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HK1121678A - N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof - Google Patents

N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof Download PDF

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Publication number
HK1121678A
HK1121678A HK08113128.0A HK08113128A HK1121678A HK 1121678 A HK1121678 A HK 1121678A HK 08113128 A HK08113128 A HK 08113128A HK 1121678 A HK1121678 A HK 1121678A
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Hong Kong
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formula
aryl
cycloalkyl
pyrrolo
alkylene
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HK08113128.0A
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Chinese (zh)
Inventor
Laurent Dubois
Yannick Evanno
André MALANDA
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Sanofi-Aventis
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N- (arylalkyl) -1H-pyrrolopyridine-2-carboxamide derivatives, their preparation and their therapeutic use
The present invention relates to compounds derived from N- (aralkyl) -1H-pyrrolopyridine-2-carboxamides which exhibit in vitro and in vivo antagonist activity at TRPV1 (or VR1) type receptors.
The first object of the present invention relates to a compound of the following general formula (I).
Another object of the present invention relates to a process for the preparation of the compounds of general formula (I).
Another object of the invention relates to the use of compounds of general formula (I), in particular in pharmaceutical or pharmaceutical compositions.
The compounds of the invention correspond to general formula (I):
wherein
n is equal to 0, 1, 2 or 3;
the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group, or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the carbon positions 4, 5, 6 and/or 7 with one or more substituents X, which may be identical or different from each other, selected from halogen atoms and C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5Or aryl, aryl being substituted with one or more groups selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
Z1、Z2、Z3、Z4and Z5Independently of one another, represents a hydrogen atom or a halogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5aryl-C1-C6Alkylene or aryl, aryl and aryl-C1-C6Alkylene with one or more groups selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
R1and R2Independently of one another, represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl; or R1And R2Together with the nitrogen atom to which they are attached form azetidine, pyrrolidine, piperidine, aza *, morpholine, thiomorpholine, piperazine, homopiperazine radicals, the radicals being substituted with C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl is optionally substituted;
R3and R4Independently of one another, represents a hydrogen atom or C1-C6Alkyl, aryl-C1-C6-alkylene or aryl;
R5is represented by C1-C6-an alkyl or aryl group;
w represents a fused bicyclic group of the formula:
which is attached to the nitrogen atom via position 1, 2, 3 or 4;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
one or more carbon atoms of A are selected from hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C1-C6-the radical of an alkylene, oxo (oxo) or thio group is optionally substituted;
when the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Is optionally substituted, otherwise with R7Substitution;
R6represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6Alkylene (E) sA group or an aryl group;
R7represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6Alkylene radical, C1-C6alkyl-C (O) -, C3-C7-cycloalkyl-C1-C3Alkylene- (CO) -, C1-C6fluoroalkyl-C (O) -, C3-C7cycloalkyl-C (O) -, aryl-C1-C6alkylene-C (O) -, C1-C6alkyl-S (O)2-、C1-C6fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-S (O)2-or aryl-C1-C6alkylene-S (O)2-or an aryl group.
In the compounds of formula (I):
one or more sulfur atoms of the heterocycle A may be in oxidized form (S (O) or S (O)2)；
-one or more nitrogen atoms of the heterocycle a may be in oxidized form (N-oxide);
the nitrogen atom in position 4, 5, 6 or 7 of the pyrrolopyridine may be in oxidized form (N-oxide).
Examples of groups W that may be mentioned throughout the present invention include indolinyl, isoindolyl, indolyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuranyl, dihydroisobenzofuranyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, 2, 3-naphthyridinyl (phthalazinyl), Dihydronaphthyridinyl, tetrahydronaphthyridinyl, tetrahydrobenzo [ b ] azepine * yl, tetrahydrobenzo [ c ] azepine * yl, tetrahydrobenzo [ d ] azepine * yl, tetrahydrobenzo [ b ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ e ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ b ] [1, 4] oxazepinyl * yl (oxazepinyl) or tetrahydrobenzo [ b ] [1, 4] thiazepinyl * yl (thiazepinyl);
these groups may be optionally substituted as defined in formula (I).
In the compounds of general formula (I) which are the subject of the present invention, a first subclass of compounds consists of compounds in which n is equal to 1 or 2.
In the compounds of general formula (I) which are the subject of the present invention, a second subclass of compounds consists of compounds wherein the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the 4, 5, 6 and/or 7 carbon position with one or more substituents X, equal to or different from each other, chosen from hydrogen atoms or halogen atoms such as fluorine, bromine or chlorine, or C1-C6Alkyl radicals such as methyl, propyl, isopropyl, sec-butyl, tert-butyl, pentyl, C3-C7Cycloalkyl radicals such as cyclopentyl or cyclohexyl, C1-C6Fluoroalkyl radicals such as trifluoromethyl, C1-C6Alkoxy radicals such as methoxy or ethoxy, C1-C6Fluoroalkoxy radicals such as trifluoromethoxy, nitro, NR1R2、C1-C6Sulfanyl, e.g. thiomethyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl radicals such as-S (O)2-CH3Or aryl such as phenyl; r1And R2Independently of one another, represent a hydrogen atom.
Among the compounds of general formula (I) which are the subject of the present invention, a third subclass of compounds consists of compounds wherein the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the 4, 5, 6 and/or 7 carbon position, for example in the 5 carbon position, with one or more substituents X, which are identical to or different from each other, for example with one substituent X, X being chosen from halogen atoms, for example chlorine or fluorine atoms, or C1-C6Fluoroalkyl such as trifluoromethyl or aryl such as phenyl.
Of the compounds of general formula (I) which are the subject of the present invention, a fourth subclass of compounds consists of compounds wherein the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the carbon positions 4, 5, 6 and/or 7 with one or more substituents X, equal to or different from each other, chosen from halogen atoms or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5Or aryl, aryl optionally with one or more substituents selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituted with fluoroalkoxy, nitro or cyano;
R1and R2Independently of one another, represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl; or R1And R2Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, aza *, morpholine, thiomorpholine, piperazine, homopiperazine group, the group being substituted with C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl is optionally substituted;
R3and R4Independently of one another, represents a hydrogen atom or C1-C6Alkyl, aryl-C1-C6-alkylene or aryl;
R5is represented by C1-C6-alkyl or aryl.
Among the compounds of general formula (I) which are the subject of the present invention, a fifth subclass of compounds is that of formula (I) consisting of Z1、Z2、Z3、Z4And Z5Independently of one another, a hydrogen atom or a halogen atom, for example a fluorine atom.
In the compounds of the general formula (I) which are the subject of the present invention, a sixth subclass of compounds consists of W which is selected from the group consisting of indolinyl, indolyl, isoindolyl, isoindolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuranyl, dihydroisobenzofuranyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, Tetrahydroquinoxalinyl, 2, 3-naphthyridinyl, dihydronaphthyridinyl, tetrahydronaphthyridinyl, tetrahydrobenzo [ b ] azepine * yl, tetrahydrobenzo [ c ] azepine * yl, tetrahydrobenzo [ d ] azepine * yl, tetrahydrobenzo [ b ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ e ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ b ] [1, 4] oxazepine * yl, or tetrahydrobenzo [ b ] [1, 4] thiazepine * yl;
the carbon atom and/or the nitrogen atom of the group W is optionally substituted as defined in formula (I).
Among the compounds of general formula (I) which are the subject of the present invention, a seventh subclass of compounds consists of compounds in which W represents a fused bicyclic group of formula:
which is attached to the nitrogen atom via the 1, 2, 3 or 4 position;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
and W is selected from indolyl, benzimidazolyl, tetrahydroquinolinyl, quinolinyl, benzothiazolyl; and/or
One or more carbon atoms of A are selected from hydrogen atom and C1-C6-alkyl such as methyl or oxo optionally substituted; and/or
When the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Optionally substituted or atIn other cases with R7Substitution;
R6represents a hydrogen atom;
R7represents a hydrogen atom or C1-C6Alkyl groups such as methyl.
n、X、Z1、Z2、Z3、Z4、Z5And W are all compounds as defined in the subclass of compounds of formula (I) above to form the eighth subclass.
Among the compounds of general formula (I) which are the subject of the present invention, the compounds of the ninth subclass are those compounds in which:
n is equal to 0, 1, 2 or 3;
the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group, or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the 4, 5, 6 and/or 7 carbon position with one or more substituents X, equal to or different from each other, chosen from halogen atoms or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5Or aryl, aryl with one or more selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
Z1、Z2、Z3、Z4and Z5Independently of one another, represents a hydrogen atom or a halogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5aryl-C1-C6Alkylene or aryl, aryl and aryl-C1-C6Alkylene with one or more groups selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
R1and R2Independently of one another, represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl; or R1And R2Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, aza *, morpholine, thiomorpholine, piperazine, homopiperazine group, the group being substituted with C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl is optionally substituted;
R3and R4Independently of one another, represents a hydrogen atom or C1-C6-an alkyl or aryl group;
R5is represented by C1-C6Alkyl, aryl-C1-C6-alkylene or aryl;
w represents a fused bicyclic group of the formula:
which is attached to the nitrogen atom via position 1, 2, 3 or 4;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
one or more carbon atoms of A are selected from hydrogen atom and C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C1-C6-the group of alkylene, oxo or thio groups is optionally substituted;
when the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Is optionally substituted, otherwise with R7Substitution;
R6represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl;
R7represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6Alkylene radical, C1-C6alkyl-C (O) -, C3-C7-cycloalkyl-C1-C3Alkylene- (CO) -, C1-C6fluoroalkyl-C (O) -, C3-C7cycloalkyl-C (O) -, aryl-C1-C6alkylene-C (O) -, C1-C6alkyl-S (O)2-、C1-C6fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-S (O)2-or aryl-C1-C6alkylene-S (O)2-or an aryl group,
the conditions are as follows:
when Z is1、Z2、Z3、Z4And Z5And represents a hydrogen atom, and when the pyrrolopyridine ring is optionally substituted pyrrolo [3, 2-b ]]When the pyridine is used, the pyridine is added,
then n is equal to 2 or 3.
Among the compounds of general formula (I) which are the subject of the present invention, the following are worth mentioning:
-N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-chloro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (2-methyl-1H-benzothiazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-phenyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide;
-N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1-methyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (quinolin-7-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1-methyl-1H-indol-5-yl) -1- (phenylmethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1-methyl-1H-indol-5-yl) -1- (phenylethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (2-methyl-benzothiazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1-methyl-1H-indol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (2-methyl-benzothiazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-c ] pyridine-2-carboxamide;
-N- (1-methyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide;
-N- (2-methyl-benzothiazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide;
-N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- (phenyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide.
Within the compounds of general formula (I) which are the subject of the present invention, a sub-class of compounds consists of compounds of general formula (I'):
wherein
n is equal to 1, 2 or 3;
the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group, or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the 4, 5, 6 and/or 7 carbon position with one or more substituents X, equal to or different from each other, selected from halogen atoms and C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5Or aryl, aryl with one or more selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
Z1、Z2、Z3、Z4and Z5Independently of one another, represents a hydrogen atom or a halogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5aryl-C1-C6Alkylene or aryl, aryl and aryl-C1-C6Alkylene with one or more groups selected from halogen and C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
R1and R2Independently of one another, represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl; or R1And R2Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, aza *, morpholine, thiomorpholine, piperazine, homopiperazine group, the group being substituted with C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl is optionally substituted;
R3and R4Independently of one another, represents a hydrogen atom or C1-C6Alkyl, aryl-C1-C6-alkylene or aryl;
R5is represented by C1-C6-an alkyl or aryl group;
w represents a fused bicyclic group of the formula:
which is attached to the nitrogen atom via position 1, 2, 3 or 4;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
one or more carbon atoms of A are selected from hydrogen atom and C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C1-C6-the group of alkylene, oxo or thio groups is optionally substituted;
when the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Optionally substituted or otherwise substituted with R7Substitution;
R6represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl;
R7represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6Alkylene radical, C1-C6alkyl-C (O) -, C3-C7-cycloalkyl-C1-C3Alkylene- (CO) -, C1-C6fluoroalkyl-C (O) -, C3-C7cycloalkyl-C (O) -, aryl-C1-C6alkylene-C (O) -, C1-C6alkyl-S (O)2-、C1-C6-fluoroalkanesradical-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-S (O)2-or aryl-C1-C6alkylene-S (O)2-or an aryl group.
