Pyrrolopyridine derivatives and their use as crth2 antagonists

The present invention relates to organic compounds, their preparation and their use as pharmaceutical compounds.

In a first aspect, the present invention relates to compounds of formula (I)

<img file="RS50552B_D0001.tif" />

in free form or in salt form, where

Q represents a bond or a C1-C10-alkylene group optionally substituted with halogen;

where R¹ and R² each independently represents H, halogen, or C1-C8-alkyl, or

R * and R² together with the carbon atom to which they are attached, they form a divalent C₃-C₈a cycloaliphatic group;

where R³ represents H, C1-C8-alkyl, C3-C15-carbocyclic group, C1-C8-haloalkyl, alkoxy C1-C₈ alkyl, C1-C1-hydroxyalkyl;

where R⁴ and R³ each independently, represent halogen, C1-C₈-alkyl, C1-C₈haloalkyl, C3-C₁₅-carbocyclic group, nitro, cyano, C1-C8-alkylsulfonyl, C_rC₈alkylsulfinyl, C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, C1-C8-alkoxy, C1-C₈haloalkoxy, carboxy, carboxy-C1-C₈-alkyl, amino, C1-C₈-alkylamino, di [C] -C₈alkyl) amino, SO₂NH₂, (Ci-C₈-alkylamino) sulfonyl, di (C1-C8-alkyl) aminosulfonyl, aminocarbonyl, C1-C8-alkylaminocarbonyl, di (C1-C8)₈-alkyl) aminocarbonyl or a 4-membered to 10-membered heterocyclic group with one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

R⁶ is H or C 1 -C 6 -alkyl;

50552 Β

W is a C6-C15-aromatic carbocyclic group or a 4-membered to 10-membered heterocyclic group containing at least one ring with a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur;

X is -SO₂. -CH₂-, -CON (C, -C₈-alkyl) -, -CH (C, -C₈-alkyl) - or a bond; where min each represents an average number of 0-3, and where p is 1.

The terms used in the description have the following meanings:

The term "optionally substituted" as used herein means a group that may be substituted in one or more positions by one or more combinations of radicals listed later in the text.

The term "halogen" or "halo" may represent fluorine, chlorine, bromine or iodine; preferably it is bromine or chlorine or fluorine.

The term "C 1 -C 6 alkyl" means a straight chain or branched C 1 -C 6 -alkyl, which may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight-chain or branched pentyl, straight or branched hexyl, straight or branched heptyl or straight or branched octyl. Preferably, C 1 -C 6 alkyl is C 1 -C 6₄alkyl.

The term “C₃-C 1-5 carbocyclic group "as used herein, means a carbocyclic ring group having from 3 to 15 carbon atoms, such as, for example, a monocyclic group, or a cycloaliphatic group, such as C₃-C8-cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; or an aromatic group, such as phenyl; or a bicyclic group such as bicyclooctyl, bicyclononyl comprising indanyl and indenyl, and bicyclodecyl comprising naphthyl. Preferably, C₃C |₅-carbocyclic group is C₃-C_]0-carbocyclic group, for example, phenyl or naphthyl. C₃C |₅-carbocyclic group may be substituted with 1-3 substituents or is unsubstituted. Preferred substituents include halo, cyano, amino, nitro, carboxy, C1-C8-alkyl, C1-C8-haloalkyl, C1-C₈-alkoxy, C1-C8-alkylcarbonyl, C1-C8-alkylsulfonyl, SO₂NH₂, (C1-C8-alkylamino) sulfonyl, di (C1-C8)₈-alkyl) aminosulfonyl, aminocarbonyl, C1-C6₈-alkylaminocarbonyl and di / C1-C8-alkylaminocarbonyl, C₃-Cio-carbocyclic group and

50552 Β a heterocyclic group of 5 to 12 atoms with one or more heteroatoms selected from oxygen, nitrogen and sulfur.

The term "C 1 -C 18 aromatic carbocyclic group" as used herein means an aromatic group having 6 to 15 ring carbon atoms, such as a phenylene, naphthylene or anthrilene group. C₆-C |₅-aromatic group may be substituted with 1-3 substituents or may be unsubstituted. Preferred substituents include halo, cyano, amino, nitro, carboxy, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkylcarbonyl, C1-C8-alkylsulfonyl, -SO₂NH₂, (C1-C8-alkylamino) sulfonyl, di (C1-C6alkyl) aminosulfonyl, aminocarbonyl, C1-C8-alkylaminocarbonyl and di (C1-C6alkyl) aminocarbonyl, C₃-C 1-5 carbocyclic group and a heterocyclic group of 5 to 12 atoms with one or more heteroatoms selected from oxygen, nitrogen and sulfur.

The term "divalent S2-C8-cycloaliphatic group" means a cycloalkylene group with

3- to 8-ring carbon atoms, such as a monocyclic group, such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene, any of which may be substituted by one or more, usually one or two C1- C₄-alkyl groups; or with a bicyclic group such as bicycloheptylene or bicyclooctylene. Preferably, the term "C1-C8-cycloalkylene" refers to C3-C8-cycloalkylene, for example, cyclopropylene, cyclobutylene or cyclopentylene.

The term "C1-C8-alkoxy" means a straight-chain branched C1-C8-alkoxy group which may be, for example, methoxy, ethoxy, n-propoxy. isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy group, straight or branched hexyloxy group. a straight or branched heptyloxy group or a straight or branched octyloxy group. Preferably, C 1 -C 6 alkoxy is S_GS₄alkoxy.

As defined hereinbefore, the terms "C1-C8-haloalkyl" and "C1-C8-haloalkoxy" mean C1-C8-alkyl and C1-C8-alkoxy moieties substituted by one or more halogen atoms, preferably by one , two or three halogen atoms, such as fluorine, bromine, or chlorine atoms. Preferably, C1-C8-haloalkyl is C1-C₄-alkyl substituted with one, two or three fluorine atoms. bromine or chlorine. Preferably, C_rC_s-haloalkoxy is C1-C₄-alkoxy substituted with one, two or three fluorine, bromine or chlorine atoms.

50552 Β

As previously defined herein, the term “Ci-C₈-alkylsulfonyl "means C1-C8-alkyl attached to -SO2-. Preferably C1-C8-alkylsulfonyl is C1-C4-alkylsulfinyl, especially methylsulfonyl.

As previously defined here, the term “Cj-C₈-alkylsulfinyl "means C1-C8-alkyl attached to -SO-. Preferably C1-C8-alkylsulfinyl is C1-C₄-alkylsulfinyl, especially methylsulfinyl.

The terms "amino-C1-C8-alkyl" and "amino-C1-C6-alkoxy" denote an amino group which is attached to a C1-C8-alkyl via a nitrogen atom, for example, NH2- (C1-C4) -, or for C 1 -C 6 -alkoxy, for example NH 2 - (C 1 -C 6) -O-, are defined earlier herein. Preferably, amino-C1-C8-alkyl and amino-C1-C₈-alkoxy are amino-C1-C₄-alkyl or amino-C1-C₄-Alkoxy.

The term “Amino- (hydroxy) -C 1 -C_g-alkyl "means an amino group attached through a nitrogen atom to C₄-C₈-alkyl and a hydroxy group attached via an oxygen atom to the same C1-C₈-alkyl group. Preferably amino- (hydroxy) -C1-C is given₈-alkyl, amino- (hydrocyanic) -C2-C₄-alkyl.

As previously defined herein, the terms “Carboxy-C1-C₈-alkyl "and" carboxy-C1-C6-alkoxy "mean a carboxy group attached via a carbon atom to C1-C₈-alkyl or C 1 -C 6_g-alkoxy. Preferably, carboxy-C1-C8-alkyl or carboxy-C1-C₈-alkoxy represents carboxy-C1-C₄-alkyl and carboxy-C1-C₄-alkoxy.

The terms "C1-C8-alkylcarbonyl", "C1-C8-alkoxycarbonyl" and "S_GS₈haloalkylcarbonyl ”means C1-C₈-alkyl, C_rC₈-alkoxy or C1-C₈-haloalkyl as previously defined herein and which are joined by carbon atoms to a carbonyl group. As previously defined, the term “Ci-C₈-alkoxycarbonyl "means C1-C₈-alkoxy group, where the oxygen from the alkoxy group is attached to a carbon atom. Preferably C1-C_g-alkylcarbonyl, C1-C₈-alkoxycarbonyl and C 1 -C 6₈haloalkylcarbonyl each independently of one another represent C1-C₄-alkylcarbonyl, C1-C6₄-alkoxycarbonyl and C1-C₄-haloalkylcarbonyl.

As defined herein, the terms “C | -C₈-alkylamino "and" di (C1-C₈alkyl) amino "means C1-C8-alkyl bonded via a carbon atom to amino

50552 Β group. C1-C8-alkyl groups in di- (C1-C6₈-alkyl) amino groups may be the same or different. Preferably C1-C₈-alkylamino and di (C1-C_s-alkyl) amino represent, C1-C4alkylamino and di (C1-C₄-alkyl) amino.

As previously defined herein, the terms “C | -C₈-alkylaminocarbonyl "and" di (C1-C₈alkyl) aminocarbonyl "denoting C1-C8-alkylamino and di (C1-C₈-alkyl) amino, are attached via a nitrogen atom to a carbon atom from the carbonyl group. Preferably CiC₈-alkylamino-carbonyl and di (C1-C₈-alkyl) -aminocarbnoyl, represent C1-C4alkylaminocarbonyl and di (C1-C4)₄-alkyl) -aminocarbonyl.

As previously defined, “0J (S | -Sga1kJ1) atJpo-S_gS₈a1k11 "and" di (Ci-C₈alkyl) amino-C1-C₈-alkoxy denoting di- (C1-C₈-alkyl) amino group, are attached via a nitrogen atom to the carbon atom CrC₈-alkyl or C1-C₈-alkoxy groups. Preferably di (Ci-C_s-alkyl) amino-C1-C₈-alkyl and di (C1-C8-alkyl) amino-C1-C₈-alkoxy, represent di (C1-C₄-alkyl) amino-C1-C4alkyl and di (C1-C4)₄-alkyl) amino-C1-C₄-alkoxy.

As used herein, the term "Ileterocyclic group consisting of 4 to 10 atoms, containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur", may be monocyclic or bicyclic. such as, for example, furan, tetrahydrofuran, pyrrole, pyridine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperidine, piperidine oxazine, thiazole, quinoline, isoquinoline, benzothiophene, benzoxazole, benzisoxazole, benzthiazole. benzisothiazole, benzofuran, indole, indazole or benzimidazole. Preferred beterocyclic groups include piperazine, morpholine, imidazole, isotriazole, pyrazole, pyridine, furan, oxazole, isoxazole, thiazole, tetrazole, benzothiophene, benzoxazole, benzothiazole and benzofuran. A heterocyclic group consisting of 4 to 10 atoms may be unsubstituted or substituted. Preferred substituents include halo, cyano, oxo, hydroxy, carboxy, nilro, C1-C₈-alkyl, C 1 -C 6 alkylcarbonyl, hydroxy-C_rC_g-alkyl, C1-C8-haloalkyl, amino-C1-C8-alkyl, amino (hydroxy) C1-C₈-alkyl and C 1 -C 6₈-alkoxy, optionally substituted with an aminocarbonyl group. Particularly preferred substituents include halo. oxo, C1-C4alkyl, C1-C₄-alkylcarbonyl, hydroxy-C1-C₄-alkyl, C1-C₄-haloalkyl, amino-C1-C₄-alkyl and amino (hydroxy) C1-C₄-alkyl.

50552 Β

In this description as well as in the following claims, unless the context otherwise requires, the term "comprising" or variations thereof, such as "comprising" or "comprising", is intended to encompass the contents of said whole (integer) or step or group which belongs to a whole or steps but not the exclusion of any other whole (integer) or step or group belonging to the whole or steps.

When in formula (I), m or n 2, the two substituents may be the same or different. When ni or n is 3, two or all substituents may be the same, or all three may be different.

According to another aspect, the present invention relates to compounds of formula (I) in free form or in salt form. where

Q represents a bond or a C1-C10-alkylene group optionally substituted with halogen;

R¹ and R² are each independently H, halogen, or C1-C8-alkyl, or

R and R together with the carbon atom to which they are attached form a divalent C₃-C_ga cycloaliphatic group;

where R³ represents H, C1-C_g-alkyl, C1-C6-carbocyclic group, C1-C8-haloalkyl, alkoxy C1-C₈ alkyl, C1-C₈-hydroxyalkyl;

where R⁴ and R⁵ each independently, represent halogen, C1-C_s-alkyl, C1-C_ghaloalkyl, S2-Cis-carbocyclic group, nitro, cyano, C_rC1-6alkylsulfonyl, C1-C6alkylsulfinyl, C1-C8-alkylcarbonyl, C1-C8-alkoxycarbonyl, C1-C6₈-alkoxy, C1-C_ghaloalkoxy. carboxy, carboxy-C1-C8-alkyl, amino, C1-C8-alkylamino, di (C1-C₈alkyl) amino, SO₂NH₂, (C1-C1-alkylamino) sulfonyl, di (C1-C6)₈-alkyl) aminosulfonyl, aminocarbonyl, C1-C8-alkylaminocarbonyl, di (C1-C8-alkyl) aminocarbonyl or a 4-membered to 10-membered heterocyclic group with one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur;

R⁶ is H or C1-C8-alkyl;

50552 Β

W is a Sb-Sp-agapaPbpa carbocyclic group or a 4-membered to 10-membered heterocyclic group containing at least one ring with a heteroatom selected from the group consisting of nitrogen. oxygen and sulfur;

X is -SO₂. -SNJ-. -CON (C1-C8-alkyl) -. -CH (C 1 -C 5 -alkyl) - or a bond; where min each represents an average number of 0-3, ip is 1.

According to another aspect. the present invention relates to compounds of formula (I) in free form or in salt form, wherein

Q represents a bond;

R¹ and R² are each independently H or C1-C8-alkyl, or

X where R³ represents C1-C₈-alkyl;

where R⁴ and R⁵ each independently, represent halogen, C1-C8-alkyl, C1-C8haloalkyl, C3-C1 |₅-carbocyclic group, nitro, cyano, C1-C8-alkylsulfonyl, C1-C6-alkoxycarbonyl, C1-C8-alkoxy or C1-C8-haloalkoxy;

R⁶ is H or C1-C8-alkyl;

W is a group of formula (W_ai) or (W_a2)

<img file="RS50552B_D0002.tif" />

in which A is each C or N, or

W is a group of formula (W_b);

y — z where Y is each C or N; i

Z is N, O or S; or

W is a group of formula (W_e)

50552 Β

<img file="RS50552B_D0003.tif" />

wherein Y is each independently C or N; i

Z is 0 or S;

X is -SO₂-, -CH₂-, -CH (C, -C₈-alkyl) -, -CON (C_rC₈-alkyl) - or a bond;

minse each independently, integer from 0-3; i

Pjel.

According to another aspect, the present invention relates to compounds of formula (I) in free form or in salt form, wherein

Q represents a bond;

R¹ and R² are each for itself, H or C1-C₄-alkyl, or where R³ represents C1-C₄-alkyl;

where R⁴ and R⁵ each independently, represent halogen, C1-C₄-alkyl, C1-C₄haloalkyl. cyano, S2-C10-carbocyclic group, C1-C4-alkoxycarbonyl, C1-C₄alkylsulfonyl, C 1 -C 6₄-alkoxy or C1-C₄-haloalkoxy;

R is H or C 1 -C 6 alkyl;

W is a group of formula (W_ai) or (W_a2)

<img file="RS50552B_D0004.tif" />

in which AC or N, and where the other two groups are each C, or is

W is a group of formula (Wb);

A <^wb>

wherein Y is each independently C or N; i

ZjeN.OiliS;

X is -SO₂-, -CH₂-, or -CH (C1-C1-alkyl) -;

min are each independently. integer from 0-3; and pje 1.

50552 Β

According to another aspect, the present invention relates to the use of a compound of formula (I) in any of the above embodiments. in free form or in salt form, for the manufacture of a medicament for the treatment of inflammation or allergic conditions, in particular inflammation or obstructive disease of the respiratory tract.

Salts and isomers

Many of the compounds represented by formula (I) may form acid salts, in particular pharmaceutically acceptable acid salts. Pharmaceutically acceptable acid salts of the compounds of formula (I) include those inorganic acids which belong to the group of hydrohalic acids, such as hydrochloric acid or hydrobromic acid; nitric acids; sulfuric acids; phosphoric acids; as well as organic acids such as aliphatic monocarboxylic acids, such as formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoroacetic acid, hypumic acid, propionic acid and propionic acid; aliphatic hydroxy acids, such as lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid or malic acid; dicarboxylic acids such as adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, sebacic acid or amber acid; aromatic carboxylic acids, such as benzoic, p-chlorobenzoic acid or nicotinic acid; aromatic hydroxy acids such as hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid or 3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such as ethanesulfonic acid, ethane-1,2 , 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+) - camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid or p-toluenesulfonic acid. These salts can be prepared from the compounds of formula (I) by known methods for their preparation.

