds of the present invention, the seventh group of compounds includes compounds of the following formula (Va), wherein:
a together with the C-N bond of the benzimidazole structural element to which it is fused represents a monocyclic heterocycle or monocyclic heteroaryl having 5 to 7 members and containing 1 or 2 heteroatoms selected from O, S or N, including the nitrogen atom of the benzimidazole structural element;
x represents a carbon atom or a nitrogen atom; these said xs being identical to or different from each other, and the number X ═ N is not more than 1;
R1arepresents one or more identical or different atoms or groups chosen from hydrogen atoms, halogen atoms, more particularly fluorine, bromine, chlorine, or C1-C6Alkyl radicals, more particularly methyl, ethyl, isopropyl, tert-butyl, C1-C6-fluoroalkyl, more particularly trifluoromethyl, C1-C6Alkoxy, more particularly methoxy, C1-C6Alkylthio radicals, more particularly SCH3、C1-C6alkyl-S (O)2-, more particularly-SO2CH3、NR4R5A nitro group;
R1brepresents a hydrogen atom, C1-C6Alkyl radicals, more particularly methyl, heteroaryloxy-C1-C6Alkyl, more particularly pyridyloxy-ethyl, aryl-C1-C3Alkylene oxide radical-C1-C6-alkyl, more particularly benzyloxyethyl, R4R5NC(O)-C1-C3Alkylene, more particularly R4R5NC(O)CH2-, aryl, more particularly phenyl, heteroaryl, more particularly pyridyl, aryl-C1-C6Alkylene, more particularly benzyl or naphthylmethyl, phenylethyl, phenylpropyl, or heteroaryl-C1-C6Alkylene, more particularly pyridylmethyl, pyridylethyl, pyridylpropyl, thiazolylmethyl, pyrimidinylmethyl, quinolylmethyl, quinoxalylmethyl, furylmethyl, pyrazinylmethyl, benzothiazolylmethyl;
these said R1bIs optionally substituted by one or more substituents R which are identical to or different from one another9Substitution;
R2represents a hydrogen atom;
when the carbon atom carries R3When R is3Represents a hydrogen atom, C1-C6Alkyl, more particularly methyl, C1-C6-an atom or group of an alkoxy, more particularly methoxy, or hydroxyl group;
or
When the nitrogen atom carries R3When R is3Represents a hydrogen atom, C1-C6Alkyl, more particularly methyl, C1-C6-alkyl-O-C (O) -, more particularly (CH)3)3An atom or group of a C-O-C (O) -group;
R4and R5Represent C independently of one another1-C6-an alkyl group, more particularly methyl or ethyl;
or R4And R5Together with the nitrogen atom it carries, form a pyrrolidinyl or morpholinyl group;
R9represents a halogen atom, more particularly fluorine or chlorine, or C1-C6Alkyl, more particularly methyl, C1-C6Alkoxy, more particularly methoxy, C1-C6Fluoroalkyl, more particularly trifluoromethyl, aryl, more particularly phenyl, heteroaryl, more particularly imidazolyl, NR4R5Arylthio, more particularly phenylthio, these said aryl radicals optionally substituted by one or more C1-C6-alkyl groups, more particularly methyl.
Among the compounds of the present invention, the eighth group of compounds includes compounds of formula (I) wherein R is1And/or R2And/or R3And/or A, and/or P and/or Y are simultaneously as defined in the preceding groups.
Among the compounds of the present invention, the ninth group of compounds includes compounds of the following formula (I'):
in the formula
A together with the C-N bond of its fused benzimidazole structural unit represents a 4-7 membered monocyclic heterocycle or monocyclic heteroaryl group containing 1-3 heteroatoms selected from O, S or N, including the nitrogen atom of the benzimidazole structural unit;
p represents an 8-, 9-, 10-or 11-membered bicyclic heterocycle or bicyclic heteroaryl group containing 1 to 6 heteroatoms selected from N, O and S;
with the proviso that when A represents a saturated heterocycle having 7 members, P is different from 2, 3-dihydro-1, 4-benzodiAlkyl and 1-benzopyran-2-one groups;
R1represents 1 to 4 identical or different atoms or groups selected from hydrogen, halogen, oxo, thio, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3Alkylene oxide radical, C1-C6-fluoroalkoxy, cyano, C (O) NR4R5Nitro, NR4R5、C1-C6Alkylthio radical, C3-C7Cycloalkylthio radical, C3-C7-cycloalkyl-C1-C3-alkylenethio, -S (O) -C1-C6-alkyl, -S (O) -C3-C7-cycloalkyl radical、-S(O)-C1-C3alkylene-C3-C7-cycloalkyl, C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-、SO2NR4R5、NR6C(O)R7、NR6SO2R8、R4R5NC(O)-C1-C3Alkylene, aryl, heteroaryl, aryl-C1-C5Alkylene, heteroaryl-C1-C5-alkylene, aryloxy, arylthio, heteroaryloxy or heteroarylthio groups, these said heteroaryl or aryl groups being optionally substituted by one or more groups chosen from halogen atoms, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C1-C6-fluoroalkoxy, nitro, cyano, NR4R5、R4R5N-C1-C3-substituent substitution of an alkylene group;
with the proviso that when R1When attached to the nitrogen atom of P, then R1Different from halogen atoms, oxo, thio, cyano, nitro, NR4R5、C1-C6Alkylthio, arylthio, heteroarylthio, C1-C6Alkoxy, aryloxy, heteroaryloxy, -NR6COR7and-NR6SO2R8A group;
y represents an oxygen or sulfur atom;
R2represents a hydrogen atom, a halogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl or C1-C6-an alkoxy group;
when the carbon atom carries R3When R is3Represents 1 to 3 identical or different atoms or groups selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl radical, C1-C6-alkoxy, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3-an alkyleneoxy group;
or
When the nitrogen atom carries R3When represents 1 to 2 identical or different atoms or groups selected from hydrogen, halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C (O) -, C1-C6alkyl-C (O) -, C3-C7cycloalkyl-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-C (O) -, C1-C6fluoroalkyl-C (O) -, aryl-S (O)2-、C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-、C1-C6alkyl-O-C (O) -, C3-C7cycloalkyl-O-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-O-C (O) -, C1-C6-fluoroalkyl-O-c (O) -, aryl-O-c (O) -, heteroaryl-O-c (O) -groups;
R4and R5Independently of one another represent a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C5-an alkylene or aryl group;
or R4And R5Together with the nitrogen atom it carries, to azetidine, pyrrolidine, piperidine, azepineMorpholine, thiomorpholine, piperazine, homopiperazine, which group is optionally substituted with: c1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6Alkylene, aryl, heteroaryl, aryl-S (O)2-、C1-C6alkyl-S (O)2-、C1-C6-fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-C (O) -, C1-C6alkyl-C (O) -, C3-C7cycloalkyl-C (O) -, C3-C7-cycloalkyl-C1-C3alkylene-C (O) -, C1-C6-a fluoroalkyl-c (o) -group;
R6and R7Independently of one another represent a hydrogen atom, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene-, aryl-C1-C6-an alkylene-or aryl group;
R8represents C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene-, aryl-C1-C6-alkylene-or aryl groups.
Among the compounds of the present invention, the tenth group of compounds includes compounds of the following formula (II'): in the formula:
in the formula:
x represents a carbon atom or a nitrogen atom; these said xs being the same or different from each other, and the number X ═ N is not more than 2;
R1、R2、R3y and A are as defined for formula (I); r1May be linked to structural units of the bicyclic ring having 5 or 6 elements.
Among the compounds of the present invention, the eleventh group of compounds includes compounds of the following formula (III'):
in the formula
R1aRepresents one or more identical or different atoms or groups selected from hydrogen, halogen or C1-C6-a fluoroalkyl group;
R1brepresents a hydrogen atom, C1-C6Alkyl, aryl, heteroaryl, aryl-C1-C6Alkylene-or heteroaryl-C1-C6Alkylene radicals, these said radicals being optionally substituted by one or more identical or different radicals or atoms, selected from halogen atoms or C1-C6-an alkyl group;
R2、R3a, X and Y are as defined for formula (II).
Among the compounds of the present invention, the twelfth group of compounds includes compounds of the following formula (IV'):
wherein W is a tricyclic heterocycle or tricyclic heteroaryl selected from the group consisting of:
R1、R2、R3p and Y are as defined for formula (I).
Among the compounds of the present invention, the thirteenth group of compounds includes compounds of the following formula (V'):
in the formula:
R1、R2、R3a, P and Y are as defined for formula (I).
Among the compounds of the present invention, the fourteenth group of compounds includes compounds of formula (V') wherein:
R2and R3Independently of one another represent a hydrogen atom or C1-C6-an alkyl group;
R1a, P and Y are as defined for formula (I).
Among the compounds of the present invention, the fifteenth group of compounds includes compounds of formula (I) wherein R is1And/or R2And/or R3And/or A and/or P and/or Y are simultaneously as defined above in groups 9-14.
In the following, a leaving group X is understood to be a group which is susceptible to cleavage from the molecule by heterolytic bond cleavage, with simultaneous electron pair departure. Thus, this group is easily replaced by another group upon, for example, a substitution reaction. For example, such leaving groups are halogens or activated hydroxyl groups like methane sulfonate, benzene sulfonate, p-toluene sulfonate, trifluoromethyl sulfonate, acetate, and the like. Examples of leaving groups and references to their preparation are given in J.March, Advances in Organic Chemistry, 5 th edition, Wiley Interscience 2001.
In the following, a protecting group is understood to be a group which, when reacted, can temporarily enter into a chemical structure with the aim of temporarily deactivating the molecule and which can be easily removed in a subsequent step of the synthesis. Examples of protecting groups and references to their properties were given in t.w.greene, p.g.m.wutz, 3 rd edition, Wiley Interscience, 1999.
According to the invention, compound (I) of formula (I) can be prepared according to the following procedure, which is illustrated in general scheme 1:
scheme 1
Allowing a compound of the formula (Vl) in which B represents C1-C6-alkoxy, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3Alkylene oxide radical, aryl radical-C1-C3Alkylene oxy with P, Y and R1Is an amide with a compound of formula (VII) as defined by the general formula (I), wherein A, R2And R3These compounds (I) can be obtained by carrying out the reaction under reflux of a solvent such as toluene as defined in the above formula (I). The aluminum amides of the compounds of the formula (VII) are prepared by pre-reaction of trimethylaluminum with amines of the formula (VII).
When a compound of formula (VI) is used, B represents a hydroxy group, P, Y and R1As defined in formula (I), under reflux of a solvent such as dichloromethane or dichloroethane, by the action of, for example, thionyl chloride,the carboxylic acid function may be previously converted to an acid halide, such as an acid chloride. In this case, by reacting a compound of the formula (Vl) in which B represents a chlorine atom, and P, Y and R are1Is a reaction with a compound of the general formula (VII) as defined in formula (I), wherein A, R2And R3As defined above for formula (I) to give compounds of general formula (I).
Optionally, in coupling agents, such as dialkylcarbodiimide, hexafluorophosphoric acid [ (benzotriazol-1-yl) oxy group][ Tris (pyrrolidinyl)]A compound of formula (Vl) wherein B represents a hydroxyl group, and P, Y and R are1Are as defined for formula (I) and can be coupled with compounds of formula (VII).
In scheme 1, compounds of formulae (Vl) and (VII) and other reagents, when their preparation is not described, are commercially available, are described in the literature or are prepared using methods similar to those described in the literature (e.g. r.s. begnov et al, [ Russian j. org. chem., 2004, 40(11), 1740. 1742; v.m.reddy et al, [ j.indian chem. soc., 1984, (111), 89-91; k.v.b. rao et al, [ eur.j.med. chem., 1981, 16(1), 35-38; r.j.north et al, [ j.het.chem., 1969, 6, 655; a.r.freedman et al, [ j.het.chem., 1966, 3. bullion., sec. C., bec. 833, 3. bullion, 3. chem., bec. C., 3. beck., bec. C., 3, etc.).
Compounds of formula (Vl) or (I) in which the aryl or heteroaryl group is C-substituted with an alkyl group can be obtained, for example, by coupling reactions catalysed with a metal, for example palladium or iron, with the corresponding compounds of formula (Vl) or (I) substituted with a halogen atom, for example chlorine, in the presence of, for example, an alkylmagnesium halide or alkylzinc halide according to methods described in the literature (A.Furstner et al, J Am Chem Soc, 2002, 124(46), 13856; G.Que guiner et al, J Org Chem, 1998, 63(9), 2892) or known to the person skilled in the art.
Compounds of formula (Vl) or (I) in which the aryl or heteroaryl group is C-substituted with a cyano, aryl or heteroaryl group can be obtained by coupling reaction with the corresponding compound of formula (Vl) or (I), for example substituted with a bromine atom, catalysed by a metal such as palladium, or by any other method described in the literature or known to the person skilled in the art, in the presence of trimethylsilylcyanide, arylboronic acid or heteroarylboronic acid.
Compounds of formula (Vl) or (I) can be obtained according to the method of Buchwald (S.L. Buchwald et al, J Am Chem Soc, 2002, 124, 11684) by coupling reactions with the corresponding amines of formula (Vl) or (I) catalysed by a metal, for example copper, in the presence of aryl or heteroaryl halides, or by any other method described in the literature or known to the person skilled in the art, in which P is substituted by a substituent R corresponding to an aryl or heteroaryl group1To N-substitution.
The aryl or heteroaryl group substituted by NR, for example, can be obtained from the corresponding compound of formula (I) or (Vl) by a bromine atom, according to any other method described in the literature or known to the person skilled in the art, by coupling reaction with an amine, amide or sulfonamide, respectively, in the presence of a base, a phosphine and a palladium-based catalyst4R5、NR6COR7Or NR6SO2R8A group C-substituted compound of formula (I) or (Vl).