In the compounds of general formula (I') which are the subject of the present invention, a first subclass of compounds consists of compounds in which n is equal to 1 or 2.
Of the compounds of general formula (I') which are the subject of the present invention, a second subclass of compounds consists of those in which the pyrrolopyridine ring is pyrrolo [2, 3-c ] optionally substituted in the 4, 5, 6 and/or 7 carbon position with one or more substituents X]Pyridyl group or pyrrolo [2, 3-b]A pyridine group, X being identical or different from each other and being selected from a hydrogen atom or a halogen atom such as fluorine, bromine or chlorine, or C1-C6Alkyl radicals such as methyl, propyl, isopropyl, sec-butyl, tert-butyl, phenyl, C3-C7Cycloalkyl radicals such as cyclopentyl or cyclohexyl, C1-C6Fluoroalkyl radicals such as trifluoromethyl, C1-C6Alkoxy radicals such as methoxy or ethoxy, C1-C6Fluoroalkoxy radicals such as trifluoromethoxy, nitro, NR1R2、C1-C6Sulfanyl, e.g. thiomethyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl radicals such as-S (O)2-CH3Or aryl such as phenyl; r1And R2Independently of one another, represent a hydrogen atom.
In the compounds of general formula (I') which are the subject of the present invention, a third class of compounds consists of compounds in which the pyrrolopyridine ring is pyrrolo [2, 3-c ] optionally substituted at the 4, 5, 6 and/or 7 carbon position, for example at the 5 carbon position, with one or more substituents X]Pyridyl group or pyrrolo [2, 3-b]A pyridine group, X being identical or different from each other, or, for example, being substituted with one substituent X chosen from halogen atoms such as chlorine or fluorine atoms, or C1-C6-fluoroalkanesSuch as trifluoromethyl.
In the compounds of the general formula (I') which is the subject of the invention, a fourth class of compounds is represented by Z1、Z2、Z3、Z4And Z5Independently of one another, a hydrogen atom or a halogen atom, for example a fluorine atom.
In the compounds of the general formula (I') which is the subject of the present invention, a fifth subclass of the compounds consists of W which is selected from the group consisting of indolinyl, indolyl, isoindolyl, isoindolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuranyl, dihydroisobenzofuranyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, Tetrahydroquinoxalinyl, 2, 3-naphthyridinyl, dihydronaphthyridinyl, tetrahydronaphthyridinyl, tetrahydrobenzo [ b ] azepine * yl, tetrahydrobenzo [ c ] azepine * yl, tetrahydrobenzo [ d ] azepine * yl, tetrahydrobenzo [ b ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ e ] [1, 4] diazepinyl * yl, tetrahydrobenzo [ b ] [1, 4] oxazepine * yl, or tetrahydrobenzo [ b ] [1, 4] thiazepine * yl;
the carbon atom and/or nitrogen atom of the group W is optionally substituted as defined in formula (I).
In the compounds of general formula (I') which is the subject of the present invention, a sixth subclass of compounds consists of compounds in which W represents a fused bicyclic group of formula:
which is attached to the nitrogen atom via position 1, 2, 3 or 4;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S or N;
and W is selected from indolyl, benzimidazolyl, dihydroquinolinyl, quinolinyl, and benzothiazolyl; and/or
One or more carbon atoms of A are selected from hydrogen atom and C1-C6-alkyl, such as methyl, optionally substituted; and/or
One or more nitrogen atoms of A are represented by R7Optionally substituted;
R7represents a hydrogen atom or C1-C6Alkyl groups such as methyl.
n、X、Z1、Z2、Z3、Z4、Z5And W are all compounds as defined in the subclass of compounds of formula (I') above to form the seventh subclass.
Throughout the present invention, the following definitions apply:
-Ct-Czwhere t and z may take values of 1-7: the carbon chain may contain t-z carbon atoms, e.g. C1-C3Is a carbon chain which may contain 1 to 3 carbon atoms;
-an alkyl group: saturated, straight or branched chain aliphatic groups. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and the like;
-alkylene groups: saturated, straight-chain or branched, divalent alkyl radicals, e.g. C1-3Alkylene represents a linear or branched divalent carbon chain of 1 to 3 carbon atoms, such as methylene, ethylene, 1-methylethylene, propylene;
-a cycloalkyl group: cyclic carbon chains. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
-fluoroalkyl: alkyl groups in which one or more hydrogen atoms have been substituted with fluorine atoms;
-an alkoxy group: a group-O-alkyl, wherein alkyl is as defined above;
-fluoroalkoxy: alkoxy in which one or more hydrogen atoms have been substituted with a fluorine atom;
-a sulfanyl group: a group-S-alkyl, wherein alkyl is as defined above;
-aryl: cyclic aromatic groups containing 6 to 10 carbon atoms. Examples of the aryl group to be mentioned include phenyl and naphthyl;
-a heterocycle: a saturated, partially unsaturated or aromatic 5-to 7-membered cyclic group containing 1-3 heteroatoms selected from O, S and N;
-a halogen atom: fluorine, chlorine, bromine or iodine;
- "oxo" means "═ O";
- "thio" means "═ S".
The compounds of formula (I) may contain one or more asymmetric carbon atoms. Thus, it may exist as enantiomers or diastereomers. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.
The compounds of formula (I) may exist in the form of base or acid addition salts. Such addition salts form part of the present invention.
These salts are advantageously prepared with pharmaceutically acceptable salts, but salts of other acids, for example for purifying or isolating the compounds of formula (I), also form part of the invention.
The compounds of formula (I) may exist in the form of hydrates or solvates, i.e. in association with or mixed with one or more water molecules or solvents. Such hydrates and solvates are also part of the present invention.
Hereinafter, the term "leaving group" refers to a group which can be easily separated from the molecule by cleavage of heterolytic bonds, electron pair separation. This group can thus be easily replaced by other groups, for example in the case of substitution reactions. Such leaving groups are, for example, halogen or activated hydroxy groups such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, acetate and the like. Examples of leaving groups and references for their preparation are given in "Advances in organic Chemistry", J.March, 5th Edition, Wiley Interscience, 2001.
According to the present invention, the compounds of formula (I) can be prepared according to the methods illustrated in scheme 1 below.
According to scheme 1, the compound of formula (IV) can be obtained by reacting a compound of formula (II) wherein X is as defined above for formula (I) and B represents C with a compound of formula (III)1-C6Alkoxy or hydroxy, Z in formula (III)1、Z2、Z3、Z4、Z5And n is as defined above for formula (I), and when n equals 1, 2 or 3, R 'represents a leaving group or a hydroxyl group, and when n equals 0, R' represents a leaving group.
When a compound of formula (III) is so defined, n equals 1, 2 or 3 and R' represents a leaving group such as a bromine or iodine atom, the reaction may be carried out in a polar solvent such as dimethylformamide, dimethylsulfoxide or acetone in the presence of a base such as sodium hydride or potassium carbonate (n-1: kolas t., bioorg.med.chem.1997, 5(3)507, n-2: Abramovitch R., synth.commun., 1995, 25(1), 1).
Scheme 1
When the compound of formula (III) is defined such that n is equal to 1, 2 or 3 and R' represents a hydroxyl group, the compound of formula (IV) may be obtained by reaction of the compound of formula (II) with the compound of formula (III) in a solution in a solvent such as dichloromethane or tetrahydrofuran in the presence of a phosphine such as triphenylphosphine and a reagent such as diethyl azodicarboxylate (o.mitsonobu, Synthesis, 1981, 1-28).
When the compound of formula (III) is defined such that n is equal to 0 and R' represents a leaving group such as chlorine, bromine or iodine atom, the reaction can be carried out at a temperature between 80 ℃ and 250 ℃ in the presence of a copper-based catalyst such as copper bromide or copper oxide and in the presence of a base such as potassium carbonate (Murakami Y., chem. pharm. Bull., 1995, 43(8), 1281). Mild conditions described in s.l Buchwald, j.am. chem. soc.2002, 124, 11684 may also be used.
Throughout the present invention, B represents C according to methods known to those skilled in the art, for example in the presence of a base such as sodium hydroxide in a solvent such as methanol or ethanol1-C6-the compound of formula (IV) with alkoxy group can be converted into a compound of formula (IV) with B representing hydroxyl group.
Throughout the present invention, a compound of formula (IV) wherein B represents a hydroxyl group may be converted to B represents C according to methods known to those skilled in the art, for example in the presence of an acid such as sulfuric acid in a solvent such as methanol or ethanol1-C6-alkoxy groups of the general formula (IV).
In B represents C1-C6In the case of compounds of formula (IV) with alkoxy groups, the compounds of formula (I) can be obtained by reacting the compound of formula (IV) obtained above with an amide of a compound of formula (V) in which W is as defined above for formula (I) in a solvent at the reflux point, such as toluene. The aluminum amide of the compound of the formula (V) is prepared by first reacting trimethylaluminum with an amine of the formula (V).
In the case of compounds of formula (IV) in which B represents a hydroxyl group, the carboxylic acid function may be converted beforehand to an acid halide, for example to an acid chloride by reaction with thionyl chloride, in a solvent such as dichloromethane or dichloroethane at the reflux point. The compound of formula (I) is then obtained by reaction of a compound of formula (IV) wherein B represents a chlorine atom, with a compound of formula (V) in the presence of a base such as triethylamine or sodium carbonate.
Alternatively, the compound of formula (IV) wherein B represents a hydroxyl group may be coupled with a compound of formula (V) in the presence of a coupling agent such as a dialkylcarbodiimide, [ (benzotriazol-1-yl) oxy ] [ tris (pyrrolidine) ] * hexafluorophosphate, diethyl cyanophosphonate or any other coupling agent known to those skilled in the art, in the presence of a base such as triethylamine, in a solvent such as dimethylformamide.
In scheme 1, the compounds of formulae (II), (III) and (V) and other reagents, when their preparation is not described, are commercially available, are described in the literature or are similarly prepared by a number of methods described in the literature (e.g., M.Nazare et al Angew Chem Int Ed 2004, 43(34), 4526-4528; P.M.Fresneda et al Tetrahedron Lett 2000, 41(24), 4777-4780; M.H.Fisher et al J Heterocyclic Chem 1969, 6, 775; B.Frydman et al J Am Chem Soc 1965, 87, 3530; L.N.Yakhotov Tetrahedron Chronic Leut 1969, 1909; G.P.Fisgan et al J.Chem 1985, 944; OSmalesan et al J2004009302; WO 0304109; WO 030749; WO 0307412; WO 030749).
Compounds of formula (II), (IV) or (I) in which X represents an alkyl group, can be obtained by coupling reactions, in which case they are catalyzed by a metal such as palladium or iron, by corresponding compounds of formula (II), (IV) or (I) in which X represents a halogen atom, for example chlorine, in which case, for example, an alkylmagnesium or alkylzinc halide is present, according to the methods described in the literature (for example, 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.
X, Z therein1、Z2、Z3、Z4And &Or Z5The compounds of formulae (II), (IV) and (I) representing cyano or aryl groups may be obtained by a coupling reaction, in which case they are catalysed by a metal such as palladium, by a process wherein X, Z1、Z2、Z3、Z4And/or Z5The corresponding compounds of the general formula (II), (IV) or (I) representing, for example, a bromine atom, in this case in the presence of trimethylsilyl cyanide or arylboronic acids, or by any of the methods described in the literature or known to the person skilled in the art.