Compounds of formula (I) containing acid groups, for example carboxyl groups, may also form salts with bases, in particular with pharmaceutically acceptable bases, such as those well known in the art; these salts include metal salts, in particular alkali or alkaline earth metal salts, such as sodium, potassium, magnesium, calcium or zinc salts; or ammonia salts or

50552 Β pharmaceutically acceptable organic amines or heterocyclic bases such as benetamine, benzathine. diethanolamine, ethanolamine, 4 (2-hydroxy-ethyl) morpholine. 1- (2-hydroxyethyl) pyrrolidine, N-methyl glycamine, piperazine, triethanolamine or tromethanin. These salts can be prepared from compounds of formula (I) by known methods for their preparation.

In these compounds where there is an asymmetric carbon atom or chiral axis, the compounds exist in individual optically active isomeric forms or mixtures thereof, for example in the form of racemic or diastereoisomeric mixtures. The present invention also includes the individual optically active R and S isomers, as well as mixtures, of their racemic or diastereoisomeric mixtures.

Specific preferred compounds of formula (I) are described herein by way of examples.

The invention also provides a process for the preparation of a compound of formula (I), in free form or in salt form, comprising the steps of:

(i) (A) preparing a compound of formula (1), wherein R⁶ represents H, by cleavage of the ester group -COOR⁶ in a compound of formula (I),

<img file="RS50552B_D0005.tif" />

where R⁶ C1-C8-alkyl and where

Q. R¹, R², R³, R⁴, R \ W, X, m, nip, as previously defined in this text; or (B) preparing a compound of formula (I), wherein R⁶ C 1 -C 4 -alkyl, which is reacted with a compound of formula (II)

50552 Β

Ο

<img file="RS50552B_D0006.tif" />

Q, R¹, R², R³, R⁴, m, nip previously defined, with a compound of formula (III)

G — X — W— (R⁵) n (III), where

G is a leaving group, for example, a halogen atom or an arylsulfonate group; i

R⁵, W, X ί n are previously defined; or (C) for the preparation of compounds of formula (I).

where

R⁶ C1-C8-alkyl;

R¹ is H or C1-C_g-alkyl;

R² is C1-C8-alkyl; ip is 1, reacts with a compound of formula (I), in which it is

R 1 is H or C 1 -C 8 -alkyl; i

R₂ is H, with a compound of formula R^AG, where is'

R^A C1-C8-alkyl; i

G is previously defined; and (II) recovering the resulting compound of formula (I) in free form or in salt form.

Process variant (A) can be performed using known methods (or similarly as described in the examples below) for cleavage of carbocyclic ester groups and can be performed in situ after preparation of compounds of formula (I), wherein R⁶represents C1-C1-alkyl. A compound of formula (I), wherein R⁶ represents C1-C8-alkyl, in solution constituting a polar organic solvent or a mixture thereof with water, may react with an inorganic base, such as NaOH or LiOH to hydrolyze

50552 Arska ester group; when the base is NaOH, the reaction can be carried out at a temperature of 10-40 ° C, preferably at ambient temperature, while in the case where the base is LiOH, the reaction begins at a temperature of -5 ° C to 5 ° C and then continues at 10-40 ° C, preferably at ambient temperature. Alternatively, a compound of formula (I), wherein R⁶C 1 -C 6 -alkyl, which is present in a solution with an organic solvent, such as CH 2 Cl 2, can react with Lewis acid, such as boron tribromide to cause cleavage of the ester group; the reaction usually takes place at a temperature of 50-60 ° C, with the help of microwave radiation.

Process variant (B) can be performed using known methods or analogously as described in the examples. The compound of formula (II) may for example be reacted with a sulfonyl halide of formula (III), wherein G is halogen;

X -SO2-;

and R 1 W and are as previously described, in the presence of an organic base, such as 2-tert-butylimino-1,3-dimethyl-2 lambda * 5 * - [1,3,2] diazaphosfinan-2-yl) -diethyl -amine (BEMP); the reaction may be carried out in an organic solvent, for example a polar aprotic solvent, such as N, N-dimethylformamide (DMF) and may be carried out at 10-40 ° C, preferably at ambient temperature. In another example, a compound of formula (II) may be reacted with a compound of formula (III), wherein

G represents halogen;

X is -SN₂-; i

R⁵, W and are as previously described, in the presence of an organic base, such as BEMP, for example, with a polar aprotic solvent, such as Ν, Ν-DMF; reaction takes place at 10-40^uC, preferably at ambient temperature. In another example, a compound of formula (II) may be reacted with a compound of formula (III), wherein

G represents halogen; i

X is -CH₂-;

W has the formula (W_a), where one AN; i

50552 Β

R⁵, W and η are previously described, in the form of a salt, such as a hydrohalide, in the presence of an inorganic base. such as NaH or an organic base such as BEMP, for example, in a polar aprotic solvent, such as N, N-DMF; the reaction takes place at 10-40 ° C, preferably at ambient temperature. In another example, a compound of formula (II) may be reacted with a compound of formula (III), wherein

G represents arylsulfonate;

X is -CH2-; i

R⁵, W and are previously described, in the presence of an organic base, such as BEMP, for example, in a mixture of a polar aprotic solvent, such as N, N-DMF and an ether solvent; the reaction is carried out at 1040 ° C, preferably at ambient temperature. In another example, a compound of formula (II) may be reacted with a compound of formula (III), wherein

G represents halogen; X represents a bond;

W is phenylene or naphthylene; i

R⁵ in are as previously defined, in the presence of a metal catalyst, an in situ is formed from a metal salt, such as CuJ and diamine, and an organic base, such as sodium phosphate, a transition metal complex, the reaction preferably taking place in an organic solvent, e.g. , a polar aprotic solvent, such as dioxane, the reaction temperature may be from 140-180⁰ C, preferably 150 ° C-170 ° C.

Process variant (C) can be performed using known methods for alkylation of carboxyl esters or in an analogous manner. as later described in the examples. The reaction is carried out in the presence of an inorganic base, for example, lithium diisopropyl amide, with the addition of alkyl iodide, for example methyl iodide. The reaction temperature may be from about -90 ° C to about -60 ° C, but is preferably -78 ° C.

The compounds of formula (II) are known or can be obtained by known methods, such as those described in U.S. Pat. 3, 320, 268, or in an analogous manner described hereinafter in the examples. The compounds of formula (III) are known or can be obtained by known methods, or in an analogous manner, which is described hereinafter in the examples.

50552 Β

The compounds of formula (I) in free form may be converted into the salt form in the customary manner, and vice versa. The compounds in free form or in the form of salts can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of formula (I) and (II) may be recovered from the reaction mixtures and purified in a conventional manner. Isomers, such as enantiomers, can be obtained in a conventional manner, for example, by fractional crystallization, chiral HPLC resolution or asymmetric synthesis from the same asymmetric and optically active starting material.

Pharmaceutical use and trial

The compounds of formula (I) and (II) and their pharmaceutically acceptable salts, which are hereinafter referred to herein, alternatively refer to "agents of the invention", which are useful as pharmaceuticals. The compounds have good activity as CRTh2 receptor antagonists and can be tested in the experiments that follow.

Experimental protocol for the determination of receptor binding by filtration

Binding of CRTh2 receptor antagonists was tested on membranes prepared from human CHO cells expressing the CRTh2 receptor (CHO.Kl-CRTh2). For the production of cell membranes, CHO.Kl-CRTh2 cells grown in bottles in a shaker were collected using cell dissociation buffer (Invitrogen). Cells were precipitated by centrifugation (167 g, 5 min). Cell pellet was incubated in hypotonic buffer (15 mM Tris-OH, 2 mM MgCl₂, 0.3 mM EDTA, I mM EGTA, lx Complete^1M tablet) at 4 ° C for 30 min. The cells were homogenized at 4 ° C with a Polytron® (IKA Ultra Tiggah T25) mixer 5 times for 1 second. The homogenate was then centrifuged (Beckman OptimaTM TL ultracentrifuge, 48000 g, 30 min at 4 ° C). The supernatant was removed and the membrane pellet was resuspended in homogenization buffer (75 mM Tris-OH, 12.5 mM MgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose, lx Complete ™ table). Membranes prepared in this way were aliquoted and stored at -80 ° C. Protein content was determined by the Bradford method (Bio Rad).

Binding [³H] -PGD₂ (157 Ci / mmol) on CHO.Kl-CRTh2 membranes was determined in the absence (total binding) and in the presence (non-specific binding)

50552 Β unlabeled PGD₂ (1 μΜ). Result of subtraction of cpm (beats per minute) binding [³H] -PGD2 in the presence of excess unlabeled PGD2 from the number of cpm measured in the absence of excess unlabeled PGD2 is defined as specific binding. Active CRTh2 receptor antagonists can compete with [³H] -PGD2 for binding sites at CRTh2 receptors and are identified through a reduction in the number of bound cpm.

The experiment was performed on Greiner plates with 96 U-shaped wells, in a formal volume of 100 μΙ. per well. CHO.Kl-CRTh2 membranes were diluted in buffer (10 mM HEPES-KOH (pH 7.4), 1 mM EDTA and 10 mM MnCl₂) and 10 pg of this suspension was added to each well. [^.H] -PGD₂was diluted in the same buffer and added to each well at a final concentration of 2.5 pM. To determine nonspecific binding, unlabeled PGD is added₂ in a final concentration in a 1 μΜ well, and it competes with [H] -PGD₂ for CRTh2 receptor binding sites. The experiment is performed in triplicate, and the reagents are added to the wells in the following order:

- 25 pL total binding buffer or pL PGD₂ to determine nonspecific binding

- 25 pL [³H] -PGD₂

- 50 pL membrane

- 25 pL of test compound, in DMSO / buffer solution

The plates were incubated at room temperature on a shaker for 1 hour and then collected (Tomtec Harvester 9600) on GF / C filter plates using wash buffer (10 mM HEPES-KOH, pH 7.4). The plate was dried for 2 hours, before Micro-Scint 20) (50 pL) was added and sealed with TopSeal-S ™ foil. The plates are then placed in a Packard Top Count counter, and the result is read on a Packard Topcount in the ZN Scintillation program (1 min per well).

Ki values ​​(dissociation inhibitory constant) for CRTh2 receptor antagonists have been published. Ki values ​​are determined using Sigma Plot ™ software, using the ChengPrusof equation.

Ki = IC₅₀/ l + [S] / Kd where S is the radioligand concentration and Kd is the dissociation constant.

50552 Β

Protocol for CRTh2 - cAMP functional assays

This experiment was performed in CHO.Cl-CRTh2 cells. cAMP is generated in the cell by stimulating the cell with 5 μΜ forskolin, an adenylate cyclase activator. PGD₂ is added to activate the CRTh2 receptor, resulting in attenuation of forskolin-induced cAMP accumulation. Potential CRTh2 receptor antagonists are tested based on their ability to inhibit PGD₂-mediated attenuation of forskolin-induced cAMP accumulation in CHO.Kl-CRTh2 cells.

For each concentration-dose curve concentration, test compounds were prepared in stimulation buffer (HBSS, 5 mM HEPES, 10 μΜ ΙΒΜΧ ± 0.1% human serum albumin) containing DMSO (3% v / v) and 5 pL / well is added to the test plate (white optiplate plate with 384 wells).

CHO.Kl-CRTh2 grown in cell culture flasks were washed with PBS buffer and collected using dissociation buffer. Cells were washed in PBS and resuspended in stimulation buffer to a concentration of 0.4 h 10⁶ / mL and added to the test plate (10 pL / well).

The test plate was incubated at room temperature on a shaker for 15 minutes.

Agonist mixture (10 mM Prostaglandin D₂) and 5 μΜ of forskolin were prepared in stimulation buffer and added to the test plate (5 pL / well).

Additionally, the cAMP standard was serially diluted in stimulation buffer and added to separate empty wells on a test plate (20 pL / well). The cAMP standard allows the quantification of cAMP generated in CHO, Kl-CRTh2 cells.

The test plate was incubated at room temperature on a shaker for 60 minutes. Cell lysis buffer (Lysis buffer: H2O, 5 mM HEPES, 0.3% Tween-20, 0.1% human serum albumin) was added to the bead mixture containing Alphascreen ™ anti-cAMP acceptor beads 0.06 units / pL, Alphascreen^IMstreptavidin-wrapped donor beads 0.06 units / pL, biotinylated cAMP 0.06 units / pL, 10 μΜ ΙΒΜΧ), prepared in a darkened medium 60 minutes before

50552 Β additions to the test plate. The resulting lysis mixture was added to all wells on the test plate (40 pL / well).

The test plate was closed with Topseal-S® foil and incubated in the dark at room temperature on a shaker for 45 minutes. The plate is then placed in the Packard Fusion ™ counter, where the measurement is performed.

The obtained beats in mmut (cpm) are converted to nM cAMP using the prepared standard cAMP curve. IC50 values ​​(CRTh2 receptor antagonist concentration required to inhibit 50% PGD₂-mediated attenuations of forskolin-induced cAMP accumulation in CHO.Kl-CRTh2 cells) were then determined using Prism^{1 m} software.

The compounds of the Examples contained herein generally have Ki values ​​in the SPA binding assay below 1 μΜ. For example, the compounds of Primcra 3, 18, 31, 54, 59, 84, 90, 92, 93,94, 95, 96, 97, 99, 100, 102, 103, 105, 112, 115, 117,119, 122, 125, 127,129,130 ​​and 148 have Ki values ​​of 0.048, 0.090, 0.122, 0037, 0.033, 0.10, 0.003, 0.022, 0.008, 0.007, 0.004, 0.029, 0.011, 0.012, 0.005, 0.056, 0.035, 0.098, 0.031, respectively. , 0.045, 0.025.0.029, 0.147, 0.027, 0.043, 0.043, 0.050 and 0.064 μΜ.

The compounds of the Examples contained herein generally have. IC50 values ​​in the functional test below 1 μΜ. For example, the compounds of Examples 3, 18, 31, 54, 59 and 84 have 1C, the values ​​of which are 0.276, 0.171, 0.178, 0.168, 0.150, 0.084, 0.014, 0.040, 0.022, 0.016, 0.019, 0.021, 0.013, respectively. , 0.019, 0.009, 0.091, 0.041, 0.046, 0.026, 0.080, 0.021, 0.064, 0.144, 0.095, 0.031, 0.143, 0.060 and 0.131 μΜ.

The compounds of formulas (I) and (II), in free or salt form, are antagonists of the G-protein coupled receptor (GPCR receptor), the chemoattractant CRTh2 receptor, which is expressed on Th2 cells, eosinophids and basophils. PGD₂ is a natural ligand of the CRTh2 receptor. Therefore, they are antagonists, which inhibit PGD binding₂ for CRTh2, useful in the treatment of allergic and anti-inflammatory conditions. Treatment according to the present invention may be symptomatic or prophylactic.

50552 Β

Accordingly, the agents of the present invention are useful in the treatment of inflammation or obstructive airways diseases, acting e.g. to reduce the degree of tissue damage, to inflammatory reactions of the respiratory tract, to reduce bronchial hyperreactivity, as well as to remodeling and the course of the disease itself. Inflammation or obstructive airways diseases to which the present invention is applicable include asterisks of any type or genesis, including congenital (non-allergic) and external factor-induced asthma (allergic), mild asthma, moderate asthma, severe asthma, bronchial asthma, stress-induced asthma, occupational asthma, and asthma induced by bacterial infection. This asthma treatment can also be used as an initial treatment in patients e.g. younger than 4-5 years, and who show symptoms of difficult (wheezing) and in whom a diagnosis of "children with wheezing" has been made or can be established, which is an established category of patients of great medical importance and today often identified as asthmatics in the initial phase. (For practical reasons, this asthmatic condition is called "wheezing syndrome.")

The effectiveness of prophylaxis in the treatment of asthma is shown in the reduced frequency or severity of the symptoms of an asthma attack, e.g. acute asthmatic or bronchoconstrictor attack, as improved lung function or as an improvement in airway hyperactivity. Further efficacy may be manifested by a reduced need for other, symptomatic therapy, e.g. therapy intended to limit or stop a symptomatic attack when it occurs, e.g. anti-inflammatory (e.g. corticosteroid) or bronchodilator therapy. The prophylactic benefits of asthma may be particularly evident in patients prone to morning drowning. "Morning drowning" is an established asthmatic syndrome common to a relatively large percentage of asthmatics, which is characterized by an asthma attack that occurs e.g. between 4 and 6 o'clock in the morning, i.e. at a time quite far from any previous time of taking symptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions to which the present invention may be applied include acute lung injury (ALI), adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease. respiratory or pulmonary disease (COPD, COAD or COLD), including chronic bronchitis or accompanying dyspnea, emphysema, as well as exacerbation of respiratory hyperreactivity as a consequence of other drug therapy, especially inhaled. The invention is also applicable in the treatment of bronchitis either

50552 Β what type and genesis, including e.g. acute, arachidic, catarrhal, croup, chronic and phtinoid bronchitis. Other inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (inflammatory, often occupational, lung disease, often accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation and dust) of any type or genesis including e.g. . aluminosis, anthracosis, asbestosis, calicosis, ptylosis, siderosis, silicosis, tobacco and bizinosis.