From the corresponding compound of formula (I) or (Vl) substituted by a cyano group, the compounds of formula (I) or (Vl) may be obtained by C (O) NR according to any other method described in the literature or known to the person skilled in the art4R5Group-substituted compounds of formula (I) or (Vl)
According to any other method described in the literature or known to the person skilled in the artBy oxidation of the corresponding compounds of formula (Vl) or (I) substituted by alkylthio groups, it is possible to obtain a compound substituted by-S (O) -alkyl or-S (O)2-compounds of formula (I) or (Vl) substituted with an alkyl group.
By NR from the corresponding compounds of formula (Vl) or (I) substituted by nitro groups, obtained, for example, by reduction, followed by acylation or sulfonylation, according to any other method described in the literature or known to the person skilled in the art4R5、NR6COR7Or NR6SO2R8A group-substituted compound of formula (Vl) or (I).
SO may be obtained by methods similar to those described in Pharmazie, 1990, 45, 346, or according to any other method described in the literature or known to those skilled in the art2NR4R5A group-substituted compound of formula (Vl) or (I).
For example, compounds of formula (I) or (Vl) wherein Y represents a sulfur atom, can be obtained by reaction of a corresponding compound of formula (I) or (Vl) wherein Y represents an oxygen atom, with a reagent such as Lawesson's reagent.
The compounds of formula (I) wherein R is3Corresponding to a protecting group carried by the nitrogen, e.g. an ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl group, to give a compound of formula (I) wherein R is3Is a hydrogen atom.
According to another aspect of the invention, another object of the invention is a compound of formula (VII-x) wherein x is a-n. These compounds are useful as intermediates in the synthesis of compounds of formula (I).
The amines (VII-b), (VII-j), (VII-k) and (VII-l) can be prepared according to scheme 2 below:
flow chart 2
Scheme 2 summarizes the process by which the amines (VII-b), (VII-j), (VII-k) and (VII-I) can be prepared in their racemic form. The first step is the substitution of the 2-fluoro-5-nitroaniline (IX) with the racemic amine (VIII). This reaction is carried out, for example, by heating the two reagents without solvent. The addition product (X) thus obtained is then cyclized to the heterocycle (X1) in the presence of a reagent such as trifluoroacetic acid and a reagent such as hydrogen peroxide, this reaction being carried out in a solvent solution such as dichloromethane (by optimizing the method described in a.r. freedman et al, j.het.chem., 1966, 3(3), 257). At R3In the case where it is not a hydrogen atom, the cyclization can give a mixture of positional isomers.
Compound (XI) (R) can be prepared, for example, by alkylation in the presence of a base such as sodium hydride and an alkylating agent such as methyl iodide or dimethyl sulfate3Hydroxy) to compound (XII), wherein R is3Is methoxy. The nitro group of compound (XI) or (XII) is then reduced in the presence of a catalyst such as palladium on charcoal or by any other method known to those skilled in the art for reducing nitro groups to amines to give amines (VII-b), (VII-j), (VII-k) or (VII-l).
The amines (VII-e) and (VII-f) can be prepared according to scheme 3 below:
flow chart 3
First step of a Process capable of preparing amines (VII-e) and (VII-f)Consists in substituting 2-fluoro-5-nitroaniline (IX) with piperazine (XIII) substituted on one of the nitrogens with a protecting group G. This reaction is carried out, for example, by heating the two reagents without solvent. The addition product (XIV) thus obtained is then cyclized to the heterocyclic compound (XV) in the presence of a reagent such as trifluoroacetic acid or formic acid and a reagent such as hydrogen peroxide, the reaction being carried out in a solution of a solvent such as dichloromethane. This heterocyclic compound (XV) may then be deprotected; for example if G ═ CO2CH3Hydrolysis in the presence of an acid such as hydrochloric acid (XV) affords an amine (XVI) which may be alkylated in a solvent such as tetrahydrofuran or dimethylformamide, for example in the presence of a base such as sodium hydride and an alkylating agent such as methyl iodide, to give the heterocycle (XVII). The nitro group of compound (XVII) is then reduced to give amine (VII-e) by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal or by any other method known to those skilled in the art for the reduction of nitro groups to amines. For example if G ═ CO2CH2Ph, in a solvent such as dimethylformamide, reduces the nitro group of the compound (XV) by reaction with a reagent such as tin chloride to prepare the amine (VII-f).
The amines (VII-a), (VII-c) and (VII-d) can be prepared according to scheme 4 below:
flow chart 4
The amine (VII-a) may be prepared, for example, by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal, by reduction of the corresponding nitro precursor (XVIII) described in the literature (r.j.north et al, j.het.chem., 1969, 6, 655), or by any other method of reduction of nitro groups to amines known to those skilled in the art.
The amine (VII-c) can be prepared in two steps from the nitro (XVIII) precursor described previously. Intermediate (XIX) may be prepared from precursor (XVIII) using a base such as sodium hydride and an alkylating agent such as methyl iodide in a solvent such as tetrahydrofuran or dimethylformamide. The compound (XIX) thus obtained is then converted into the amine (VII-c) by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal or by any other method known to the person skilled in the art for the reduction of nitro groups to amines.
The amine (VII-d) can be prepared in two steps from the nitro (XVIII) precursor described previously. Intermediate (XX) is prepared from precursor (XVIII) using a base such as sodium hydride and di-tert-butyl dicarbonate. The compound (XX) thus obtained is then converted into the amine (VII-d) by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal or by any other method known to the person skilled in the art for the reduction of the nitro group to the amine.
The amine (VII-g) was prepared according to scheme 5 below:
flow chart 5
Amines (VII-g) may be prepared in two steps from 2-iodo-4-nitro-chlorobenzene (XXI) (G.A.Olah, J.Org.chem., 1993(58) 3194-. First, compound (XXI) is reacted with aminopyrazine (XXII) in a solvent such as toluene in the presence of a catalyst such as palladium diacetate, phosphine, and a base such as cesium carbonate. The cyclized product (XXIII) is isolated under these conditions and finally the amine (VII-g) is obtained from the product by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal or by any other method known to the person skilled in the art for the reduction of nitro groups to amines.
The amines (VII-h) and (VII-i) can be prepared according to scheme 6 below:
flow chart 6
Condensation of 2-amino-5-nitrobenzimidazole (XXIV) with a reagent such as diethylacetal (XXV) enables isolation of the cyclized product (XXVI), a mixture of the two isomers. The nitro group of the heterocycle (XXVI) may be reduced to an amine group by reaction with tin chloride, or according to any other method known to those skilled in the art for the reduction of nitro groups to amines. Thus, amines (VII-h) and (VII-i) were obtained.
The amines (VII-m) and (VII-n) can be prepared according to scheme 7 below:
flow chart 7
The amines (VII-m) and (VII-n) can be prepared from formamide (XXVII) (S.L. Chupak, US2006135447) in four steps. By reaction with SOCl2And SO2Cl2Reaction of the mixture, formamide (XXVII) may be activated to the dichloroimine (XXVIII) form. Compound (XXVIII) may then be substituted with a diamine of structure (XXIX) wherein n is 3 or 4 to give a compound of structure (XXX). This compound can then be converted to the benzimidazole tricyclic (XXXI) in the presence of a catalyst such as palladium diacetate, a phosphine, and a base such as cesium carbonate. Reduction of the (XXXI) nitro group can give the amine (VII-m) or (VII-n) by catalytic hydrogenation in the presence of a catalyst such as palladium on charcoal, or by any other method known to those skilled in the art for reduction of nitro groups to amines.
The following table illustrates the chemical structures and physical properties of some examples of intermediate compounds of formula (VII) of the present invention.
In this table:
the column "PF (. degree. C.)" indicates the melting point of the product in degrees Celsius (. degree. C.), and if NMR is not "available", NMR spectra are described in the examples;
in the column "salts/bases" - "represents the compound in free base form and" HCl "represents the compound in hydrochloride form, and the ratio between the brackets is (acid: base) ratio.
TABLE 1
The following examples describe the preparation of some of the intermediate compounds of formula (VII) of the present invention. These exemplary compound numbers are those in table 1. Elemental microanalysis, LC-MS analysis (liquid chromatography coupled with mass spectrometry), i.r. or NMR spectroscopy confirmed the structure of the resulting compound.
Example I(Compound N ° VII-a)
6-amino-2, 3-dihydro-1H-imidazo [1, 2-a ] benzimidazoles
To a solution of 2.7g (13.22 moles) of 2.3-dihydro-6-nitro-1H-imidazo [1, 2-a ] benzimidazole (r.j.north et al, j.het.chem., 1969, 6, 655) in 100mL of methanol under argon with vigorous stirring was added 1g of 10% palladium on charcoal. To the reaction mixture 15g (0.23 mol) ammonium formate were added and the suspension was then stirred for 12 h. The solid was recovered by filtration and purified by silica gel column chromatography (eluent: dichloromethane-methanol). After drying under reduced pressure, 0.82g of the expected product is obtained as a gray solid.
Melting point (base): 235 ℃ C
1H NMR(DMSO D6)，δ(ppm)：3.89(m，4H)；4.38(m，2H)；6.18(dxd，1H)；6.46(d，1H)；6.58(s，1H)；6.73(d，1H)。
Example II(Compound N ° VII-b)
6-amino-2, 3-dihydro-1-methyl-1H-pyrrolo [1, 2-a ] benzimidazoles
II-12- (2-methylpyrrolidin-1-yl) -5-nitroaniline
To the shaft reactor, 5g (32.03 mmol) of 2-fluoro-5-nitroaniline and 4.9mL (48.04 mmol) of 2-methyl-pyrrolidine (rac) were added. The reactor was closed and the mixture was heated at 100 ℃ for 5 h. After cooling, the mixture was dissolved with 100mL of water and 100mL of dichloromethane. The organic phase is separated, washed with 50mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The product obtained was used as such in the subsequent reaction.
II-22, 3-dihydro-1-methyl-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole
2mL (22.6 mmol) of 35% aqueous hydrogen peroxide solution are added dropwise to a solution of 1g (4.52 mmol) of the 2- (2-methyl-pyrrolidin-1-yl) -5-nitroaniline from the previous step and 4mL (51.92 mmol) of trifluoroacetic acid in 20mL of dichloromethane. The mixture was heated to reflux for 30min, then cooled and redissolved in 100mL dichloromethane and 100mL saturated aqueous sodium bicarbonate. The organic phase is separated, washed with 50mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting orange oil (0.89g) was used as such in the subsequent reaction.
II-36-amino-2, 3-dihydro-1-methyl-1H-pyrrolo [1, 2-a ] benzimidazole (VIIb)
A suspension of 0.25g (1.15 mmol) of the mixture of 2, 3-dihydro-1-methyl-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole obtained in the preceding step and 10mg of 10% palladium on charcoal in 15mL of ethanol and 1mL of 1N aqueous hydrochloric acid was stirred at room temperature under 4 bar of hydrogen for four hours. After this time, the mixture was filtered, concentrated under reduced pressure, and dissolved with 100mL of dichloromethane and 100mL of 30% aqueous sodium hydroxide solution. The organic phase is separated, washed with 50mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (eluent: dichloromethane-methanol). After drying under reduced pressure, 0.133g of the expected product is obtained as a light brown solid. Melting point (base): 168-
1H NMR(DMSO D6)，δ(ppm)：1.49(d，3H)；2.16(m，1H)；2.75(m，1H)；2.9(m，2H)；3.2(m，2H)；4.41(sext.，1H)；6.51(dxd，1H)，6.92(d，1H)；7.08(d，1H)。
Example III: 6-amino-2, 3-dihydro-3-methyl-1H-imidazo [1, 2-a ]]Benzimidazole (Compound N)0VII-c)
III-12, 3-dihydro-3-methyl-6-nitro-1H-imidazo [1, 2-a ] benzimidazole (Compound XIX)
To the stirred suspension at 20 ℃ under argon were added 0.023g (0.59 mmol) 60% sodium hydride in 5mL tetrahydrofuran, 0.1g (0.49 mmol) 2, 3-dihydro-6-nitro-1H-imidazo [1, 2-a ] benzimidazole in 10mL tetrahydrofuran (r.j.north et al, j.het.chem., 1969, 6, 655). After stirring at 20 ℃ for 45 minutes, 30. mu.l (0.54 mmol) of methyl iodide was added, followed by stirring at 20 ℃ for 12 hours. After this time, the reaction mixture was poured into 100mL of water and then extracted three times with 30mL of dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. Thus 0.1g of the expected product (XIX) is obtained as a yellow solid, which is then taken up as such in the subsequent synthesis.
Melting point (base): 208 ℃ and 209 ℃.
III-26-amino-2, 3-dihydro-3-methyl-1H-imidazo [1, 2-a ] benzimidazole (Compound N ° VII-c)
To a vigorously stirred solution of 0.81g (3.71 mmol) of the compound (XIX) prepared in the preceding step in 70mL of methanol under argon was added 0.5g of 10% palladium on charcoal. To the reaction mixture was added 10g (0.153 mol) of ammonium formate, and then the suspension was stirred for 12 h. A solid was recovered by filtration and purified by silica gel column chromatography (eluent: dichloromethane-methanol). After drying under reduced pressure, 0.26g of the expected product is obtained as a gray solid.
Melting point (base): 185 deg.C and 190 deg.C
1H NMR(DMSO D6)，δ(ppm)：2.84(s，3H)；3.76(m，2H)；3.91(m，2H)；4.41(s，NH2)；6.19(dxd，1H)；6.48(d，1H)；7.71(d，1H)。
Example IV: 6-amino-2, 3-dihydro-3-tert-butoxycarbonyl-1H-imidazo [1, 2-a]Benzimidazole compounds
(Compound N ° VII-d)
IV-16-nitro-2, 3-dihydro-3-tert-butoxycarbonyl-1H-imidazo [1, 2-a ] benzimidazole (compound N ° XX):
to the stirred suspension at 20 ℃ under argon, 3.47g (86.8 mmol) of 60% sodium hydride in 482mL of tetrahydrofuran, 13.9g (57.86 mmol) of 2, 3-dihydro-6-nitro-1H-imidazo [1, 2-a ] benzimidazole (r.j.north et al, j.het.chem., 1969, 6, 655) are added in portions. After stirring for 2 hours at 20 ℃ 15.1mL (65.73 mmol) of di-tert-butyl dicarbonate was added, followed by stirring for 1h30 at 20 ℃. After this time, the reaction mixture was poured into 50mL of water. The precipitate was recovered by filtration and dried under reduced pressure. 14.31g of the expected product (XX) are thus obtained as a yellow solid, which is then taken up as such in the subsequent synthesis.
