Process for Preparing Bicyclic Compounds

1 . A process for preparing compounds of formula (IA) starting from compounds of formula (I) by a coupling reaction catalysed by copper between compounds of formula (I) and a reactive derivative of the upper residue—W-Z

wherein:

R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups J selected from:

halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 2 , nitro, hydroxy, —NR 3 R 4 , cyano, and a group Z;

R 1 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 3 R 4 or cyano;

R 2 is C1-C4 alkyl, —OR 3 or —NR 3 R 4 ;

R 3 is hydrogen or C1-C6 alkyl;

R 4 is hydrogen or C1-C6 alkyl;

R 5 is C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR 3 R 4 or —C(O)R 2 ;

X is halogen;

R′ corresponds to R;

R′ 1 corresponds to R1;

R′ 2 corresponds to R2;

R′ 3 corresponds to R3;

R′ 4 corresponds to R4;

R′ 5 corresponds to R5;

R′ 6 is C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR′ 3 R′ 4 or —C(O)R′ 2 ;

R′ 7 is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;

R′ 8 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR′ 3 R′ 4 or cyano;

R′ 9 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR′ 3 R′ 4 or cyano;

R′ 10 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR′ 3 R′ 4 or cyano;

R′ 11 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, NR′ 3 R′ 4 or cyano;

R′ 12 is R′ 3 or —C(O)R′ 2 ;

D is CR′ 8 R′ 9 or is CR′ 8 when double bonded with G;

G is CR′ 10 R′ 11 or is CR′ 10 when double bonded with D or is CR′ 10 when double bonded with X when X is carbon;

W is a 4-8 carbocyclic membered ring, which may be saturated or may contain one to three double bonds, and

in which:

one carbon atom is replaced by a carbonyl or S(O) m ; and

one to four carbon atoms may optionally be replaced by oxygen, nitrogen or NR′ 12 , S(O) m , carbonyl, and such ring may be further substituted by 1 to 8 R′ 6 groups;

Z is a 5-6 membered heterocycle, which may be substituted by 1 to 8 R′ 5 groups; and

m is an integer from 0 to 2.

2 . A process, according to claim 1 , for preparing the following compounds:

1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one;

1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}-3-methylimidazolidin-2-one;

1-{1-[1-(2,4-Dichlorophenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}imidazolidin-2-one;

1-Acetyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-Acetyl-3-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-(1-{1-[4-(Ethyloxy)-2-methylphenyl]-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-[1-(6-Methyl-1-{2-methyl-4-[(1-methylethyl)oxy]phenyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;

1-[1-(6-Methyl-1-{2-methyl-4-[(trifluoromethyl)oxy]phenyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]-2-imidazolidinone;

1-(6-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-2-pyridinyl)-2-imidazolidinone;

1-(4-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-2-pyrimidinyl)-2-imidazolidinone;

1-(2-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-4-pyrimidinyl)-2-imidazolidinone;

1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-(3-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}phenyl)-2-imidazolidinone;

1-(5-Methyl-1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}pyrrolidin-2-one;

1-{1-[1-(4-Methoxy-2-methylphenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}tetrahydropyrimidin-2(1H)-one;

3-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one;

Methyl 5-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide);

4-[3-(1,1-Dioxido-1,2,5-thiadiazolidin-2-yl)-1H-pyrazol-1-yl]-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

4-[3-(1,1-Dioxido-2-isothiazolidinyl)-1H-pyrazol-1-yl]-6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;

3-Methyl-1-(1-{6-methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2(1H)-pyridinone;

2-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-3(2H)-pyridazinone;

1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-1,3-dihydro-2H-imidazol-2-one;

1-(1-{6-Methyl-1-[2-methyl-4-(methyloxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)-2-imidazolidinone;

3-Methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile; and

1-(4-Methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

3 . A process for preparing compounds of formula (I) according to the following Scheme 1:

wherein R, R 1 , X are defined as in claim 1 , and Lg is a leaving group selected among the reactive derivatives of an alkylsulphonic acid;

step f stands for the formation of a reactive derivative of the hydroxy pyridine of compounds (VII); and

step g stands for nucleophilic displacement of the reactive derivative of compounds (VIII) to give the halogenated compounds (I).

4 . An intermediate compound of formula (VII)

wherein:

R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups J selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 2 , nitro, hydroxy, —NR 3 R 4 , cyano, and a group Z;

R 1 is hydrogen, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 thioalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen NR 3 R 4 or cyano;

R 2 is C1-C4 alkyl, —OR 3 or —NR 3 R 4 ;

R 3 is hydrogen or C1-C6 alkyl;

R 4 is hydrogen or C1-C6 alkyl;

R 5 is C1-C6 alkyl, halo C1-C6 alkyl C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR 3 R 4 or —C(O)R 2 ; and

Z is a 5-6 membered heterocycle, which may be substituted by 1 to 8 R′ 5 groups.

5 . A process for the preparation of compounds (IV) starting from compounds of formula (II) and comprising the following steps according to Scheme 2:

wherein R is defined as in claim 1 , Rg is a reactive group selected from: halogen or a reactive derivative of an alkylsulphonic acid;

step a stands for alkylation of the suitable aryl or heteroayl amine of formula (II) with a reactive derivative of butyrronitrile in presence of a base by heating; and

step b stands for the formation of the pyrrolidinone moiety of compounds (IV) which will form the cycle B present in the final compounds (I), by cyclisation of compounds (III), acid catalised and by heating to give the desired compounds (IV).

6 . A process for preparing compounds of formula (IVB) according to claim 3 in which step a and step b are performed continuously without isolating intermediate (III), according to the following Scheme 3:

7 . An intermediate compound of formula (IVB)

wherein:

R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups J selected from: halogen C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 2 , nitro, hydroxy, —NR 3 R 4 , cyano, and a group Z;

R 2 is C1-C4 alkyl, —OR 3 or —NR 3 R 4 ;

R 3 is hydrogen or C1-C6 alkyl;

R 4 is hydrogen or C1-C6 alkyl;

R′ 5 is C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C7 cycloalkyl, hydroxy, halogen, nitro, cyano, —NR 3 R 4 or —C(O)R 2 , and

Z is a 5-6 membered heterocycle which may be substituted by 1 to 8 R′ 5 groups; and

Rg is a reactive group selected from: halogen or a reactive derivative of an alkylsulphonic acid.

8 . A process for the preparation of compounds (VII) starting from compounds of formula (IV) and comprising the following steps:

wherein R and R 1 , are defined as in claim 1 , and

step c stands for a Michael addition of compounds (IV) to a butynoate derivative by heating;

step d stands for cyclisation in basic conditions to give the aromatic compounds (VI); and

step e stands for salt formation by addition of the suitable acid to the compounds (VI).

9 . A process for preparing compounds of formula (VII), according to claim 7 , starting from compounds of formula (IV) in which compounds (IV) are replaced by compounds (IVB) according to the following Scheme 5:

wherein step c′ stands for a basic treatment of compounds (IVB) with a suitable base.