The agents of the present invention have an anti-inflammatory effect based on the inhibition of eosinophil activation, and are therefore also useful in the treatment of eosinophil-related disorders, e.g. in eosinophilia, and especially in eosinophil-related airway disorders, which e.g. include morbid infiltration of eosinophils into pulmonary tissues including hypereosinophilia affecting the airways and / or lungs, as well as e.g. eosinophil-related airway disorders caused by or associated with Loffler syndrome; in eosinophilic pneumonia; in parasitic, especially in metazoam invasion, including tropical eosinophilia: in bronchopulmonary aspergillosis; in thiodotic polyarteritis including Churg-Strauss syndrome; in eosinophilic granuloma; and eosinophil-related disorders affecting the airways caused by drug reactions.

The agents of the present invention are also useful in the treatment of inflammatory or allergic skin conditions, e.g. in psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis. scleroderma, vitiligo, hypersensitivity angiitis, urticaria. bullous pemphigoid, lupus erythematosys, pemphysis, epidermolysis bullosa acquisita and other inflammatory or allergic skin conditions. The agents of the present invention may also be used to treat other diseases and conditions, in particular those containing an inflammatory component, e.g. treatment of diseases and conditions of the eye, such as conjunctivitis, keratoconjunctivitis and vernal conjunctivitis; nasal diseases including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having an autoimmune component or etiology, including autoimmune hematological disorders, e.g. hemolytic anemia, aplastic anemia, red blood cell anemia, and idiopathic thrombocytopenia; systemic lupus erythematosus; polychondritis; scleroderma; Wegener's granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Steven-Johnson syndrome; idiopathic tropical disease with intestinal inflammation; autoimmune inflammatory bowel disease, e.g. ulcerative colitis and Crohn's disease; endocrine ophthalmopathy; Grave's 20

50552 Β disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; multiple sclerosis; primary biliary cirrhosis: uveitis (anterior and posterior); scratoconjunctivitis and vcmal ccratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis; and glomerulonephritis, with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or “minal change” nephropathy.

Other diseases and transmissions that can be treated with the agents of the present invention include septic shock; rheumatoid arthritis; osteoarthritis; proliferative diseases, such as cancer; atherosclerosis; allograft rejection after transplantation; stroke; obesity; restenosis; diabetes, e.g. type 1 diabetes mellitus (juvenile diabetes mellitus) and type II diabetes mellitus; diarrhea; ischemic / reperfusion injuries; retinopathy, such as diabetic retinopathy or retinopathy induced by hyperbaric oxygen; as well as conditions characterized by increased intraocular pressure or secretion of ocular aqueous fluid, such as glaucoma.

The efficacy of the agent of the invention in inhibiting inflammatory conditions, for example, in inflammatory diseases of the respiratory tract, may be demonstrated in an animal model, such as a mouse or rat model, in inflammatory reactions of the respiratory tract or other inflammatory conditions, such as described by Szarka ii et al., J. Immunol Methods, Vol. 202, p. 49-57 (1997); Renzi et al., Am Rev Respir Dis., Vol. 148, p. 932-939 (1993); Tzuyuki et al., J. CLin. Invest, Vol. 96, p. 2924-2931 (1995); Cernadas et al., Am J. Respir Cell Mol Biol, Vol 20, p. 1-8 (1999); and Williams and Galli, J Ehr Med. Vol. 192, p. 455-462 (2000).

The compositions of the invention are also useful as co-therapeutic agents for use in combination with other drugs, such as anti-inflammatory drugs, bronchodilators or antihistamines, in particular for the treatment of obstructive or inflammatory diseases of the respiratory tract, such as those mentioned hereinbefore, for example, agents for enhancing the efficacy of the therapeutic activity of these drugs or as agents for reducing the standard dose or potential side effects of these drugs. The composition of the invention may be mixed with other drugs in a particular pharmaceutical composition or may be administered separately, before, simultaneously with or after other drugs. Accordingly, the invention encompasses the previously described combinations of agents of the invention with anti-inflammatory drugs, bronchodilators, antihistamines or

50552 Antitussives, wherein said agent of the invention and said drug are present in the same or different pharmaceutical composition.

Such anti-inflammatory drugs include steroids, in particular, glucocorticosteroids such as budesonide. beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those described in examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51 , 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445 and WO 03/072592; non-steroidal agonies of glucocorticosteroid receptors, such as those described in WO 00/00531, WO 02/10143, WO 03/082280. WO 03/082787, WO 03/104195 and WO 04 / 005229C LTB4 antagonists, such as those described in U.S. Pat. 5, 451, 700; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cyclomilast (Ariflo (reg. Trademark) GlaxoSmithKline). Roflumilast (Vuk Guldcn), V-11294A (Napp), ΥΑΥ19-8004 (Vaueg), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 (Paike-Davis), AWD-12-28i ), CDC-801 (Cclgene), SelCID (TM) CC-10004 (Celgene), KW-4490 (Kyowa Hakko Kogyo), WO 03-104204, WO 03/104205, WO 04/000814, WO 04/000839 I WO 04/005258 (Mcrck), as well as those described in WO 98/18796 and WO 03/39544; A2a agonists, such as those described in EP 1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02542, WO 96/0553, WO 98/28319. WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO

00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO

01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO

02/96462 and WO 03/086408; A2b antagonists, such as those described in WO 02-42298; and beta (p) -2-adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, phenoterol, procaterol, and in particular, formoterol and its pharmaceutically acceptable salts, and compounds (in free form or in the form of solvates) of formula (I) from WO 00-75114, which is fully incorporated by reference, probably the compounds of the example, in particular the compounds of formula

HO

OH

50552 And pharmaceutically acceptable salts thereof, as well as compounds (in free form or in salt form) of formula (I) from WO 04/16601. Other β-2-adrenoceptor agonists include compounds such as those described in WO 99/64035, WO 01/42193, WO 01/834462, WO 02/066422, WO 02/070490, WO 02/076933, WO 2004/011416 and US 2002/0055651.

These bronchodilators include antiocholinergics or antimuscarinic agents, in particular ipratropium bromide, oxytropium bromide, tiotropium salts CHF 4226 (Chiesi), but are also described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03 / 87094, WO 04/05285, WO 02/00652, WO 03/33495, WO 03/53966, EP 0424021, US 5171744 and US 3714357.

Such co-therapeutic antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.

Compositions of the compositions of the invention and steroids, β-2-agonists, PDE4 inhibitors or LTD4 antagonists can be used in the treatment of COPD or, in particular, asthma. Combinations of the agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists may be used in the treatment of asthma or in particular COPD.

Other useful combinations of agents of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9, CCR-9, CCR-10, CXCR1, CXCR2, CXCR3. CXCR4 and CXCR5; wherein CCR-3 antagonists, such as those described in WO 2002/026723, are particularly useful, in particular 4- {3 - [(S) -4- (3,4-dichlorobenzyl) trifluoro-2-ylmethyl] -ureidomethyl} ' benzamide and those described in WO 2003/077907, WO 2003/007939 and WO 2002/102775.

Also particularly useful are CCR-5 antagonists, such as Schering-Plow SC-351 125, SCH-55700 and SCFI-D; Takeda antagonists, such as

50552 Β

N - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) -5H-benzo-cyclohepten-8-yl] carbonyl] amino] phenyl] -methyl] tetrahydro-N, N-dimethyl-2H- pyran-4-ammonium chloride (TAK-770); and CCR-5 antagonists, also described in US 6166037, WO 00/66558 and WO 00/66559. The compositions of the invention are administered by any of the conventional routes of administration, for example, orally, in the form of a tablet or capsule; parentally. for example, intravenously; by inhalation, in the treatment of inflammatory or obstructive diseases of the respiratory tract; intranasally, for example for the treatment of allergic rhinitis; topically on the skin, for the treatment of atopic dermatitis; or rectally, for example, to treat inflammatory bowel disease.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier. The composition may contain a co-therapeutic agent, such as the aforementioned anti-inflammatory drug, bronchodilator or antihistamine. These compositions can be prepared using conventional diluents or excipients and known galenic techniques. Oral doses include tablets and capsules. Formulations for topical administration may be in the form of creams, tinctures, gels or transdermal release systems, such as, for example, patches. Compositions for inhalation may include acrosol or other finely divided formulations or powder formulations.

When the composition comprises acrosol formulations, it is preferred to contain, for example a propellant such as hydro-fluoro-alkane (HFA), for example HFA134a or HFA227 or mixtures thereof, and which may not contain one or more co-solvents known in the art, such as ethanol (up to 20% by weight) and / or one or more surfactants, such as oleic acid or sorbitan trioleate;

and / or one or more fillers such as lactose. When the composition comprises a powder formulation, it preferably contains, for example, a compound of formula (I) with a particle size of up to 10 microns, optionally with a diluent or carrier, such as lactose, or a desired particle size and compound that helps to there is no decomposition of the product due to moisture. When the composition comprises a spray formulation, it is preferred to contain a compound of formula (1) either in dissolved or suspended form, in a water-containing agent, a co-solvent such as ethanol or propylene glycol and a stabilizer, which may be a surfactant.

50552 Β

The invention includes:

(a) an agent of the invention in a form suitable for inhalation, such as an aerosol or other form (b) an inhalable medicament comprising an agent according to the invention in a form suitable for inhalation; (c) a pharmaceutical product comprising an agent according to the invention in a form suitable for inhalation for inhalation together with an inhalation device; and (d) an inhalation device comprising an agent of the invention in a form suitable for inhalation.

The dosages in which the agents of the invention are used may vary depending on the condition being treated, the desired effect and the route of administration. Generally, suitable daily doses for oral administration are from 0.01-100 mg / kg.

EXAMPLES

<img file="RS50552B_D0007.tif" />

R² = X except in example 40, where R²= CH₃.

R^3_ CH₃ except in Example 81, where R^.= X and except in examples 87 and 153, where

R₃= CH2CH3. R⁴ = X except in examples 62 and 89, where R⁴= Cl.

R '= H except in Examples 99 and 100, where R⁶ - S1

50552 Β

<td>\ Prirner 1</td><td>XW-4R ^</td><td>ΜΗ *</td>

<td>Τ — I</td><td>0 ° Ό</td><td> 331</td>

<td> 2 .........,</td><td>iQ ··. /</td><td> 365</td>

<td> 3</td><td> .../? ⁰ μ</td><td> 376</td>

<td> 4</td><td>b</td><td> 281</td>

<td> 5</td><td> 0</td><td> 381</td>

<td> 1 ⁶</td><td>, 0 νπ ^</td><td> 345</td>

<td> 7</td><td>ο 1 1</td><td> 349</td>

<td> &amp;</td><td>0 ^ ϋγ.</td><td> 373</td>

<td> 9</td><td>Λ »V</td><td> 409</td>

<td> 10 [ !</td><td>0 F ? qy &lt;</td><td> 399</td>

50552 Β

<img file="RS50552B_D0008.tif" />

50552 Β

<td> Example</td><td>XW- {R'ln</td><td>ΜΗ *</td>

<td> 21</td><td>ί5</td><td> 282</td>

<td> 22</td><td>........ 'H; ....</td><td> 282</td>

<td> 23</td><td>'Ό ,,</td><td> 315</td>

<td> 24</td><td>'p .Ι</td><td> 306</td>

<td> 25</td><td>-χτ °,</td><td> 315</td>

<td> 26</td><td></td><td> 306</td>

<td> 27</td><td></td><td> 295</td>

<td> 28</td><td>C ^</td><td> 34$</td>

<td> 29</td><td></td><td> 299</td>

<td> 30</td><td>'ό</td><td> 313</td>

<td> 31</td><td>ΊΧ στ F</td><td> 349</td>

<td> 32</td><td>σ '</td><td> 299</td>

50552 Β

<td>Example</td><td>х-ш-Л</td><td>ΜΗ *</td>

<td> 33</td><td>F</td><td> 399</td>

<td>• 'Μ</td><td>Αχ &lt;,</td><td> 397</td>

<td> 35</td><td></td><td> 379</td>

<td> 36</td><td>Αχ.</td><td> 379</td>

<td> 37</td><td>A5</td><td> 365</td>

<td>j 38</td><td>Αχ</td><td> 356</td>

<td> 39</td><td>AJ α</td><td> 399</td>

<td> 40</td><td>'Αχ</td><td> 413</td>

<td> 41</td><td>ρ *&gt;⁰</td><td>(Μ-ΗΓ 354</td>

50552 Β

<td>Primpr</td><td>X-_W 4R «)„</td><td>mn *</td>

<td> 42</td><td></td><td> 399</td>

<td> 43 . .</td><td>..... F % ·</td><td>[M-Hf 413</td>

<td> 44</td><td>F</td><td>[M-NG 365</td>

<td>ι ^4S</td><td>b V ° I u</td><td>(m-ng 354</td>

<td> 46</td><td>• &lt;x o ' -p</td><td> 383</td>

<td> 47</td><td></td><td>[M-NG 383</td>

<td> 48</td><td>o = s = o ₀ \\ / 0 ’</td><td> 395</td>

<td> 49</td><td>⁰ Ψ F</td><td> 367</td>

<td> 50</td><td>/ r Ci</td><td> 405</td>

50552 Β

<td>Example. '</td><td>X AW— (Η *) «</td><td>mn '</td>

<td> 51</td><td></td><td> 365</td>

<td> 52</td><td>. , 0 &gt; V'Č^l' ⁰ φ Cl</td><td> 399</td>

<td> 53</td><td>• č 'R f UH^S!XX</td><td> 399</td>

<td> 54</td><td>HS '</td><td> 374</td>

<td> 55</td><td>X £ ο Ύ</td><td> 383</td>

<td> 56</td><td></td><td> 363</td>

<td> 57</td><td></td><td> 301</td>

<td> 58</td><td></td><td> 367</td>

<td> 59</td><td>^?p:</td><td> 367</td>

<td> 80</td><td>, 0 'Oh</td><td> 332</td>

<td> 81</td><td>'b</td><td> 271</td>

50552 Β

<td>Prirner</td><td>X ^ 4r5.</td><td>mn *</td>

<td> 62</td><td>Αχ</td><td> 433</td>

<td> 63</td><td></td><td> 317</td>

<td> 64</td><td>'X)</td><td> 271</td>

<td colspan="2"> “ 1</td><td> 295</td>

<td> 66</td><td></td><td> 313</td>

<td> 67</td><td>ž</td><td> 312</td>

<td> 68</td><td>πχ</td><td> 333</td>

<td> 69</td><td> . ...................................... ................</td><td> 387</td>