Melting point (base): 222 ℃ and 224 ℃.
IV-26-amino-2, 3-dihydro-3-tert-butoxycarbonyl-1H-imidazo [1, 2-a ] benzimidazole (compound N ° VII-d):
a suspension of 0.1g (0.33 mmol) of compound (XX) and 0.5g of 10% palladium on charcoal in 150mL of ethanol is stirred at 20 ℃ for four hours under 5 bar of hydrogen. After insoluble matter was removed by filtration, the obtained ethanol solution was concentrated under reduced pressure. Thus, 70mg of the desired product are obtained as a white solid.
Melting point (base): 198-200 deg.C
1H NMR(CDCl3) δ (ppm): 1.51(s, 9H); 2.25-3.55 (broad, NH)2)；4.01(m，2H)；4.32(m，2H)；6.48(dxd，1H)；6.83(d，1H)；6.91(d，1H)。
Example V: 7-amino-3-methyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] s]Benzimidazole (Compound N)0VII-e)
V-12- [4- (ethoxycarbonyl) pyrazin-1-yl]-5-nitroaniline (compound N ° XIV, G ═ CO)2Et)：
A mixture of 10g (64.06 mmol) of 2-fluoro-5-nitroaniline and 20.08mL (137.72 mmol) of N- (ethoxycarbonyl) piperazine was heated at 140 ℃ for 12 h. After this time, the mixture was concentrated under reduced pressure, and then 5mL of acetic acid was added. The precipitate was recovered by filtration, washed with water and then dried under reduced pressure. 18.5g of the desired product are then isolated as a yellow solid.
1H NMR(DMSO D6)，δ(ppm)：1.15(t，3H)；2.82(m，4H)；3.51(m，4H)；4.02(q，2H)；5.35(s，NH2)；6.95(d，1H)；7.38(dxd，1H)；7.5(d，1H)。
V-23-ethoxycarbonyl-7-nitro-1, 2, 3, 4-tetrahydropyrazino [1, 2-a)]Benzimidazole (compound N ° XV, G ═ CO)2Et)：
15mL (169.5 mmol) of a 35% aqueous hydrogen peroxide solution was added dropwise to a solution of 17g (57.76 mmol) of the compound (XIV) obtained in the preceding step and 60mL (51.92 mmol) of formic acid. The mixture was heated at 50 ℃ for one hour, then cooled, concentrated under reduced pressure, and dissolved in 200mL of dichloromethane and 300mL of saturated aqueous potassium bicarbonate. The organic phase is separated, washed with 100mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting foam was purified by column chromatography on silica eluting with a mixture of dichloromethane and methanol. Thus 3.9g of the desired compound are isolated as a solid, which is used as such for the subsequent synthesis.
V-37-Nitro-1, 2, 3, 4-Tetrahydropyrazino [1, 2-a ] benzimidazole (Compound N ° XVI)
A solution of 3.9g (13.44 mmol) of the compound (XV) obtained in the preceding step in 100mL of 6N hydrochloric acid was heated under reflux for 12 hours. After this time, the cold solution was adjusted to a pH > 9 by successive addition of concentrated sodium hydroxide and then extracted three times with 100mL of dichloromethane. The organic phases are combined, washed with 150mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol. 0.3g of the desired compound is then isolated as a solid, which is used as such for the subsequent synthesis.
1H NMR(CDCl3) δ (ppm): 1.91(1 broad peak, NH); 5.56(m, 2H); 4.28(m, 2H); 4.48(s, 2H); 7.5(d, 1H); 8.31(dxd, 1H); 8.72(d, 1H).
V-43-methyl-7-nitro-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazole (Compound N ° XVII)
To the stirred suspension at 20 ℃ under argon was added 0.07g (1.65 mmol) of 60% sodium hydride in 15mL of tetrahydrofuran, 0.3g (1.37 mmol) of the compound (XVI) obtained in the previous step in 20. mu.L (1.65 mmol) of methyl iodide, followed by stirring at 20 ℃ for 12 hours. After this time, the reaction mixture was poured into 100mL of water and then extracted three times with 30mL of dichloromethane. The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. Thus 0.13g of the desired product (XVII) is obtained, which is used as such in the subsequent synthesis.
1H NMR(CDCl3)，δ(ppm)：2.49(s，3H)；2.93(m，2H)；3.82(s，2H)；4.11(m，2H)；7.29(d，1H)；8.09(dxd，1H)；8.49(d，1H)。
V-57-amino-3-methyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazole (Compound N ° VII-e)
A suspension of 0.13g (0.56 mmol) of the compound (XVII) obtained in the preceding step, 0.2g of 10% palladium on charcoal and 5g (79.36 mmol) of ammonium formate is stirred at 20 ℃ for 12 hours. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure. 80mg of the expected product are then obtained as an oil.
1H NMR(CDCl3) δ (ppm): 2.48(s, 3H); 2.89(m, 2H); 3.75(s, 2H); 3.85 (broad, NH)2)；3.97(m，2H)；6.57(dxd，1H)；6.91(d，1H)；7(d，1H)。
Example VI: 7-amino-3-benzyloxycarbonyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] s]Benzimidazole (Compound N degree VII-f)
VI-12- [4- (benzyloxycarbonyl) pyrazin-1-yl]-5-nitroaniline (compound N ° XIV, G ═ CO)2CH2Ph)：
A mixture of 9.44g (60.5 mmol) of 2-fluoro-5-nitroaniline and 24.98mL (130.08 mmol) of N- (benzyloxycarbonyl) piperazine was heated at 140 ℃ for 12 h. After this time, the mixture was dissolved in 200mL of dichloromethane. The organic phase is successively washed with saturated aqueous potassium carbonate solution, three times with 50mL of water each time, then dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate. Thus 8.6g of the expected product are isolated.
1H NMR(CDCl3)，δ(ppm)：2.91(m，4H)；3.68(m，4H)；4.16(s，NH2)；5.18(s，2H)；6.92(d，1H)；7.35(m，5H)；7.6(m，2H)。
VI-23-Benzyloxycarbonyl-7-nitro-1, 2, 3, 4-tetrahydropyrazino [1, 2-a]Benzimidazole (compound N ° XV, G ═ CO)2CH2Ph)：
17.7mL (0.2 mol) of 35% aqueous hydrogen peroxide solution were added dropwise over a period of two hours to a solution of 8.6g (24.13 mmol) of the 2- [4- (benzyloxycarbonyl) pyrazin-1-yl ] -5-nitroaniline obtained in the preceding step and 34.4mL (29.4 mmol) of formic acid stirred at 0 ℃. The mixture was stirred at 0 ℃ for 3 hours, at 20 ℃ for 12 hours, and then poured into 300g of ice. The pH of the medium is adjusted to 8 by addition of aqueous ammonia solution and then extracted with 200mL of dichloromethane. The organic phase is washed with 100mL of saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of dichloromethane and ethyl acetate. Thus 1.2g of the expected product are isolated.
1H NMR(CDCl3)，δ(ppm)：4.11(m，2H)；4.21(m，2H)；5.05(s，2H)；5.18(s，2H)；7.38(m，6H)；8.21(dxd，1H)；8.61(d，1H)。
VI-37-amino-3-benzyloxycarbonyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazole (Compound N ° VII-f)
7.68g (34.06 mmol) of tin chloride dihydrate were added in portions to a solution of 2g (5.68 mmol) of the compound (XV) obtained in the preceding step and 2.6g (8.85 mmol) of tetrabutylammonium bromide in 56mL of dimethylformamide. The mixture is stirred at 20 ℃ for 24 hours, then concentrated and dissolved with 100ml of water. The pH of the solution thus obtained was adjusted to 9 by adding an ammonia solution. The mixture was then extracted with 100mL of ethyl acetate. The organic phases are combined, washed twice with 50mL of water and once with 50mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica eluting with a mixture of dichloromethane and methanol. Thus 1.45g of the expected product are isolated.
PF＝115-118℃
1H NMR(CDCl3)，δ(ppm)：3.89(m，2H)；4(m，2H)；4.7(m，4H)；5.12(s，2H)；6.51(dxd，1H)；6.71(d，1H)；7.12(d，1H)；7.38(m，5H)。
Example VII: 7-Aminopyrazino [1, 2-a ]]Benzimidazole (Compound N ° VII-g)
VII-17-Nitropyrazino [1, 2-a ] benzimidazole (Compound N.degree XXIII):
0.6g (2.12 mmol) 2-iodo-4-nitro-chlorobenzene (XXI) (G.A.Olah, J. org. chem. 1993(58)3194-A mixture of (9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene) and 30mg (0.13 mmol) of palladium diacetate in 20mL of anhydrous toluene was heated at 120 ℃ for 12 hours. After this time, the mixture was concentrated under reduced pressure and then dissolved in 350mL of dichloromethane and 200mL of water. The organic phase is separated, washed with 100mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting product was dissolved in 10mL of dichloromethane and 0.23g of the desired product was isolated as a precipitate, which was recovered by filtration. The filtrate was purified by silica gel column chromatography eluting with a mixture of ethyl acetate and heptane. 25mg of additional product are thus isolated.
VII-27-Aminopyrazino [1, 2-a ] benzimidazole (Compound N ° VII-g)
A suspension of 0.22g (1.03 mmol) of 7-nitro-pyrazino [1, 2-a ] benzimidazole obtained in the preceding step, 0.5g of Raney nickel and 0.1mL of hydrazine monohydrate (2.05 mmol) in 100mL of ethanol is stirred at 20 ℃ for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Thus, 0.16g of the expected product is obtained in the form of a light brown solid.
PF＝249-253℃
1H NMR(DMSO D6) δ (ppm): 5.27 (broad, NH)2)；6.72(m，2H)；7.71(d，1H)；7.89(d，1H)；8.73(d，1H)；8.89(s，1H)。
Example VIII: 7-aminopyrimidino [1, 2-a)]Benzimidazole (Compound N.degree.VII-h) and 8-aminopyrimidino [1, 2-a ]]Benzimidazole (Compound N degree VII-i)
VIII-17-Nitropyrimidino [1, 2-a ] benzimidazole hydrochloride and 8-Nitropyrimidino [1, 2-a ] benzimidazole hydrochloride (Compound N ℃ XXVI)
A mixture of 2g (11.2 mmol) of 2-amino-5-nitrobenzimidazole (J.Med.chem., 1995, 38(20), 4098-. 1.97g of a light brown precipitate is recovered by filtration and it is dried under reduced pressure. A mixture of isomers was obtained which was used as such in the subsequent steps.
VIII-27-Aminopyrimidino [1, 2-a ] benzimidazole (Compound N ° VII-h)
4.5g (19.95 mmol) of tin chloride dihydrate in 4mL of water are added to a suspension of 1g (3.99 mmol) of the mixture of compounds (XXVI) prepared in the preceding step in 8mL of concentrated hydrochloric acid, which is heated to 100 ℃. The reaction mixture was heated for 3 hours and then cooled, and the pH of the medium was adjusted to 8 by successive addition of 30% ammonia solution. The mixture was extracted three times with 100mL of dichloromethane. The organic phases are combined, dried over magnesium sulfate, concentrated under reduced pressure and then purified by column chromatography on silica, eluting with a mixture of dichloromethane and methanol. 7-aminopyrimidino [1, 2-a ] benzimidazole was then isolated as an orange solid.
1H NMR(DMSO D6)，δ(ppm)：5.21(m，NH2)；6.7(d，1H)；6.81(s，1H)；6.95(m，1H)；7.9(d，1H)；7.58(m，1H)；9.25(dxd，1H)。
VIII-38-Aminopyrimidino [1, 2-a ] benzimidazole (Compound N ° VII-i)
Insoluble material precipitated in the aqueous phase during the extraction described in example VIII-2. This insoluble material was recovered by filtration using a sintered glass filter, so that 0.13g of an orange solid, which corresponds to the compound n ° VII-i, could be isolated.
1H NMR(DMSO D6)，δ(ppm)：5.21(m，NH2)；6.91(m，2H)；7.2(d，1H)；7.51(d，1H)；8.57(m，1H)；9.12(dxd，1H)。
Example IX: 6-amino-2, 3-dihydro-3-hydroxy-1H-pyrrolo [1, 2-a ]]Benzimidazole (Compound N)0VII-j) and 6-amino-2, 3-dihydro-2-hydroxy-1H-pyrrolo [1, 2-a ]]Benzimidazole hydrochloride (Compound N degree VII-k)
IX-I2- (3-hydroxypyrrolidin-1-yl) -5-nitroaniline
In a similar manner to that described in example II-1, from 3g (19.22 mmol) of 2-fluoro-5-nitroaniline and 1.76ml (21.14 mmol) of 3-hydroxypyrrolidine, 2g of the desired compound are obtained as a yellow solid.
IX-22, 3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole and 2, 3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole
According to a similar manner to that described in example II-2, 2g (7.7 mmol) of the 2- (3-hydroxypyrrolidin-1-yl) -5-nitroaniline from the preceding step, after purification by silica gel column chromatography, gave 48mg of a yellow solid corresponding to 2, 3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole and 280mg of a yellow solid corresponding to 2, 3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole.
IX-36-amino-2, 3-dihydro-3-hydroxy-1H-pyrrolo [1, 2-a ] benzimidazole (Compound N ° VII-j)
According to a similar manner to that described in example VII-2, from 0.13g (0.56 mmol) of 2, 3-dihydro-3-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole prepared in step IX-2, 0.1g of the desired amine is isolated as a maroon solid (in this case the reaction mixture is stirred at 20 ℃ for 2 days).