X, Z therein1、Z2、Z3、Z4And/or Z5Represents a group NR1R2、NR3COR4Or NR3SO2R5The compounds of the general formulae (I), (II) and (IV) from which X, Z is derived1、Z2、Z3、Z4And/or Z5The compounds of the corresponding general formulae (I), (II) and (IV) representing, for example, a bromine atom are obtained by coupling reactions with amines, amides or sulfonamides, respectively, in the presence of a base, a phosphine and a palladium-based catalyst, according to any of the methods described in the literature or known to the person skilled in the art.
X, Z therein1、Z2、Z3、Z4And/or Z5Represents a group C (O) NR1R2The compounds of the general formulae (II), (IV) and (I), from which X, Z can be derived1、Z2、Z3、Z4And/or Z5The corresponding compounds of formula (II), (IV) or (I) representing a cyano group are obtained according to methods described in the literature or known to the person skilled in the art.
X, Z therein1、Z2、Z3、Z4And/or Z5Represents a group-S (O) -alkyl or-S (O)2-alkyl compounds of the general formulae (II), (IV) and (I), from which X, Z can be drawn1、Z2、Z3、Z4And/or Z5Is represented by C1-C6Oxidation of the corresponding compound of formula (II), (IV) or (I) to a sulfanyl group, according to what is described in the literatureOr methods known to those skilled in the art.
X, Z therein1、Z2、Z3、Z4And/or Z5Represents a group NR1R2、NR3COR4Or NR3SO2R5The compounds of the general formulae (II), (IV) and (I) which may be represented by X, Z1、Z2、Z3、Z4And/or Z5The corresponding compounds of the general formula (II), (IV) or (I) which represent nitro groups are obtained, for example, by reduction, followed by acylation or sulfonylation, according to methods described in the literature or known to the person skilled in the art.
X, Z therein1、Z2、Z3、Z4And/or Z5Represents a group SO2NR1R2The compounds of the general formulae (II), (IV) and (I) can be obtained by methods analogous to those described in Pharmazie 1990, 45, 346 or according to methods described in the literature or known to the person skilled in the art.
Wherein R is7The compound of formula (I) representing a hydrogen atom may be represented by the formula (I) wherein R7The compounds of formula (I) representing a phenylmethyl group are obtained by hydrogenation in the presence of a catalyst based on palladium or by all other methods described in the literature or known to the person skilled in the art.
The following examples describe the preparation of certain compounds of the invention. These examples are non-limiting and are intended to be illustrative of the invention only. The amounts of the compounds given as examples refer to those given in table 1. The structure of the obtained compound was confirmed by elemental microanalysis, LC-MS (liquid chromatography-Mass Spectrometry) analysis, and IR or NMR spectroscopy.
Example 1(Compound 1)
N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
1.13- (3-Nitropyridin-4-yl) -2-oxopropanoic acid ethyl ester
3.1g (22.44mmol) of 4-methyl-3-nitropyridine and 16.39g (112.22mmol) of ethyl oxalate are placed in a 100ml three-necked flask equipped with a magnetic stirrer and kept under a nitrogen purge. Then, 3.69ml (24.69mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene were added to the reaction medium, which was stirred at room temperature. The reaction mixture was then stirred at room temperature for 1 hour and diluted with a mixture of ethyl acetate (150ml), water (100ml) and acetic acid (4 ml). The mixture was extracted twice with ethyl acetate. The combined organic phases are washed with 100ml of water, 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude reaction product is then triturated from pentane, filtered and heated in petroleum ether, filtered and dried under reduced pressure. 3.9g (16.37mmol) of the product were thus isolated and used in the next step without further purification.
1H NMR(CDCl3)，δ(ppm)；9.4(s，1H)；8.9(d，1H)；7.4(d，1H)4.65(s，2H)；4.5(q，2H)；14(t，3H)。
1.21H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
Method A: to a solution of 3.9g (6.37mmol) of the product obtained in step 1.1 in 140ml of ethanol and 60ml of tetrahydrofuran are added a single portion of 60ml of saturated aqueous ammonium chloride solution and 5.48g (98.2mmol) of iron powder. The reaction mixture was then stirred at reflux for 2 hours. The cooled solution was filtered through celite and rinsed several times with ethyl acetate. After concentrating the filtrate under reduced pressure, the residue is taken up in water and ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The first 0.7g (3.68mmol) of product was isolated. The aqueous phase was concentrated under reduced pressure, the residue was taken up in hot ethyl acetate, the precipitate was removed by filtration and the filtrate was concentrated again. The residue obtained was purified by silica gel column chromatography eluting with a mixture of heptane and ethyl acetate. A further 0.7g (3.68mmol) of product are obtained.
Method B: go to stepTo a solution of 0.25g (1.05mmol) of the product obtained in step 1.1 in 10ml of ethanol was added 0.11g (0.1mmol) of 10% palladium on charcoal. The reaction mixture was hydrogenated under reduced pressure of 30psi for 2.5 hours at room temperature. After filtration through glass fibre, the filtrate was evaporated under reduced pressure and the crude reaction product obtained was recrystallised from ethanol to give 0.08g (0.42mmol) of product.
1H NMR(DMSO D6)，δ(ppm)：8.9(s，1H)；8.3(d，1H)；7.7(dd，1H)；7.2(d，1H)；4.4(q，2H)；1.4(t，3H)。
1.31- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
To a solution of 2g (10.52mmol) of the product obtained in step 1.2 maintained under an inert atmosphere in 105ml of anhydrous tetrahydrofuran are added, with stirring, 2.03g (15.77mmol) of 3-fluorobenzol and then 4.17g (15.77mmol) of triphenylphosphine. 2.83g (15.77mmol) of diethyl azodicarboxylate were then added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. The oil obtained was purified by continuous chromatography on a silica gel column eluted with a mixture of heptane and ethyl acetate. 1.9g (6.37mmol) of product are isolated.
1H NMR(CDCl3)，δ(ppm)：8.8(s，1H)；8.3(d，1H)；7.6(d，lH)；7.2(s，1H)；7.1(m，1H)；6.85(m，2H)；6.65(m，1H)；5.8(s，2H)；4.3(q，2H)；1.3(t，3H)。
1.4N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide (Compound 1)
To a solution of 1.68ml (3.35mmol) of trimethylaluminum in 5ml of dry toluene under argon blanket and magnetic stirring is added a solution of 0.29g (2.01mmol) of 5-amino-1-methylindole in 10ml of dry toluene under cold conditions. The reaction medium is maintained at 50 ℃ for 15 minutes. Then 15ml of toluene in which 0.5g (1.68mmol) of the ester obtained in step 1.3 was dissolved were slowly added and the mixture was refluxed for 20 hours. To the cooled solution was added ice, dilute hydrochloric acid and then ethyl acetate. The insoluble material was collected and taken up with dichloromethane and sodium hydroxide solution. The organic phase is washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of dichloromethane and ethyl acetate. The resulting solid was triturated with petroleum ether, collected by filtration and dried under reduced pressure. 0.385g of the expected product is isolated.
Melting point: 213-214.5 deg.C
1H NMR(DMSO D6)，δ(ppm)：10.45(s，1H)；8.95(s，1H)；8.2(d，1H)；7.95(s，1H)；7.7(d，1H)；7.3(m，5H)；7.0(m，3H)；6.4(d，1H)；5.95(s，2H)；3.75(s，3H)。
Example 2(Compound 2)
N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
2.13- (2-fluoro-5-nitropyridin-4-yl) -2-oxopropanoic acid ethyl ester
2g (12.81mmol) of 2-fluoro-4-methyl-5-nitropyridine and 9.36g (32.03mmol) of ethyl oxalate are placed in a 100ml three-necked flask equipped with a magnetic stirrer and kept under a nitrogen purge. Then, 2.11ml (14.09mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene were added to the reaction medium, which was stirred at room temperature. The reaction mixture was then stirred at room temperature for 4 hours. A mixture of ethyl acetate (100ml), water (40ml) and acetic acid (2ml) was added thereto. The mixture was extracted twice with ethyl acetate. The combined organic phases are washed with 100ml of water, 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a mixture of heptane and ethyl acetate. 1.53g of product was thus isolated and used in the next step without further purification.
1H NMR(DMSO D6)，δ(ppm)：8.9(s，1H)；7.9(s，1H)；6.7(s，1H)；4.7(s，OH)；4.3(q，2H)；1.3(t，3H) (ii) a Predominantly the keto-enol form.
2.25-fluoro-1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.6g (2.34mmol) of the product obtained in step 2.1 in 30ml of ethanol and 15ml of tetrahydrofuran are added a single portion of 15ml of saturated aqueous ammonium chloride solution and 0.39g (7.03mmol) of iron powder. The reaction mixture was then stirred at reflux for 3 hours. The cooled solution was filtered through celite and the filtrate was rinsed several times with methanol. After concentrating the filtrate under reduced pressure, the residue was taken up with ethyl acetate and water. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. 0.43g (2.06mmol) of product was obtained and used in the next step without further purification.
1H NMR(DMSO D6)，δ(ppm)；12.5(s，NH)；8.5(s，1H)；7.3(s，1H)；7.1(s，1H)；4.4(q，2H)；1.35(t，3H)。
2.35-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.4g (1.92mmol) of the product obtained in step 2.2 maintained under an inert atmosphere in 20ml of anhydrous tetrahydrofuran are added successively, with stirring, 0.37g (2.88mmol) of 3-fluorobenzol and 0.76g (2.88mmol) of triphenylphosphine. Then 0.52g (2.88mmol) of diethyl azodicarboxylate were added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. The oil obtained is purified by chromatography on a silica gel column eluted with a mixture of n-pentane and diethyl ether. 0.49g (1.55mmol) of product was isolated and used in the next step without further purification.
1H NMR(DMSO D6)，δ(ppm)：8.7(s，1H)；8.5-7.1(m，6H)；5.9(s，2H)；4.3(q，2H)；1.25(t，3H)。
2.4N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide (Compound 2)
0.3g (2.05mmol) of 5-amino-1-methylbenzimidazole and 10ml of anhydrous toluene were placed in a 100ml three-necked flask cooled to 0 ℃ and equipped with a magnetic stirrer under a nitrogen stream. To this solution was then slowly added 1.58ml (3.16mmol) of a 2M solution of trimethylaluminum in toluene. The resulting reaction mixture was maintained under a nitrogen atmosphere and stirred to gradually increase the temperature to 70 ℃. A solution of 0.5g (1.58mmol) of the product from step 2.3 in 10ml of dry toluene is added dropwise over 5 minutes via an addition funnel. The reaction mixture was refluxed for an additional 2 hours. 10ml of 1N hydrochloric acid and 20ml of ice water are added to the solution cooled to 0 ℃. After stirring at room temperature for 1 hour, the precipitate formed was collected by filtration, washed with water, dried under reduced pressure and recrystallized from isopropanol. The desired product was isolated as a yellow solid.
Melting point: 279-281 deg.C
1H NMR(DMSO D6)，δ(ppm)：10.6(s，1H)；8.65(s，1H)；8.15(s，1H)；8.05(s，1H)；7.65(m，2H)；7.35(m，3H)6.99(m，3H)；5.9(s，2H)；3.9(s，3H)。
Example 3(Compound 3)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-chloro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
3.13- (2-chloro-5-nitropyridin-4-yl) -2-oxopropanoic acid ethyl ester
Under a nitrogen stream, 1g (5.79mmol) of 2-chloro-4-methyl-5-nitropyridine and 4.23g (28.94mmol) of ethyl oxalate were placed in a 100ml three-necked flask equipped with a magnetic stirrer. 0.96ml (6.4mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene are added to the stirred reaction medium at room temperature. The reaction mixture was then stirred at room temperature for 1 hour and diluted with a mixture of ethyl acetate (40ml), water (30ml) and acetic acid (1 ml). The mixture was extracted twice with ethyl acetate. The combined organic phases are washed with 100ml of water, 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column eluted with a mixture of heptane and ethyl acetate. 1.33g (4.87mmol) of the extracted product are thus isolated as pink powder.