<td> 70</td><td>hs</td><td> 383</td>

<td> 71</td><td>f * » /% A Η CHj</td><td> 299</td>

<td> 72</td><td>Αχ</td><td> 379/381</td>

<td> 73</td><td> \</td><td> 300</td>

50552 Β

<td>Prirner</td><td></td><td>ΜΗ *</td>

<td> 74</td><td>^zYx X</td><td> 353</td>

<td> 75</td><td>• χ » SNz</td><td> 286</td>

<td> 76</td><td>'' Χ- ™ * sn *</td><td> 316</td>

<td> 77</td><td>ύ</td><td> 299</td>

<td> 78</td><td>F 0</td><td>34θ</td>

<td> 78</td><td></td><td> 311</td>

<td> 80</td><td>1 Ό</td><td> 306</td>

<td> 81</td><td>'Ž</td><td> 335</td>

<td> 82</td><td></td><td>2S5</td>

<td> 83</td><td> ---—...............................</td><td> 321</td>

50552 Β

<td>Prirner</td><td>X-— · №— {Κ *) β</td><td>ΜΗ *</td>

<td> 84</td><td>Λχ</td><td> 329</td>

<td> 85</td><td>Hdž ..</td><td> 311 .</td>

<td> 86</td><td>_usn. 0 'H</td><td> 311</td>

<td> 87</td><td>F</td><td> 363</td>

<td> 88</td><td>αχ · Λ CH,</td><td> 373</td>

<td> 80</td><td>'Όν X //^sch 0 *</td><td> 393</td>

<td> 90</td><td></td><td> 393</td>

<td> 91</td><td>Χς</td><td> 296</td>

50552 Β

<td>Example</td><td></td><td>ΜΗ *</td>

<td> 92</td><td>II, &lt;&gt; - ^X &lt;A</td><td> 427</td>

<td> 93</td><td>'T l CHj</td><td> 441</td>

<td> 94</td><td></td><td> 407</td>

<td> 95</td><td>^pS £^{% sn}» F 0</td><td> 427</td>

<td> 96</td><td>4ί</td><td> 369</td>

<td> 87</td><td>&lt;? n » χχ ° g ** Enantfomer 1</td><td> 373/373</td>

<td> 99</td><td>Ό, // 0 '</td><td> 343</td>

50552 Β

<td></td><td>h-adchn⁵).</td><td>ΜΗ *</td>

<td> 99</td><td>'Όγ 0 ⁴</td><td> 393</td>

<td> 100</td><td>jG D / R FJ J / ^HSN. r 0</td><td> 461</td>

<td> 101</td><td>H-tf s. f n, s</td><td> 336</td>

<td> 102</td><td>r &lt;h // _l⁰ XX,</td><td> 379</td>

<td> 103</td><td>ΑΧ</td><td> 390</td>

<td> 104</td><td></td><td> 413</td>

<td> 105</td><td>XX / _no/ γ^0Η· GHj</td><td> 387</td>

<td>1OS</td><td>..... Υ, r CH,</td><td> 329</td>

50552 Β

<td>Rpgpeg</td><td></td><td>ΜΗ *</td>

<td> 107</td><td>'V n, s &lt;</td><td> 329</td>

<td> 108</td><td>X F</td><td> 350</td>

<td>1W</td><td>-V · μ</td><td> 324</td>

<td> 110</td><td></td><td> 333</td>

<td> 111</td><td>h ^ksn,</td><td> 345</td>

<td> 112</td><td>HC, 3h £ PN. 0 ¹</td><td> 373</td>

<td> 113</td><td>CHj</td><td> 311</td>

<td> 114</td><td>ρ sn.</td><td> 311</td>

50552 Β

<td>Prirner.</td><td>Χ-VMR'ln</td><td>ΜΗ *</td>

<td> 115</td><td>sn, F ^₽</td><td> 363</td>

<td> 116</td><td>V</td><td> 329</td>

<td> 117</td><td>'Ui g-CH,</td><td> 373</td>

<td> 118</td><td>F</td><td> 367</td>

<td> 119</td><td>F f Ž GR FF</td><td> 417</td>

<td> 120</td><td>F</td><td> 363</td>

<td> 121</td><td>-9 o = s = o &lt;k</td><td> 359</td>

50552 Β

<td>Pnmer</td><td>XW-4R *) n</td><td>in '</td>

<td> 122</td><td>· / .... · L 0</td><td> 326</td>

<td> 123</td><td>,.,</td><td> 359</td>

<td> 124</td><td>XX.</td><td> 348</td>

<td> 125</td><td>| l 1, o f // tn. Cl θ</td><td> 393</td>

<td> 126</td><td>II and Fr. T #^hsK p u *</td><td>zp</td>

<td> 127</td><td>G ' 5h X IJL</td><td> 400</td>

<td> 128</td><td></td><td> 363</td>

<td> 129</td><td></td><td> 386</td>

<td> 130</td><td>/ «*&gt;%. Z&gt; '</td><td> 414</td>

50552 Β

<td>Example</td><td>χ — w- (R⁶k</td><td>ΜΗ *</td>

<td> 131</td><td>p</td><td> 428</td>

<td> 132</td><td></td><td> 442</td>

<td> 133</td><td>p V Y.</td><td> 357</td>

<td> 134</td><td>&gt; w ^⁰ L J</td><td> 390</td>

<td> 135</td><td>p _cw^g0 II</td><td> 370</td>

<td> 136</td><td>0 $ n * h / _l 1 # Ύ ^ τ rLč # L._a</td><td> 413</td>

<td> 137</td><td>““ “· ................. '...... · -ί'&gt; ι« · '·····^{,, Γ}'——— · - sn,</td><td> 386</td>

<td> 138</td><td>_No./ R</td><td> 380</td>

<td> 139</td><td>9 / γ%</td><td> 390</td>

50552 Β

<td colspan="2">Example j Χ — W -— (R%</td><td>'in *</td>

<td> 140</td><td>, 0 4zJ ° Dj</td><td> 395</td>

<td> 141</td><td> P? Art</td><td> 395</td>

<td> 142</td><td>^No./ 8 - · ϊ&gt;</td><td> 337</td>

<td> 143</td><td>, o G _sSl - Ji</td><td> 424</td>

<td> 144</td><td></td><td> 390</td>

<td> 145</td><td></td><td> 383</td>

<td> 146</td><td>° 'ΥΧ F</td><td> 433</td>

<td>147 | I.</td><td>.0 ć ΥΥ F</td><td> 417</td>

<td>I Ί48 t</td><td>č / ϊ^.Ι</td><td> 395</td>

50552 Β

<td colspan="2">p ™ 1 Χ-VMR '!.</td><td>MFT</td>

<td> 149</td><td>Oh 0</td><td> 351</td>

<td>15.1L.</td><td></td><td> 433</td>

<td> 151</td><td></td><td> 441</td>

<td> 152</td><td>l ^H .0</td><td> 434</td>

<td> 153</td><td></td><td> 404</td>

Obtaining specific examples - general experimental conditions

Unless otherwise indicated. NMR spectra were recorded at 400 MHz in CDCl1₃. LCMS were recorded on an Agilent 1100 LC system with a Waters Xterra MS S18 4.6 x 100 5 mM column, eluting with a 5-95% 10 mM aqueous solution of ammonium bicarbonate in acetoritrile over 10 minutes, with negative ion ionization by electrospray or with 5-95% water. + 0.1% TFA in acetonitrile with positive ion ionization by electrospray. MH + and refer to monoisotopic molecular weights.

Emrys ^W1 The optimizer nicotwave device (PersonalChemistrv AB) is used in the standard configuration as supplied.

50552 Β

Example 4 (1-Benzyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid

4a) In a mixed solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester, obtained according to U.S. Pat. 3, 320, 268 (80 mg, 0.39 mmol) in DMF (2.4 mL) was added BEMP (182 [mu] L, 0.63 mmol). After 30 minutes, benzyl bromide (75 [mu] L, 0.63 mmol) was added and the reaction mixture was stirred for 3 days before being separated between water and a solvent mixture of EtOAc / ether (1: 1). The organic layer was washed with concentrated brine and then reduced in vacuo. The residue was purified by flash column chromatography (3: 1, iso-hexane / EtOAc elution) to give (1-benzyl-2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl) acetic acid methyl ester. , MH + = 295.

4b) 1M Aqueous NaOH (364 [mu] L, 0.364 mmol) was added to a mixed solution of (1-benzyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) acetic acid methyl ester (65 mg , 0.22 mmol) in a solvent mixture of THF / MeOH (5: 1, 2.4 mL). After 5.5 hours, the reaction mixture was evaporated and partitioned between water and EtOAc. The aqueous layer was acidified to pH 3. and the resulting precipitate was collected by filtration to give 1-benzyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) acetic acid; MH + = 281.

Examples 18,19,23-32, 63, 65-70, 77-80, 82 and 85-86

These examples are [1- (3,4-Dichloro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [2-Methyl-1- (2-methyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid [1- (4-Chloro-benzyl) -2-methyl- [1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid [1 (3-Cyano-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] [1- (3-Chloro benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (4-Cyano-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [2-Methyl-1- (3-methyl-benzyl) -1H

<td>pyrrolo [2,3-b] pyridin-3-yl] -acetic acid Pyrrolo [2,3-b] pyridin-3-yl] -acetic pyrrolo [2,3-b] pyridin-3-yl] -acetic b] pyridin-3-yl] -acetic acid;</td><td>acid; [2-Methyl-1- (3-trifluoromethyl-benzyl) -1H-acid; [1- (4-Fluoro-benzyl) -2-methyl-1H acid; [1- (2-Chloro-benzyl) -1H-pyrrolo [2,3 [2-Methyl-1- (4-trifluoromethyl-benzyl) -1H-pyrrolo [2,3</td>

b] pyridin-3-yl] -acetic acid; [1- (3-Fluoro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine

50552 Β

3-yl] -acetic acid; [1- (3,4-Difluoro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [2-Methyl- (1-4-methyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (4-Fluoro-3-methyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (3-Fluoro-4-methyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (3-Chloro4-fluoro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; ; [1- (3-Fluoro-4-trifluoromethyl-benzyl) -2-methyl-4H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [1- (4-Chloro-3-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl] -acetic acid; [1- (2-Fluoro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [2-Methyl-1- (2-trifluoromethyl-benzyl) -1H-pyrrolo [1,3-b] pyridin-3-yl] acetic acid; [1- (3-Methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (2-Cyano-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [2-Methyl-1- (1-phenyl-ethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (4-Methoxybenzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; and (1- (2-Methoxybenzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid, were obtained by the same procedure as that described for Example 4, using of the corresponding benzyl halide.

Example 6 [2-Methyl 4- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

A solution of BEMP (90 μL, 0.31 mmol) in DMF (400 μL) was added to a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (40 mg , 0.20 mmol) in DMF (400 pL) After 40-50 minutes, a solution of 4-methyl-benzenesulfonyl chloride (60 mg, 0.31 mmol) in DMF (400 pL) was added.After an additional 30 minutes, 1M aqueous NaOH (800 [mu] L) was added and the reaction mixture was mechanically stirred for 105 minutes, after which 1M aqueous FICl (800 [mu] L) was added.The reaction mixture was partitioned between water and SN?₂. The organic phase is applied directly to the pre-packaged Isolute^tma column packed with silka gel and eluted with EtOAc to give a crude product which was triturated with water to give [2-methyl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; MH + = 345.

Examples 3, 5, 7-15, 17, 34, 35 and 37-39

50552 Β

These examples are 2-Methyl-1- (4-nitro-benzenesulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [2-Methyl-1- (naphthalene-2-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (4-Fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (4-Isopropyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (3-Bromo-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid, [2-Methyl-1- (3-trifluoromethyl-benzenesulfonyl) -2- methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl acetic acid; [1- (4-Methanesulfonyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl acetic acid; [1- (3-Methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl acetic acid; [1- (Biphenyl-4-sulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl acetic acid; [1- (3-Fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (2-Fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (4-Methoxy-benzenesulfonyl) -2-methyl-) -1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; [1- (4-Difluoromethoxy-benzenesulfonyl) -2-methyl ”-1H-pyrrolo [2,3b] pyridin-3-yl] acetic acid; [1- (3-Chloro-2-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [1- (2-Chloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; [1- (3-Cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl acetic acid; and 1- (2,5-Dichloro-benzenesulfonyl) -2-methylH-pyrrolo [2,3-b] pyridin-3-yl acetic acid were prepared using the same procedure as described in Example 6, with use of the appropriate benzenesulfonyl halide.

Example 16 [1- (3,4-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

16a) To a suspension of NaH (60% dispersion in mineral oil; 63 mg, 1.6 mmol) in THF (3 mL) ice-cooled, a solution of 2-methyl-1H-pyrrolo [2,3b] pyridine-3- methyl ester was added. yl) -acetic acid (200 mg, 1 mtnol) in a 3: 1 (4mL) solvent mixture of THF / DMF. After 45 minutes, a solution of 3,4-dichlorobenzenesulfonyl chloride (214 [mu] L, 1.4 mmol) in THF (3 mL) was added. 10 minutes later. the reaction mixture was added to ice / water and extracted with EtOAc. The organic layer was washed with brine and then evaporated. The crude product was purified by flash chromatography (3: 1 iso-hexane / EtOAc elution) to give the methyl ester.

50552 L [1- (3,4-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid; MH + = 413.

16b) 1M aqueous NaOH (1.5 mL) was added to a solution of [1- (3,4-dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester ( 218 mg, 0.53 mmol) in a solvent mixture consisting of THF / MeOH (1: 1, 6 mL). After 18 hours, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was acidified to pH 1, and then the resulting precipitate was collected by filtration to give [1- (3,4-dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl ] acetic acid; MH + = 399.

Examples 1 and 2

These examples, respectively (1-Benzenesulfonyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid, and [1- (4-Chloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid were prepared by the same procedure as described in Example 16, using the appropriate benzenesulfonyl halide.

Example 20 [2-Methyl-1-pyridin-3-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

20a) NaH (60% dispersion in mineral oil; 17 mg, 0.43 mmol) was added to a stirred solution of 3- (bromomethyl) pyridine hydrobromide (109 mg, 0.43 mmol) in ice-cooled THF (1.2 mL). After 20 minutes, a solution of (2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl) -acetic acid methyl ester (80 mg, 0.39 mmol) and BEMP (125 μΕ, 0.43 mmol) in 1.2 mL DMF- and is added in drops. After 1 h and 40 minutes, 25 mL of water was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was then washed with brine, dried (MgSO 4)₄) and evaporates.

The crude product was purified using flash chromatography (elution with EtOAc) to give 2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester, MH⁺ - 296.

50552 Β

b) 1Μ aqueous NaOH (0.5 mL) was added to a solution of 2-methyl-pyridin-3-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester (35 mg, 0.12 mmol) in a solvent mixture consisting of THF / MeOII (1: 1.2 mL) After 2 hours, the reaction mixture was evaporated and the residue was dissolved in water, the aqueous solution was acidified to pH 3-4 and the resulting precipitate was collected by filtration. to give (2-methyl-1-pyridin-3-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid;⁺ = 282.

Examples 21 and 22

These examples are (2-Methyl-1-pyridin-2-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) acetic acid; and (2-Methyl-1-pyridin-4-ylmethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid, were prepared by the same procedure as described in Example 20, with use of the appropriate (bromomethyl) pyridine hydrobromide.

Example 36 1- (3-Chloro-4-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

36a) To a solution of 2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.06 g, 0.294 mmol) in DMF (0.5 mL) was added a solution of BEMP 0.136 mL, 0.45 mmol) in DMF (0.5 mL ·). After 1 h, a solution of 3-chloro-4-methylbenzenesulfonyl chloride (0.105 g, 0.47 mmol) in DMF (0.5 mL) was added. The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure to minimum volume. The residue is added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted using an elution gradient from 100% isohexane to 30% ethyl acetate in isohexane to give [1- (3-chloro-4-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-methyl ester]. -b] pyridin-3-yl] -acetic acid; MH + - 393.

36b) 1M aqueous NaOFI solution (0.25 mL) was added to the methyl ester solution [1- (3-Chloro-

4-Methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (80 mg, 0.20 mmol) in a dioxane / water solvent mixture (1: 1.2 mL) ). After 2.5 hours, the reaction mixture was acidified to pH 1 with LM HCl to give a precipitate. Solid

50552 The product is isolated by filtration, washed with water and dried to give [1- (3-Chloro-4-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] - acetic acid; MH⁺ = 379.

Examples 33 and 46

These examples are, respectively, [2-Methyl-1- (4-trifluoromethyl-benzenesulfonyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid; -2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid were prepared by the same procedure as described in Example 36, using the appropriate benzenesulfonyl halide.

Example 40

2- [1- (3,4-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] propionic acid

40a) To a stirred solution of diisopropylamine (34 [mu] L, 0.24 mmol) in THF (1 mL), at 78 [deg.] C., was added a 2.5 M solution of n-BuLi in hexane (105 [mu] L, 0.26 mmol). After 20 minutes, a solution of [1- (3,4-dichloro-benzenesulfonyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (Method B; 100 mg, 0.24 mmol) and Mel (15.2 μL, 0.24 mmol) in THF (1 mL) The reaction mixture was stirred for another 30 minutes and then allowed to warm to room temperature. The reaction mixture was evaporated to dryness and purified by flash chromatography (4: 1 isohexane / EtoAc elution) to give 2- (1- (3,4-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo methyl ester [2, 3-b] pyridine-

3-yl] -propionic acid; MH + = 427.

40b) 1M aqueous NaOH solution (0.25 mL) was added to 2- (1- (3,4-dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] - methyl ester solution. propionic acid (17 mg, 0.04 mmol) in THF / MeOH (1: 1, 1 mL) After 4 h, the reaction mixture was evaporated and the residue was dissolved in water.Aqueous solution was acidified to pH 1 and the resulting solid was collected by filtration . The crude product was purified by flash chromatography (10: 1 EtoAc / MeOH), trituration (isolation) with isohexane to give 2- (1- (3,4-Dichloro-benzenesulfonyl) -2-methyl-1H -pyrrolo [2,3-b] pyridin-3-yl] -propionic acid;⁺ = 413.

50552 Β

Example 54 [1- (3-Cyano-4-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

54a) To a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.5 g, 2.45 mmol) in DMF (3 mL) was added a solution of BEMP 1.13 mL, 3.92 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure to minimum volume. The residue is added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted using an elution gradient of 100% isohexane to 50% ethyl acetate in isohexane to give [1- (3-Cyano-4-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-methyl ester]. -b] pyridin-3-yl] -acetic acid; MH + = 388.

54b) 1M VVgz in CH2Cl2 (7.66 mL, 7.66 mmol) was added to a solution of [1- (3-cyano-4-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-3 methyl ester -yl] -acetic acid (0.495 g, 1.27 mmol) in CH 2 Cl 2? (2 mL). The reaction mixture was exposed to microwave radiation at 60 ° C for 45 minutes. Water is added to the reaction mixture which is stirred for a further 20 minutes. The organic layer was separated using Isoluta^tm cartridges (vessels) for phase separation and then evaporates. The residue is added to (previously prepared) Isolutc^tm a column packed with silica gel and eluted using an elution gradient of 100% CH2O2 to 5% methanol in CH2Cl2 to give the title compound. Μ11 + = 374.