1H NMR(CDCl3)，δ(ppm)：2.61(m，1H)；2.92(m，1H)；3.94(m，1H)；4.18(m，1H)；5.29(m，1H)；6.61(d，1H)；6.98(s，1H)；7.05(d，1H)。
IX-46-amino-2, 3-dihydro-2-hydroxy-1H-pyrrolo [1, 2-a ] benzimidazole hydrochloride (Compound N ° VII-k)
A mixture of 0.3g (1.36 mmol) of 2, 3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole obtained in step IX-2 and 100mg of 10% palladium on charcoal in 15mL of ethanol and 2mL of 1N hydrochloric acid is stirred at 20 ℃ under 4 bar of hydrogen for several hours. After this time, the reaction mixture was filtered through a celite buffer, and the filtrate was concentrated under reduced pressure to give 0.35g of the desired product as a solid.
1H NMR(DMSO D6)，δ(ppm)：3.05(m，1H)；3.55(dxd，1H)；4.15(m，1H)；4.45(dxd，1H)；5.1(m，1H)；7.0(m，1H)；7.3(m，1H)；7.66(m，1H)。
Example X: 6-amino-2, 3-dihydro-2-methoxy-1H-pyrrolo [1, 2-a ]]Benzimidazole (Compound N degree VII-I)
X-12, 3-dihydro-2-methoxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole
To a suspension of 60% 0.2g (5 mmol) of sodium hydride in 10mL of tetrahydrofuran under argon and stirring at 20 ℃ is added a solution of 0.28g (1.28 mmol) of 2, 3-dihydro-2-hydroxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole (example IX, step IX-2) in 5mL of tetrahydrofuran. After stirring for fifteen minutes, 0.24mL (2.5 mmol) of dimethyl sulfate was added. The reaction mixture was stirred at 20 ℃ for 12 hours, then poured into 100mL of water and extracted three times with 50mL of ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel, eluting with a mixture of dichloromethane and methanol. 70mg of the desired product are then isolated in the form of a foam.
X-26-amino-2, 3-dihydro-2-methoxy-1H-pyrrolo [1, 2-a ] benzimidazole (Compound N ° VII-l)
According to a similar manner to that described in example VII-2, 0.185g (0.79 mmol) of 2, 3-dihydro-2-methoxy-6-nitro-1H-pyrrolo [1, 2-a ] benzimidazole gave, after purification by silica gel column chromatography, 60mg of a beige solid corresponding to the desired product.
PF＝140-142℃
1H NMR(CDCl3)，δ(ppm)：3.01(dxd，1H)；3.25(dxd，1H)；3.38(s，3H)；3.94(dxd，1H)；4.19(dxd，1H)；4.62(m，1H)；6.57(dxd，1H)；6.95(d，1H)；7.02(d，1H)。
Example XI: 7-amino-4-methyl-1, 2, 3, 4-tetrahydropyrimidino [1, 2-a)]Benzimidazole hydrochloride (1: 1) (Compound N)0VII-m)
XI-1N- (2-bromo-5-nitrophenyl) imidized methyl (XXVIII)
A solution of 5g (20.4 mmol) of N- (2-bromo-5-nitrophenyl) formamide (XXVII) in 12mL (164 mmol) of thionyl chloride and 4.5mL (56 mmol) of sulfuryl chloride is heated at 60 ℃ for 24 hours. The reaction mixture was concentrated under reduced pressure to give 5.3g of a grey solid which was used as such in the subsequent synthesis.
XI-2N- (2-bromo-5-nitrophenyl) -N- (1-methyl-1H-3, 4, 5, 6-tetrahydropyrimidin-2-ylidene) amine (XXX)
To a solution of 10.5ml (0.1 mol) of N-methyl-1, 3-propanediamine (XXIX, N ═ 3) in 50ml of tetrahydrofuran was added, with stirring at 0 ℃, a suspension of 5.3g (17.8 mmol) of intermediate (XXVIII) in 30ml of tetrahydrofuran in portions. The reaction mixture was then stirred at 20 ℃ for 48 hours and poured into 200mL of water. The mixture was extracted three times with 50ml of ethyl acetate each time. The organic phases are combined, washed with 100mL of saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by column chromatography on silica eluting with a mixture of dichloromethane and methanol. Thus 0.72g of the desired product (XXIX) is isolated as a yellow solid.
XI-34-methyl-7-nitro-1, 2, 3, 4-tetrahydropyrimidino [1, 2-a ] benzimidazole (XXXI)
0.72g (2.3 mmol) of intermediate (XXX), 0.16g (0.28 mmol)A mixture of (9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene), 1.5g (4.6 mmol) of cesium carbonate and 30mg (0.14 mmol) of palladium diacetate in 20ml of toluene was heated at 120 ℃ for 24 hours. After this time, the mixture was concentrated under reduced pressure and then purified by silica gel column chromatography eluting with a mixture of dichloromethane and methanol. Thus 0.44g of the desired product (XXXI) are isolated.
PF＝172-178℃
1H NMR(CDCl3) δ (ppm): 2.42 (quintuple, 2H); 3.39(s, 3H); 3.58(t, 2H); 4.15(t, 2H); 7.09(d, 1H); 8.09(dxd, 1H); 8.38(d, 1H).
XI-47-amino-4-methyl-1, 2, 3, 4-tetrahydropyrimidino [1, 2-a ] benzimidazole hydrochloride (1: 1) (Compound N ° VII-m)
0.2mL (3.8 mmol) of hydrazine monohydrate was added to a suspension of 0.44g (1.89 mmol) of compound (XXX) and 0.3g of Raney nickel. The mixture was stirred at 20 ℃ for 3 hours, then filtered through a celite buffer, concentrated under reduced pressure and purified by silica gel column chromatography, eluting with a mixture of dichloromethane and methanol. Thus, 0.36g of the desired product (VII-m) was isolated. The product obtained is dissolved in 50ml of 0.1N isopropanol hydrochloride solution and the solution obtained is concentrated under reduced pressure, optionally the compound can be isolated in the form of its hydrochloride salt. Thus, the amine hydrochloride (VII-m) was isolated.
PF(HCl 1∶1)：335-340℃
1H NMR(CDCl3) δ (ppm): 2.17 (quintuple, 2H); 3.1(s, 3H); 3.25(t, 2H); 3.82(t, 2H); 6.31(dxd, 1H); 6.7(d, 1H); 6.76(d, 1H).
Example XII: 8-amino-5-methyl-1, 2, 3, 4-tetrahydro-5-H- [1, 3]Diaza derivativesAnd [1, 2-a ]]Benzimidazole (Compound N degree VII-N)
Compound (VII-n) was prepared from intermediates (XXVIII) and (XXIX, n ═ 4) according to a similar method to that described in example (XIII).
PF(2HCl)：330-336℃
1H NMR(CDCl3)，δ(ppm)：1.84(m，4H)；3.06(s，3H)；3.08(m，2H)；3.8(m，2H)；6.42(dxd，1H)；6.81(d，1H)；6.85(s，1H)。
The following examples describe the preparation of certain compounds of the invention. These examples are not intended to be limiting and are merely illustrative of the present invention. Exemplary compound numbers are those of tables 2, 3 and 4. Elemental microanalysis, LC-MS analysis (liquid chromatography coupled with mass spectrometry), i.r. or NMR spectroscopy confirmed the structure of the resulting compound.
Example 1(Compound N ° 1 of Table 2)
N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide
1.1.5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxylic acid ethyl ester
A solution of 5.5g (21.72 mmol) of 1, 1' -azobiscarbonyldipiperidine in 15mL of dry toluene is added dropwise to a solution of 3g (14.48 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 2.37g (21.72 mmol) of 4-pyridinemethanol and 5.45mL (21.72 mmol) of n-tributylphosphine in 200mL of toluene at 20 ℃ under argon. The mixture was stirred at 20 ℃ for 48 h. The reaction mixture was then concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: heptane/ethyl acetate). Thus 3.2g of the desired product are isolated, which is used as such for the subsequent synthesis.
1.2N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide (Compound n.o.1)
To a solution of 0.376g (2.01 mmol) of 7-amino-1, 2, 3, 4-tetrahydropyridine [1, 2-a ] benzimidazole (Saunders et al, J.chem.Soc., 1955, 3275-3287) in 70mL of anhydrous toluene under argon was added 1.26mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was then cooled to 0 ℃. 0.5g (1.68 mmol) of ethyl 5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxylate obtained in step 1.1 was added. The reaction mixture was heated to reflux for 12h, then cooled and added to 20mL ice cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to 9. The insoluble matter collected by filtration was purified by silica gel column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a mixture of dichloromethane and heptane. After drying under reduced pressure, 0.41g of a white solid was obtained.
Melting point (base): 292 ℃ and 293 DEG C
1H NMR(DMSO D6)，δ(ppm)：1.91(m，4H)，2.89(t，2H)，4.02(t，2H)；5.9(s，2H)；6.93(d，2H)；7.09(txd，1H)；7.5(m，5H)；7.89(d，1H)；8.4(d，2H)；10.35(s，1H)。
Example 2(Compound N.cndot.2 of Table 2)
N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
2.15-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid ethyl ester
A suspension of 1.035g (5 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate, 0.865g (6 mmol) of 3-fluorobenzyl chloride and 1.38g (10 mmol) of potassium carbonate in 50mL of dimethylformamide is stirred at 60 ℃ for 24H. The reaction mixture was then cooled and poured into a mixture of ice water and ethyl acetate. After decantation, the organic phase is separated and washed twice with 200mL of water and then with 200mL of saturated sodium chloride solution. The solution was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 0.97g of oil used as such in the subsequent steps is obtained.
2.2N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide (Compound n.degree.2)
To a solution of 0.426g (2.28 mmol) of 7-amino-1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazole (Saunders et al, J.chem.Soc., 1955, 3275-3287) in 70mL of anhydrous toluene under argon was added 1.43mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.6g (1.9 mmol) of ethyl 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylate obtained in step 2.1 was added. The reaction mixture was heated to reflux for 12h, then cooled and added to 20mL of cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to pH 9. The insoluble matter was recovered by filtration, and it was purified by silica gel column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. After drying under reduced pressure, 0.46g of a white solid was obtained.
Melting point (base): 286-287 deg.C
1H NMR(DMSO D6)，δ(ppm)：2(m，4H)，2.9(t，2H)，4.05(t，2H)；5.88(s，2H)；7.11(m，10H)；7.91(s，1H)；10.38(s，1H)。
Example 3(Compound N.cndot.3 of Table 2)
N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -1-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
3.11-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a suspension of 0.44g (11 mmol) of sodium hydride in 50ml of DMF was added 2g (10 mmol) of pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester (WO2004101563) in portions with stirring at 20 ℃. After stirring at room temperature for 1h, 2.1g (12 mmol) of benzyl bromide are added dropwise and the reaction mixture is stirred at room temperature for 20 h. Then 150mL of water and 150mL of diethyl ether were added with stirring. The aqueous phase was separated and extracted twice with 50mL of ether each time. The organic phases are combined, washed with 100mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on a silica gel column, eluting with a mixture of heptane and dichloromethane. Thus 2.3g of the expected product are isolated.
The melting point is 71-72 DEG C
3.2N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -1-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide (Compound n.degree.3)
To a solution of 0.32g (1.71 mmol) of 7-amino-1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazole (Saunders et al, J.chem.Soc., 1955, 3275-3287) in 20mL of anhydrous toluene under argon was added 1.1mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.4g (1.43 mmol) of ethyl 1-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate obtained in step 3.1 was added. The reaction mixture was heated under reflux for 6h, then cooled and 150mL of water, 2 drops of 35% aqueous sodium hydroxide solution and 150mL of dichloromethane were added with stirring. The aqueous phase was separated and extracted twice with 50mL of dichloromethane. The organic phases are combined, washed with 100mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel, eluting with a methanol-dichloromethane mixture. 0.55g of the product is then isolated, recrystallized from ethanol and, after drying in vacuo, 0.45g of the expected compound is obtained in the form of a powder.
The melting point is 233-
1H NMR(DMSO D6)，δ(ppm)：1.91(m，4H)，2.91(t，2H)，4.02(t，2H)；5.9(s，2H)；7.12(m，6H)；7.38(m，2H)；7.48(m，1H)，7.9(s，1H)，8.18(dxd，1H)，8.4(dxd，1H)。
Example 4(Compound N.cndot.4 of Table 2)
N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
4.11-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a suspension of 0.9g (3.5 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (Nazare, M. et al, Angewandte Chemie, International Ed., 2004, 43(34), 4526-propan 4528) in 45mL of anhydrous tetrahydrofuran were added, with stirring, 0.58g (5.23 mmol) of benzyl alcohol, 1.4g (5.23 mmol) of triphenylphosphine and 0.94g (5.23 mmol) of diethyl azodicarboxylate (DEAD). After stirring at room temperature for 20h, the reaction mixture was concentrated under reduced pressure and the product obtained was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and heptane. Thus 1g of the expected product is obtained.
Melting point of 72-73 deg.C
4.2N- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide (Compound N ° 4)
To a solution of 0.19g (1.03 mmol) of 7-amino-1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazole (Saunders et al, J.chem.Soc., 1955, 3275-3287) in 20mL of anhydrous toluene under argon was added 0.65mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.3g (0.86 mmol) of ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate obtained in step 4.1 was added. The reaction mixture was heated under reflux for 6h, then cooled and 150mL of water, 2 drops of 35% aqueous sodium hydroxide solution and 150mL of dichloromethane were added with stirring. The aqueous phase was separated and extracted twice with 50mL of dichloromethane. The organic phases are combined, washed with 100mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel, eluting with a methanol-dichloromethane mixture. 0.4g of the product is then isolated, it is recrystallized from acetonitrile and, after drying in vacuo, 0.35g of the expected compound is obtained in the form of a powder.