3.25-chloro-1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
To a solution of 1.5g (5.5mmol) of the product obtained in step 3.1 in 50ml of ethanol and 25ml of tetrahydrofuran were added in one portion 25ml of a saturated aqueous ammonium chloride solution and 0.92g (16.5mmol) of iron powder. The reaction mixture was then stirred at reflux for 3 hours. The cooled solution is filtered through kieselguhr, the filtrate is extracted with ethyl acetate, and the combined organic phases are washed with 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure. The product was purified by chromatography on a silica gel column eluted with a mixture of n-heptane and ethyl acetate. 0.98g (4.36mmol) of the desired product is obtained in the form of a white powder.
1H NMR(CDCl3)，δ(ppm)：9.25(s，NH)；8.75(s，1H)；7.70(s，1H)；7.2(d，1H)；4.5(q，2H)；1.4(t，3H)。
3.35-chloro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.25g (1.11mmol) of the product obtained in step 3.2 maintained under an inert atmosphere in 10ml of anhydrous tetrahydrofuran are added successively, with stirring, 0.21g (1.67mmol) of 3-fluorobenzol and 0.44g (1.67mmol) of triphenylphosphine. Then 0.3g (1.67mmol) of diethyl azodicarboxylate was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. The resulting oil was purified by chromatography on a silica gel column eluted with a mixture of n-heptane and ethyl acetate (50/50). 0.32g (0.96mmol) of the desired product are isolated as a white powder.
1H NMR(DMSO D6)，δ(ppm)：8.9(s，1H)；7.9(s，1H)；7.3(s，1H)；7.25(m，1H)；7.1(m，1H)；6.9(m，2H)；5.9(s，2H)；4.3(q，2H)；1.3(t，3H)。
3.45-chloro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid
To a solution of 0.3g (0.9mmol) of the product obtained in step 3.3 in 10ml of ethanol was added 0.6ml (1.17mmol) of 2N sodium hydroxide solution. The reaction mixture was refluxed for 2 hours and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in 15ml of water. Acetic acid was added at 0 ℃ to acidify the pH of the solution to 3 and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off, rinsed several times with water and dried under reduced pressure. 0.25g (0.82mmol) of the desired product are isolated as a white powder.
1H NMR(DMSO D6)，δ(ppm)：8.9(s，1H)；7.9(s，1H)；7.3(s，1H)；7.25(m，1H)；7.1(m，1H)；6.9(m，2H)；5.9(s，2H)。
3.5N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-chloro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
To a solution containing 0.25g (0.82mmol) of the product obtained in step 3.4 in 20ml of dry dichloromethane were added successively 0.43g (0.82mmol) of [ (benzotriazol-1-yl) oxy ] [ tris (pyrrolidine) ] * of hexafluorophosphate and 0.17g (0.98mmol) of 5-amino-1, 2-dimethylbenzimidazole. To this solution was then added dropwise 0.45ml (2.46mmol) of N-N- (diisopropyl) ethylamine. The mixture was stirred at room temperature for 2 hours. The pink precipitate formed on the sinter funnel was filtered off and rinsed several times with dichloromethane and dried under reduced pressure. 0.15g of the desired product is thus isolated in the form of a white powder.
Melting point: 240 ℃ and 242 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.75(s，1H)；8.85(s，1H)；7.95(s，1H)；7.85(s，1H)；7.5(m，2H)；7.3(m，2H)；6.95(m，3H)；5.9(s，2H)；3.75(s，3H)；2.5(s，3H).
Example 4(Compound 4)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide hydrochloride (1: 2)
To a solution of 0.34g (2mmol) of 1, 2-dimethyl-1H-benzimidazole in 20ml of dry toluene was added 1.26ml (2.51mmol) of trimethylaluminum (2M in toluene) with stirring and under nitrogen. After a few minutes, a solution of 0.5g (1.68mmol) of ethyl 1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylate prepared according to the procedure described in example 1, step 1.3, in 40ml of dry toluene is added. The reaction medium is refluxed at room temperature for 3 hours. After cooling to room temperature, it was poured into a mixture of dichloromethane and water. After removal of insoluble material, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed, dried under reduced pressure and concentrated. The residue was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and methanol. 0.52g (1.26mmol) of the expected product are isolated.
Melting point: 257 ℃ C. -
The corresponding hydrochloride was obtained by reacting 0.5g (1.21mmol) of the product obtained above in base form (as a solution in 30ml of a dichloromethane/methanol mixture (9/1)) with 0.7ml of dioxane containing 4N hydrochloric acid. The resulting salt was recrystallized from an ethanol/water mixture (95/5). 0.27g (0.55mmol) of the expected product is obtained.
Melting point: 309 ℃ and 310 DEG C
1H NMR(DMSO D6)，δ(ppm)：11.5(s，NH)；9.6(s，1H)；8.4-8.5(s，1H)；8.3(s，2H)；7.9(m，3H)；7.4(m，2H)；7.4(d，1H)；7.1(m，2H)；6.1(s，2H)；3.9(s，3H)，2.9(s，3H)。
Compound 5(Compound 8)
N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
5.12- (tert-Butoxycarbonylamino) -3-methylpyridine
31g (142.03mmol) of di-tert-butyl dicarbonate and 35ml of hexane were placed in a 100ml three-necked flask equipped with a magnetic stirrer and allowed to reflux. A solution of 10g (88.77mmol) of 2-amino-3-methylpyridine in 10ml of ethyl acetate was added dropwise over a period of 2 hours. After the addition was complete, reflux was continued for 1 hour. After cooling to room temperature, 20ml of hexane was added, and a white precipitate formed after stirring the reaction mixture was collected by filtration, rinsed with hexane, and dried under reduced pressure. 15.5g (74.43mmol) of white crystals were obtained.
1H NMR(CDCl3)，δ(ppm)：8.3(dd，1H)；7.5(dd，1H)；7.4(s，NH)；7.1(ddd，1H)；2.3(s，3H)；1.5(s，9H)。
5.21H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
5g (24.01mmol) of the product obtained in step 5.1 and 50ml of anhydrous tetrahydrofuran are placed in a 250ml three-necked flask equipped with a magnetic stirrer and maintained under nitrogen atmosphere. 30ml (48.02mmol) of a 1.6 molar solution of butyllithium in THF are added dropwise while maintaining the temperature below 5 ℃. After stirring at 0 ℃ for 1 hour, the lithiated derivative thus obtained was added to a solution of 7.08g (48.02mmol) of diethyl oxalate in 50ml of anhydrous tetrahydrofuran, maintained at-3 ℃. The reaction medium is allowed to warm to room temperature. The medium is then poured into 25ml of 6N hydrochloric acid solution cooled to 0 ℃ while maintaining the temperature below 10 ℃. The resulting mixture was stirred at 50 ℃ for 2 hours and then at room temperature overnight. The reaction medium is adjusted to pH3 with sodium hydroxide and extracted with diethyl ether. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. 1.8g (9.46mmol) of product were obtained and used without further purification in the following step.
1H NMR(CDCl3)，δ(ppm)：8.8(dd，1H)；8.15(dd，1H)；7.2(m，2H)；4.5(q，2H)；1.5(t，3H)。
5.31- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
Method A: 1.64g (41.01mmol) of sodium hydride previously washed with n-pentane and 180ml of anhydrous dimethylformamide are placed in a 500ml three-necked flask equipped with a magnetic stirrer and maintained under an argon atmosphere. 6g (31.55mmol) of the product obtained in step 5.2 are added dropwise. The reaction medium is then maintained at 50 ℃ for 1 hour. Then, a solution of 7.15g (37.85mmol) of 3-fluorobenzyl bromide in 10ml of anhydrous dimethylformamide was added dropwise. The reaction mixture was then stirred at reflux for 16 hours. The cooled solution is diluted in a mixture of 200ml of ice-water and 200ml of ethyl acetate. After separation by settling, the aqueous phase is extracted with ethyl acetate and the combined organic phases are successively washed with 100ml of water and 100ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The oil obtained is purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and n-heptane. 5.73g of product was obtained, which was used without further purification in the following step.
Method B: to a solution of 5.2g (27.34mmol) of the product obtained in step 5.2 maintained under an inert atmosphere in 250ml of anhydrous tetrahydrofuran are added, with stirring, 5.28g (41mmol) of 3-fluorobenzol and 10.87g (41mmol) of triphenylphosphine in succession. 7.36g (41mmol) of diethyl azodicarboxylate were then added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. A mixture of pentane and diethyl ether was added and the precipitate was removed by filtration. After concentration under reduced pressure, the resulting oil was purified by continuous chromatography on silica gel column. 6.2g of product are isolated.
1H NMR(CDCl3)，δ(ppm)：8.6(dd，1H)；8.1(dd，1H)；7.4(s，1H)；7.2(m，2H)；6.95(m，3H)；6.0(s，2H)；4.4(q，2H)；1.4(t，3H)。
4N- (1-methyl-1H-indol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
A solution of 0.31g (1.75mmol) of 5-amino-1-methylindole in 10ml of dry toluene is added to a solution of 1.75ml (3.50mmol) of trimethylammonium in 5ml of dry toluene, while stirring under magnetic force under argon, while cold. The reaction medium is maintained at 50 ℃ for 2 hours. Then 0.52g (1.75mmol) of the ester obtained in step 5.3 dissolved in toluene was added and the solution refluxed for 5 hours. To the cooled solution were added ethyl acetate, ice water and 1N hydrochloric acid. After separation of the settled phases, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and with saturated sodium chloride solution, dried under reduced pressure and concentrated. The residue was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and ethyl acetate. The solid is taken up in a solution of sodium hydroxide and ethyl acetate and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The resulting solid was triturated in petroleum ether, collected by filtration and dried under reduced pressure. 0.56g of the expected product is isolated.
Melting point: 191-191.5 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.3(s，1H)；8.45(dd，1H)；8.2(dd，1H)；7.95(s，1H)；7.35(m，3H)；7.25(m，3H)；6.95(m，3H)；6.4(d，1H)；5.95(s，2H)；3.75(s，3H)。
Example 6(Compound 9)
N- (1-methyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide hydrochloride (2: 3)
The process is carried out according to the method described in step 5.4 of example 5, starting from 0.5g (1.68mmol) of ethyl 1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate prepared by the method described in step 5.3 of example 5, 1.68ml (3.35mmol) of toluene containing 2M trimethylaluminum and 0.30g (2.01mmol) of 5-amino-1-methylbenzimidazole. After refluxing for 3 hours and reacting at room temperature overnight, ice water and 1N hydrochloric acid were added. The precipitate was collected by filtration, washed with water and dried under reduced pressure. 0.42g (1.05mmol) of the product is isolated and taken up in 15ml of diethyl ether, to which 1.1ml of diethyl ether containing 2N hydrochloric acid are added. The mixture was stirred at room temperature overnight, the solid collected by filtration, washed with ether and dried under reduced pressure. 0.48g of the expected product is obtained in the form of the hydrochloride.
Melting point: 171 ℃ 177 ℃
1H NMR(DMSO D6)，δ(ppm)：10.85(s，NH)；9.5(s，1H)；8.45(m，2H)；8.25(dd，1H)；7.9(m，2H)；7.6(s，1H)；7.3(m，2H)；6.9(m，3H)；5.9(s，2H)；4.0(s，3H)。
Example 7(Compound 10)
N- (2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
0.33g (2.01mmol) of 7-amino-3, 4-dihydroquinolin-2 (1H) -one are added portionwise to a solution of 2.51ml (5.03mmol) of trimethylaluminum in 20ml of dry toluene under argon and magnetic stirring. The reaction medium is kept at 50 ℃ for 30 minutes. Then 0.5g (1.68mmol) of the ester obtained in step 5.3 of example 5 dissolved in 5ml of toluene was slowly added and the solution refluxed for 2 hours. To the cooled solution was added water and dilute hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under reduced pressure. The residue is taken up in dichloromethane and the organic phase is washed with water and saturated sodium chloride solution, dried under reduced pressure and concentrated. The residue was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and methanol. 0.48g (1.16mmol) of the expected product is isolated.