Examples 41-45, 47-53,55, 56, 58 and 60

These examples, namely [1- (4-Cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (2,4-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl] -acetic acid; [2-Methyl-1- (3-trifluoromethoxy-benzenesulfonyl) -1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid; [1- (2,5-Difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (2-Cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[2-Methyl-1- (2,3,4-trifluoro-benzenesulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

50552 3- 3- (3-Carboxymethyl-2-methyl-pyrrolo [2,3-b] pyridine-1-sulfonyl) -thiophene-2-carboxylic acid methyl ester;

[1- (3,5-Difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[1- (2,5-Dichloro-thiophene-3-sulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[1- (3-Chloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (3,5-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[1- (2,3-Dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[1- (3-Chloro-4-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid;

[1- (3-Fluoro-4-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

[1- (2,4-Difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; and [2-Methyl-1- (pyridine-3-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; are obtained by the same procedure as described in Example 54, using the appropriate benzenesulfonyl halide.

Example 57 1- (4-Chloro-phenyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

57) Mixture of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (100 mg, 0.49 mmol), 1-chloro-4-iodo-benzene (117 mg, 0.49 mmol), Cul (5 mg, 0.03 mmol), cyclohexane-1,2-diamine (6 pL, 0.05 mmol), potassium phosphate (218 mg, 1.0 mmol) and

The 1,4-dioxane (0.5 mL) was heated at 160 ° C for 140 minutes. The reaction mixture was cooled, washed with EtOAc, filtered through a pad of silica gel and evaporated to dryness. The residue was purified by flash column chromatography (5: 1, isohexane / EtOAc) to give [1- (4-fluoro-phenyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-methyl ester.

3-yl] -acetic acid, MII + = 315.

57b) A 1M aqueous solution of NaOH (0.5 mL) was added to a solution of [1- (4-chlorophenyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (4 mg, 0.013 mmol) u

50552 Β

TIIF / MeOH (1: 1, 1 mL). After 18 hours, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was acidified to pH 1, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO 4)₄) is then evaporated to give 1- (4-Chloro-phenyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid; M1 ~ G = 301.

Example 59 [1 (3,4-Difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

59a) To a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.8 g, 3.92 mmol) in DMF (3 mL) was added a solution of BEMP 1.81 mL, 6.27 mmol). After 1 h, the reaction mixture was allowed to cool to 0 ° C and a solution of 3,4-difluoro-benzenesulfonyl chloride (0.83 mL, 6.27 mmol) in DMF (3 mL) was added.

The reaction mixture was allowed to warm and stirred overnight at room temperature, after which it was concentrated under reduced pressure to minimum volume. The residue is added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted using an elution gradient of 100% isohexane to 30% ethyl acetate in isohexane to give [1- (3,4-difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] methyl ester [pyridin-3-yl] -acetic acid; MH + = 381.

59b) A 1M aqueous solution of LiOH (0.52 mL) was added at 0 ° C to a mixed solution of [1- (3,4-difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine- 3-yl] -acetic acid (200 mg, 0.526 mmol) in a solvent mixture of dioxane / water (1: 1, 4 mL). After

2.5 hours, the reaction mixture was neutralized to pH 7 with 1M HCl and the solvent was removed under reduced pressure. The residue is added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted using an elution gradient from 100% CH2Cl2 to 5% methanol in CH₂C1₂ in isohexane to give [1- (3,4-difluorobenzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; MH + = 367.

Example 72 [1- (4-Chloro-3-methyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

50552 Β

This example was prepared by the same procedure as described in Example 59, using the appropriate benzenesulfonyl halide.

Priiner 61 (1-Furan-3-ylmethyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

61a) BEMP (182 [mu] L, 0.63 mmol) was added to a mixed solution of [2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (80 mg, 0.39 mmol) in DMF (1.2 mL) After 30 minutes, a solution of toluene-4-sulfonic acid furan-3-ylmethyl ester in THF (1.4 mL, 0.45 mmol) was added and after 18 h, the reaction mixture was partitioned between water and ether. the layer is washed with concentrated brine and then its volume is reduced in vacuo. The residue was purified by flash column chromatography (3: 1 isohexane / EtOAc elution) to give methyl ester (1-furan-3-ylmethyl-

2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; Mfl '= 285.

61b) 1M aqueous NaOH (0.25 mL) was added to a solution of 1-furan-3-methyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (7.5 mg, 0.026 mmol) in a solvent mixture of THF / MeOH (1: 1, 1 mL) After 18 hours, the reaction mixture was evaporated and the residue was dissolved in water, the aqueous solution was acidified to pH 3-4, and extracted with ethyl acetate. is washed with water and concentrated brine, dried (MgSO 4)₄) is then evaporated to give (1-furan-3-ylmethyl-

2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; MH⁺ 271.

Example 64

The exemplified compound (1-furan-2-ylmethyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid was prepared in the same manner as that described in Example 61 , using the appropriate furan methyl ester.

Example 62 [4-Chloro-1- (3,4-dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

50552 Β

62) m-Chloroperoxybenzoic acid (1.35 g, 7.8 mmol) was added to a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (1 g, 4.9 mmol). in 1,2-dimethoxyethane (15 mL) and stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into water with pH adjustment to 9-10 (base medium) with aqueous saturated potassium carbonate solution. The precipitate was filtered off and the filtrate was extracted with CH₂C1₂, then dried (Na₂CO4) and evaporated to dryness in vacuo. The residue obtained is purified by chromatography on a column packed with silica gel using a mixture of SN solvents.₂S1₂(MeO) (10: 1) as eluent, followed by 2-methyl-7-oxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester; MH + = 221.

62b) To excess of POCl 3 (2-methyl-7-oxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid (250 mg, 1.14 mmol) was added while cooling in a water bath. 20 mL). The reaction mixture was heated at reflux for 5 hours. POCl3 was removed in vacuo. The residue was dissolved in CH₂C1₂, rinsed with water, concentrated brine and then dried (Na₂SO4) and concentrated to dryness in vacuo. The crude product is purified by column chromatography on silica gel using a mixture of SN solvents.₂S1₂/ MeON (10: 1) as eluent to give (4-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester: MH + = 239.

62c) To a solution of methyl ester (4-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid (58 mg, 0.24 mmol) in DMF (1.2 mL) was added BEMP (113 uL, 0.39 mmol). The reaction mixture was stirred at ambient temperature for 40 minutes. 3,4-Dichloro-benzenesulfonyl chloride (60 [mu] L, 0.39 mmol) was added and the reaction mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was poured into ice-cold water, extracted with EtOAc, washed with brine, dried (Na₂SO4) and evaporates. The crude product was purified by column chromatography on silica gel using EtOAc / isohexane (1: 8) as eluent to give [4-Chloro-1- (3,4-dichloro-benzenesulfonyl) -2-methyl ester. -1H-pyrrolo [2,3b] pyridin-3-yl) -acetic acid; MH + = 449.

62d) [4-Chloro-1- (3,4-dichloro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (40 mg, 0.39) was added to the solution. mmol) in CH₂C1₂ (1 mL)

50552 Β 1 M BBr is added₃ in CH 2 Cl 2 (536 pL, 0.54 mmol). The solution was subjected to microwave irradiation in a closed reaction vessel for 45 minutes with stirring at 60 ° C. The reaction mixture was evaporated to dryness, water was added and the suspension was subjected to ultrasonic waves and then filtered, washed with water and dried in vacuo to give [4-Chloro-1- (3,4-dichloro-benzenesulfonyl) - 2-Methyl-1H-pyrrolo [2,3-b] pyridin3-yl] -acetic acid; MH + = 433.

Example 71 [1- (2,5-Dimethyl-2H-pyrazol-3-ylmethyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) acetic acid

71a) To a solution of (2,5-dimethyl-2H-pyrazol-3-yl) -methanol (100 mg, 0.79 mmol) in stirred diethyl ether (3 mL) was added PBr₃ (25 [mu] L, 0.26 mmol). The reaction mixture was stirred at room temperature for 18 hours, after which water was added. The diethyl ether layer was separated and stored above solid NaOII and used in reaction phase 71b without further characterization.

71b) BEMP (137 [mu] L, 0.47 mmol) was added to a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (60 mg, 0.29 mmol) in DMF ( 0.8 mL). After 35 minutes, a layer of diethyl ether from reaction phase 71a (1.8 mL) was added. After 3 days, the reaction mixture was partitioned between water and a solvent mixture of EtOAc / ether (1: 1). The organic layer was washed with brine and allowed to evaporate. The residue was purified by flash column chromatography (49: 1 EtOAc / MeOH elution) to give [1- (2,5-Dimethyl-2H-pyrazol-3-ylmethyl-2-methyl-pyrrolo] methyl ester [2,3b] pyridin-3-yl) -acetic acid, MH + = 313.

71c) 1M aqueous NaOII solution (0.5 mL) was added to a mixed solution of [1 (2,5-Dimethyl-2H-pyrazol-3-ylmethyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine methyl ester -3-yl] -acetic acid (29 mg, 0.0 mmol) in a solvent mixture of THF / MeOH (2 mL). After 18 hours, the reaction mixture was evaporated and the residue was dissolved in water. The aqueous solution was acidified to pH 1, and the resulting precipitate was collected by filtration to give [1- (2,5-Dimethyl2H-pyrazol-3-ylmethyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3 -yl) -acetic acid; MH + = 299.

50552 Β

Examples 73-76 and 83-84

These examples, namely (1- (3,5-Dimethyl-isoxazol-4-ylmethyl) -2-methyl-1H-pyrrolo [2,3b [pyridin-3-yl] -acetic acid; [2-Methyl-1- (5-methyl-2-trifluoromethyl-furan-3-ylmethyl) 1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [2-Methyl-1- (5-methyl-isoxazol-3-ylmethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1- (2,4-Dimethyl-thiazol-5-ylmethyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; [1-Benzofuran-2-ylmethyl-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; ί [1- [1- (4-Chloro-phenyl) ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl} -acetic acid were obtained by the same procedure as described in Example 71, using the appropriate heterocyclic methanol.

Example 81 {1- (3,4-Dichloro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

81a) 1H-Pyrrolo [2,3-b] pyridine (0.500 g, 4.2 mmol) was added to a stirred suspension of aluminum chloride (2.8 g, 21 mmol) in CH2Cl2 (100 mL) at 25 ° C. The suspension was stirred for 1 h at 25 ° C. Methyl oxalyl chloride (1.93 mL, 21 mmol) was added dropwise to the reaction mixture and the resulting suspension was stirred for 72 hours at 25^UC. The reaction mixture was cooled to 0 ° C in an ice bath. MeOH (20 mL) was added dropwise after which the reaction mixture was evaporated to dryness in vacuo. The crude material was triturated with ElOAc / MeOH (10: 1) and filtered. The combined solid residue was further triturated with water and dried in vacuo to give oxo- (1H-pyrrolo [2,3-b [pyridin-3-yl]] acetic acid methyl ester, MII + = 335.

81b) A mixture of oxo- (1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (0.300 g, 1.47 mmol) was refluxed 1h in hydrazine monohydrate (10 mL) to give a solution. KOH in beads (0.300 g, 5.35 mmol) was added and reflux was maintained for a further 1 h.The reaction mixture was evaporated to dryness in vacuo, dry MeOP (10 mL) was added to the residue and the solution was cooled in an ice bath.Concentrated H2SO4 (0.5 mL) ) was carefully added and the reaction mixture was refluxed at 80 ° C for 1 h. The reaction mixture was evaporated to dryness in vacuo, then partitioned between saturated NaHCO 3 solution and EtOAc. The EtOAc layer was separated and the aqueous phase was extracted with another

50552 Β portion of EtOAc. The organic layers are combined, dried (Na₂SO₄) and evaporated in vacuo. The crude product is purified by flash chromatography on (previously prepared) Isolute^{, m} a column packed with silica gel and eluted with an EtOAc / iso-hexane-fine gradient of EtOAc (1: 8) to give [1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester MH + = 191.

81c) To an ice-cold solution of (1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (50 mg, 0.26 mmol) was added BEMP (0.122 mL, 0.42 mmol). was stirred at ambient temperature for 40 minutes, then 3,4-dichlorobenzyl bromide (0.101 g, 0.42 mmol) was added and stirring was continued for 16 h at ambient temperature.The reaction mixture was poured into ice-cold water (40 mL) and extracted with EtOAc, then washed with concentrated brine, dried (Na₂SO₄), filtered and evaporated in vacuo. The crude product is purified by chromatography on a column packed with silica gel using (pre-prepared) Isolute^tm columns and eluted with a solvent mixture of EtOAc / iso-hexane (1:20) to give {1- (3,4-dichloro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] - methyl ester. acetic acid; MH⁺ = 349.

81d) To a solution of {1- (3,4-dichloro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester (23 mg, 0.066 mmol) in MeOH (5 mL) , 4N NaOH (0.25 mL) was added. The reaction mixture was stirred at 25 ° C for 5 minutes. The reaction mixture was evaporated in vacuo to remove MeOH, then cooled in an ice bath and acidified with concentrated HCl. The resulting solid product was collected by filtration and powdered into SNS1₃ to give [1- (3,4-dichloro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid; MH⁺ = 335.

Example 87 [2-EN1-1- (44β-Alkyl-Phenyl) -GN-pyrrolo [2,3-f] p1p0t-3-11] -81gseic acid

87a) 2-Ethyl-1H-pyrrolo [2,3-b] pyridine:

To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 mL) at room temperature under an inert atmosphere was added n-BuLi (18.8 mL of a 1.6 M solution in hexane, 30 mmol) with the addition of t -BuOK (2.24 g, 20 mmol). The reaction mixture was stirred at room temperature for 40 minutes and then cooled to -70 ° C, after which it was added.

50552 Β Methyl iodide dropwise (1.25 mL, 20 mmol). Stirring was continued for a further 2 hours, after which the reaction mixture was cooled with water (2 mL) and allowed to warm slightly to room temperature. The cooled solution was poured into water (200 mL), neutralized with 1N HCl and then extracted with diethyl ether (80 mL). The organic portion was washed with water (2 x 60 mL), dried₂SO₄) and concentrated in vacuo to give the title compound as orange crystals. [MH + CH₃CN]⁺ = 188).

87b) (2-Ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -oxo-acetic acid methyl ester:

A suspension of aluminum chloride (1.87 g, 14 mmol) in DCM (100 mL) under an inert atmosphere at room temperature was treated with 2-ethyl-1H-pyrrolo [2,3-b] pyridine (0.415 g, 14 mmol). After stirring for one hour at room temperature, methyl oxalyl chloride (1.29 mL, 14 mmol) was added dropwise to the reaction mixture with stirring overnight. The reaction mixture was cooled in an ice bath and methanol was added dropwise. The mixture is then poured into an ice / water vessel and mixed. The organic part is separated, dried (Na₂SO₄) and concentrated in vacuo. The resulting crude product was ground to a powder using ice water (20 ml) and then subjected to ultrasonic waves. The solid was swirled and dried in vacuo at 50 ° C to give the title compound (MH + 233).

87c) (2-Ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester

To a solution of triethylsilane (818 μΐ. 5.2 mmol) in TFA (1.6 mL) at -10 ° C was added in portions methyl ester (2-Ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -oxo -acetic acid (0.34 g, 1.46 mmol). After stirring overnight at room temperature, the solvent was removed in vacuo and the resulting residue was neutralized with saturated sodium bicarbonate solution. The solution was extracted with DCM (3 x 20 mL) and the organic portions were combined, dried (Na₂SO₄) and concentrated in vacuo. The residue is added to the (previously prepared) Isolute^tm silica gel column and eluted with DCM / MeOH (100: 0 growing to 98: 2) to give the title compound as a yellow powder. (MH + 219).

87d)) (2-Ethyl-1- (4-trifluoromethyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester

50552 Β

In a solution of methyl ester (2-ethyl-1H-pyrrolo [2₎3-b] pyridin-3-yl) -acetic acid (80 mg, 0.37 mmol) in DMF (1 mL) was stirred and cooled with ice, BEMP (171 μΐ, 0.59 mmol) was added. The solution was stirred at room temperature for 40 minutes and then cooled again. 4- (Trifluoromethyl) -benzyl bromide (91 μΐ, 0.59 mmol) was added and stirring was continued during which time the reaction mixture was gradually warmed to room temperature overnight. The resulting mixture was poured into water (30 mL) and extracted with an EtOAc / water solvent combination (1: 1). The organic layer was washed with brine, dried (Na₂SO₄) and concentrated in vacuo. The residue was added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted with DCM to give the title compound as a pale yellow oil. (MH + 377).

87e) (2-Ethyl-1- (4-trifluoromethyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid:

0.5 M aqueous NaOH (1.0 mL) was added to a solution of [2-ethyl-1- (4-trifluoromethyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (48 mg, 0.13 mmol) in a solvent mixture of THF / MeOH (1 mL). After 3 h, the reaction mixture was concentrated in vacuo, and the residue was dissolved in water. The aqueous solution was cooled in an ice bath and acidified to pH 2 using concentrated HCl. The resulting precipitate was filtered off and dried under high vacuum at 50 ° C to give the title compound as a white powder. (MH + 363).

Example 88 [1- (4- (Ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

88a) BEMP (182 μΐ, 0.64 mmol) was added to a mixed solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (obtained according to the procedure described for U.S. Pat. 3320268. 82 mg, 0.40 mmol) in DMF (2.6 mL). After 80 minutes, 1-bromomethyl-4-ethanesulfonyl-benzene (75 μΐ, 0.63 mmol) was added and the reaction mixture was stirred for 2 hours before being separated between water and a solvent mixture of EtOAc / diethyl ether (1: 1). The organic layer was washed with concentrated salt solution and then its volume was reduced by evaporation in vacuo. The residue was purified by flash column chromatography (1: 1 isohexane / EtOAc elution) to give

50552 Β obtained [1- (4- (Ethanesulfonyl-benzyl) '- 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester as a solid product.