Melting point 241-
1H NMR(DMSO D6)，δ(ppm)：1.91(m，4H)，2.93(t，2H)，4.05(t，2H)；5.98(s，2H)；7.15(m，5H)；7.42(m，3H)；7.9(d，1H)，8.7(dxd，2H)，10.5(s，1H)。
Example 5(Compound N.cndot.5 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide
To a solution of 0.35g (2.01 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259) in 70mL of dry toluene under argon was added 1.26mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.5g (1.68 mmol) of ethyl 5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxylate obtained in step 1.1 was added. The reaction mixture was heated to reflux for 12h, then cooled and poured into 20mL of cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to 9. The insoluble matter was recovered by filtration, and it was purified by silica gel column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a dichloromethane-heptane mixture. After drying under reduced pressure, 0.23g of a white solid was obtained.
Melting point (base): 266 ℃ and 267 DEG C
1H NMR(DMSO D6)，δ(ppm)：2.6(m，2H)，2.9(t，2H)，4.08(t，2H)；5.9(s，2H)；6.95(d，2H)；7.1(txd，1H)；7.45(m，5H)；7.92(d，1H)；8.42(d，2H)，10.31(s，1H)。
Example 6(Compound N.cndot.6 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
To a solution of 0.39g (2.28 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259) in 70mL of anhydrous toluene under argon was added 1.43mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.6g (1.9 mmol) of ethyl 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylate obtained in step 2.1 was added. The reaction mixture was heated under reflux for 12h, then cooled and poured into 20ml of cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to 9. The insoluble matter was recovered by filtration, and it was purified by silica gel column chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from a mixture of dichloromethane and heptane. After drying under reduced pressure, 0.45g of a white solid was obtained.
Melting point (base): 257 ℃ of 256 materials
1H NMR(DMSO D6)，δ(ppm)：2.56(m，2H)，2.91(t，2H)，4.04(t，2H)；5.9(s，2H)；7.2(m，10H)；7.92(d，1H)；10.32(s，1H)。
Example 7(Compound N ° 7 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
To a solution of 0.185g (1.07 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259) in 20mL of anhydrous toluene under argon was added 0.67mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled again to 0 ℃ and 0.25g (0.89 mmol) of ethyl 1-benzyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate obtained in step 3.1 was added. The reaction mixture was heated under reflux for 6h, then cooled and 150mL of water, 2 drops of 35% aqueous sodium hydroxide solution and 150mL of dichloromethane were added with stirring. The aqueous phase was separated and extracted twice with 50mL of dichloromethane. The organic phases are combined, washed with 100mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel eluting with a mixture of methanol and dichloromethane. 0.34g of the product is then isolated, it is recrystallized from ethanol and, after drying in vacuo, 0.31g of the expected compound is obtained in the form of a powder.
Melting point of 251 ℃ and 252 DEG C
1H NMR(DMSO D6)，δ(ppm)：2.6(m，2H)，2.9(t，2H)，4.04(t，2H)；5.9(s，2H)；7.15(m，9H)；7.9(d，1H)，8.18(dxd，1H)，8.4(dxd，1H)。
Example 8(Compound N.cndot.8 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
To a solution of 0.18g (1.03 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259) in 20mL of anhydrous toluene under argon was added 0.65mL of trimethylaluminum (2M in toluene). After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.3g (0.86 mmol) of ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate obtained in step 4.1 was added. The reaction mixture was heated under reflux for 6h, then cooled and 150mL of water, 2 drops of 35% aqueous sodium hydroxide solution and 150mL of dichloromethane were added with stirring. The aqueous phase was separated and extracted twice with 50mL of dichloromethane. The organic phases are combined, washed with 100mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel, eluting with a methanol-dichloromethane mixture. 0.37g of the product is then isolated, it is recrystallized from acetonitrile and, after drying in vacuo, 0.3g of the expected compound is obtained in the form of a powder.
Melting point 268 ℃ and 270 DEG C
1H NMR(DMSO D6)，δ(ppm)：2.6(m，2H)，2.9(t，2H)，4.04(t，2H)；6(s，2H)；7.12(m，5H)；7.42(m，3H)；7.92(s，1H)，8.7(d，2H)。
Example 9(Compound N ° 148 of Table 3)
N- (pyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
To a solution of 0.348g (1.9 mmol) of 7-amino-pyrido [1, 2-a ] benzimidazole (Begunov et al, Russian J.org.chem., 2004, (40), 11, 1694-. After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.5g (1.9 mmol) of ethyl 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylate obtained in step 2.1 was added. The reaction mixture was heated to reflux for 12h, then cooled and added to 20mL of cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to 9. The insoluble material was recovered by filtration and purified by preparative chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. After drying under reduced pressure, 0.53g of the expected product is obtained as a white solid.
Melting point (base): 261 ℃ plus 262 DEG C
1H NMR(DMSO D6)，δ(ppm)：5.9(s，2H)；7.01(m，6H)；7.55(m，6H)；8.2(d，2H)；9.0(s，1H)。
Example 10(Compound N ° 149 Table 3)
N- (pyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide
To a solution of 0.442g (2.41 mmol) of 7-amino-pyrido [1, 2-a ] benzimidazole (Begusov et al, Russian J.org.chem., 2004, (40), 11, 1694-. After stirring at 0 ℃ for 15min, the mixture was warmed to 50 ℃ and kept stirring for 30 min. The mixture was cooled to 0 ℃ and 0.6g (2.01 mmol) of ethyl 5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxylate obtained in step 1.1 was added. The reaction mixture was heated to reflux for 12h, then cooled and added to 20mL of cold 1N hydrochloric acid solution. The pH of the aqueous phase was adjusted to 9. The insoluble material was filtered and purified by preparative chromatography (eluent: dichloromethane-methanol). The product thus purified is recrystallized from methanol. After drying under reduced pressure, 0.35g of the expected product is obtained as a white solid.
Melting point (base): 277 heat treatment 278 DEG C
1H NMR(DMSO D6)，δ(ppm)：5.9(s，2H)；6.99(m，3H)；7.11(dxt，1H)；7.58(m，6H)；8.21(m，2H)；8.44(d，2H)；9.05(d，1H)。
Example 11(Compound N ° 150 of Table 3)
N- (pyrimido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
11.15-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid
An aqueous sodium hydroxide solution prepared from 1.15g (28.92 mmol) of sodium hydroxide particles in 50mL of water was added to a solution of 7.6g (24.10 mmol) of ethyl 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylate (from step 2.1) in 240mL of ethanol. The mixture was heated for two hours and then concentrated under reduced pressure. The resulting solid was dissolved in 200mL of water. The solution is washed twice with 100mL of ether and acidified by successive addition of small amounts of concentrated hydrochloric acid, and then extracted with 200mL of ethyl acetate. Finally, the organic phase is washed twice with 100mL of water, once with 50mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Drying at 50 ℃ under reduced pressure gives 6.4g of the expected product as a solid, which is used as such in the subsequent steps.
11.2N- (pyrimido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide (Compound n.degree.150)
To a solution of 0.22g (0.76 mmol) of the compound prepared in step 11.1, 146mg (0.76 mmol) of N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (EDAC) and 103mg (0.76 mmol) of 1-Hydroxybenzotriazole (HOBT) in 5ml of DMF was added 140mg (0.532 mmol) of 70% pure 7-amino-pyrimido [1, 2-a ] benzimidazole (VII-h) with stirring at 20 ℃. The reaction mixture was stirred at 20 ℃ for 48 hours and then poured into 50ml of water. The mixture was then extracted 3 times with 30mL of ethyl acetate. The combined organic phases were washed twice with 20mL of water, dried over magnesium sulfate and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol. 90mg of the desired product are then isolated.
PF＝295-298℃
1H NMR(DMSO D6)，δ(ppm)：10.7(s，1H)；9.49(d，1H)；8.82(d，1H)；8.3(m，2H)；7.79(d，1H)；7.6(m，2H)；7.47(s，1H)；7.31(m，1H)；7.17(m，2H)；7.05(m，1H)；6.82(m，2H)；5.93(s，2H)。
Example 12(Compound N.degree.154 of Table 4)
N- (2-methoxy-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide hydrochloride (1: 1)
Compound 154 was prepared according to a similar procedure as described in example 11.2 from the acid prepared in step 11.1 and 6-amino-2-methoxy-pyrrolo [1, 2-a ] benzimidazole (VII-1). The solid obtained is then dissolved hot in a mixture of 2.1mL of 0.1N propanol hydrochloride solution and 1mL of methanol. After cooling the medium, the precipitate is recovered by filtration and dried under reduced pressure. The desired product is then isolated as the hydrochloride salt.
PF(HCl 1∶1)＝220-225℃
1H NMR(DMSO D6)，δ(ppm)：3.21(d，1H)；3.35(s，3H)；3.52(dxd，1H)；4.38(m，2H)；4.8(m，1H)；5.89(s，2H)；6.89(m，2H)；6.91-7.33(m，3H)；7.4-7.8(m，4H)；8.27(s，1H)；10.68(s，1H)。
Example 13(N of Table 3. 151.)
N- (pyrazino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide hydrochloride (1: 1)
Compound 151 was prepared from the acid prepared in step 11.1 and 7-amino-pyrazino [1, 2-a ] benzimidazole (VII-g) according to a similar method to that described in example 12.
PF(HCl 1∶1)＝225-230℃
1H NMR(DMSO D6)，δ(ppm)：5.91(s，2H)；6.81-7.38(m，5H)；7.58(m，3H)；7.91(d，1H)；8.22(d，1H)；8.49(m，2H)；9.2(d，1H)；9.33(s，1H)；10.8(s，1H)。
Example 14(N degree 26 of Table 2)
N- (2, 3-dihydro-3-methylimidazo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
Compound 26 was prepared according to a similar method to that described in example 1.2 from ethyl 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylate obtained in step 2.1 and 6-amino-2, 3-dihydro-1-methyl-imidazo [1, 2-a ] benzimidazole (VII-c).
PF＝281-282℃
1H NMR(DMSO D6)，δ(ppm)：3.1(s，3H)；4.1-4.35(m，4H)；5.89(s，2H)；6.82(m，2H)；6.92-7.2(m，2H)；7.21-7.35(m，2H)；7.39(s，1H)；7.53(m，3H)；7.91(s，1H)。
Example 15(N50 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (quinolin-2-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
15.11- [ (Quinolin-2-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a suspension of 0.15g (0.581 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (Nazare, M. et al, Angewandte Chemie, International Ed., 2004, 43(34), 4526-propan 4528) in 2mL of anhydrous tetrahydrofuran were added, with stirring, 0.14g (0.871 mmol) (quinolin-2-yl) methanol, 0.228g (0.871 mmol) triphenylphosphine and 0.151g (0.871 mmol) of diethyl azodicarboxylate (DEAD). After stirring at room temperature for 20h, the reaction mixture was concentrated under reduced pressure and the product obtained was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and heptane. Thus 0.18g of the expected product is obtained as a yellow oil.
15.2N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (quinolin-2-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide (Compound n.degree.50)
Compound 50 was prepared according to a similar method to that described in example 5 from 0.18g (0.45 mmol) of the compound obtained in step 15.1 and 0.094g (0.541 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259). Thus 0.22g of the expected product is obtained.
PF＝300-301℃
1H NMR(DMSO D6)，δ(ppm)：2.61(q，2H)；2.94(t，2H)；4.08(t，2H)；6.26(s，2H)；7.22(d，1H)；7.37(d，1H)；7.55-7.46(m，2H)；7.6(s，1H)；7.67(dxt，1H)；7.8(d，1H)；7.95-7.81(m，2H)；8.27(d，1H)；8.73(s，2H)；10.65(s，1H)。
Example 16(N25 of Table 2)
N- (1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
1N- (2-Benzyloxycarbonyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide.
This compound was prepared according to a similar procedure to that described in example 11.2 from 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid and amine (VII-f) described in example 11.1.
16.2N- (1, 2, 3, 4-Tetrahydropyrazino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide (Compound n.degree.25)
A suspension of 1g (1.69 mmol) of the compound prepared in the preceding step and 0.1g of 10% palladium on charcoal in 100ml of ethanol is stirred at 20 ℃ under 5.5 bar of hydrogen for 6 hours. This suspension was then filtered through a celite buffer and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol. The purified product was dissolved in 10mL of 0.1N isopropanol hydrochloride solution, the solution was concentrated under reduced pressure, the resulting solid was triturated in ether and 0.48g of the desired product was isolated.
PF(1HCl)＝276-284℃
1H NMR(DMSO D6)，δ(ppm)：3.73(t，2H)；4.38(t，2H)；4.59(s，3H)；5.59(s，2H)；6.9(m，2H)；7.02(txd，1H)；7.15(txd，1H)；7.31(m，1H)；7.45(s，1H)；7.58(m，3H)；8.1(s，1H)；9.97(s，1H)；10.45(s，1H)。
Example 17(N degree 81 of Table 2)
N- (3-methyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
Compound 81 was prepared according to a similar method to that described in example 6 from 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid ethyl ester obtained in step 2.1 and 7-amino-3-methyl-1, 2, 3, 4-tetrahydropyrazino [1, 2-a ] benzimidazole (VII-e).
1H NMR(DMSO D6)，δ(ppm)：2.45(s，3H)，2.89(t，2H)，3.74(s，2H)；4.1(t，2H)；5.9(s，2H)；6.81-7.6(m，10H)；7.97(d，1H)；10.46(s，1H)。
Example 18(N degree 84 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (2-benzyloxyethyl) -1H-indole-2-carboxamide
18.15-fluoro-1- (2-benzyloxyethyl) -1H-indole-2-carboxylic acid ethyl ester
Mu.l (0.657 mmol) of 2-benzyloxyethanol and 50.4mg (0.438 mmol) of (cyanomethylene) trimethylphosphine (phoshsrane) (Tet. Lett., 1996, 37, 2459-2459) are added with stirring to a solution of 68mg (0.329 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in 2mL of toluene at 20 ℃. The reaction mixture was heated at 110 ℃ for 12 hours, then concentrated under reduced pressure, dissolved in 20mL of diethyl ether, filtered with a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC eluting with a mixture of water, acetonitrile and trifluoroacetic acid. 99mg of a yellow oil are thus isolated.