Melting point: 280 ℃ and 282 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.45(s，NH)；10.1(s，NH)；8.45(d，1H)；8.2(d，1H)；7.4(m，2H)；7.3-6.8(m，7H)；5.9(s，2H)；2.8(t，2H)；2.4(t，2H)。
Example 8(Compound 11)
N- (quinolin-7-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide hydrochloride (1: 1)
8.11- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid
A solution of 0.6g (2.01mmol) of the ester obtained in step 5.3 in 0.23g (4.02mmol) of potassium hydroxide in 60ml of methanol is refluxed for 2 hours. The solution was concentrated under reduced pressure and the residue was taken up in water and acidified with dilute hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under reduced pressure. 0.37g of product was obtained, which was used without further purification in the following step.
2N- (quinolin-7-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide hydrochloride (1: 1)
0.37g (1.37mmol) of the acid obtained in step 8.1, 40ml of dichloromethane and 1ml (13.69mmol) of thionyl chloride are placed in a 100ml round bottom flask equipped with a magnetic stirrer. The suspension thus obtained was refluxed for 2 hours. After evaporation of the solvent under reduced pressure, 50ml of dehydrated ether, 0.35g (64mmol) of 7-aminoquinoline dihydrochloride (WO 03/068749) and 5ml of an aqueous solution containing 0.58g (5.48mmol) of sodium carbonate were added. The reaction medium is stirred overnight and the organic solvent is evaporated off under reduced pressure. Water was added and the precipitate was collected by filtration. The solid obtained is taken up in dichloromethane and the organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and ethanol (95/5). The product is taken up in 20ml of diethyl ether and 1ml of diethyl ether with 2N hydrochloric acid, and the solution is stirred overnight. The solid was collected by filtration and washed with ether. It was washed with hot ethanol. After cooling to room temperature, collected by filtration and oven-dried under reduced pressure. 0.19g of the expected product is obtained.
Melting point: 260 ℃ to 262 DEG C
1H NMR(DMSO D6)，δ(ppm)：11.2(s，1H)；9.15(d，1H)；8.9(m，2H)；8.5(m，1H)；8.3(m，2H)；8.15(m，1H)；7.85(m，1H)；7.65(s，1H)；7.3(m，2H)；6.9(m，3H)；6.0(s，2H)。
Example 9(Compound 12)
N- (1-methyl-1H-indol-5-yl) -1- (phenylmethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
Ethyl 1- (phenylmethyl) -1H-pyrrolo [2, 3-B ] pyridine-2-carboxylate, prepared beforehand according to the procedure described in example 5.3B, starting from the product obtained in example 5.2 and benzyl alcohol. The process was then carried out according to the method described in step 5.4 of example 5, starting with ethyl 1- (phenylmethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (1 eq), toluene containing 2M trimethylaluminum (1.5 eq) and 5-amino-1-methylindole (1.2 eq). The crude reaction product was purified by silica gel column chromatography.
Melting point: 181 plus 182 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.3(1H，NH)；8.45(d，1H)；8.2(d，1H)；7.95(s，1H)；7.4-7.05(m，10H)；6.4(d，1H)；5.95(s，2H)，3.8(s，3H)。
Example 10(Compound 13)
N- (1-methyl-1H-indol-5-yl) -1- (phenylethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
Ethyl 1- (phenylethyl) -1H-pyrrolo [2, 3-B ] pyridine-2-carboxylate, prepared beforehand according to the procedure described in example 5.3B, starting from the product obtained in example 5.2 and 2-phenylethanol. The process was then carried out according to the method described in step 5.4 of example 5, starting with ethyl 1- (phenylethyl) -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (1 eq), toluene containing 2M trimethylaluminum (1.5 eq) and 5-amino-1-methylindole (1.2 eq). The crude reaction product was purified by silica gel column chromatography.
Melting point: 196 ℃ C, 199 ℃ C
1H NMR(DMSO D6)，δ(ppm)：10.25(s，NH)；8.45(d，1H)；8.15(dd，1H)；8.0(s，1H)；7.5-7.1(m，10H)；6.45(d，1H)；4.9(t，2H)；3.8(s，3H)；3.05(t，2H)。
Example 11(Compound 14)
N- (2-methyl-benzothiazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide hydrochloride (2: 3)
1.68ml (3.35mmol) of a 2M solution of trimethylaluminum in toluene with 20ml of anhydrous toluene are placed in a 100ml round-bottomed flask cooled to 0 ℃ and equipped with a magnetic stirrer, while flushing with nitrogen. Then 0.33g (2.01mmol) of 5-amino-2-methylbenzothiazole was added in small portions. The reaction mixture is kept at 50 ℃ for 30 minutes and then a solution of 0.5g (1.68mmol) of the ester obtained in step 5.3 in 20ml of dry toluene is added dropwise over 5 minutes. The reaction mixture was then refluxed for 4 hours. 50ml of ice water and 20ml of ethyl acetate are added to the solution which is cooled to 0 ℃. After stirring for 30 minutes, the solid formed was removed by filtration and washed with water and ethyl acetate. After separation of the settling phases, the aqueous phase is extracted with ethyl acetate and the combined organic phases are subsequently washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and ethyl acetate. The corresponding hydrochloride was obtained by treatment with a solution of hydrochloric acid in ether. 0.475g of the expected product is isolated.
Melting point: 211 ℃ and 212 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.65(s，1H)；8.5(dd，1H)；8.4(d，1H)；8.2(dd，1H)；7.95(d，1H)；7.75(dd，1H)；7.5(s，1H)；7.3(m，2H)；6.9(m，3H)；5.9(s，2H)；2.8(s，3H)。
Example 12(Compound 15)
N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
12.12-amino-3-iodo-5-fluoropyridines
5g (44.6mmol) of 2-amino-5-fluoropyridine, 13.9g (44.6mmol) of silver sulfate and 400ml of ethanol were placed in a 500ml two-necked flask equipped with a magnetic stirrer. 11.31g (44.6mmol) of iodine powder were then added in small portions. Stirring was continued at room temperature for 24 hours. The resulting yellow suspension was filtered, the precipitate was rinsed with ethanol and the filtrate was concentrated under reduced pressure. The residue thus obtained was taken up in a mixture of ethyl acetate (200ml) and sodium carbonate solution (200 ml). After separation, the organic phase is successively washed with a 25% aqueous solution of sodium thiosulfate, saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is purified by chromatography on a silica gel column eluted with a mixture of n-heptane and ethyl acetate. 2.67g (11.22mmol) of the expected product are obtained.
1H NMR(DMSO D6)，δ(ppm)：7.95(s，1H)；7.85(s，1H)；5.9(s，NH2).
12.25-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid
0.5g (2.10mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in step 12.1, 0.55g (6.3mmol) of pyruvic acid, 0.71g (6.3mmol) of 1, 4-diazabicyclo [2.2.2] octane (DABCO) and 15ml of anhydrous dimethylformamide were placed in a 25ml closed tube equipped with a magnetic stirrer and kept under argon gas sparging. After a few minutes, 0.05g (0.22mmol) of palladium acetate are added. The reaction mixture was stirred for 20 minutes while sparging with argon, quickly sealed and held at 100 ℃ for 2.5 hours. The cooled solution was concentrated to dryness under reduced pressure. The residue was then taken up in ethyl acetate (100ml) and water (75 ml). The organic phase is washed with water and extracted twice with 50ml of 2N aqueous sodium hydroxide solution. The aqueous alkaline phases are combined, cooled to 0 ℃ and acidified (pH 3) by addition of hydrochloric acid. The medium is extracted with ethyl acetate (4X 50ml) and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. 0.158g (0.88mmol) of the desired product is 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)。
12.35-fluoro-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
0.2g (1.11mmol) of the acid obtained in step 12.2 and 10ml of ethanol are placed in a 100ml round-bottom flask equipped with a magnetic stirrer. 1ml of concentrated sulfuric acid was added to the reaction mixture, which was refluxed for a further 18 hours. The cooled solution was concentrated under reduced pressure and dried. The residue was taken up in ethyl acetate (50ml) and washed successively with standard aqueous sodium hydroxide (2X 10ml), water (10ml) and then saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate and 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)。
12.45-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.2g (0.96mmol) of the product obtained in step 12.3 in 15ml of anhydrous tetrahydrofuran, maintained under an inert atmosphere, 0.18g (1.44mmol) of 3-fluorobenzol and 0.39g (1.44mmol) of triphenylphosphine are added successively with stirring. Then 0.26g (1.44mmol) of diethyl azodicarboxylate was added dropwise at 0 ℃. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. The oil obtained is purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and methanol. 0.26g (0.82mmol) of the expected product are isolated.
12.5N- (1-methyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
0.18g (1.23mmol) of 5-amino-1-methylbenzimidazole and 10ml of dry toluene are placed, under a nitrogen purge, in a 100ml three-necked flask cooled to 0 ℃ and equipped with a magnetic stirrer. To this solution was then slowly added 0.95ml (1.90mmol) of a 2M solution of trimethylaluminum in toluene. The resulting reaction mixture was maintained under nitrogen and stirred, and the temperature was gradually increased to 70 ℃. Using an addition funnel, a solution of 0.3g (0.95mmol) of the product obtained in step 12.4 in 10ml of dry toluene was added dropwise over 5 minutes. The reaction mixture was refluxed for an additional 5 hours and stirred at room temperature overnight. To the solution cooled to 0 ℃ 20ml of cold water was added, followed by 10ml of 1N hydrochloric acid. After stirring for 1 hour, the precipitate was recovered by filtration, washed with water, and dried under reduced pressure. 0.22g (0.53mmol) of the expected product are obtained in the form of a white solid.
Melting point: 266 ℃ 268 DEG C
1H NMR(DMSO D6)，δ(ppm)：9.5(s，1H)；8.5(s，1H)；7.9(s，2H)；7.5(m，3H)；7.3-6.8(m，5H)；5.9(s，2H)；3.95(s，3H)。
Example 13(Compound 16)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
13.12-amino-3-iodo-5- (trifluoromethyl) pyridine
2g (12.34mmol) of 2-amino-5-trifluoromethylpyridine, 3.85g (12.34mmol) of silver sulfate and 80ml of ethanol were placed in a 500ml two-necked flask equipped with a magnetic stirrer. 3.13g (12.34mmol) of iodine powder are added in small portions to the reaction medium which is stirred at room temperature. The reaction mixture was then stirred at room temperature for 48 hours. The resulting yellow suspension was filtered, the precipitate rinsed with ethanol and the filtrate evaporated under reduced pressure. The residue thus obtained was taken up in dichloromethane (200 ml). The organic phase was washed successively with 5% aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution. It was dried over sodium sulfate and concentrated under reduced pressure. The solid obtained is purified by chromatography on a silica gel column eluted with a mixture of n-heptane and ethyl acetate. 1.71g (5.94mmol) of product are obtained in the form of a pink powder.
1H NMR(DMSO D6)，δ(ppm)：8.3(s，1H)；8.1(s，1H)；6.8(s，NH2).
13.25-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid
2g (6.94mmol) of the product obtained in step 13.1, 151g (20.83mmol) of pyruvic acid, 2.41g (20.83mmol) of 1, 4-diazabicyclo [2.2.2] octane (DABCO) and 20ml of anhydrous dimethylformamide were placed in a 25ml closed tube equipped with a magnetic stirrer and kept under argon gas sparging. After a few minutes, 2g (8.91mmol) of palladium acetate are added. The reaction mixture was stirred for 20 minutes while sparging with argon, quickly sealed and held at 110 ℃ for 6 hours. The cooled solution was concentrated to dryness under reduced pressure. The residue was then taken up in ethyl acetate and water. After separation of the settling phases, the organic phase is washed with water and extracted twice with 50ml of 2N aqueous sodium hydroxide solution. The aqueous alkaline phases are combined, cooled to 0 ℃ and acidified (pH 3) by addition of hydrochloric acid. The medium is extracted with ethyl acetate (4X 50ml) and the combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. 0.67g (2.91mmol) of the desired product is obtained in the form of a yellow powder, which is used without purification in the following step.