88b) A 1M aqueous solution of NaOII (1 ml) was added to a mixed solution of 1- (4 (ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester. (89 mg, 0.23 mmol) in a THF / MeOH solvent mixture (4 mL) After 1 h the reaction mixture was evaporated and the resulting oil was dissolved in water (8 mL) and acidified to pH 3. The resulting precipitate was collected by filtration and dried in vacuo to would give [1- (4 (Ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (MH + 373).

Example 89 [4-Chloro-1- (4- (methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

89a) (2-Methyl-7-oxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester

Mixed suspension of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (5 g, 24.5 mmol) in 1,2-dimethoxyethane (100 mL) at room temperature argon was treated in portions with m-chloroperoxybenzoic acid (9.7 g, from 77% w / w solid product, 39.2 mmol). Due to the exothermic nature of the acid addition, the reaction temperature is maintained at room temperature using a water bath. The reaction mixture was stirred at room temperature for 3 h and then poured into water (400 mL) and basified to pH 9-10 (basic sediment) using saturated potassium carbonate solution. The aqueous layer was extracted with DCM (2 x 100 mL), the organic portions were collected, dried (Na2SO).₄) and concentrated in vacuo to give (2-methyl-7-oxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester. (MH + = 221).

89b) (4-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester

A suspension of 2-methyl-7-oxy-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (360 mg, 1.63 mmol) in phosphorus oxychloride (5ml) was stirred and heated using microwave radiation in Personal Chemistry Emrys ^{, m} Microwave reactor optimizer for 5 minutes at 160 ° C. After standing the suspension overnight on

50552 At room temperature, the reaction mixture was carefully poured into ice water and extracted with DCM (3 x 40 mL). Organic parts are collected, washed with water, dried (Na₂SO4) and concentrated in vacuo. The resulting dark brown residue was added to the (previously prepared) Isolute^tm a column packed with silica gel and eluted with a solvent mixture of DCM / methanol (10: 1) to give the title compound as a foam. (Μ1Ι + 239).

89c) 4-Chloro-1- (4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester

In a cooled (0 ° C) stirred solution of 4-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin3-yl] -acetic acid methyl ester (0.1 g, 0.42 mmol) in dry DMF- sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mmol) was added in (2.5 ml) After stirring at room temperature for 5 hours, the reaction mixture was cooled again to 0 ° C and then treated with 4-methylsulfonylbenzyl bromide (0.105 g, 0.42 mmol) The resulting mixture was mixed with meat and allowed to warm to room temperature overnight. The reaction mixture was diluted with water (3 mL) and extracted with ether (3 x 15 mL). Organic parts are collected, washed with water, dried (Na₂SO4) and concentrated in vacuo. The resulting crude residue was added to (previously prepared) Isolute^tmcolumn with silica gel and eluted with a solvent mixture of isohexane / ethyl acetate (1: 8) to give the title compound as a white powder. (MH + 407).

89d) 1M aqueous NaOH solution (0.5 ml) was added to a mixed solution of [4-chloro-1- (4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl methyl ester. ] -acetic acid (38 mg, 0.093 mmol) in a solvent mixture of THF / MeOH (1: 1, 1ml). After stirring for 4 hours at room temperature, the reaction mixture was filtered to remove any undissolved material and then evaporated to dryness. The resulting oil was dissolved in water (Iml) and acidified to pH 2. The resulting precipitate was collected by filtration and dried in vacuo to give [4-Chloro-1- (4- (methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid . (MH + 393).

Example 90 [1- (2-Chloro-4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

50552 Β

90a) 2-Chloro-4-methanesulfonyl-benzaldehyde:

A suspension of 2-chloro-4-fluorobenzenedehyde (24.9 g, 0.16 mol) and dry sodium methanesulphate (17.9 g, 0.175 mmol) in dry DMSO (60 mL) was stirred overnight at 90 ° C. The reaction mixture was allowed to cool to room temperature and then poured into ice-cold water (400 ml). The resulting precipitate was collected by filtration and dried under high vacuum to give the title compound as a yellow powder.

90b) (2-Chloro-4-methanesulfonyl-phenyl) -methanol

To a mixed dispersion of 2-chloro-4-methanesulfonyl-benzaldehyde (25 g, 0.11 mmol) in absolute ethanol (120 mL), sodium borohydride (4.6 g, 0.12 mmol) was added while cooling the dispersion in an ice bath to maintain room temperature. . After stirring at room temperature for 3 hours, the reaction mixture was carefully poured into an ice / water vessel (600 ml) and acidified to pH 1-2 with 1N HCl. The resulting suspension was extracted with ethyl acetate (400 ml) and the organic portions were combined, washed with concentrated brine, dried (MgSO 4).₄) and concentrated in vacuo. The resulting crude product was dried overnight in a vacuum oven at 40 ° C to give the title compound which was used in crude form for the next reaction step.

90c) 1-Bromomethyl-2-chloro-4-methanesulfonyl-benzene

A cooled (0 ° C) suspension of (2-Chloro-4-methanesulfonyl-phenyl) -methanol (19.1 g, 0.087 mmol) in diethyl ether (250 mL) under an inert atmosphere was treated with phosphorus tribromide (5.2 mL, 0.029 mmol). and allowed to stir overnight and warm to room temperature. The resulting mixture was diluted with water (100 mL) and the organic portion was separated and dried over NaOH granules for 5 minutes. The solvent was removed in vacuo and the resulting crude residue was added to (previously prepared) Isolute.^tm a column packed with silica gel and eluted with a solvent mixture of isohexane / ethyl acetate (4: 1) to give the title compound as a white powder.

50552 Β

90d) 1- (2-Chloro-4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl] -acetic acid

To a stirred solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (2.25 g, 1.1 mmol) in dry DMF (15 mL) cooled with ice ( 0 ° C), sodium hydride (0.484 g, of a 60% dispersion in mineral oil, 12.1 mmol) was added. After stirring at room temperature for 3 hours, the reaction mixture was cooled again to 0 ° C and then treated with 1-bromomethyl-2-chloro-4-methanesulfonylbenzene (5.0 g, 17.6 mmol) and sodium iodide (2.64 g. 17.6 mmol). The resulting mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was diluted with water (300 mL) and extracted with a solvent mixture of ethyl acetate / ether (1: 1). Organic parts are collected, washed with water, dried (Na₂SO4) and concentrated in vacuo. The resulting crude residue was added to (previously prepared) Isolute^tma column packed with silica gel and eluted with an ethyl acetate / isohexane solvent mixture (1: 4 increased to 1: 2) to give the title compound. (MH + 407).

90e) [1- (2-Chloro-4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

1M aqueous NaOH (15 mL) was added to a mixed solution of methyl ester [1- (2-Chloro-

4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (2.6 g, 6.39 mmol) in a solvent mixture of THF / MeOH (1: 1, 1ml) . After stirring at 45 ° C for 1 h, the reaction mixture was filtered to remove any undissolved material and then evaporated to dryness. The resulting oil was dissolved in water (30 ml) and acidified to pH

2-3 using concentrated HCl. The resulting suspension was collected by filtration and dried in vacuo at 50 ° C to give a solid which was purified by recrystallization from a solvent mixture of 1RA / water (1: 3) to give the title compound. (MH + 393).

Example 91 [1- (4-Amino-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

To a mixed solution of 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (0.78 g, 3.8 mmol) in DMF (10 mL) was added dropwise BEMP ( 1.21 ml, 4.2 mmol)

50552 Β in a time interval of 2 minutes. After stirring at room temperature for 1 hour. The resulting solution was treated with a portion of 4-nitrobenzyl bromide (1.0 g, 4.6 mmol) and stirring was continued overnight. The reaction mixture was concentrated in vacuo with toluene and the resulting oil was purified by column chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (3: 1) to give methyl ester [2-methyl-1- (4). -nitro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid. (MH + 340).

91b) [2-Methyl-1- (4-nitro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

1M aqueous NaOH solution (1.18 ml) was added to a mixed suspension of [2-methyl-1- (4-nitro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (0.2 g, 0.54 mmol) in a solvent mixture of THF / MeOH (4: 1, 5ml). The reaction mixture was allowed to stand for 4 hours at room temperature and then the solvent was removed in vacuo. The crude residue was dissolved in a solvent mixture of TFIF / water and acidified to pll 3-4 using 6M HCl. After stirring for 30 minutes, the resulting suspension was filtered and dried in vacuo at 110 ° C to give the title compound as a yellow solid. (MH + 326).

91c) [1- (4-Amino-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

[2-Methyl-1- (4-nitro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid, dissolved in a solvent mixture of methanol / acetic acid (25: 3) in in an inert argon atmosphere and then treated with palladium on carbon (10% w / w). The resulting suspension was stirred for 4 hours under a hydrogen atmosphere and then filtered. The solvent was removed in vacuo to give the title compound as a yellow solid. (MH + 296).

Example 92 [1- (4-Methanesulfonyl-3-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

92b) 1-Bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene:

50552 Β

The title compound was prepared in an analogous manner to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro3-trifluoromethylbenzaldehyde.

92b) [1- (4-Methanesulfonyl-3-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester:

To a stirred solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (12.8 g, 62.8 mmol) in dry DMF (200 mL) under an inert argon atmosphere was added in drops of BEMP (19.9 mL, 69.1 mmol) over a time interval of 5 minutes. After stirring at room temperature for 1 hour, the resulting solution was added dropwise to a stirred solution of 1-bromomethyl-4-methanesulfonyl-3-trifluoromethyl-benzene (23.9 g, 75.4 mmol) and stirred for 18 hours. The reaction mixture was concentrated in vacuo with toluene and left at reflux for 5 minutes in the presence of activated carbon. The solution was filtered and the solvent was removed in vacuo. The resulting solid was recrystallized from a solvent mixture of ethyl acetate and iso-hexane to give the title compound as a white solid. (MH + 441).

92c) [1- (4-Methanesulfonyl-3-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

[1- (4-Methanesulfonyl-3-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester (14.1 g, 32 mmol) in THF (150 ml) was treated with 1M (64 ml) NaOH dropwise at room temperature and after heating to 50 ° C, the suspension was treated with methanol (50 ml). The reaction mixture was stirred at 50 ° C for 2 hours and then the solvent was removed in vacuo. The crude residue was triturated with ethyl acetate (200 ml) and the resulting product was filtered and then dissolved in a water / dioxane solvent mixture (250 ml in a 2: 1 mixture). The solution was acidified to pH 3-4 using concentrated HCl and the resulting suspension was filtered, washed with water and then dried in vacuo. Further purification of the solid by recrystallization from a solvent mixture of TRA / water (1: 3) gave the title compound (MH + 427).

Example 93

50552 Β [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

93a) 1-Bromomethyl-4-ethanesulfonyl-2-trifluoromethylbenzene:

The title compound was prepared in an analogous manner to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-3-trifluoromethylbenzaldehyde and replacing sodium methanesulphate with sodium ethanol.

b) [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester

To a stirred solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.77 g, 3.78 mmol) in dry DMF (12 mL) under an inert argon atmosphere was added in drops of BEMP (1.75 mL, 6.04 mmol). The mixture was allowed to stand at room temperature for 1 h and then treated with 1-bromomethyl-4-ethanesulfonyl-2-trifluoromethyl-benzene (2 g, 6.04 mmol). Stirring was continued for a further 2 hours after which the reaction mixture was separated with a solvent mixture of ethyl acetate / diethyl ether (80 ml for a 1: 1 mixture) and water (100 ml). The organic portion was separated and washed with concentrated brine and concentrated in vacuo. Purification of the crude product by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (3: 1 ratio increased to 2: 1) gave the title compound (MH + 455).

93c) [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

To a mixed solution of [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (0.6 g, 1.32 mmol) in a mixture methanol / THF solvent (8 mL in a 1: 1 mixture), 1M NaOH (3 mL) was added. After stirring at room temperature for 1.5 hours, the solvent was removed in vacuo and the residue was dissolved in water (3ml). The solution was acidified to pH 1 using 6 M HCl and the resulting suspension was filtered and dried to give the title compound. (MH + 441).

50552 Β

Example 94 [1- (2-Chloro-4-ethanesulfonyl-benzyl) “2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

94a) 1-Bromomethyl-2-chloro-4-ethanesulfonyl-benzene:

The title compound was prepared in an analogous manner to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing sodium methanesulfinate with sodium ethanesulfinate.

94b) [1- (2-Chloro-4-ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester:

To a stirred solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (2.68 g, 13.1 mmol) in dry DMF (95 mL) was added dropwise sodium hydride (577 mg of a 60% dispersion in mineral oil, 14.41 mmol). After stirring at room temperature for 1.5 h, the reaction mixture was cooled again to 0 ° C and treated with 1-bromomethyl-2-chloro-4-ethanesulfonyl-benzene (6.6 g, 22.2 mmol) and sodium iodide (3.3 g, 22.2 mm). The resulting mixture was stirred and allowed to warm to room temperature overnight. The reaction mixture was poured into water (600 ml), extracted with a solvent mixture of ethyl acetate / diethyl ether (4 x 300 ml for a 1: 1 mixture). The organics were washed with brine and concentrated in vacuo and the resulting crude product was purified by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (1: 8 ratio increased to 1: 2) to give the title compound. (MH + 421).

94c) [1- (2-Chloro-4-ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

To a mixed solution of [1- (2-Chloro-4-ethanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (3.32 g, 7.89 mmol) in methanol / THF (30 ml of a 1: 1 mixture) was added 1M NaOH (15 ml). After stirring overnight at room temperature, the solvent was removed in vacuo and the residue was dissolved in water (20 ml). The solution was acidified to pH 1 using 6 M HCl and

50552 Β The resulting suspension was filtered and recrystallized from an IPA / water solvent mixture to give the title compound. (MH + 407).

Example 95 [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

95a) ​​1-Bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene:

The title compound was prepared in an analogous manner to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-

2-trifluoromethylbenzaldehyde.

95b) [1- (4-Methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester;

Lf a mixed solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (12.8 g, 62.8 mmol) in dry ice-cooled DMF (400 mL), added in an inert atmosphere of argon dropwise over 2 minutes, BEMP (18.1 mL, 62.8 mmol). After stirring at 10 ° C for 40 minutes, the reaction solution was treated with 1bromomethyl-4-methanesulfonyl-2-trifluoromethylbenzene (23.8 g, 75.4 mmol) dropwise and allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo with toluene (azeotropic mixture) and the resulting oil was partitioned between water (400 mL) and DCM (500 mL) and extracted with DCM (500 mL). The organic portions were collected and washed with water (2 x 200 mL). The resulting suspension was filtered and concentrated in vacuo with toluene (azeotropic mixture). The crude product was purified by chromatography on silica gel eluting with an iso-hexane / acetone solvent mixture (16: 4) to give the title compound (MH + 441).

95c) [1- (4-Ethanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

50552 Β

To a mixture containing 1- (4-Methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (11.8 g, 26.8 mmol) in water (100 ml) and THF (250 ml), NaOH (53.6 ml of a 1M aqueous solution) was added dropwise at room temperature and the two-phase suspension was allowed to stir overnight. The solvent was removed in vacuo and the crude residue was triturated with diethyl ether, DCM and ethyl acetate. The resulting solid was dissolved in warm water (150 mL) and the pH was adjusted to 3-4 using 6 M HCl. The resulting suspension was filtered and further purified by dissolving in warm IPA (250 mL) and refluxing in the presence of activated charcoal for 5 minutes. The solution was filtered and the title compound was recrystallized from a water / IPA solvent mixture as white / pale green crystals. (MH + 427).

Example 96 [1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

96a) [1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester:

To a solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (6.8 g,

33.5 mmol) in dry DMF (150 mL) under an inert argon atmosphere, BEMP (10.5 mL, 36.5 mmol) was added dropwise over 2 minutes. The solution was stirred at room temperature for 1 hour, and then a solution of 4-methanesulfonyl benzyl bromide (10.0 g, 40.2 mmol) in DMF (60 mL) was added dropwise over an interval of 5 minutes. After stirring overnight at room temperature, the solvent was removed in vacuo using an azcotropic mixture of toluene (200 ml). The resulting crude product was purified by chromatography on silica gel eluting with a solvent mixture of ethyl acetate / iso-hexane (20-100% w / w ethyl acetate) to give the title compound as a green oil (MH + 373).

96b) [1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

To a solution of [1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester (6.54 g, 17.6 mmol) in THF (100 mL) ) is added in drops, 1M

50552 Β

NaOH (35.2 mL). The turbid solution was heated to 40 ° C and methanol (10 mL) was added to give a clear solution. After stirring at room temperature for 4 hours, the solvent was removed in vacuo and the crude product was triturated with ethyl acetate. The resulting solid was filtered and dissolved in a water / THF solvent mixture (200 ml in a 3: 1 mixture) and then acidified to pH 3. The solvent was removed in vacuo and the resulting solid was recrystallized from an ethanol / water solvent mixture to give the title compound (MH + 359).