1H NMR(DMSO D6)，δ(ppm)：1.3(t，3H)，3.72(t，2H)，4.28(q，2H)；4.38(s，2H)；4.81(t，2H)；7.28-7.07(m，7H)；7.45(dxd，1H)；7.68(dxd，1H)。
18.2N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (2-benzyloxyethyl) -1H-indole-2-carboxamide (Compound n.degree.84)
Compound 84 was prepared from 5-fluoro-1- (2-benzyloxyethyl) -1H-indole-2-carboxylic acid ethyl ester and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole obtained in the preceding step (Freedman et al, J.het.chem., 1966, 3, (3), 257) -259) according to a similar procedure to that described in example 6.
PF＝186-187℃
1H NMR(DMSO D6)，δ(ppm)：2.63(m，2H)；2.93(m，2H)；3.75(m，2H)；4.09(m，2H)；4.39(s，2H)；4.81(m，2H)；7.01-7.19(m，6H)；7.25(s，1H)；7.31-7.62(m，3H)；7.62(dxd，1H)；7.97(m，1H)；10.23(s，1H)。
Example 19(N degree 82 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- {2- [ (5-methylpyridin-2-yl) oxy ] ethyl } -1H-indole-2-carboxamide
19.12- [ (5-methylpyridin-2-yl) oxy ] ethanol
A suspension of 0.291mL (4.12 mmol) of 2-bromoethanol, 0.3g (2.75 mmol) of 2-hydroxy-5-methylpyridine and 0.85g (6.18 mmol) of potassium carbonate in 3mL of dimethylformamide was vigorously stirred, and heated under reflux for 12 hours. The mixture was then diluted with 100mL of water and extracted with 100mL of dichloromethane. The organic phase was washed with 50mL of water, dried over sodium sulfate, concentrated under reduced pressure and then purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate. The desired product is then isolated.
1H NMR(DMSO D6)，δ(ppm)：2.2(s，3H)；3.66-3.71(m，2H)；4.22(t，2H)；4.77(t，1H)；6.71(d，1H)；7.51(dxd，1H)；7.95(dxd，1H)。
19.25-fluoro-1- {2- [ (5-methylpyridin-2-yl) oxy ] ethyl } -1H-indole-2-carboxylic acid ethyl ester
In a similar manner to that described in example 18.1, from ethyl 5-fluoro-1H-indole-2-carboxylate prepared in the preceding step and 2- (5-methylpyridin-2-yloxy) ethanol, the intermediate ethyl 5-fluoro-1- [2- [ (5-methylpyridin-2-yl) oxy ] ethyl ] -1H-indole-2-carboxylate was prepared.
19.3N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- {2- [ (5-methylpyridin-2-yl) oxy ] ethyl } -1H-indole-2-carboxamide (Compound n.degree.82)
Compound 82 was prepared from the compound obtained in the previous step and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259) according to a similar method to that described in example 6.
PF＝209-210℃
1H NMR(DMSO D6)，δ(ppm)：2.11(s，3H)；2.61(m，2H)；2.91(m，2H)；4.09(m，2H)；4.49(m，2H)；4.91(m，2H)；6.41(d，1H)；7.11(dxt，1H)；7.21(s，1H)；7.32-7.56(m，4H)；7.62(dxd，1H)；7.89(d，1H)；7.97(d，1H)；10.29(s，1H)。
Example 20(N degree 83 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- [2- { [ (5-trifluoromethyl) pyridin-2-yl ] oxy } ethyl ] -1H-indole-2-carboxamide
20.12- [ (5-trifluoromethyl) pyridin-2-yl) oxy ] ethanol
This compound was prepared according to a similar procedure to that described in example 19.1 from 2-bromoethanol and 2-hydroxy-5- (trifluoromethyl) pyridine.
20.2.5-fluoro-1- [2- { [ (5-trifluoromethyl) pyridin-2-yl ] oxy } ethyl ] -1H-indole-2-carboxylic acid ethyl ester
This intermediate was prepared in a similar manner to that described in example 18.1 from ethyl 5-fluoro-1H-indole-2-carboxylate and 2- [ [5- (trifluoromethyl) pyridin-2-yl ] oxy ] ethanol prepared in the previous step.
20.3N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1 [2- { [ (5-trifluoromethyl) pyridin-2-yl ] oxy } ethyl ] -1H-indole-2-carboxamide (Compound n.degree.83)
Compound 83 is prepared according to a similar procedure to that described in example 6 from ethyl 5-fluoro-1- [2- [ [ (5-trifluoromethyl) pyridin-2-yl ] oxy ] ethyl ] -1H-indole-2-carboxylate and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole obtained in the preceding step (Freedman et al, j.het.chem., 1966, 3, (3), 257-259).
[MH]+＝524
1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)；2.89(m，2H)；4.05(m，2H)；4.59(m，2H)；4.98(m，2H)；6.69(d，1H)；7.11(dxt，1H)；7.23(s，1H)；7.3-7.52(m，3H)；7.63(dxd，1H)；7.84(dxd，1H)；7.97(s，1H)；8.45(s，1H)；10.28(s，1H)。
Example 21(N degree 127 Table 2)
N- (3, 4-dihydro-1H-Oxazino [1, 4 ]][4，3-a]Benzoimidazol-7-yl) -1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b]Pyridine-2-carboxamides
21.12-amino-3-iodo-5-fluoropyridines
In a 500mL two-necked flask equipped with a magnetic stirrer, 5g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9g (44.6 mmol) of silver sulfate and 400mL of ethanol were added. Then 11.31g (44.6 mmol) of iodine powder was added in small portions. Followed by stirring at room temperature for 24 hours. Insoluble matter was removed by filtration, it was washed with ethanol, and the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in a mixture of ethyl acetate (200mL) and sodium carbonate solution (200 mL). After separation, the organic phase is washed successively first with 25% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is purified by chromatography on a silica gel column, eluting with a mixture of n-heptane and ethyl acetate. 2.67g (11.22 mmol) of the expected product are obtained.
1H NMR(DMSO D6)，δ(ppm)：7.95(s，1H)；7.85(s，1H)；5.9(s，NH2)。
21.25-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid
To a 25mL sealed tube equipped with a magnetic stirrer and kept bubbling of argon, 0.5g (2.10 mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in step 5.1, 0.55g (6.3 mmol) of pyruvic acid, 0.71g (6.3 mmol) of 1, 4-diazabicyclo [2.2.2] octane (DABCO), and 15mL of anhydrous dimethylformamide were added. After a few minutes, 0.05g (0.22 mmol) of palladium acetate is added. The reaction mixture was kept under stirring and bubbled with argon for 20 minutes, then sealed quickly and heated at 100 ℃ for 2h 30. The cold solution was concentrated under reduced pressure. The residue was then dissolved in ethyl acetate (100mL) and water (75 mL). The organic phase is washed with water and then extracted twice with 50mL portions of 2N aqueous sodium hydroxide solution. The basic aqueous phases are combined, cooled to 0 ℃ and acidified (pH3) by addition of hydrochloric acid. The medium was extracted with ethyl acetate (4 × 50mL), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. 0.158g (0.88 mmol) of the expected product are obtained in the form of a yellow powder.
1H NMR(DMSO D6)，δ(ppm)：13.2(s，1H)；12.4(s，1H)；8.4(d，1H)；7.95(dd，1H)；7.1(d，1H)。
21.35-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
In a 100mL round bottom flask equipped with a magnetic stirrer, 0.2g (1.11 mmol) of the acid obtained in step 21.2 and 10mL of ethanol were added. To the reaction mixture was added 1mL of concentrated sulfuric acid, followed by heating and refluxing for 18 hours. The cooled solution was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (50mL), which was washed successively with standard aqueous sodium hydroxide (2X 10mL), water (10mL), and then with saturated aqueous sodium chloride. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. 0.21g of the expected product is isolated
1H NMR(DMSO D6)，δ(ppm)：12.6(s，NH)；8.4(d，1H)；8.0(dd，1H)；7.1(d，1H)；4.35(q，2H)；1.35(t，3H)。
21.41-benzyl-5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester was prepared from benzyl alcohol and ethyl 5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate prepared in the previous step according to a similar procedure as described in example 4.1.
PF＝74-75℃。
21.5N- (3, 4-dihydro-1H-)Oxazino [1, 4 ]][4，3-a]Benzoimidazol-7-yl) -1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b]Pyridine-2-carboxamide (Compound n.degree.127)
Compound n ° 127 was prepared according to a similar method to that described in example 4.2 from ethyl 1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate and 7-amino-morpholino [4, 3-a ] benzimidazole (mulloc, e.b., j.chem.soc., Section C, 1970, (6), 829-.
PF＝231-232℃
1H NMR(DMSO D6)，δ(ppm)：4.15(m，4H)，4.91(s，2H)，5.9(s，2H)；7.02-7.26(m，5H)；7.35(s，1H)；7.5(m，2H)；8.01(s，1H)；8.12(dxd，1H)；8.46(m，1H)；10.44(s，1H)。
Example 22(Compound N of Table 20128)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
The compound n ° 128 was prepared from 1-benzyl-5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole described in example 21.4 (Freedman et al, j.het.chem.), 1966, 3, (3), 257-259) according to an analogous procedure to that described in example 4.2.
PF＝259-260℃
1H NMR(DMSO D6)，δ(ppm)：2.59(m，2H)，2.89(t，2H)，4.05(t，2H)；5.89(s，2H)；7.01-7.24(m，5H)；7.35(m，2H)；7.45(dxd，1H)；7.91(s，1H)；8.1(dxd，1H)；8.41(m，1H)；10.41(s，1H)。
Example 23(Compound N ° 129 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide
23.13-amino-2-iodo-6- (trifluoromethyl) pyridine
To a mixture of 1g (6.17 mmol) of 3-amino-6- (trifluoromethyl) pyridine and 1.25g (6.17 mmol) of silver sulfate in 40ml of ethanol under stirring at 20 ℃ under argon, 1.56g (6.17 mmol) of iodine was added in portions. This stirring was maintained for 18 hours. Insoluble matter was removed by filtration, it was washed with ethanol, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 100mL of methylene chloride. The organic phase was successively washed with 20mL of 5% aqueous sodium hydroxide solution, 40mL of water and 20mL of saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: heptane-ethyl acetate). 1.17g of the expected product are then isolated and passed as such to the subsequent synthesis.
23.25-trifluoromethyl-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid
To a sealed tube were added 0.5g (1.74 mmol) of 3-amino-2-iodo-6- (trifluoromethyl) pyridine obtained in step 23.1, 0.45g (5.21 mmol) of pyruvic acid, 0.51mL (5.21 mmol) of 1, 4-diazabicyclo [2.2.2] octane and 10mL of anhydrous dimethylformamide under argon. The solution was degassed for a few minutes. Then 0.19g (0.87 mmol) of palladium acetate was added, the tube was closed, and the mixture was heated under reflux at 130 ℃ for 4 hours. The solution was cooled and then concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate. The organic phase was extracted twice with 50mL portions of 2N aqueous sodium hydroxide solution. The aqueous alkaline phases are combined, cooled to 0 ℃ and acidified by addition of hydrochloric acid, and then extracted 4 times with 50mL portions of ethyl acetate. The organic phases are combined, washed with 20mL of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. 0.22g of product is obtained, which is used as such in the subsequent steps.
23.35- (trifluoromethyl) pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.2g (0.87 mmol) of 5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid obtained in step 23.2 in 10mL of ethanol was added 1mL (18.71 mmol) of concentrated sulfuric acid. The solution was stirred at reflux for 20 hours, then cooled and concentrated under reduced pressure. The residue obtained is then dissolved in 50mL of dichloromethane and washed successively with 20mL of saturated aqueous sodium bicarbonate solution, 40mL of water and 20mL of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. 0.19g of the product was obtained as such for the subsequent steps.
23.41-benzyl-5-trifluoromethyl-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester
Ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate was prepared from benzyl alcohol and the compound prepared in the previous step according to a similar method to that described in example 4.1.
23.5N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide (Compound N ° 129)
The compound n ° 129 was prepared according to a similar procedure to that described in example 4.2 from ethyl 1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-d ] pyridine-2-carboxylate and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole described in the previous step (Freedman et al, j.het.chem., 1966, 3, (3), 257-259).
PF＝251-252℃
1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)，2.91(t，2H)，4.09(t，2H)；5.92(s，2H)；7.05-7.29(m，5H)；7.31-7.5(m，2H)；7.56(s，1H)；7.7(d，1H)；7.91(s，1H)；8.29(d，1H)；10.51(s，1H)。
Example 24(Compound N130 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (pyridin-4-yl) methyl ] -5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
24.11- [ (pyridin-4-yl) methyl ] -5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a solution of 5g (24.02 mmol) of ethyl 5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (example 21.3), 3.97g (36.02 mmol) of (pyridin-4-yl) methanol and 7.5g (36.02 mmol) of tributylphosphine in 150mL of toluene were added 9.18g (36.02 mmol) of 1, 1' - (azodicarbonyl) dipiperidine over 15 minutes with stirring at 20 ℃. The reaction mixture was stirred at 20 ℃ for 16 hours, filtered through a celite buffer, concentrated under reduced pressure, and then dissolved in 100mL of dichloromethane. The organic solution was washed twice with 50mL of 5% aqueous potassium carbonate solution and then once with 50mL of water, dried over sodium sulfate and concentrated under reduced pressure. The product obtained is purified by column chromatography on silica eluting with a mixture of heptane and ethyl acetate, whereupon 4.5g of the desired ester are isolated.
PF＝120-121℃
24.2N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (pyridin-4-yl) methyl ] -5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide (Compound N ° 130)
The compound n ° 130 was prepared from ethyl 1- [ (pyridin-4-yl) methyl ] -5-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate and 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole described in the preceding step (Freedman et al, j.het.chem., 1966, 3, (3), 257-259) according to a similar procedure to that described in example 1.2.