1H NMR(DMSO D6)，δ(ppm)：12.8(s，1H)；8.7(d，1H)；8.5(d，1H)；7.2(s，1H).
13.35-trifluoromethyl-1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
0.3g (1.3mmol) of the acid obtained in step 13.2 and 50ml of ethanol are placed in a 100ml round-bottom flask equipped with a magnetic stirrer. 0.5ml of concentrated sulfuric acid was added to the solution. The reaction mixture was refluxed for 18 hours. The cooled solution was concentrated under reduced pressure and dried. The residue was taken up in dichloromethane (100ml) and the organic phase was successively washed with usual aqueous sodium hydroxide solution (30ml), water (20ml) and saturated aqueous sodium chloride solution. It was dried over sodium sulfate and concentrated under reduced pressure. 0.29g (1.12mmol) of the desired product are isolated in the form of a yellow powder.
1H NMR(DMSO D6)，δ(ppm)：12.95(s，NH)；8.8(d，1H)；8.6(d，1H)；7.3(s，1H)；4.4(q，2H)；1.35(t，3H)。
13.45-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.3g (1.16mmol) of the product obtained in step 13.3 in 20ml of anhydrous tetrahydrofuran, maintained under an inert atmosphere, 0.23g (1.74mmol) of 3-fluorobenzol and 0.46g (1.74mmol) of triphenylphosphine are added successively with stirring. Then 0.31g (174mmol) of diethyl azodicarboxylate was added dropwise. The reaction mixture was stirred at room temperature for a further 20 hours and then concentrated under reduced pressure. The oil obtained was purified by chromatography on a silica gel column eluted with a mixture of heptane and ethyl acetate. 0.34g (0.93mmol) of the expected product are isolated.
1H NMR(DMSO D6)，δ(ppm)：8.9(d，1H)；8.7(d，1H)；7.5(s，1H)；7.4-6.95(m，2H)；6.85(m，2H)；5.9(s，2H)；4.3(q，2H)，1.3(t，3H)。
13.5N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
0.17g (1mmol) of 5-amino-1-methylbenzimidazole and 10ml of anhydrous toluene are placed, under a nitrogen purge, in a 100ml three-necked flask cooled to 0 ℃ and equipped with a magnetic stirrer. To this solution was then slowly added 0.77ml (1.54mmol) of a 2M solution of trimethylaluminum in toluene. The resulting reaction mixture was maintained under nitrogen and stirred, and the temperature was gradually increased to 70 ℃. At this temperature, a solution of 0.3g (0.77mmol) of the product obtained in step 13.4 in 10ml of dry toluene is added dropwise over a period of 5 minutes. The reaction mixture was refluxed for an additional 4 hours. To the solution cooled to 0 ℃ 20ml of cold water was added. After stirring for 90 minutes, the precipitate formed is extracted three times with ethyl acetate (3X 50ml), and the combined organic phases are 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.
The resulting solid was purified by chromatography on a silica gel column eluted with a mixture of dichloromethane and methanol. The resulting solid was recrystallized from an isopropanol/ethanol mixture (9/1) to give 0.23g (0.48mmol) of the desired product in the form of white crystals.
Melting point: 263, 265 deg.C
1H NMR(DMSO D6)，δ(ppm)：11(s，1H)；8.85(s，1H)；8.75(s，1H)；8.3(s，1H)；7.9(m，2H)；7.7(s，1H)；7.3(m，1H)；6.95(m，3H)；5.95(s，2H)；3.9(s，3H)；2.8(s，3H)。
Example 14(Compound 18)
N- (2-methyl-1H-benzothiazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
The process is carried out according to the method described in step 13.5 of example 13, starting with 0.35g (0.96mmol) of ethyl 5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (example 13.4) and 0.17g (1.06mmol) of 5-amino-2-methylbenzothiazole. 0.34g of the expected compound is isolated.
Melting point: 204 ℃ and 206 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.78(s，1H)；8.8(s，1H)；8.7(s，1H)；8.31(s，1H)；7.97(d，1H)；7.71(d，1H)；7.6(s，1H)；7.28(m，1H)；6 95(m，3H)；5.95(d，2H)；2.8(s，3H)。
Example 15(Compound 19)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxamide
The process is carried out as described in example 11, starting with 0.4g (1.34mmol) of ethyl 1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-b ] pyridine-2-carboxylate (example 5.3) and 0.25g (1.61mmol) of 5-amino-1, 2-dimethylbenzimidazole. 0.477g of the expected compound is isolated.
Melting point: 242 ℃ and 244 DEG C
1H NMR(DMSO D6)，δ(ppm)：2.49(s，3H)；3.69(s，3H)；5.91(s，2H)；6.94(m，3H)；7.22(m，2H)；7.39(m，3H)；7.79(s，1H)；8.19(dxd，1H)；8.41(d，1H)；10.31(s，1H)。
Example 16(Compound 6)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
The process is carried out according to the method described in step 2.4 of example 2, starting with 0.3g (0.95mmol) of ethyl 5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylate (example 2.3) and 0.183g (1.14mmol) of 5-amino-1, 2-dimethylbenzimidazole. 0.21g of the expected compound is isolated.
Melting point: 245 ℃ 247 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.59(s，1H)；8.62(s，1H)；7.91(s，1H)；7.4(m，5H)；7.01(m，3H)；5.91(s，2H)；3.71(s，3H)；2.49(s，3H)。
Example 17(Compound 5)
N- (2-methyl-1H-benzothiazol-5-yl) -5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
The process is carried out according to the method described in step 2.4 of example 2, starting with 0.3g (0.95mmol) of ethyl 5-fluoro-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylate (example 2.3) and 0.189mg (1.14mmol) of 5-amino-2-methylbenzothiazole. 0.36g of the expected compound is isolated.
Melting point: 193- & ltSUB & gt 195 & deg.C-
1H NMR(DMSO D6)，δ(ppm)：10.87(s，1H)；8.68(s，1H)；8.32(s，1H)；7.98(d，1H)；7.71(d，1H)；7.35(m，3H)；6.99(m，3H)；5.9(s，2H)；2.79(s，3H)。
Example 18(Compound 7)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-phenyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide
18.14-methyl-5-nitro-2-phenylpyridine
A mixture of 2g (11.59mmol) of 2-chloro-4-methyl-5-nitropyridine, 1.41g (11.59mmol) of phenylboronic acid, 1.33g (1.16mmol) of tetrakis (triphenylphosphine) palladium and 4g (28.97mmol) of palladium carbonate was suspended in 50ml of degassed dioxane and heated at reflux for 12 h. The mixture is then cooled, diluted with 50ml of ethyl acetate, washed twice with 20ml of water and subsequently with 20ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is chromatographed on a column of silica gel (eluent: heptane/ethyl acetate) and then recrystallized from an isopropanol/isopropyl ether mixture. This gave 2.19g of a yellow solid which was used without further purification in the following synthesis.
18.23- (5-Nitro-2-phenylpyridin-4-yl) -2-oxopropanoic acid ethyl ester
A mixture of 1.3g (6.07mmol) of 4-methyl-3-nitro-2-phenylpyridine obtained in step 18.1 and 4.14ml of diethyl oxalate containing 1.01g (6.68mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene was stirred at room temperature for 4 hours. Thereafter, the mixture was diluted with 30ml of ethyl acetate, 20ml of water and 2ml of acetic acid. The resulting solution was extracted twice with 50ml of ethyl acetate. The combined organic phases were washed twice with 20ml of water and subsequently with 20ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: heptane/ethyl acetate). 1.46g of the expected product are thus isolated in the form of a white solid.
18.35-phenyl-1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
A mixture of 1.3g (4.3mmol) of ethyl 3- (5-nitro-2-phenylpyridin-4-yl) -2-oxopropanoate obtained in step 18.2 and 0.71g (12.89mmol) of iron powder in 20ml of saturated ammonium chloride, 20ml of tetrahydrofuran and 40ml of ethanol was refluxed for 3 hours. The reaction mixture was then cooled and filtered through a plug of celite. Under reduced pressure, the filtrate was concentrated to one third of its volume, and then extracted three times with 50ml of ethyl acetate. The combined organic phases are washed twice with 20ml of water and then with 20ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (eluent: heptane/ethyl acetate). This gives 0.93g of the expected product as a light brown powder.
18.45-phenyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylic acid ethyl ester
0.72g (5.63mmol) of 3-fluorobenzyl alcohol, 1.47g (5.63mmol) of triphenylphosphine and 1.01g (5.63mmol) of diethyl azodicarboxylate are successively added, with stirring under argon at 0 ℃ to a solution of 1g (3.76mmol) of ethyl 5-phenyl-1H-pyrrolo [2, 3-c ] pyridine-2-carboxylate obtained in step 18.3 in 30ml of anhydrous tetrahydrofuran. The mixture was stirred at 20 ℃ for 20 hours, concentrated under reduced pressure and purified by column chromatography on silica gel (eluent: heptane/ethyl acetate). This gives 1.1g of the expected product as a white powder.
18.5N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-phenyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxamide (Compound 7)
0.217g (1.35mmol) of 5-amino-1, 2-dimethylbenzimidazole and 5ml of dry toluene are placed, under a nitrogen purge, in a 100ml three-necked flask cooled to 0 ℃ and equipped with a magnetic stirrer. To this solution was then slowly added 0.84ml (1.68mmol) of a 2M solution of trimethylaluminum in toluene. The resulting reaction mixture was maintained under nitrogen and stirred, and the temperature was gradually increased to 70 ℃. At this temperature, a solution of 0.42g (112mmol) of ethyl 5-phenyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [2, 3-c ] pyridine-2-carboxylate, obtained in step 18.4, in 10ml of anhydrous toluene is added dropwise over 5 minutes. The reaction mixture was refluxed for an additional 4 hours. To the solution cooled to 0 ℃ 20ml of cold water was added. After stirring for 90 minutes, the precipitate formed is extracted three times with ethyl acetate (3X 50ml) and the combined organic phases are successively washed 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.
The resulting solid was triturated with boiling isopropyl ether and then recrystallized from an isopropanol/methanol mixture (9/1) to give 0.187g of the desired product as a light brown powder.
Melting point: 288, 290 DEG C
1H NMR(DMSO D6)，δ(ppm)：10.6(s，1H)；9.08(s，1H)；8.27(s，1H)；8.1(d，2H)；7.98(s，1H)；7.41(m，7H)；7.01(m，3H)；5.98(s，2H)；3.71(s，3H)；2.48(s，3H)。
Example 19(Compound 24)
N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide
19.13-amino-2-iodo-6-trifluoromethylpyridine
1.56g (6.17mmol) of iodine are added in portions to a stirred mixture under argon at 20 ℃ of 1g (6.17mmol) of 3-amino-6-trifluoromethylpyridine and 1.25g (6.17mmol) of silver sulfate in 40ml of ethanol. Stirring was carried out for 18 hours. The resulting yellow suspension was filtered and rinsed with ethanol. The filtrate was concentrated under reduced pressure and the residue was taken up in 100ml of dichloromethane. The organic phase is washed successively 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 chromatography on a silica gel column (eluent: heptane/ethyl acetate). 1.17g of the expected product are isolated and used without further purification for the next synthesis.