Example 97 {1- [1- (4-Methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid-Enantiomers 1 and 2

97a) {1- [1- (4-Methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester

A solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (2.37 g, 11.12 mmol) in dry DMF (38 mL) at room temperature was treated with BEMP in drops (4.39 mL, 15.19 mmol). The reaction mixture was stirred for 35 minutes at room temperature, and then 1- (1-bromo-ethyl) -4-methanesulfonyl-benzene was added (4. g, 15.18 mmol) and sodium iodide (12.29 g, 15.28 mmol). After stirring at 60 ° C for 1 hour, the reaction mixture was allowed to warm to room temperature and then diluted with a solvent mixture of ethyl acetate / ether (200 ml of a 1: 1 mixture) and water (150 ml). . The organic portions were washed with brine, dried (Na₂SO4) and concentrated in vacuo and the resulting crude product was purified by chromatography on silica gel eluting with a solvent mixture of ethyl acetate / iso-hexane (2: 3 ratio increased to 1: 1 ethyl acetate) to give the title compound as racemic mixtures. The enantiomers were separated using a hiracel OD column and eluted with 30% IPA in hexane to give enantiomer A (retention time = 14.33 minutes) and enantiomer B (retention time = 17.68 minutes).

97b) [1- [1- (4-Methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid-Enantiomer 1

50552 Β

{1- [1- (4-Methanesulfonyl-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester solution (Enantiomer A) (22 mg, 0.05 mmol) in THF (0.5 ml) and methanol (0.5 ml), treated with 2M lithium hydroxide (0.2 ml) and stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the crude product was dissolved in water (10 mL) and acidified to pH 1 using concentrated HCl. The mixture was extracted with ethyl acetate (2 x 10 mL) and the organics were washed with brine, dried (MgSO 4).₄) and concentrated in vacuo to give the title compound as a colored glassy substance. (MH + 373). The enantiomer of the compound of the invention (Enantiomer 2) is prepared in an analogous manner using the procedure described previously by replacing enantiomer A with enantiomer B. (MH + 373).

Example 98 [1- (4-Methanesulfinyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

98a) [1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester:

A solution of (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.512 g, 2.51 mmol) in dry DMF (5.6 mL) was treated with BEMP (1.17 mL, 4.01 mmol) dropwise. The reaction mixture was stirred for 80 minutes at room temperature and then treated with 1-bromomethyl-4-ethanesulfonyl-benzene (0.934 g, 4.01 mmol). After stirring at room temperature for the next 2 hours. the reaction mixture was partitioned between ethyl acetate (300 ml for a 1: 1 mixture) and water (30 ml). The organics were separated and washed with brine, dried (Na₂SO₄) and concentrated in vacuo. The resulting crude product was purified by chromatography on silica gel eluting with a solvent mixture of DCM / methanol (10: 1) to give the title compound (MH + 357).

98b) [1- (4-Methanesulfinyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid:

To a mixed solution of [1- (4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester (0.340 g, 0.95 mmol) in a THF / MeOH solvent mixture

50552 8 (8 ml of a 1: 1 mixture) was added 1M NaOH (2 ml) and the reaction mixture was stirred for 2 hours. The solvent was removed in vacuo and the resulting oil was dissolved in water and acidified to pH 2 using concentrated HCl. The precipitated forms were filtered, washed with water and dried in vacuo to give the title compound. (MH + 343).

Example 99 [6-Chloro-1- (4-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

99a) 2-Methyl-1H-pyrrolo [2,3-b] pyridine-7-oxide:

To a cooled solution (0 ° C) of 2-methyl-7-azaindole (0 ° C) (5 g, 37.8 mmol) in 1,2-dimethoxyethane (40 mL) was added m-chloroperoxybenzoic acid (10.4, from 77% w / w solid product). The reaction mixture was stirred at 0 ° C for 30 minutes, then warmed to room temperature for 3 hours and then poured into water (400 ml). The solution was basified to pH 9-10 using saturated potassium carbonate solution. The aqueous solution was extracted with DCM (2 x 100 mL) and the organic portions were combined, dried (MgSO 4).₄) and concentrated in vacuo. Purification of the resulting crude product by silica gel lyromatography first with pure ethyl acetate with a solvent mixture of DCM / MeOH (10: 1) resulted in the title compound as a pure powder. (MH + 297 appears as dimcr).

99b) 6-Chloro-2-methyl-pyrrolo [2,3-b] pyridine-1-carboxylic acid methyl ester:

To a solution of 2-methyl-1H-pyrrolo [2,3-b] pyridine-7-oxide (0.89 g, 6 mmol) in THF (20 mL) under an inert argon atmosphere was added HMDS (1.25 mL, 6 mmol). at room temperature. The solution was cooled (0 ° C) and treated with methyl chloroformate (1.16 mL, 15 mmol). The reaction mixture was stirred overnight at room temperature and the solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with saturated sodium bicarbonate solution. The aqueous solution was re-extracted with ethyl acetate (2 x 20 mL) and the organic portions were combined, dried (MgSO 4).₄) and concentrated in vacuo. By purifying the resulting crude product

50552 Β Chromatography on silica gel eluting with a solvent mixture of ethyl acetate / isohexane (1: 8) gave the title compound. (MH + 225).

99c) 6-Chloro-2-yntyl-1H-pyrrolo [2,3-b] pyridine;

6-Chloro-2-methyl-pyrrolo [2,3-b] pyridine-1-carboxylic acid methyl ester (0.225 g, 1 mmol) was dissolved in methanol (30 mL) and 1M NaOH (10 mL) and stirred overnight at room temperature. The methanol was removed in vacuo and the resulting white suspension was extracted with chloroform (3 x 20 mL), dried (MgSO 4).₄) and concentrated in vacuo to give a white powder which was dried under high vacuum to give the title compound (MH + 167).

99d) (6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -oxo-acetic acid methyl ester:

A stirred suspension of aluminum chloride (0.56 g, 4.2 mmol) in DCM (10 mL) at room temperature under an inert argon atmosphere was treated with a solution of 6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine: ( 0.14 g, 0.84 mmol) and stirred for 1 h. Methyl oxalyl chloride (0.386 mL, 4.2 mmol) was added and the resulting suspension was stirred at room temperature overnight. The reaction mixture was poured into an ice / water vessel (100 ml) and the organic layer was separated, dried (Na2SO).₄) and concentrated in vacuo. The resulting crude product was triturated with ice / water, subjected to ultrasonic waves and then a solid was obtained to form the title compound (MH + 253) after drying under high vacuum.

99d) (6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester:

To a solution of triethylsilane (0.343 mL, 2.15 mmol) in TFA (2 mL) cooled to -10 ° C was added dropwise methyl ester (6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridine -3-yl) -oxoacetic acid (0.155 g, 0.61 mmol). The reaction mixture was stirred for 1 h at -10 ° C and the solvent was removed in vacuo. The residue was washed with saturated sodium hydrogen carbonate solution and this aqueous solution was extracted with DCM (3 x 10 mL). Organic parts are collected, dried (Na2SO₄) and concentrated in vacuo and the resulting crude product was purified by chromatography on silica gel eluting with the mixture.

50552 Β methanol / DCM solvent (0-0.5% methanol) to give the title compound as a white powder. (MH + 239).

99f) 6-Chloro-1- (4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester:

To a stirred solution of (6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.045 g, 0.19 mmol) in DMF (1.5 mL) cooled on ice, under an inert atmosphere of argon, sodium hydride (0.008 g of a 60% dispersion in mineral oil, 0.21 mmol) was added. After stirring for 30 minutes at 0 ° C, the reaction mixture was stirred at room temperature for two hours and then re-cooled to 0 ° C. 4-Methylsulfonylbenzyl bromide (0.076g, 0.3 mmol) in DMF (1.5 mL) was added along with sodium iodide (0.076 g, 0.30 mmol) and the resulting solution was stirred overnight at room temperature. Water (20 ml) was added to the reaction mixture, which was then extracted with a solvent mixture of ethyl acetate / diethyl ether. The organics were then washed with brine, dried (MgSO 4)₄) and concentrated in vacuo. The resulting crude product is purified by chromatography on silica gel and eluted with a solvent mixture of ethyl acetate / iso-hexane (1: 8 ratio increasing to 1:

4) to give the title compound (MH + 407).

99g) [6-Chloro-1- (4-methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

A 1M aqueous NaOl solution (0.25 mL) was added to a mixed suspension of methyl ester (6Hloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (0.018 g, 0.044 mmol) in the mixture. of the THF / MeOH solvent (1; 1.1 ml) After stirring at room temperature for 20 minutes, the reaction mixture was evaporated to dryness, the resulting solid was dissolved in water (1 ml) and extracted with ethyl acetate to remove any the remainder of 4-methylsulfonylbenzyl bromide. The aqueous phase was acidified to pH 2-3 using 2M HCl and extracted with ethyl acetate. The organics were concentrated in vacuo and the resulting crude product was purified by chromatography on silica gel, eluting with a solvent mixture of DCM / MeOH (20: 1 ratio) to give the title compound (MH + 393).

50552 Β

Example 100 [6-Chloro-1- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-

b] pyridin-3-yl] -acetic acid:

100a) [6-Chloro-1- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester:

To a stirred solution of 6-Chloro-2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) which is cooled on ice under an inert argon atmosphere, sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol) is added. The reaction mixture was stirred for 45 minutes at 0 ° C, and then treated with 1-bromomethyl-4-methylsulfonyl-2-trifluoromethylbenzene (Example 95a) (0.067 g, 0.21 mmol) with the addition of sodium iodide (0.076 g, 0.30 mmol). Stirring was continued for 2 h at 0 ° C and then the reaction mixture was poured into water (15 mL) and extracted with DCM (5 mL). The organic portions were separated and concentrated in vacuo. The resulting crude product was purified by chromatography on silica gel eluting with a solvent mixture of ethyl acetate / iso-hexane (1: 8 ratio increasing to 1: 4) to give the compound which was further purified by trituration with a solvent mixture of ethyl acetate / isohexane to give the compound from solution (MH + 475).

100 b) [6-Chloro-1- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2.3b] pyridin-3-yl] -acetic acid:

1M aqueous NaOH solution (0.25 ml) was added to a mixed suspension of [6-chloro-1- (4-methanesulfonyl-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] methyl ester. ] -acetic acid (0.01 g, 0.021 mmol) in a solvent mixture of THF / MsOI (1: 1, 0.5 mL). The resulting suspension is subjected to ultrasonic vibration and allowed to stir at room temperature overnight. The solvent was removed in vacuo and the crude product was dissolved in water (0.5 mL) and acidified to pH 2-3 using 1N HCl. The resulting suspension was filtered, washed with water (0.5 mL) and dried under high vacuum to give the title compound (MH + 461).

Example 101

50552 N- [2-Methyl-1- (3-methyl-3H-benzotriazol-5-ylmethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

101a) 5-Bromomethyl-1-methyl-1H-benzotriazole:

Phosphorus tribromide (0.230 mL, 2.45 mmol) was added to a stirred solution of (1-methyl-1H-1,2,3benzotriazol-5-yl) methanol (0.4 g, 2.45 mmol) in diethyl ether (25 mL) under an inert argon atmosphere. . After stirring at room temperature overnight, the reaction mixture was dissolved in water (5 ml) and stirred vigorously for a further 10 minutes. The organics were separated, washed with water (2x5 ml), brine (2x5 ml) and concentrated in vacuo to give the title compound (MH + 226).

101b) [2-Methyl-1- (3-methyl-3H-benzotriazol-5-ylmethyl) -1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester

To a solution of (2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.025 g, 0.122 mmol) in dry DMF (1 mL) under an inert argon atmosphere was added in drops of BEMP (56.6 μΐ, 0.196 mmol). The mixture was stirred at room temperature before cooling to 0 ° C on an ice bath. A solution of 5-bromomethyl-1-methyl-1H-benzotriazole (0.044 g, 0.196 mmol) in DMF (1 mL) was added to the cooled solution and the resulting mixture was stirred for 2 days at room temperature. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (0% -20% ethyl acetate) to give the title compound (MH + 350).

101c) [2-Methyl-1- (3-methyl-3H-benzotriazol-5-ylmethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

1M LiOH (116 μΐ) was added to a cooled (0 ° C) solution of [2-Methyl-1- (3-methyl3H-benzotriazol-5-ylmethyl) -1H-pyrrolo [2,3-b] pyridin-3 methyl ester. -i] -acetic acid (0.041 g, 0.116 mmol) in a solvent mixture of THF / water (4 ml of the mixture in a ratio of 1: 1). After stirring at room temperature for 4 hours, the reaction mixture was diluted with DCM (3 mL) and stirred vigorously for 10 minutes. The resulting mixture is passed through a cartridge for

50552 Β phase separation and the solution was acidified to pll 1-3 with 1M HCl. This portion was extracted with DCM (2x3 mL) and the organic extracts were combined and concentrated in vacuo to give the title compound as a white solid (MH + 336).

Example 102 [1- (4-Fluoro-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

102a) 4-Fluoro-3-methoxy-benzenesulfonyl chloride:

4-Fluoro-3-methoxy aniline (0.5 g, 3.55 mmol) in suspension in glacial acetic acid (15 mL) was treated with concentrated HCl (5 mL). The resulting solution was then cooled to approximately 0 ° C and treated with a solution of sodium nitrite (0.245, 3.55 mmol) dropwise in water (5 mL). After 10 minutes, the reaction mixture was added to a stirred solution of CO₂/ AcOH / CuCl₂/ H₂O (40 ml) (reagent preparation is described below). The reaction mixture was allowed to warm and stir overnight at room temperature. Water (250 ml) was added to the reaction mixture and then extracted with ethyl acetate (3 x 100 ml). The resulting organic layers were washed with water (2 x 100 mL) with the addition of concentrated brine (100 mL) and dried over MgSO 4. After filtration, the solvent was removed in vacuo to give the title compound which was used in crude form in the next reaction step.

Preparation of reagents SO2 / ACOH / CUCI2 / H2O:

According to a published procedure (EE Gilbert, Synthesis 1969, 1-10, p. 6), glacial acetic acid (100 ml), which is stirred vigorously at room temperature, is treated with SO gas bubbles.₂. When a saturated solution (approximately 10 g per 100 ml) is obtained, the solution is treated with copper (II) chloride (4 g) in water (5 ml). The resulting mixture was allowed to stand to give a green solution.

102b) [1- (4-Fluoro-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester:

50552 Β

To a mixed solution of sodium hydride (0.026 g of a 60% dispersion in mineral oil, 0.686 mmol) in THF (3 ml) on ice_oC), under an inert argon atmosphere, 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid methyl ester (0.1 g, 0.49 mmol) in dry DMF was added dropwise. (3 ml). The reaction mixture was stirred for 1 h at 0 ° C and then treated with 4-Fluoro-3-methoxy-benzenesulfonyl chloride (0.154 g, 0.686 mmol) in dry THF (3 mL). Stirring was continued for 30 minutes at 0 ° C and then water (100 ml) was added to the reaction mixture which was then extracted with ethyl acetate (3 x 50 ml). The organics were separated and washed with water (2 x 50 mL), brine (50 mL), dried (MgSO 4) and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (0% -20% ethyl acetate) to give the title compound (MH + 392).

102c) [1- (4-Fluoro-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

1M Lilium hydroxide (119 [mu] l) was added to the capine in a cooled (0 [deg.] C.) solution of [1- (4-fluoro-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] ] pyridin-3-yl] -acetic acid (0.044 g, 0.119 mmol) in a solvent mixture of THF / water (4 ml of the mixture in a 1: 1 ratio). After stirring at room temperature for 4 hours, the reaction mixture was diluted with DCM. The resulting mixture was passed through a phase separation cartridge and the solution was acidified to pH 1-3 with 1M HCl. This portion was extracted with DCM and the organic extracts were combined and concentrated in vacuo to give the title compound as a pale yellow solid (MH + 379).

Example 103 [1- (4-Chloro-3-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

103a) 4-Chloro-3-cyano-benzenesulfonyl chloride:

A suspension of 2-Chloro-5-aminobenzonitrile (0.405 g, 2.66 mmol) in glacial acetic acid (20 mL) was treated with concentrated HCl (5 mL). The resulting solution is after

50552 It is then cooled to a temperature below 5 ° C and treated with a solution of sodium nitrite (0.183 g,

2.66 mmol) in drops. in water (2ml). After 10 minutes, the reaction mixture was added to a stirred solution of SO₂/ AcOH / CuCl2 / H₂O (40 ml) (reagent preparation is described below). The reaction mixture was allowed to warm and stir overnight at room temperature. Water (150 ml) was added to the reaction mixture, and it was extracted with ethyl acetate (3 x 100 ml). The resulting organic layers were washed with water (2 x 100 mL) with the addition of concentrated brine (100 mL) and dried over MgSO 4.₄. After filtration, the solvent was removed in vacuo to give the title compound which was used in unpurified form in the next reaction step.