PF＝283-285℃
1H NMR(DMSO D6)，δ(ppm)：2.62(m，2H)，2.92(t，2H)，4.09(t，2H)；5.93(s，2H)；7.01(d，2H)；7.38(d，1H)；7.49(m，2H)；7.95(s，1H)；8.2(d，1H)；8.45(m，3H)；10.42(s，1H)。
Example 25(Compound N131 of Table 2)
N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (pyridin-4-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide
25.11- [ (pyridin-4-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester
In a similar manner to that described in example 24.1, from 5g (18.4 mmol) of ethyl 5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxylate (example 23.3) and 3.04g (27.6 mmol) of (pyridin-4-yl) methanol, 4.2g of the expected compound are isolated.
PF＝130-131℃
25.2N- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1- [ (pyridin-4-yl) methyl ] -5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide (Compound N ° 131)
According to a similar manner to that described in example 24.2, from 0.3g (0.86 mmol) of the compound obtained in the preceding step and 0.178g (1.03 mmol) of 6-amino-2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazole (Freedman et al, J.het.chem., 1966, 3, (3), 257-259), 0.25g of the desired compound is isolated as a white solid.
PF＝270-271℃
1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)12.92(t，2H)，4.09(t，2H)；5.99(s，2H)；7.01(d，2H)；7.43(m，2H)；7.71(s，1H)；7.79(d，1H)；7.95(s，1H)；8.25(d，1H)；8.43(d，2H)；10.51(s，1H)。
Example 26(Compound N ° 132 of Table 2)
N- (4-methyl-1, 2, 3, 4-tetrahydropyrimidino [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide hydrochloride (1: 1)
Compound 132 was prepared according to a similar procedure as described in example 11.2 from 0.312g (1.09 mmol) 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid and 0.22g (1.09 mmol) 7-amino-4-methyl-1, 2, 3, 4-tetrahydropyrimidino [1, 2-a ] benzimidazole (VII-m). 0.41g of the expected product is isolated as a pale yellow solid. The compound was dissolved in 50ml of 0.1n propanol hydrochloride solution. The resulting solution was concentrated under reduced pressure, whereupon compound 139 was isolated as the hydrochloride salt.
PF(HCl 1∶1)＝343-349℃
1H NMR(DMSO D6)，δ(ppm)：
Example 27(Compound N.cndot.24 of Table 2)
N- (3, 4-dihydro-1H-Oxazino [1, 4 ]][4，3-a]Benzoimidazol-7-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b]Pyridine-2-carboxamides
According to a similar method to that described in example 4.2, by 1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] described in example 4.1]Pyridine-2-carboxylic acid ethyl ester and 7-aminoOxazino [1, 4 ]][4，3-a]Compound 24 was prepared by reaction between benzimidazole (Mullock, e.b., Section C, 1970, (6), 829-.
PF＝236-237℃
1H NMR(DMSO D6)，δ(ppm)：4.12(m，4H)，4.91(s，2H)，5.95(s，2H)；7.02-7.28(m，5H)；7.5(m，3H)；8.01(d，1H)；8.68(d，1H)；8.78(d，1H)；10.55(s，1H)。
Example 28(Compound N15 of Table 2)
N- (3, 4-dihydro-1H-Oxazino [1, 4 ]][4，3-a]Benzoimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide
According to andexample 6 analogously as described by reaction of 5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxylic acid ethyl ester obtained in step 2.1 with 7-aminoOxazino [1, 4 ]][4，3-a]Compound 15 was prepared by reaction between benzimidazole (Mullock, e.b., Section C, 1970, (6), 829-.
PF＝216-217℃
1H NMR(DMSO D6)，δ(ppm)：4.15(m，4H)，4.91(s，2H)，5.85(s，2H)；6.82-7.61(m，10H)；8(s，1H)；10.39(s，1H)。
Example 29(Compound N.cndot.133 of Table 2)
N- [2, 3-dihydro-3- (tert-butoxycarbonyl) imidazo [1, 2-a ] benzimidazol-6-yl ] -1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide
Compound 133 was prepared according to the procedure described for example 11 from 6-amino-2, 3-dihydro-1-tert-butoxycarbonyl-imidazo [1, 2-a ] benzimidazole (VII-d) and ethyl 1-benzyl-5-trifluoromethyl-pyrrolo [3, 2-b ] pyridine-2-carboxylate (23.4).
PF＝169-174℃
1H NMR(DMSO D6)，δ(ppm)：1.51(s，9H)，4.27(m，4H)，5.94(s，2H)；7.09-7.31(m，6H)；7.42(dxd，1H)；7.58(s，1H)；7.71(d，1H)；7.84(s，1H)；8.29(d，1H)；10.52(s，1H)。
Example 30(Compound N ° 137 of Table 2)
N- (2, 3-dihydro-imidazo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide
A solution of 0.18g (0.31 mmol) of compound 133 (example 29) in 10mL of 2M ethereal hydrochloride is stirred at 20 ℃ for 16 h. After this time, the yellow precipitate was filtered off, which was dried under reduced pressure, and the desired product 137 was isolated.
1H NMR(DMSO D6)，δ(ppm)：4.3(m，4H)，5.98(s，2H)；7.11(m，1H)；7.25(m，3H)；7.41(d，1H)；7.59(dxd，1H)；7.68(s，1H)；7.78(d，1H)；7.89(s，1H)；8.35(d，1H)；9.39(s，1H)；10.82(s，1H)；13.35(s，1H)。
Tables 2, 3 and 4 below illustrate the chemical structures and physical properties of certain examples of compounds of the present invention.
In these tables:
column "G1" represents an atom or group of atoms listed from left to right;
the column "PF (. degree. C.) or [ MH]+"represents the melting point of the product in degrees centigrade (. degree. C.) or the peak obtained by mass spectrometry after chemical ionization;
in the column "salts/bases" - "represents the compound in free base form and" HCl "represents the compound in hydrochloride form, the ratio between brackets being (acid: base) ratio;
-“CH3"corresponds to a methyl group" CF3"corresponds to a trifluoromethyl group," Et "corresponds to an ethyl group," t-Bu "corresponds to a tert-butyl group," i-Pr "corresponds to an isopropyl group, and" benzyl "corresponds to a benzyl group;
TABLE 2
The NMR data for some examples of the table are listed below as examples.
NMR of Compound N.cndot.9：1H NMR(DMSO D6)，δ(ppm)：2.68(m，2H)；2.98(t，2H)；3.04(t，2H)；4.11(t，2H)；4.82(t，2H)；7.1(dxt，1H)；7.2(m，1H)；7.3(s，1H)；7.49(m，5H)；8(s，1H)；8.3(s，1H)；8.32(d，1H)；10.11(s，1H)。
NMR of Compound N.cndot.10：1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)；2.92(t，2H)；4.08(t，2H)；7.05(dxt，1H)；7.41(m，5H)；8.03(s，1H)；10.19(s，1H)；11.8(s，1H)。
NMR of Compound N.cndot.11：1H NMR(DMSO D6)，δ(ppm)：2.32(s，3H)；2.4(s，3H)；2.61(m，2H)；2.8(t，2H)；4.06(t，2H)；7.11(m，3H)；7.41(m，5H)；7.89(s，1H)；10.4(s，1H)；
NMR of Compound N.cndot.12：1H NMR(DMSO D6)，δ(ppm)：4.27(m，4H)；5.88(s，2H)；6.89(m，2H)；7.02(txd，1H)；7.14(txd，1H)；7.31(m，2H)；7.42(s，1H)；7.59(m，3H)；7.99(s，1H)；9.39(s，1H)；10.61(s，1H)；
NMR of Compound N.cndot.13：1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)；2.91(t，2H)；4.03(s，3H)；4.1(t，2H)；7.11(dxt，1H)；7.25(s，1H)；7.48(m，4H)；8.1(s，1H)；10.25(s，1H)；
NMR of Compound N.cndot.14：1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)；2.90(t，2H)；4.08(t，2H)；7.4(m，3H)；8.01(s，1H)；8.6(d，2H)；10.3(s，1H)；12.78(s，1H)；
NMR of Compound N.cndot.17：1H NMR(DMSO D6)，δ(ppm)：2.39(m，1H)；2.89(m，1H)；4.02(m，1H)；4.18(m，1H)；5.07(m，1H)；5.85(s，2H)；6.8(m，2H)；6.97-7.32(m，3H)；7.34-7.6(m，5H)；8.02(s，1H)。
NMR of Compound N.cndot.18：1H NMR(DMSO D6)，δ(ppm)：2.4(s，3H)；2.59(m，2H)；2.9(t，2H)；4.05(t，2H)；5.95(s，2H)；6.92-7.11(m，2H)；7.27-7.58(m，6H)；7.89(d，1H)；8.02(d，1H)；10.09(s，1H)。
NMR of Compound N.cndot.49：1H NMR(DMSO D6)，δ(ppm)：2.66(m，2H)；2.95(dxd，2H)；4.11(dxd，2H)；6(s，2H)；6.93(m，2H)；7.05(dxt，1H)；7.3-7.5(m，3H)；7.59(s，1H)；7.95(d，1H)；8.71(d，1H)；8.81(d，1H)；10.55(s，1H)。
NMR of Compound N.cndot.136：1H NMR(DMSO D6)，δ(ppm)：1.51(s，9H)；4.27(m，4H)；5.92(s，2H)；7.09-7.3(m，6H)；7.41(dxd，1H)；7.61(s，1H)；7.85(s，1H)；8.66(s，1H)；8.79(s，1H)；10.45(s，1H)。
NMR of Compound N.cndot.138：1H NMR(DMSO D6)，δ(ppm)：4.3(m，4H)；5.92(s，2H)；7.1(m，2H)；7.21(m，3H)；7.39(d，1H)；7.41(s，1H)；7.58(d，1H)；7.99(s，1H)；8.17(dxd，1H)；8.49(s，1H)；9.3(s，1H)；10.62(s，1H)。
NMR of Compound N ° 139：1H NMR(DMSO D6)，δ(ppm)：4.03(m，4H)；5.92(s，2H)；6.92(s，1H)；7.05(m，3H)；7.23(d，1H)；7.46(s，1H)；7.56(s，1H)；8.19(dxd，1H)；8.41(d，3H)；10.32(s，1H)。
NMR of Compound N.cndot.143：1H NMR(CDCl3)，δ(ppm)：2.25(m，4H)；3.41(s，3H)；3.49(m，2H)；4.24(m，2H)；6.15(s，2H)；7.01-7.37(m，6H)；7.41-7.65(m，3H)；7.79(m，2H)；8.25(s，1H)。
NMR of Compound N.cndot.144：1H NMR(DMSO D6)，δ(ppm)：4.29(m，4H)；5.98(s，2H)；7.11(m，2H)；7.25(m，3H)；7.4(d，1H)；7.55(d，1H)；7.57(s，1H)；7.99(s，1H)；8.71(s，1H)；8.8(s，1H)；9.26(s，1H)；10.74(s，1H)。
NMR of Compound N.cndot.145：1H NMR(DMSO D6)，δ(ppm)：2.61(m，2H)；2.92(t，2H)；4.09(t，2H)；5.98(s，2H)；7.01(d，2H)；7.41(m，2H)；7.62(s，1H)；7.9(s，1H)；8.39(d，2H)；8.71(d，2H)；10.55(s，1H)。
NMR of Compound N.cndot.146：1H NMR(DMSO D6)，δ(ppm)：4.19(m，4H)；4.95(s，2H)；6(s，2H)；7.05(m，2H)；7.51(m，2H)；7.66(s，1H)；7.99(s，1H)；8.44(d，2H)；8.78(d，2H)。
TABLE 3
N° X Y R′ Salt/alkali PF(℃)
148. CH CH 3-fluorobenzyl - 261-262
149. CH CH (pyridin-4-yl) methyl - 277-278
150. N CH 3-fluorobenzyl - 295-298
151. CH N 3-fluorobenzyl HCl 1∶1 225-230
TABLE 4
The NMR data for some examples of the table are listed below as examples:
NMR of Compound N.cndot.152：1H NMR(DMSO D6)，δ(ppm)：1.59(d，3H)；2.38(m，1H)；2.94(m，1H)；3.33(m，2H)；4.87(m，1H)；6.5(s，2H)；7.2(dxt，1H)；7.36(d，2H)；7.5-7.7(m，3H)；7.84(m，2H)；8.35(s，1H)；8.65(d，2H)。
NMRN 153 for Compounds：1H NMR(DMSO D6)，δ(ppm)：3.11(d，1H)；3.62(dxd，1H)；4.2(dxd，1H)；4.49(dxd，1H)；5.1(m，1H)；6.09(s，2H)；7.19(dxt，1H)；7.43(d，2H)；7.5-7.7(m，3H)；7.81(d，2H)；8.32(s，1H)；8.7(d，2H)；10.7(s，1H)。
These compounds of the invention form the subject of in vitro and in vivo pharmacological tests which prove their significance as therapeutically active substances. These compounds have antagonist or agonist activity of these receptors TRPV1 (or VR 1).
Capsaicin-induced current suppression test for mouse DRG
Primary culture of mouse dorsal root lymph node (DRG) cells:
these DRG neurons naturally express the TRPV1 receptor.
Primary cultures of neonatal murine DRG were prepared from day 1 pups. Briefly, after dissection, the lymph nodes were treated with trypsin and the cells were mechanically dissociated by careful grinding. These cells were resuspended in Eagle's basal medium containing 10% fetal bovine serum, 25mM KCl, 2mM glutamine, 100. mu.g/mL gentamicin and 50ng/mL NGF, and then placed on laminin-coated glass sheets (0.25X 10 per sheet)6Cells), then they were placed in Corning 12-well culture flasks. These cells contained 5% CO at 37 deg.C2And a humid atmosphere of 95% air. Culturing for 48 hr, addingGlycocytidine β -D-arabinoside (1 μ M) to prevent non-neuronal cell development. These slices were transferred to the laboratory for patch clamp studies after 7-10 days of culture.