19.25-Trifluoromethylpyrrolo [3, 2-b ] pyridine-2-carboxylic acid
0.5g (1.74mmol) of 3-amino-2-iodo-6-trifluoromethylpyridine obtained in step 19.1, 0.45g (5.21mmol) of pyruvic acid, 0.51ml (5.21mmol) of 1, 4-diazabicyclo [2.2.2] octane and 10ml of anhydrous dimethylformamide were placed in a test tube sealed under argon. The solution was degassed for a few minutes, then 0.19g (0.87mmol) of palladium acetate was added, the tube was closed and refluxed at 130 ℃ for 4 hours. The cooled solution is then concentrated under reduced pressure, and the residue obtained is taken up in 100ml of ethyl acetate. The organic phase is washed successively with two 50ml aqueous 2N sodium hydroxide solutions. The aqueous alkaline phases are combined, cooled to 0 ℃ and acidified by addition of hydrochloric acid and then extracted 4 times with 50ml 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 was obtained and used in the next step without further purification.
19.35-Trifluoromethylpyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester
1ml (18.71mmol) of concentrated sulfuric acid was added to a solution of 0.2g (0.87mmol) of 5-trifluoromethyl-pyrrolo [3, 2-b ] pyridine-2-carboxylic acid obtained in step 19.2 in 10ml of ethanol. The solution was refluxed for 20 hours, cooled again and concentrated under reduced pressure. The residue obtained is taken up 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 product was obtained and used in the next step without further purification.
19.41- (3-Fluorobenzyl) -5-trifluoromethylpyrrolo [3, 2-b ] pyridine-2-carboxylic acid ethyl ester
To a solution of 0.2g (0.77ml) of ethyl 5-trifluoromethylpyrrolo [3, 2-b ] pyridine-2-carboxylate obtained in step 19.3 in 120ml of anhydrous tetrahydrofuran maintained at 0 ℃ under argon, 0.13ml (1.16mmol) of 3-fluorobenzyl alcohol, 0.3g (1.16mmol) of triphenylphosphine and 0.2g (1.16mmol) of diethyl azodicarboxylate were successively added. The reaction mixture was stirred at 20 ℃ for 20 hours and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: heptane/ethyl acetate). 0.21g of the expected product is thus isolated in the form of a yellow oil.
19.5N- (1, 2-dimethyl-1H-benzimidazol-5-yl) -5-trifluoromethyl-1- [ (3-fluorophenyl) methyl ] -1H-pyrrolo [3, 2-b ] pyridine-2-carboxamide (Compound 24)
0.097g (0.6mmol) of 5-amino-1, 2-dimethylbenzimidazole and 5ml of anhydrous toluene were placed in a 100ml three-necked flask cooled to 0 ℃ and equipped with a magnetic stirrer, while flushing with nitrogen. To this solution was then slowly added 0.41ml (0.59mmol) of a 2M solution of trimethylaluminum in toluene. The resulting reaction mixture was maintained under a nitrogen atmosphere and stirred while gradually increasing the temperature to 70 ℃. At this temperature, a solution of 0.2g (0.55mmol) of ethyl 1- (3-fluorobenzyl) -5-trifluoromethylpyrrolo [3, 2-b ] pyridine-2-carboxylate obtained in step 19.4 in 10ml of anhydrous toluene was added dropwise over 5 minutes. The reaction mixture was then refluxed for 18 hours. Then 20ml of cold water was added to the solution cooled to 0 ℃. After stirring for 90 minutes, the solution is extracted 3 times with ethyl acetate (3X 50ml) and the combined organic phases are 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.
The solid obtained was triturated in boiling isopropyl ether and then dried to yield 97mg of the desired product in the form of a pale yellow powder.
Melting point: 249 ℃ 251 ℃
1H NMR(DMSO D6)，δ(ppm)：10.6(s，1H)；8.3(d，1H)；7.91(s，1H)；7.75(d，1H)；7.61(s，1H)；7.49(m，2H)；7.31(m，1H)；7.01(m，3H)；5.95(s，2H)；3.72(s，3H)；2.48(s，3H).
Tables 1 and 2 below illustrate the chemical structures and physical properties of a number of compounds of general formula (I) according to the invention. Table 1 illustrates compounds of formula (I) wherein the pyrrolopyridine ring is optionally substituted pyrrolo [2, 3-c ] pyridine. Table 2 illustrates compounds of formula (I) wherein the pyrrolopyridine ring is optionally substituted pyrrolo [2, 3-b ] pyridine. Table 3 illustrates compounds of formula (I) wherein the pyrrolopyridine ring is optionally substituted pyrrolo [3, 2-c ] pyridine. Table 4 illustrates compounds of formula (I) wherein the pyrrolopyridine ring is optionally substituted pyrrolo [3, 2-b ] pyridine.
In these tables:
the column "melting point" gives the melting point of the product in degrees centigrade (c);
in the column "salts", "indicates the compound in free base form, where" HCl "indicates the compound in hydrochloride form, the ratio in the scraped arc being (acid: base) ratio;
-Ph represents a phenyl group.
TABLE 1
Numbering X n Z1，Z2，Z3，Z4，Z5 W Salt (salt) Melting Point (. degree.C.)
1 H 1 H，F，H，H，H 1-methylindol-5-yl - 213-214.5
2 5-F 1 H，F，H，H，H 1-methylbenzimidazol-5-yl - 279-281
3 5-Cl 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 240-242
4 H 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl HCl(2∶1) 309-310
5 5-F 1 H，F，H，H，H 2-methylbenzothiazol-5-yl - 193-195
6 5-F 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 245-247
7 5-Ph 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 288-290
TABLE 2
Numbering X n Z1，Z2，Z3，Z4，Z5 W Salt (salt) Melting Point (. degree.C.)
8 H 1 H，F，H，H，H 1-methylindol-5-yl 191-191.5
9 H 1 H，F，H，H，H 1-methylbenzimidazol-5-yl HCl(3∶2) 171-177
10 H 1 H，F，H，H，H 2-oxo-1, 2, 3, 4-tetrahydroquinolin-7-yl 280-282
11 H 1 H，F，H，H，H Quinolin-7-yl HCl(1∶1) 260-262
12 H 1 H，H，H，H，H 1-methylindol-5-yl 181-182
13 H 2 H，H，H，H，H 1-methylindol-5-yl 196-199
14 H 1 H，F，H，H，H 2-methylbenzothiazol-5-yl HCl(3∶2) 211-212
15 5-F 1 H，F，H，H，H 1-methylbenzimidazol-5-yl - 266-268
16 5-CF3 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 263-265
17 5-CF3 1 H，F，H，H，H 1-methylindol-5-yl - 229-231
18 5-CF3 1 H，F，H，H，H 2-methylbenzothiazol-5-yl - 204-206
19 H 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 242-244
20 5-F 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 226-228
21 H 0 H，H，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 286-288
TABLE 3
Numbering X n Z1，Z2，Z3，Z4，Z5 W Salt (salt) Melting Point (. degree.C.)
22 H 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 263-264
TABLE 4
Numbering X n Z1，Z2，Z3，Z4，Z5 W Salt (salt) Melting Point (. degree.C.)
23 H 1 H，F，H，H，H 1-methylbenzimidazol-5-yl - 277-281
24 5-CF3 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 249-251
25 H 1 H，F，H，H，H 2-methylbenzothiazol-5-yl - 263-265
26 H 1 H，F，H，H，H 1, 2-dimethylbenzimidazole-5-yl - 245-247
The compounds of the invention are subjected to in vitro and in vivo pharmacological tests which demonstrate their value as therapeutically active substances.
Test for inhibiting capsaicin-induced Current to rat DRG
-primary cultures of murine Dorsal Root Ganglion (DRG) cells:
DRG neurons naturally express the TRPV1 receptor.
Initial cultures of neonatal rat DRG were prepared using day 1 old rats. Briefly, in peelingAfter isolation, the ganglia are trypsinized and the cells are disintegrated by mechanical abrasion. The 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 deposited on laminin (0.25X 10)6Cells/slide) which is then fixed in corning 12-well dishes. The cells were at 37 ℃ with 5% CO2And incubation in a humidified atmosphere of 95% air. After 48 hours of culture, cytosine β -D-cytarabine (1 μ M) was added to prevent growth of non-neuronal cells. After 7-10 days of incubation, the slides were transferred into the laboratory of the patch clamp study.
-electrophysiology:
the meter (volume 800. mu.l) containing the cell preparation was placed on the platform of an inverted microscope (Olympus IMT2) equipped with Hoffman optics (Modulation Contrast, New York) and observed at 400 Xmagnification. The meter was constantly gravity fed (2.5ml/min) using a solution dispenser with 8 inlets and a single outlet, consisting of a polyethylene tube (500 μm caliber), placed less than 3mm from the cells under study. The patch clamp technique is used in a "whole cell" configuration. Cells were brought in by 3D piezoelectric micromanipulator (Burleigh, PC1000), borosilicate glass pipette (resistance 5-10 MOhms). The total current was recorded using an Axoatch 1D amplifier (Axon Instruments, Foster city, California) connected to a PC running Pchlamp 8 software (Axon Instrument) (the membrane potential was set at-60 mV). The current plots were recorded on paper, simultaneously digitized (sampling frequency 15-25Hz) and obtained on a hard drive of a PC.
The incoming cation current was induced on DRG cells (voltage set at-70 mV) using 300nM capsaicin solution. To minimize desensitization of the receptor, a brief minimum interval between two applications of capsaicin was observed. During the control period (stabilization of capsaicin response alone), test compounds were used alone at a given concentration (10nM or 1 nM) for a period of 4-5 minutes, during which time various capsaicin + compound tests were completed (to obtain maximum inhibition). The results are expressed as a percentage of inhibition of capsaicin response.
The percent inhibition of capsaicin response (300nM) for most of the active compounds of the invention tested at concentrations of 0.1-10nM is between 20% and 100%. The compounds of the invention are therefore effective in antagonizing TRPV1 type receptors in vitro.
Test for corneal irritation in mice
The stimulatory properties of capsaicin are readily assessed on the cornea, as this organ is one of the most densely innervated with C fibers. Throughout this text, very small amounts of capsaicin (2 μ Ι at 160 μ Μ concentration) applied to the corneal surface of animals resulted in a defined number of stimuli-related stereounique behavioral characteristics, which were easily documented, from initial experiments. Among these, the following are recorded: blinking eyes, rubbing dropped eyes with the ipsilateral forepaw, rubbing face with the double forepaws, and scratching the same side face with the hind paw. The duration of these behaviors did not exceed the 2 minutes observed, and the animals then resumed their normal activities. In addition, its appearance is normal. The mice were not hidden in the corners with raised saw-tooth shape and did not produce any observable signs of distress. It can be concluded that the duration of capsaicin action at these doses is less than 2 minutes.
Summary of methodology:
the principle of a series of experiments was to determine whether the compounds of the present invention could affect the behavioral response elicited by a given amount of capsaicin. Capsaicin was initially diluted to 25mM with saline in DMSO and, at the end of use, diluted to 10% with saline in Tween 80. From the control study, as if the solvent was not acting in these cases.
In practice, the test product is administered orally, with a delay (pretreatment time: t) depending on the pharmacokinetic data, and the animals receive 2. mu.l of an eye drop of 160. mu.M capsaicin solution prepared as described above. The number of times the instilled eye was rubbed with the ipsilateral anterior paw during the 2 minute observation period following instillation was recorded.
From the animals given, the percentage of protection was calculated as follows:
p ═ 100- ((number of observed scratching behavior/average number of scratching behavior in solvent-treated group) × 100)
The percentage of protection is the average of each group of animals (n-the number of animals tested with the compound of the invention).
The percentage of protection evaluated in the model for most active compounds of the invention is between 20% and 100% (see the examples in table 5), said compounds being used at a dose (po) of 1-10 mg/kg.
TABLE 5
Compound numbering % of P- (t) - (n ═ 10) at 1mg/kg (po)
15 50％-(1h)
The results of these experiments show that most of the active compounds of the present invention block the effects caused by TRPV1 receptor stimulation.
The compounds of the invention may thus be useful for the preparation of medicaments, in particular medicaments for the prophylaxis or treatment of diseases in which the TRPV1 receptor is involved.