103b) [1- (4-Chloro-3-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester

To a stirred solution of sodium hydride (15.8 mg of a 60% dispersion in mineral oil, 0.411 mmol) in dry THF (2 mL) on ice (0 ° C), under an inert atmosphere of argon, was added dropwise methyl ester (2 -methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid (0.06 g, 0.294 mmol) in a THF / DMF solvent mixture (4 mL of a 3: 1 mixture). The reaction mixture was stirred at 0 ° C for 45 minutes and then treated with 4-chloro-3-cyano-benzenesulfonyl chloride (97.1 mg, 0.411 mmol) in dry THF (3 mL). Stirring was continued for 15 minutes at 0 ° C and then water (30 ml) was added to the reaction mixture which was then extracted with ethyl acetate (100 ml). The organic portion was separated and washed with concentrated brine (50 mL), dried (MgSO 4).₄) and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (0% -20% ethyl acetate) to give the title compound (MH + - 404).

103c) [1- (4-Chloro-3-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

1M Lithium hydroxide (78 μΐ) was added dropwise to a cooled (0 ° C) solution of methyl ester [1- (4-chloro-3-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (0.026 g, 0.064 mmol) in a solvent mixture of THF / water (4 ml of a 1: 1 mixture). After stirring at room temperature for 4 hours, the reaction mixture was diluted with DCM (3 mL). The resulting mixture is passed through a cartridge (container)

50552 Β for phase separation and the solution is acidified to pH 1-3 with 1M HCl. This portion was extracted with DCM (2x3 mL) and the organic extracts were combined, passed through a phase separation cartridge, and concentrated in vacuo to give the title compound as a solid off-white product (MH + 390).

Examples 104-105 [2-Methyl-1- (4-trifluoromethanesulfonyl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 104) and [2-Methyl-1- [4 -propane-2-sulfonyl) -benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 105), were prepared in an analogous manner to compound u. example 90 using the appropriate benzyl halide. The preparation of benzyl halides is described herein.

Examples 106-111

These examples, respectively [1- (3-fluoro-4-methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 106), [1 - (4-Fluoro-3-methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 107), [2-Methyl-1- (6) -trifluoromethyl-pyridin-3-ylmethyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 108), [1- (3-cyano-4-fluoro-benzyl) -2 -methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 109), [1- (2-chloro-5-fluoro-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 110), and [1- (4- Chloro-3-methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 111) was prepared in an analogous manner to the compound in Example 96 using the appropriate bcnzil halida. The benzyl halides used to prepare these exemplified compounds are also commercially available or can be prepared by the methods described herein.

50552 Β

Examples 112-126

These compounds, respectively [1- (4-Methanesulfonyl-2-methyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 112), [1 - (4-Methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example

113), [1- (2-Methoxy-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example

114), {2-Methyl-1- [1- (4-trifluoromethyl-phenyl) -ethyl] -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 115), [1- (1- (3-Chloro-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 116), {1- [1- (4) -Methanesulfonyl-2-phenyl) -ethyl] -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 117),

- (4-Fluoro-2-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 118), [1- (2,4- Bis-trifluoromethyl-benzyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 119), [2-Methyl-1- [1- (2-trifluoromethyl- Phenyl) -ethyl] -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 120), [1- (3-Methanesulfonyl-benzyl) -2-methyl-1H-pyrrolo [2,3 -b] pyridin-3-yl] -acetic acid (Example 121), [2-Methyl-1- (4-nitro-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example

122), [1- (4-Bromo-benzyl) -2-methylH-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example

123), [2-Methyl-1- (4- [1,2,4] triazol-1-yl-benzyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 124), [1- (3-Chloro-4-methanesulfonyl-benzyl) -2-methyl-1-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 125) and [ 1- (3-Fluoro-4-methanesulfonyl-benzyl) -2'-ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 126),

50552 Β were prepared in an analogous manner to the compound in Example 91 using the appropriate benzyl halide. The benzyl halides used to prepare these compounds from the example are either commercially available or can be prepared by the methods described herein.

4-Bromomethyl-2-fluoro-1-methanesulfonyl-benzene:

a) 3-Fluoro-4-methanesulfonyl-benzaldehyde:

Sodium salt of methane sulfinic acid (20.1 g, 200 mmol) was added to a stirred solution of 3,4-difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 mL) at 75 ° C. After 2 hours, 200 ml of water / ice are added to the reaction mixture. The precipitate was filtered off, washed with water and dissolved in chloroform (400 ml). The organic extract was washed with water (2 x 200 mL), dried over MgSO 4 and the solvent was removed in vacuo to give the title compound as a white solid.

b) (3-Fluoro-4-methanesulfonyl-phenyl) -methanol:

To a suspension of 3-fluoro-4-methanesulfonyl-benzaldehyde (1.3 g, 6.44 mmol) in ethanol (5 mL) under an inert argon atmosphere was added sodium borohydride (0.275 g, 7.27 mmol) dropwise over 2-3 minutes. After stirring for 4 hours, ice water was carefully added to the reaction mixture and acidified to pH 1 using 1M HCl. The product was extracted with ethyl acetate (80 ml) and the organic portion was washed with concentrated brine, dried over MgSO 4 and the solvent removed in vacuo to give an oil which solidified on drying to give the title compound.

c) 4-Bromomethyl-2-fluoro-1-methanesulfonyl-benzene:

To a stirred suspension of (3-Fluoro-4-methanesulfonyl-phenyl) -methanol (0.269 g, 1.31 mmol) in diethyl ether (5 mL) under an inert argon atmosphere was added dropwise phosphorus tribromide (46 μΐ, 0.434 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water (2 ml) and the diethyl ether layer was separated. The organic portion was placed over NaOH pellets and after 20 minutes was used as a reagent in diethyl ether solution.

50552 Β 1-Bromomethyl-4-methanesulfonyl-2-methyl-benzene:

The title compound was prepared in an analogous manner to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluoro-2-methylbenzaldehyde.

1-Bromomethyl-4-trifluoromethanesulfonyl-benzene:

The title compound was prepared in an analogous manner to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3-fluoro-4-methanesulfonyl-benzaldehyde with 4-trifluoromethanesulfonyl-benzaldehyde.

4-Bromomethyl-2-chloro-1-methanesulfonyl-benzene:

The title compound was prepared in an analogous manner to 4-bromomethyl-2-fluoro-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 3-fluoro-4-fluorobenzaldehyde.

1-Bromomethyl-4- (propane-2-sulfonyl) -benzene:

The title compound was prepared in an analogous manner to 4-bromomethyl-2-fluoro-1-methanesulfonyl-benzene by replacing 3,4-difluorobenzaldehyde with 4-fluoro-benzaldehyde and replacing the sodium salt of methane sulfonic acid with the sodium salt of 2-propane sulfonic acid.

Examples 127 [1- (4-Cyano-3-ethoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b} pyridin-3-yl] acetic acid

127a) 2-Ethoxy-4-nitro-benzonitrile

To a solution of 2-hydroxy-4-nitrobenzonitrile (0.5 g, 3.04 mmol) in DMF (5 mL) was added potassium carbonate (0.631 g, 4.56 mmol) with bromomethane (0.238 mL, 3.19 mmol) and

50552 Β The reaction mixture was allowed to stir for 5 days at room temperature. The solvent was removed in vacuo and the crude residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layers were separated, washed with water (2 x 100 mL), saturated sodium hydrogen carbonate solution (100 mL) and concentrated in vacuo to give the title compound as a pale yellow product which was used in crude form in the next reaction step.

127b) 4-Amino-2-ethoxy-benzonitrile:

To a suspension of 2-Ethoxy-4-nitro-benzonitrile (0.49 g, 2.54 mmol) in ethanol (50 mL) was added tin (II) chloride dihydrate (2.87 g, 12.7 mmol) and the suspension was stirred at 70 ° C for 3 hours. and thereafter overnight at room temperature. Water was added to the reaction mixture, and the pH of the solution was adjusted to 7-8 by the addition of sodium hydrogen carbonate solution (5% aqueous solution). The aqueous emulsion was filtered off in vacuo and the product was extracted with ethyl acetate (2 x 150 mL). The organics were combined, washed with brine (100 mL), dried.₄) and concentrated in vacuo to give the title compound as a pale yellow product which was used in the next reaction step without further purification.

127c) 4-Cyano-3-ethoxy-benzenesulfonyl chloride

The title compound was prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4 amino-2-ethoxy-benzonitrile.

127d) [1- (4-Cyano-3-ethoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester

To a mixed suspension of sodium hydride (26.3 mg in a 60% dispersion in mineral oil, 0.686 mmol) υ dry THF (10 ml) cooled on ice (0 ° C) under an inert argon atmosphere, methyl was added dropwise. (2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl) -acetic acid ester (0.1 g, 0.49 mmol) in a TIIF / DMF solvent mixture (4 mL of a 3: 1 mixture). The reaction mixture was stirred for 1 h at 0 ° C and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF.

50552 ) (Lml). Stirring is continued for 10 minutes at 0 [deg.] C. and for a further 10 minutes at room temperature after which water (50 ml) is added to the reaction mixture. The mixture was extracted with ethyl acetate (2 x 50 mL) and the organic portions were combined and washed with concentrated brine (50 mL), dried (MgSO 4).₄) and concentrated in vacuo. The resulting crude residue was purified by chromatography on silica gel eluting with a solvent mixture of iso-hexane / ethyl acetate (0% -20% ethyl acetate) to give the title compound (MH + 414).

127e) [1- (4-Cyano-3-ethoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid

1M Lithium hydroxide (57 μΐ) is added dropwise to a cooled (0 ° C) solution of methyl ester [1- (4-cyano-3-ethoxybenzenesulfonyl) -2-methyl-1H-pyrrolo [2_!3-b] pyridin-3-yl] -acetic acid (0.024 g, 0.057 mmol) in a THF / water solvent mixture (4 mL of a 1: 1 mixture). After stirring at room temperature for 2.5 hours, the reaction mixture was diluted with DCM (4 mL). The resulting mixture was passed through a phase separation cartridge and the solution was acidified to pH 4 with 1M HCl. This portion was extracted with DCM (2x4 mL) and the organic extracts were combined, passed through a phase separation cartridge, and concentrated in vacuo to give the title compound as a white solid (MH + 390).

Examples 128-150

These examples, respectively, [1- (3-Fluoro-2-methyl-benzenesulfonyl) -2-nethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 128), [1- ( 4-Cyano-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 129), [1- (4-Cyano-3-propoxy) -benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 130),

50552 N- [1- (3-Butoxy-4-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 131), [1- (4- Cyano-3-pentyloxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 132), [1- (6-Cyano-pyridine-3-sulfonyl) -2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 133), [1- (2-Chloro-5-cyano-benzenesulfonyl) -2-methyl-1H- pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 134), [1- (4-Cyano-3-methyl-benzenesulfonyl) '- 2-methyl-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 135), [1- (4-Chloro-2 Fluoro-5-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 136), [1- (5-Cyano-2-methoxy-benzenesulfonyl) ) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 137), [1- (5-Chloro-2-cyano-benzenesulfonyl) -2-methyl-1H -pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 138), [1- (2-Chloro-4-cyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 139), [1- (2-Chloro -5-Methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 140), [1- (5-Chloro-2-methoxy-benzenesulfonyl) 2 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 141),

50552 N- [2-Methyl-1- (thiophene-2-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 142), [1- (4-Cyano-3- trifluoromethyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 143), [1- (3-Chloro-4-cyano-benzenesulfonyl) -2-methyl -pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 144), [1- (4-Chloro-3-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3- b] pyridin-3-yl] -acetic acid (Example 145), [1- (3-Chloro-4-trifluoromethyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 146), [1- (3-Fluoro- 4-Trifluoromethyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 147), [1- (4-Chloro-3-methoxy-benzenesulfonyl) - 2-Methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 148), [1- (3,4-Dicyano-benzenesulfonyl) -2-methyl-1H-pyrrolo [2 , 3-b] pyridin-3-yl] -acetic acid (Example 149), and [1- (4-Chloro-3-trifluoromethyl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] acetic acid (Example 150) were prepared in an analogous manner as the compound of Example 127 using the appropriate sulfonyl chloride. The sulfonyl chlorides used to prepare the compounds of the example are commercially available or can be prepared by the methods described herein.

4-Cyano-3-methoxy-benzenesulfonyl chloride:

50552 Β

The title compound was prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with 2methoxy-4-nitro-benzonitrile.

5-Chloro-2-cyano-benzenesulfonyl chloride:

The title compound was prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing -4-fluoro-3-methoxyaniline with 2 amino-4-chloro-benzonitrile.

4-Cyano-3-propoxy-benzenesulfonyl chloride:

The title compound was prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1bromopropane.

3- Butoxy-4-cyano-benzenesulfonyl chloride:

The title compound was prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromobutane.

4- Cyano-3-pentyloxy-benzenesulfonyl chloride:

The title compound was prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromopentane.

6- Cyano-pyridine-3-sulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 5 amino-pyridine-2-carbonitrile.

2-Chloro-5-cyano-benzenesulfonyl chloride:

50552 Β

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 3 amino-4-chloro-benzonitrile.

4-Cyano-3-methyl-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by substituting 2-ethoxy-4-nitro-benzonitrile with

2-methyl-4-nitro-benzonitrile.

4- Chloro-2-fluoro-5-methoxy-benzenesulfonyl chloride ·

The compound of the invention is prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitrobenzonitrile with 1chloro-5-fluoro-2-methoxy-4-nitro-benzene.

5- Cyano-2-methoxy-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-cyano-3-ethoxybenzenesulfonyl chloride (Intermediate 127c) by replacing 2-ethoxy-4-nitro-benzonitrile with

4-methoxy-3-nitro-benzonitrile.

5- Chloro-2-Cyano-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 2 amino-4-chloro-benzonitrile.

2-Chloro-5-methoxy-benzenesulfonyl chloride ·

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 2-chloro-5-methoxy-phenylamine.

50552 Β ^ SJjapo-Z-tAiogoteNkćepgepziIopP-MogJs !:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 4 amino-2-trifluoromethyl-benzonitrile.

3- Chloro-4-Cyano-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 4 amino-2-chloro-benzonitrile.

4- Chloro-3-fluoro-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-fluoro-phenylamine.

3-Chloro-4-trifluoromethyl-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 3-chloro-4-trifluoromethyl-phenylanine.

3- Fluoro-4-trifluoromethyl-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102c) by replacing 4-fluoro-3-methoxyaniline with 3fluoro-4-trifluoro-phenylamine.

4- Chloro-3-methoxy-benzenesulfonyl chloride:

50552 Β

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-methoxy-benzonitrile.

4-Chloro-3-trifluoromethyl-benzenesulfonyl chloride:

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102 a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-trifluoromethyl-phenylamine.

3,4-Dicyano-benzenesulfonyl chloride;

The compound of the invention is prepared in an analogous manner to 4-fluoro-3-methoxybenzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyamine with 4-amino-phthalonitrile.

Example 151 [1- (3-Cyano-4-morpholin-4-yl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

151a) [1- (3-Cyano-4-morpholin-4-yl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-

b] pyridin-3-yl] -acetic acid

In a solution of methyl ester [1- (3-Cyano-4-fluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-

b] Pyridin-3-yl] -acetic acid (Example 54a) (60.7 mg, 0.157 mmol) in acetonitrile (3 mL) was added potassium carbonate (43.4 mg, 0.314 mmol) along with morpholine (27.6 μΐ, 0.314 mmol). The reaction mixture was stirred for 2 hours at room temperature and then filtered and concentrated in vacuo to give the title compound as an orange oil which was used in crude form in the next reaction step. (MH + 455).

151b) (1- (3-Cyano-4-morpholin-4-yl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridine-

3-yl] -acetic acid

50552 Β

The title compound was obtained in the atiologic manner as well as [1- (4-fluoro-3-methoxybenzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 102) by replacing (1- (4-Fluoro-3-methoxy-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3b] pyridin-3-yl] -acetic acid methyl ester with [1- (3-Cyano-) methyl ester 4-Morpholin-4-ylbenzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid. (MH + 441).

Example 152 [1- (3-Fluoro-4-morpholin-4-yl-benzenesulfonyl) -2-methylH-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

The title compound was prepared in an analogous manner to [1- (3-cyano-4-morpholin-4-yl-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -methyl ester. acetic acid (Example 151b) by replacing [1- (3-cyano-4-Fluoro-3-benzenesulfonyl) -2-methylH-pyrrolo [2,3-b] pyridin-3-yl] acetic acid methyl ester with [1 - (3,4-Difluoro-benzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 59) and heating by microwave radiation in a Personal Chemistry Emrys tm Optimizer microwave reactor at 80 ° C for 4 hours. (MH + 434).

Example 153 1- (4-Chloro-3-diano-benzenesulfonyl) -2-ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid

The title compound was prepared in an analogous manner to [1- (4-chloro-3-cyanobenzenesulfonyl) -2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid (Example 103) by replacing 2-methyl-1H-pyrrolo [2,3-b] pyridin-3-yl] -acetic acid methyl ester with 2-ethyl-1H-pyrrolo [2,3-b] pyridin-3-yl) - acetic acid (Intermediate 87c). (MH + 404).