-electrophysiology:
the measurement chambers (volume 800. mu.l) containing the cell preparation were placed on the stage of an inverted microscope (Olympus IMT2) equipped with a Hoffman optical unit (modulation contrast, New York) and observed at a magnification of 400X. The chambers were continuously fed by gravity (2.5mL/min) by means of a solution dispenser with 8 inlets and a single outlet consisting of a polyethylene tube (500 μm opening) placed at a distance of less than 3mm from the cells under study. The "whole cell" structure of the patch clamp technique was used. A borosilicate glass (resistance 5-10M ohm) pipette was brought into proximity to the cell by means of a 3D piezoelectric micromanipulator (Burleigh, PC 1000). The total current (fixed at-60 mV membrane potential) was recorded using an Axoatch 1D amplifier (Axon Instruments, Foster city, Californie) connected to a PC controlled by Pchlamp 8 software (Axon Instrument). These current curves were recorded on paper, digitized (sampling frequency 15-25Hz) and collected on a PC hard disk.
DRG cells (fixed voltage-70 mV) were induced with an input cation current using 300nM capsaicin solution. To minimize desensitization of these receptors, a 1 minute interval between two applications of capsaicin was followed. After a controlled period (a single capsaicin response is stable), a number of capsaicin + compound tests (to achieve maximal inhibition) are carried out during a period of 4-5 minutes using a concentration of the compound of the invention to be tested (10 nM or 1 nM). These results are expressed as% inhibition of control capsaicin response.
In the case of the antagonistic compound VR1, the percentage inhibition of capsaicin response (1 μ M) is 20% to 100% for the most active compound of the invention at the concentrations tested 0.1-10 nM. Therefore, it is a potent antagonist of TRPV 1-type receptors. Table 5 gives some examples of the% inhibition achieved using the compounds of the present invention.
TABLE 5
Compound of degree N DGR membrane inhibition%
1 37％(10nM)
5 53％(10nM)
Intrinsic agonist effects of these compounds can be assessed by measuring the current induced in the mouse DRG at various concentrations of the compound, with or without kazazepine.
Corneal irritation test in mice
The stimulatory properties of capsaicin are readily assessed from the cornea, as this organ is one of the more innervated by these muscle fibers C. In this case, according to preliminary experiments, the application of very small amounts of capsaicin (2 μ l, concentration 160 μ M) on the surface of the animal cornea caused a certain amount of a consistent and easily tabulated behavior in relation to the stimulus. Among them, mention may be made of: squinting eyes, kneading the eyes with the same side of the paw before, kneading the face with the two paws before, and rubbing the face with the back paw. The time for these behaviors did not exceed the 2 minutes observed and the animal was still normally active at this time. In addition, the appearance was normal. The mice were not confined to the corners and had hairs that were upright and had no observable signs of distress. It can be concluded that capsaicin has a duration of action of less than 2 minutes at these doses.
Summary of the method:
the principle of this set of experiments was to determine whether the compounds of the present invention could affect the behavioral response induced by an amount of capsaicin. Initially, capsaicin was diluted to 25mM with DMSO and for final use it was diluted with physiological serum with 80-10% Tween. This solvent did not have any effect as seen from the control studies under these conditions.
In practice, DMSO is used to prepare 25mM of the product to be tested, which is diluted in physiological serum in order to be used at the end, with a 10% maximum concentration of 500. mu.M Tween80, by applying a volume of 2. mu.l of the product to be tested locally to the corneal surface 10 minutes before the capsaicin application. The eyes of the animals received instillations of 2 μ l of 160 μ M capsaicin solution prepared as indicated previously. During the observation period of 2 minutes after instillation, the number of instillation of eyes by rubbing with the ipsilateral hindpaw was calculated for each animal.
For a given group, the percent protection is calculated as follows:
p ═ 100- ((average number of abrasions of treatment group of the compound/average number of abrasions of solvent treatment group) × 100)
This percentage of protection is the average number of animals per group (n ═ number of animals tested using the compounds of the invention).
The percentage protection of the most active compounds of the invention used at a concentration of 500 μ M evaluated according to this model is from 20% to 100% (see table 6 for examples):
TABLE 6
Compound of degree N ％P500μM
8 71％
15 56％
26 46％
These test results indicate that the most active compounds of the present invention block the effects induced by the stimulation of the receptor TRPV1 in vivo.
The compounds of the invention can therefore be used for the preparation of medicaments, in particular medicaments intended for the prevention or treatment of diseases in which TRPV 1-like receptors are involved.
The compounds of the present invention may be useful for the prevention or treatment of diseases in which TRPV 1-like receptors are involved.
The present invention therefore relates to medicaments containing at least one compound of formula (I), or a pharmaceutically acceptable salt, or a hydrate or solvate of said compound.
These medicaments have their therapeutic use, in particular in the prevention and/or treatment of pain and inflammation, chronic pain, neuropathic pain (traumatic, diabetic, metabolic, infectious, toxic, induced by anticancer or iatrogenic treatment), (bone-) tubal inflammation pain, rheumatic pain, fibromyalgia, back pain, cancer-related pain, facial neuralgia, headache, migraine, dental pain, burn pain, mid-deployment pain, bite or sting pain, post-herpetic neuralgia, muscle pain, neurotic pain (central and/or peripheral), bone marrow and/or brain trauma pain, ischaemic (bone marrow and/or brain) pain, neurodegenerative pain, haemorrhagic vascular accident pain (bone marrow and/or brain), post-stroke pain.
The compounds of the invention may also be used for the prevention and/or treatment of metabolic disorders, such as diabetes.
The compounds of the invention can also be used for the prevention and/or treatment of urological disorders, such as overactive bladder, hyperreflexia of the bladder, bladder instability, incontinence, urgency, urinary incontinence, cystitis, renal colic, pelvic hypersensitivity and pelvic pain.
The compounds of the invention can also be used for the prevention and/or treatment of gynaecological disorders, such as vulvodynia (vulvodynie), pain associated with salpingitis, menstrual disorders.
These products can also be used for the prevention and/or treatment of gastrointestinal disorders, such as gastro-esophageal spasm disorder, gastric ulcer, duodenal ulcer, functional dyspepsia, colitis, NBS, Crohn's disease, pancreatitis, esophagitis, liver pain.
Likewise, the product of the invention may be used for the prevention and/or treatment of respiratory diseases such as asthma, cough, Chronic Obstructive Pulmonary Disease (COPD), bronchoconstriction and inflammatory diseases.
These products can be used for the prevention and/or treatment of psoriasis, pruritus, skin, eye or mucous membrane inflammations, herpes zoster.
The compounds of the invention may also be useful in the treatment of depression.
The compounds of the invention may also be useful in central nervous system disorders, such as multiple sclerosis.
According to other aspects, the invention relates to pharmaceutical compositions containing, as active ingredient, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable excipient. These said excipients are selected from the usual excipients known to the person skilled in the art, depending on the pharmaceutical dosage form and the desired mode of administration.
The pharmaceutical compositions of the present invention may be administered by the oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal routes. These compositions may be administered in unit dosage form in admixture with conventional pharmaceutical excipients. They are useful for administration to animals and humans for the prevention or treatment of the above-mentioned disorders or diseases.
Suitable unit dosage forms for administration include oral dosage forms, such as tablets, soft or hard capsules, powders, granules, oral liquids or suspensions, sublingual, buccal, intratracheal, intraocular, intranasal, inhalational dosage forms; topical, transdermal, subcutaneous, intramuscular, or intravenous dosage forms; rectal dosage forms and implants. For topical application, the compounds of the invention may be used in creams, gels, ointments or lotions.
By way of example, a unit dosage form for administration of a compound of the invention in the form of a tablet may contain the following components:
compound of the invention 50.0mg
Mannitol 223.75mg
Croscarmellose sodium 6.0mg
Corn starch 15.0mg
Hydroxypropyl-methylcellulose 2.25mg
Magnesium stearate 3.0mg
These unit dosage forms are in a dosage allowing the daily administration of 0.001-30mg of active ingredient per kg of body weight, according to galenic form.
There may be special cases where the dosage is either high or low; such dosages are not outside the scope of the present invention. According to common practice, the appropriate dosage for each patient is determined by the physician according to the mode of administration, the weight and the response of said patient.
The compounds of the present invention may also be used for the preparation of medicaments, in particular medicaments for the prophylaxis or treatment of diseases in which TRPV 1-like receptors are involved, such as the diseases described hereinbefore.
According to another aspect, the present invention also relates to a method for the treatment of the diseases indicated above, which comprises administering to a patient in need thereof an effective amount of at least one compound according to the invention, or a pharmaceutically acceptable salt or hydrate or solvate thereof.

Claims (10)

1. A compound of formula (I) or an addition salt thereof with an acid, characterized in that:
in the formula
A represents a 4-7 membered monocyclic heterocycle fused to the C-N bond of the benzimidazole structural unit, containing 1-3N atoms, including the nitrogen atom of the benzimidazole structural unit, and selected from azetidinyl, pyridinylPyrrolidinyl, piperidinyl, azaMesityl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydroAn oxazolyl, dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridinyl group;
p represents a 9-membered bicyclic heteroaryl group containing 1 to 6N atoms; p is linked to the-C (Y) -group through a carbon atom and is selected from the group consisting of indolyl, isoindolyl, benzofuranyl, benzothienylOxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzofuranyl, isobenzothiazolyl, pyrrolo [2, 3-c]Pyridyl, pyrrolo [2, 3-b]Pyridyl, pyrrolo [3, 2-b]Pyridyl, pyrrolo [3, 2-c]A pyridyl group;
R1represents 1 to 4 identical or different radicals selected from the following groups: hydrogen atom, halogen atom, C1-C6-fluoroalkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C5Alkylene, aryl-C1-C5-alkylene, wherein said aryl group is optionally substituted with one or more substituents selected from halogen atoms;
with the proviso that when R1When attached to the nitrogen atom of P, then R1Different from a halogen atom;
y represents an oxygen atom;
R2represents a hydrogen atom;
when the carbon atom carries R3When R is3Represents 1 to 3 identical or different radicals selected from the group consisting of a hydrogen atom, a hydroxyl group and C1-C6-an alkyl group; when the nitrogen atom carries R3When R is3Represents 1-2 hydrogen atoms or C1-C6-an alkyl group;
wherein said aryl group is a mono-or bicyclic aromatic group containing 6 to 10 carbon atoms; the heteroaryl group is a 5-14 membered mono-, bi-or tricyclic aromatic group containing 1-8 heteroatoms selected from O, S or N.
2. A compound of formula (I) according to claim 1, or an addition salt thereof with an acid, selected from:
n- (1, 2, 3, 4-tetrahydropyrido [1, 2-a ] benzimidazol-7-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide,
n- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- [ (pyridin-4-yl) methyl ] -1H-indole-2-carboxamide,
n- (2, 3-dihydro-1H-pyrrolo [1, 2-a ] benzimidazol-6-yl) -1-benzyl-5-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide,
n- (3, 4-dihydro-1H-Oxazino [1, 4 ]][4，3-a]Benzimidazol-7-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide,
n- (2, 3-dihydro-3-methylimidazo [1, 2-a ] benzimidazol-6-yl) -5-fluoro-1- (3-fluorobenzyl) -1H-indole-2-carboxamide.
3. The process for preparing a compound of formula (I) according to claim 1, wherein the compound of formula (VI) is reacted with an amide of a compound of formula (VII) under reflux of a solvent:
p, R in formula (VI)1And Y is as defined for formula (I) according to claim 1, and B represents C1-C6-alkoxy, C3-C7Cycloalkoxy, C3-C7-cycloalkyl-C1-C3Alkylene oxide, aryl-C1-C3-AAn alkoxy group, a carboxyl group,
a, R in formula (VII)2And R3As defined according to formula (I) as defined in claim 1, the amide of the compound of formula (VII) is prepared by pre-reaction of trimethylaluminum with an amine of formula (VII).
4. Process for the preparation of the compound of formula (I) according to claim 1, characterized in that the compound of formula (VI) below is converted into the acid chloride by the action of thionyl chloride under reflux of the solvent:
formula (III) P, R1And Y is as defined for formula (I) according to claim 1, and B represents a hydroxyl group, then characterized in that the resulting acid chloride compound is reacted with a compound of formula (VII) in the presence of a base:
formula (III) A, R2And R3Is as defined according to formula (I) as defined in claim 1;
or is characterized in that a compound of formula (VI) in which P, R is present in a solvent in the presence of a coupling agent and a base1And Y is as defined for formula (I) according to claim 1, and B represents a hydroxyl group, with a compound of formula (VII) wherein A, R2And R3The coupling reaction is carried out as defined according to formula (I) as defined in claim 1.
5. Compounds of formulae (VIIc) and (VIIj):
6. pharmaceutical, characterized in that it comprises at least one compound of formula (I) according to any one of claims 1 to 2, or an addition salt of such a compound with a pharmaceutically acceptable acid.
7. Pharmaceutical composition, characterized in that it contains at least one compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt of such a compound, and at least one pharmaceutically acceptable excipient.
8. Use of a compound of formula (I) according to any one of claims 1 to 2 or an addition salt thereof with an acid for the manufacture of a medicament for the prevention or treatment of diseases in which TRPV 1-like receptors are involved.
9. Use according to claim 8 for the preparation of a medicament for the prevention or treatment of pain, inflammation, metabolic disorders, urological disorders, gynaecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritus, herpes, multiple sclerosis and depressive disorders.
10. Use according to claim 9 for the preparation of a medicament for the prevention and treatment of skin, eye or mucous membrane inflammations, shingles.
HK09107854.1A 2006-02-03 2007-02-01 Tricyclic n-heteroaryl-methyl carboxamide derivatives containing a benzimedazole unit, method for preparing same and their therapeutic use HK1129670B (en)

Applications Claiming Priority (3)

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FR06/01007 2006-02-03
FR0601007A FR2897061B1 (en) 2006-02-03 2006-02-03 TRICYCLIC N-HETEROARYL-CARBOXAMIDE DERIVATIVES CONTAINING A BENZIMIDAZOLE PATTERN, THEIR PREPARATION AND THEIR THERAPEUTIC USE.
PCT/FR2007/000183 WO2007088277A1 (en) 2006-02-03 2007-02-01 Tricyclic ν-heteroaryl-carboxamide derivatives containing a benzimidazole unit, method for preparing same and their therapeutic use

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