Thus, according to another of its aspects, the present invention is directed to a medicament comprising a compound of formula (I), or a pharmaceutically acceptable salt, or a hydrate or solvate of the compound.
These medicaments find therapeutic use, in particular, in the prevention and/or treatment of pain and inflammation, chronic pain, neuropathic pain (trauma-related, diabetes, metabolism, infection-related or toxic pain, or pain caused by anticancer or iatrogenic treatments), (bone marrow) joint pain, rheumatic pain, fibromyalgia, back pain, cancer-related pain, facial neuralgia, headache, migraine, dental pain, burns, sunburn, animal bites or bites, post-herpetic neuralgia, muscle pain, compression nervuse (central and/or peripheral), spinal and/or brain trauma, ischemia (of the spine and/or brain), neurodegeneration, hemorrhagic stroke (of the spine and/or brain) and post-stroke pain.
The compounds of the invention can be used for the preparation of a medicament 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 be used for preparing medicaments for preventing and/or treating gynecological diseases such as vulvodynia and pain related to salpingitis or dysmenorrhea.
These products can also be used for the preparation of a medicament for the prevention and/or treatment of gastrointestinal disorders such as gastroesophageal reflux disease, gastric ulcer, duodenal ulcer, functional dyspepsia, colitis, IBS, Crohn's disease, pancreatitis, esophagitis and biliary colic.
The compounds of the invention can also be used for preparing medicaments for treating diabetes.
Similarly, the products of the invention are useful for the prevention and/or treatment of respiratory disorders such as asthma, cough, COPD, bronchoconstriction and inflammatory disorders. These products can also be used for the prevention and/or treatment of psoriasis, pruritus, skin, eye or mucous membrane irritations, herpes and herpes zoster.
The compound of the invention can also be used for preparing medicaments for treating depression.
According to another aspect, the invention relates to a pharmaceutical composition comprising as active ingredient a compound of the invention. These pharmaceutical compositions contain an effective amount of at least one compound or pharmaceutically acceptable salt of the present invention, a hydrate or solvate of the compound, and at least one pharmaceutically acceptable excipient.
The excipients are selected from conventional excipients known to those skilled in the art, depending on the pharmaceutical form and the desired mode of administration.
In the inventive pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or a possible salt, solvate or hydrate thereof, may be administered to humans and animals in unit dosage form (as a mixture with standard pharmaceutical excipients) for the prevention or treatment of the diseases or conditions mentioned above.
Suitable unit forms for administration include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds of the invention may be used in the form of creams, gels, balms or lotions.
By way of example, a unit form in which a compound of the invention is administered in the form of a tablet may comprise 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
The unit form is dosed such that 0.001-30mg of active ingredient per kg of body weight is administered daily, according to a galenical form.
There may be particular cases where higher or lower doses are appropriate: such dosages do not depart from the scope of the present invention. The dosage appropriate for each patient is determined by the physician according to the mode of administration, the weight and the response of the patient, according to the usual application.
According to another of its aspects, the present invention also relates to a method for treating the pathologies indicated above, which comprises the administration to a patient of an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt, or of a hydrate or solvate thereof.

Claims (13)

1. A compound according to formula (I)
Wherein
n is equal to 0, 1, 2 or 3:
the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group, or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the carbon positions 4, 5, 6 and/or 7 with one or more substituents X, equal to or different from each other, chosen from halogen atoms or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5Or aryl, aryl with one or more selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
Z1、Z2、Z3、Z4and Z5Independently of one another, represents a hydrogen atom or a halogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Cl-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, cyano, C (O) NR1R2Nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6Alkyl, SO2NR1R2、NR3COR4、NR3SO2R5aryl-C1-C6Alkylene or aryl, aryl and aryl-C1-C6Alkylene with one or more groups selected from halogen, C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6-substituents of fluoroalkoxy, nitro or cyano are optionally substituted;
R1and R2Independently of one another, represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl; or R1And R2Together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, aza *, morpholine, thiomorpholine, piperazine, homopiperazine group, the group being substituted with C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene, aryl-C1-C6-alkylene or aryl is optionally substituted;
R3and R4Independently of one another, represents a hydrogen atom or C1-C6Alkyl, aryl-C1-C6-alkylene or aryl;
R5is represented by C1-C6-an alkyl or aryl group;
w represents a fused bicyclic group of the formula:
which is linked to the nitrogen atom via position 1, 2, 3 or 4;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
one or more carbon atoms of A are selected from hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-Ringalkyl-C1-C3Alkylene radical, C1-C6Fluoroalkyl, aryl-C1-C6-the group of alkylene, oxo or thio groups is optionally substituted;
when the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Is optionally substituted, otherwise with R7Substitution;
R6represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6-alkylene or aryl;
R7represents a hydrogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C3-C7-cycloalkyl-C1-C3Alkylene radical, C1-C6-fluoroalkyl, aryl-C1-C6Alkylene radical, C1-C6alkyl-C (O) -, C3-C7-cycloalkyl-C1-C3Alkylene- (CO) -, C1-C6fluoroalkyl-C (O) -, C3-C7cycloalkyl-C (O) -, aryl-C1-C6alkylene-C (O) -, C1-C6alkyl-S (O)2-、C1-C6fluoroalkyl-S (O)2-、C3-C7cycloalkyl-S (O)2-、C3-C7-cycloalkyl-C1-C3alkylene-S (O)2-, aryl-S (O)2-or aryl-C1-C6alkylene-S (O)2-or an aryl group;
one or more of the sulfur atoms of heterocycle a may be in oxidized form;
one or more of the nitrogen atoms of heterocycle a may be in oxidized form;
the nitrogen atom at position 4, 5, 6 or 7 of the pyrrolopyridine may be in oxidized form;
the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
2. A compound of formula (I) according to claim 1, characterized in that n is equal to 1 or 2; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
3. A compound of formula (I) according to claim 1 or 2, characterized in that the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the carbon positions 4, 5, 6 and/or 7 with one or more substituents X, equal to or different from each other, chosen from a hydrogen atom or a halogen atom or C1-C6Alkyl radical, C3-C7-cycloalkyl, C1-C6-fluoroalkyl, C1-C6-alkoxy, C1-C6Fluoroalkoxy, nitro, NR1R2、C1-C6-sulfanyl, -S (O) -C1-C6-alkyl, -S (O)2-C1-C6-an alkyl or aryl group; r1And R2Independently of one another, represents a hydrogen atom; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
4. A compound of formula (I) according to claim 1 or 2, characterized in that the pyrrolopyridine ring is a pyrrolo [3, 2-b ] pyridine group, a pyrrolo [3, 2-c ] pyridine group, a pyrrolo [2, 3-c ] pyridine group or a pyrrolo [2, 3-b ] pyridine group;
the pyrrolopyridine ring being optionally substituted in the carbon positions 4, 5, 6 and/or 7 with one or more substituents X, equal to or different from each other, chosen from halogen atoms or C1-C6-fluoroalkyl or aryl; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
5. A compound of formula (I) according to any one of claims 1 to 4, characterized in that Z1、Z2、Z3、Z4And Z5Independently of one another, represents a hydrogen atom or a halogen atom; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
6. A compound of formula (I) according to any one of claims 1 to 5, characterized in that W is selected from the group consisting of indolinyl, indolyl, isoindolyl, isoindolinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, benzoxazolyl, dihydrobenzoxazolinyl, isobenzofuranyl, dihydroisobenzofuranyl, benzimidazolyl, dihydrobenzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, dihydroisobenzothiazolyl, benzotriazolyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzoxazinyl, dihydrobenzoxazinyl, benzothiazinyl, dihydrobenzothiazinyl, cinnolinyl, quinazolinyl, dihydroquinazolinyl, tetrahydroquinazolinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, 2, 3-diazanaphthyl, dihydrodiazanaphthyl, tetrahydrodiazanaphthyl, tetrahydrobenz [ b ] azepine * yl, tetrahydrobenz [ c ] azepine * yl, tetrahydrobenz [ d ] azepine * yl, tetrahydrobenz [ b ] [1, 4] diazepino * yl, tetrahydrobenz [ e ] [1, 4] diazepino * yl, tetrahydrobenz [ b ] [1, 4] oxazepine * yl, or tetrahydrobenz [ b ] [1, 4] thiazepine * yl;
one or more carbon atoms and/or nitrogen atoms of the group W are optionally substituted, as defined in formula (I) of claim 1; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
7. A compound of formula (I) according to any one of claims 1 to 5, characterized in that W represents a fused bicyclic group of formula:
which is attached to the nitrogen atom via the 1, 2, 3 or 4 position;
a represents a 5-to 7-membered heterocyclic ring containing 1-3 heteroatoms selected from O, S and N;
and W is selected from indolyl, benzimidazolyl, tetrahydroquinolinyl, quinolinyl, benzothiazolyl; and/or
One or more carbon atoms of A are selected from hydrogen atom and C1-C6-alkyl or oxo groups are optionally substituted; and/or
When the nitrogen is adjacent to a carbon atom substituted with an oxo group, one or more of the nitrogen atoms of A are substituted with R6Optionally substituted or otherwise substituted with R7Substitution;
R6represents a hydrogen atom;
R7represents a hydrogen atom or C1-C6-an alkyl group; the compounds are in the form of base or acid addition salts, also in the form of hydrates or solvates.
8. Process for the preparation of compounds of the formula (I) according to any of claims 1 to 7, characterized in that compounds of the general formula (IV)
Wherein X1、X2、X3、X4、Z1、Z2、Z3、Z4、Z5And n is as defined in formula (I) of claim 1 and B represents C1-C4-an alkoxy group,
is reacted with an amide of a compound of the formula (V) at the reflux point of the solvent
Wherein W is as defined in the general formula (I) of claim 1,
the amides of the compounds of the formula (V) are prepared by first reacting trimethylaluminum with the compounds of the formula (V).
9. Process for the preparation of compounds of the formula (I) according to any of claims 1 to 7, characterized in that compounds of the general formula (IV)
Wherein X1、X2、X3、X4、Z1、Z2、Z3、Z4、Z5And n is as defined in general formula (I) of claim 1 and B represents hydroxy,
is converted into acid chloride by the action of thionyl chloride at the reflux point of the solvent,
and is characterized in that a compound of the general formula (IV) in which X is present is obtained1、X2、X3、X4、Z1、Z2、Z3、Z4、Z5And n is as defined in formula (I) of claim 1 and B represents a chlorine atom, with a compound of formula (V) in the presence of a base,
wherein W is as defined in the general formula (I) of claim 1,
or characterized in that a compound of the general formula (IV) in which X is1、X2、X3、X4、Z1、Z2、Z3、Z4、Z5And n is as defined in general formula (I) of claim 1 and B represents hydroxy,
and a compound of formula (V) wherein W is as defined in formula (I) of claim 1.
10. Medicament, characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate of a compound of formula (I), according to any one of claims 1 to 7.
11. Pharmaceutical composition, characterized in that it comprises a compound of formula (I), or a pharmaceutically acceptable salt, or a hydrate or solvate of this compound, according to any one of claims 1 to 7, in addition to at least one pharmaceutically acceptable excipient.
12. Use of a compound of formula (I) as claimed in any one of claims 1 to 7 for the manufacture of a medicament for the prevention or treatment of diseases in which the TRPV1 receptor is involved.
13. Use of a compound of formula (I) according to any one of claims 1 to 7 in the manufacture of a medicament for the prevention or treatment of pain, inflammation, urological disorders, gynaecological disorders, gastrointestinal disorders, respiratory disorders, psoriasis, pruritus, skin, eye or mucosal irritation, herpes and herpes zoster, or for the treatment of depression or diabetes.
HK08113128.0A 2005-07-22 2006-07-19 N(arylalkyl)-1h-pyrrolopyridine-2-carboxamide derivatives, preparation and therapeutic use thereof HK1121678A (en)

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